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JOHNSON MATTHEY TECHNOLOGY REVIEW
Johnson Matthey’s international journal of research exploring science and technology in industrial applications
www.technology.matthey.com
SPECIAL ISSUE 12 ‘PALLADIUM CATALYSED CROSS-COUPLING – PRACTICAL ASPECTS’ APRIL 2017Published by Johnson Matthey
ISSN 2056-5135
www.technology.matthey.com
© Copyright 2017 Johnson Matthey
Johnson Matthey Technology Review is published by Johnson Matthey Plc.
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. You may share, copy and redistribute the material in any medium or format for any lawful purpose. You must give appropriate credit to the author and publisher. You may not use the material for commercial purposes without prior permission. You may not distribute modifi ed material without prior permission.
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Contents SPECIAL ISSUE 12 ‘PALLADIUM CATALYSED CROSS-COUPLING – PRACTICAL ASPECTS’ APRIL 2017
JOHNSON MATTHEY TECHNOLOGY REVIEW
Johnson Matthey’s international journal of research exploring science and technology in industrial applications
www.technology.matthey.com
Cleaning Up Catalysis Palladium Impurity Removal from Active Pharmaceutical Ingredient Process
StreamsBy Stephanie Phillips, Duncan Holdsworth, Pasi Kauppinen and Carl Mac NamaraOriginal publication: Johnson Matthey Technol. Rev., 2016, 60, (4), 277
Final Analysis: The Use of Metal Scavengers for Recovery of Palladium Catalyst from Solution By Stephanie Phillips and Pasi KauppinenOriginal publication: Platinum Metals Rev., 2010, 54, (1), 69
Safer, Faster and Cleaner Reactions Using Encapsulated Metal Catalysts and Microwave HeatingBy Mike R. PittsOriginal publication: Platinum Metals Rev., 2008, 52, (2), 64
Catalysis in the Service of Green Chemistry: Nobel Prize-Winning Palladium-Catalysed Cross-Couplings, Run in Water at Room TemperatureBy Bruce H. Lipshutz, Benjamin R. Taft, Alexander R. Abela, Subir Ghorai, Arkady Krasovskiy and Christophe Duplais
Original publication: Platinum Metals Rev., 2012, 56, (2), 62
The Nobel Prize The 2010 Nobel Prize in Chemistry: Palladium-Catalysed Cross-Coupling
By Thomas J. ColacotOriginal publication: Platinum Metals Rev., 2014, 58, (3), 12
Note: all page numbers are as originally published
Contents (continued)
JOHNSON MATTHEY TECHNOLOGY REVIEW
Johnson Matthey’s international journal of research exploring science and technology in industrial applications
www.technology.matthey.com
‘From the Bench’ Tips “Palladium-Catalyzed Coupling Reactions: Practical Aspects and Future Developments” A book review by Robert Hanley Original publication: Platinum Metals Rev., 2014, 58, (2), 93
The Directed ortho Metallation–Cross-Coupling Fusion: Development and Application in SynthesisBy Johnathan Board, Jennifer L. Cosman, Toni Rantanen, Suneel P. Singh and Victor SnieckusOriginal publication: Platinum Metals Rev., 2013, 57, (4), 234
Palladium/Nucleophlic Carbene Catalysts for Cross-Coupling ReactionsBy Anna C. Hillier and Steven P. Nolan
Original publication: Platinum Metals Rev., 2002, 46, (2), 50
A Highly Active Palladium(I) Dimer for Pharmaceutical ApplicationsBy Thomas J. Colacot
Original publication: Platinum Metals Rev., 2009, 53, (4), 183
And Finally...
Final Analysis: Is Gold a Catalyst in Cross-Coupling Reactions in the Absence of Palladium?By Madeleine Livendahl, Pablo Espinet and Antonio M. EchavarrenOriginal publication: Platinum Metals Rev., 2011, 55, (3), 212
Note: all page numbers are as originally published
www.technology.matthey.com JOHNSON MATTHEY TECHNOLOGY REVIEW
http://dx.doi.org/10.1595/205651316X693247 Johnson Matthey Technol. Rev., 2016, 60, (4), 277–286
Palladium Impurity Removal from Active Pharmaceutical Ingredient Process Streams A method for scale-up
By Stephanie Phillips* and Duncan Holdsworth Johnson Matthey Plc, Orchard Road, Royston, Hertfordshire, SG8 5HE, UK
Pasi Kauppinen** Johnson Matthey Finland Oy, Autokatu 6, FI-20380 Turku, Finland
and Carl Mac Namara Johnson Matthey Plc, PO Box 1, Billingham, Cleveland, TS23 1LB, UK
Email: *[email protected], **[email protected]
In this article, we will look at palladium impurity removal from active pharmaceutical ingredient (API) process streams using metal scavengers and the drivers for the implementation of such processes. The article will review some of the available scavengers and detail how Johnson Matthey approaches the trial work and the methods used for screening, optimisation and scale-up of the scavenger process. It will outline the steps taken to ensure smooth transfer of the metal impurity removal process from lab to plant. This will include Johnson Matthey data from batch isotherm, kinetic and fixed bed trials and the application of mathematical models for performance characterisation and scale-up, which all feed into the final system design. Performance data for
a number of the Johnson Matthey range of scavengers will be referenced both in batch and cartridge systems and the benefits of using the scavengers in a cartridge system will be presented.
Introduction
The need to remove palladium (Pd) from API process streams is driven by International Conference on Harmonisation (ICH) Q3D guidelines which dictate the permissible levels of Pd allowed in the final drug product. The platinum group metals (pgms), including Pd as well as platinum, rhodium and ruthenium are generally considered as route-dependent human toxicants (ICH Classification 2b), (1), therefore the limits for these metals are low – 10 µg g–1 as an oral concentration in the drug product, drug substance or excipient. This oral concentration is conver ted into a permitted daily exposure limit for each platinum group metal of 100 µg d–1, which is based on an assumed worst-case dosage level of 10 g d–1. If the dosage rate is known to be lower, the permitted oral concentration may be increased. For the pgms, it may also be an option to use a component approach, whereby the overall level of the element in the excipient would be considered. As the pgms would only come from a catalyst source, the overall level of the element in the excipient could then be determined. For a chemist developing or manufacturing the API, a target of 10 µg g–1 or even lower may still be put in place to avoid process re-works (1).
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Despite the challenges of removal, the use of homogeneous Pd catalysts offers many benefits over classical, often stoichiometric reaction protocols (2–4). It is often possible to achieve a reduction of the number of steps in a multi-step synthesis of a target compound, as well as increasing overall yields, by employing Pd catalysis. In order to achieve the benefits offered by the catalysts, there will be a subsequent need for Pd removal (4–10).
Numerous Pd removal methods are available to the chemist and the optimal method is typically selected based on cost, time, quality and ease of implementation. When considering which Pd removal method to use, the default is often to use standard methods such as distillation, crystallisation or carbon adsorption to remove the Pd (10, 11). All are efficient methods of separation; however, the process costs, and their robustness, may be challenged during scale-up. Equally, consideration needs to be given to the time taken to run the process and any impacts that the removal method may have on product yield.
Scavengers provide an excellent solution for Pd removal issues, particularly at low metal levels (6, 8). Johnson Matthey’s screening programme ensures that the best scavenger is selected based on the reaction conditions, but also that the process is robust and that consistent removal of Pd is achieved, irrespective of process scale.
Scavenger Products
There are a range of different scavengers available on the market for product purification (5–8). A significant portion of these are based on a silica support, however others, such as those based on polymer resins and polymer fibres (5, 7) are also available. The Johnson Matthey range includes all three classes of support materials and details of the core product types are listed in Table I, with specific product details provided in Table II.
Screening Method
Below is an outline of the steps involved in achieving a robust, long-term metal removal solution. This full screening package can be completed by Johnson Matthey or at the customer site with technical support provided.
The extent to which a scavenger can remove Pd to the required levels is critical. The initial trials within the screening programme look at a number of scavengers for Pd removal efficiency. Conditions can then be optimised with respect to the amount of scavenger, the temperature and whether a mix of scavengers with different functionalities should be used together. Time taken for Pd removal is considered within the batch isotherm, and kinetic and fixed bed studies are
Table I Overview of Johnson Matthey Scavenging Product Types
Product type Support material Key benefits Processing options
QuadraSil® Silica üZero swell üBatch (low shear stirring)
üImproved sorption kinetics based on the external
üCartridge preferred
functionality
üExcellent recoveries at room temperature
QuadraPure® Polymer resin üSpecific particle size distribution üBatch (low shear stirring) (PSD) for optimised flow
üCartridge preferredcharacteristics
Smopex® Fibre üFastest kinetics due to small particle size and external functionality
üVery stable in batch due to flexibility of fibres (no fines under high shear stirring)
üSuitable across the pH range üSuitable for use in column when feed flow rate is low
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Table II Chemical Functionalisation of the Core Scavenger Range
Scavenger Abbreviation Functionality
MercaptoQuadraSil® MP QS-MP SH
Primary amineQuadraSil® AP QS-AP NH2
QuadraSil® TA QS-TA H Triamine
NH2N H
N
QuadraPure® TU QP-TU S Thiourea
NH2N H
NH2 BenzylamineQuadraPure® BZA QP-BZA
Tertiary amine QuadraPure® DMA QP-DMA N
MercaptoSmopex®-234 S-234 SH
MercaptoSmopex®-111 S-111
SH
O
O
N
PyridineSmopex®-105 S-105
carried out to generate the performance data required to model, scale-up and design an optimised process for full-scale application.
The Screening Programme: Initial Screening
The initial screen is used as a feasibility study to determine the most suitable scavenger for Pd impurity removal from a particular sample or application. All scavengers used in the screen are commercially
available and all screening is completed on representative process samples. Where solid samples are provided, these are dissolved in an appropriate solvent.
Prior to carrying out any screening, customer process data is required to ensure optimal results taking into account any constraints relating to operating conditions.
Initial screening can be carried out using a variety of equipment, with the two preferred options being: (a) roller mixer machine; or (b) flask with overhead
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stirrer to allow best mixing of and contact with the scavengers. A hot plate, with a magnetic stirrer or a Radleys CarouselTM , have also been used, with care being taken to ensure suitable contact with the scavenger material.
Initial Screening: Experimental
All solutions are filtered prior to screening to ensure homogeneous sampling. A sample of mother liquor is retained for analysis. Typically 1 w/v% scavenger is allowed for Pd concentrations up to 500 mg l–1 . However, if a single element (or the total pgm concentration) has a higher concentration than this, the amount of scavenger is increased. For solutions with a pgm concentration in the region of 500–1000 ppm, for example, 3 w/v% is recommended for initial screening. During optimised screening, the amount of scavenger will be adjusted based on knowledge of the API process and the type of Pd catalyst used during it. Consideration will also be given to the presence of other reagents and metals which may be present and could compete for sites on the scavenger.
Initial screening is completed at room temperature for 2 h. Approximately six to eight scavengers are included in the initial screening. All solution samples are analysed using inductively coupled plasma-optical emission spectroscopy (ICP-OES) or atomic absorption spectroscopy (AAS) to determine the Pd concentration pre- and post-screening (12).
In the examples shown below, an organic process solution used in an API manufacturing process with an oncology indication was the selected material for the screening programme. This was a more
challenging Pd removal project, both in terms of the ease with which the Pd was removed and the low initial concentrations of the Pd in solution. The final target level was 10 µg g –1 in the API, equating to >1 mg l–1 in the solution.
Initial Screening: Results
Results from this screening can be presented in a number of ways. In this case they are shown as: (a) Table III, where the initial raw data is given and the
difference in concentration between the original solution and the solution following scavenger treatment is shown. Conversion of this to the actual concentration in the API stream is given in the final column; and
(b) Figure 1, where the scavenger performance is shown from left to right in terms of optimal performance.
In this example the solid API, with 98 µg g–1 Pd present as an impurity, was diluted with 15 volumes of process solvent prior to analysis. The analytical results on the solution were therefore multiplied, based on this dilution factor, and taking into consideration the density of the solvent to give: (a) the initial Pd levels present in the API; and (b) the Pd levels present after scavenger treatment. At this stage of the screening, the final Pd levels
following scavenger treatment were all above the target required by the process, necessitating further optimisation. For most screening, the best three performing scavengers from the initial screening are taken through to the optimisation stage.
Table III Initial Screening Results with Respect to Palladium Concentrationa
Scavenger type Scavenger added, w/v% Pd in the process solvent,mg l–1 Pd in API, calculated, µg g–1
Initial sample 0 6.5 74
Smopex®-234 0.5 5.5 62
QuadraPure® DMA 0.5 5.0 57
Smopex®-105 0.5 4.8 54
QuadraPure® TU 0.5 3.8 43
QuadraSil® AP 0.5 3.5 40
QuadraSil® MP 0.5 2.5 28 aTrials were conducted at 10 ml scale
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QS-MP
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7 7 6 6 5
5
1 w/v% loading 2 w/v% loading
Pd,
mg
l–1
3
2
1 Pd,
mg
l–1
4
3
Initial QP-TU QS-MP QS-AP sample
Initial S-234 QP-DMA S-105 QP-TU QS-AP QS-MP sample
Fig. 1. Pd concentration pre- and post-scavenger screening: initial screen
Screening Optimisation
Based on the results from the initial screening, three scavengers were taken through to the optimisation stage: QuadraPure® TU (thiourea functionalised polymer resin), QuadraSil® MP (mercapto propyl functionalised silica) and QuadraSil® AP (amino propyl functionalised silica). During this phase, testing focused on modifying the amount of scavenger used,
2
1
0
Fig. 2. Effect of amount of scavenger on Pd removal. Specification was met by QuadraSil® MP at 2 w/v% loading
7 Initial sample6
5
Pd,
mg
l–1
4
3
22ºC 40ºC
the effects of temperature increase on the scavenging performance and possible use of a multi-scavenger system. Time taken for recovery was determined during the later kinetic trials.
Optimisation: Experimental
Based on the Pd removal rates from the first screen, the amount of scavenger used was modified accordingly. As a 0.5 w/v% addition (with respect to volume of process solution) did not yield complete metal removal, the amount of scavenger added was increased to 1 w/v% and 2 w/v% (Figure 2).
Typically the higher temperature would be: (a) 60ºC
2
1
0
Fig. 3. Effect of temperature increase with 1 w/v% scavenger
7 Initial sample
6 QS-MP 5
Pd,
mg
l–1
4
3
22ºC 40ºC
(b) 10ºC below the boiling point of the solvent, or (c) dictated by the process conditions or API stability.
In this case, the agreed higher temperature was 40ºC and QuadraSil® MP was screened at 1 w/v% and 2 w/v% to determine the effect due to temperature (Figures 3 and 4).
From these results, the optimal conditions were found to be 2 w/v% of QuadraSil® MP for 2 h at room temperature to give 0.5 mg l–1 in the solution, which equated to 5.65 µg g–1 in the API. This was below the required upper limit of 10 µg g–1. No performance improvements were seen by increasing the temperature
2
1
0
Fig. 4. Effect of temperature increase with 2 w/v% scavenger
and, from a processing point of view, room temperature was preferable. It was also deemed unnecessary to test a mixture of scavengers as the targeted Pd removal was achieved with a single scavenger.
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At this stage in the screening programme, the scavenger and the conditions under which that scavenger will be best utilised have been determined using a fixed time under batch conditions. The decision for the process chemist now is whether the process will be transferred to the pilot plant in batch or in a cartridge system. To support this decision, a batch isotherm will be run followed by a kinetic trial for cartridge systems. This data is then utilised in a first principles modelling system and the actual and theoretical data compared before the system is defined.
Batch Isotherms and Kinetic Studies
During this phase of the screening, we are looking at: (a) the theoretical maximum metal loadings which can
be achieved for the target scavenging process. Data from this stage will help to determine the weight or volume of scavenger required in the larger scale process
(b) the breakthrough point (where the metal is no longer being removed by the scavenger) to determine at what point the chemist or engineer stops the process
(c) the kinetics of the adsorption process, considering the various mass transfer resistances which control the Pd from the liquid phase to the solid phase. This will indicate what contact time is required to ensure the metal content is reduced to the required levels.
For this project, a kinetic trial in batch was considered for the three best per forming scavengers, shown as raw data in Figure 5. Due to the more challenging nature of the solution, kinetics were slower than is often seen, with target recovery in 4 h. This was within process requirements. Note that kinetics for
Pd removal are typically fast with up to 99% recovery often being seen within 10 min. Factors that can affect the metal uptake are: (a) nature of the Pd catalyst (in terms of accessibility of
the Pd species) (b) presence of other reagents that can compete with
the metal uptake, and (c) reactions within the API itself.
A batch isotherm trial was carried out to determine the maximum loading capacity of the material as well as investigating how changing initial concentrations of the feed solution may affect this capacity (Figure 6).
Prior to designing a full-scale cartridge system, a column trial is carried out in which feed solution is flowed through a fixed bed of the ion exchange material and the outlet concentration from the column is measured over time. An outlet concentration of 0 mg l–1 indicates that all of the Pd has been recovered from the feed solution. An outlet concentration above 0 mg l–1 indicates that the material has almost reached its maximum loading capacity and that the feed flow should be stopped. The time before the outlet concentration rises above 0 mg l–1 can be increased by increasing the column size (Figure 7).
First Principles Modelling
The results obtained from laboratory isotherm and column trials are used to estimate several equilibrium and kinetic parameters which describe the adsorption
1.2
Equ
ilibr
ium
load
ing,
wt% 1.0
0.8
0.6
0.4
Experimental results
5 QS-MP QS-AP QP-TU
0.2
Pd,
mg
l–1 4 03
0 5 10 15 2 Equilibrium concentration, mg l–1
1 Fig. 6. Results of isotherm trial where varying masses of QuadraSil® MP material were added to 20 ml solutions of
Initial 30 120 240 30 120 240 30 120 240 customer solution with initial Pd concentration of 14 mg l–1
sample Sample intervals, min
0
and mixed until equilibrium was reached. Equilibrium concentration was measured by ICP-MS and the equilibrium
Fig. 5. Batch kinetic trial raw data: Pd removal profile with respect to time
loading estimated by calculation (10)
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Experimental results
∂C ∂C ∂2C rb ∂q = – uv + Dax – (ii)
2∂t ∂z ∂z e ∂t
Out
let c
once
ntra
tion,
mg
l–1
4
3
2
1
0 0 2 4 6 8 10 12
Time, h Fig. 7. Results of the column trial where a feed solution
Equation (ii) is fitted to the results shown in Figure 7 to determine the kinetics parameters of adsorption (contained within the ∂q/∂t parameter in the equation which represents the rate of adsorption). The results of this fitting are shown in Figure 9. Again a very high R2
value of 0.99 was obtained. Once these model parameters have been estimated,
Equations (i) and (ii) can be used to determine the performance of the QuadraSil® MP material as a function of time, feed flow rate, concentration and the size or scale of the column through which the feed is having an initial concentration of 5.5 mg l–1 Pd was flowed
through a column of QuadraSil® MP at a flow rate of flowed, effectively allowing scale-up and optimisation 17.0 ml h–1 equivalent to three bed volumes per hour, where one bed volume is equal to the volume occupied by the Quadrasil® MP in the column). The outlet Pd concentration of samples collected from the column outlet were analysed by ICP-MS (10)
of Pd from solution. The parameters are part of the models described in Equations (i) and (ii) (13, 14) and by fitting these models to the experimental data the values of these parameters are estimated.
qtKCe qe = (i)
1 + KCe
Equation (i) is fitted to the results shown in Figure 6 to determine K and qt, the material equilibrium constant and maximum capacity respectively. The results of this fitting are shown in Figure 8. An R2 value of 0.99 was obtained indicating the fitting is very good.
of the process design to ensure full Pd recovery, as further discussed in the next section.
Scale-Up
The ultimate aim of scale-up is to take the understanding obtained from the small-scale scavenger performance and propose a system that can achieve 100% scavenger utilisation at the end of the system life, i.e. the entire scavenger mass should be loaded to its maximum capacity at the point of scavenger change out. In reality this is an impossible task as, for example, in a column system axial diffusion, radial velocity gradients, near-wall effects and slow kinetics inevitably lead to broadening of the mass transfer zone and non-ideal behaviour (15, 16). However, a robust engineered solution should aim to get as close to full utilisation of the scavenger as is possible for a given set of conditions as this helps to minimise the installed
6
Equ
ilibr
ium
load
ing,
wt% 1.0
0.8
0.6
0.4
Experimental results Predicted results
R2 = 0.99
Out
let c
once
ntra
tion,
mg
l–1 Experimental results Predicted results
R2 = 0.99
0 2 6 104 8 Time, h
Fig. 9. The experimental results from Fig. 7 are shown again, as well as the predicted results from Equation (ii)
5
4
3
2
1
00 0 5 10 15
Equilibrium concentration, mg l–1
Fig. 8. The experimental results from Fig. 6 are shown, as well as the predicted results from Equation (i)
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12
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scavenger volume and, ultimately, the process cost. For a batch system, the challenge is even greater, which drives Johnson Matthey to recommend a cartridge system wherever possible. Scavenger systems using cartridges also offer the added benefit of containment when a potent API is being manufactured.
Optimisation can be achieved by manipulating variables such as the liquid linear velocity, the column diameter and the aspect ratio of the scavenger bed (17), while being mindful of customer requirements that could place limits on the proposed design. Such requirements might include the need for the system to be either a once-through or a recycle system; the processing time requirements; the need for a reusable or disposable system depending on the potency of the API; and the operability of the system. At this point the scavenger system will be well-defined, leaving only the mechanical design and the selection of the final conditions and materials of construction to satisfy the needs of the process, the relevant regulations and ultimately the characterisation of a safe and robust system. At this final stage, all of the data from the screening
programme is collated and used in the design of the final system used during piloting. Examples of a scalable system, the sealed flow cartridge system, are shown in Figure 10.
Conclusion
The use of a screening programme has been demonstrated and the steps required outlined in this article along with the results obtained, in order to design a robust plant-scale recovery process. Whether the process will be run in batch or a cartridge system, the method is essential in ensuring that optimal use of the scavenger is achieved while attaining Pd removal targets. For challenging processes, such as the one highlighted here where the nature of the process solution is complex and the initial metal levels are low (in the diluted form), the screening process becomes even more valuable.
Johnson Matthey provides screening and scale-up services to the pharmaceutical industry and has become expert through its application of knowledge in this area. To date, numerous plant-scale scavenging projects are running globally.
Acknowledgements
The authors would like to thank Steve Colley, Les Hutton, Jade Osei-Tutu and Carin Seechurn (Johnson Matthey Plc, UK) and Andrew Teasdale, Principal Scientist at AstraZeneca, UK, also Chair of the AstraZeneca impurities advisory board.
References 1. “ICH Harmonised Guideline, Guideline for Elemental
Impurities, Q3D”, Current Step 4 Version, International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, 16th December, 2014: http://www. ich.org/fileadmin/Public_Web_Site/ICH_Products/ Guidelines/Quality/Q3D/Q3D_Step_4.pdf (Accessed on 26th August 2016)
2. C. C. C. Johansson Seechurn, M. O. Kitching, T. J. Colacot and V. Snieckus, Angew. Chem. Int. Ed., 2012, 51, (21), 5062
3. J. Magano, ‘Large-Scale Applications of Transition Metal Removal Techniques in the Manufacture of Pharmaceuticals’, in “Transition Metal-Catalyzed Couplings in Process Chemistry: Case Studies from the Pharmaceutical Industry”, eds. J. Magano, J. R. Dunetz, Wiley-VCH Verlag, Weinheim, Germany, 2013, p. 313
4. E. J. Flahive, B. L. Ewanicki, N. W. Sach, S. A. O’Neill-Slawecki, N. S. Stankovic, S. Yu, S. M. Guinness and J. Dunn, Org. Process Res. Dev., 2008, 12, (4), 637
Fig. 10. Sealed flow cartridge systems for use at different scales: (a) large-scale laboratory use; (b) plant-scale system
(a)
(b)
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5. S. Phillips and P. Kauppinen, Platinum Metals Rev., 2010, 54, (1), 69
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The Authors
Stephanie Phillips is the Market Specialist for Johnson Matthey’s Advanced Ion Exchange (AIX) business at Royston, UK. Stephanie has worked in Sales and Marketing since 2001 and has been involved with the development and marketing of the Smopex® range of products since that time. Stephanie has a BSc in Chemistry and an MSc in Analytical Chemistry.
Duncan Holdsworth is a Senior Process Engineer in the Johnson Matthey AIX business and is based in Royston, UK. Duncan has worked as a Process Engineer within the various Johnson Matthey business divisions since 2010. He most recently joined AIX where he manages the scale up, design, fabrication and commissioning of the various process units operating in both the pharmaceutical and industrial chemicals markets. Duncan gained his MEng in Chemical Engineering from the University of Sheffield, UK.
Pasi Kauppinen gained his PhD in University of Oulu, Finland, and works currently as a Principal Scientist in AIX at the Johnson Matthey plant in Turku, Finland. In this role he is focused on developing AIX processes and products globally
286 © 2016 Johnson Matthey
http://dx.doi.org/10.1595/205651316X693247 Johnson Matthey Technol. Rev., 2016, 60, (4)
Carl Mac Namara is a Process Engineer within the Johnson Matthey Water Technologies group, Chilton, UK. He obtained his MEng in Chemical Engineering from Cork Institute of Technology, Ireland, and an Engineering Doctorate from the University of Birmingham, UK. His doctorate and post-doctoral projects were based in Procter & Gamble’s Newcastle Innovation Centre, UK, where he carried out fundamental research on textile cleaning processes. His current role is focused on modelling and developing new water treatment technologies all the way from R&D through to commercial stages.
69 © 2010 Johnson Matthey
doi:10.1595/147106709X481093 •Platinum Metals Rev., 2010, 54, (1), 69–70•
The Use of Metal Scavengers for Recoveryof Palladium Catalyst from SolutionIntroduction Cross-coupling reactions are among the most impor-
tant chemical processes in the fine chemical and phar-
maceutical industries. Widely used procedures such
as the Heck, Suzuki and Sonogashira cross-coupling
reactions and Buckwald-Hartwig aminations most
commonly employ a palladium-based catalyst (1).
Initially these reactions used simple Pd catalysts such
as palladium chloride and palladium acetate,often in
conjunction with a ligand.However, the need to carry
out more challenging coupling reactions (for exam-
ple those using less reactive aryl halides or pseudo-
halides, including aryl chlorides) has resulted in the
development of more advanced Pd catalysts (1, 2).
Product Clean-UpOnce the reaction is complete, the catalyst must be
separated from the product to avoid contamination
by Pd as well as the loss of precious metal into the
product or waste stream. Heterogeneous catalysts
may be separated quite easily from the product solu-
tion and sent for refining to recover the metal, but
homogeneous catalysts are more problematic. One
way to achieve separation is by recrystallisation of the
product; however this can result in the loss of up to
1% of the product yield.
Therefore an alternative method for removing the
residual Pd is required. Scavengers such as Smopex®
can be used to recover platinum group metals
(pgms) including Pd down to parts per billion
(ppb) levels. Smopex® is a fibrous material with a
polypropylene or viscose backbone grafted with
functional groups that can selectively remove the
pgms from solution (Figure 1).The fibres can carry a
metal loading of up to 10 wt%, and the loaded fibres
can then be collected and sent for traditional refining
to recover the precious metal (3).
Smopex® Metal ScavengersThe choice of scavenger for a particular process
depends on several factors. These include the oxida-
tion state of the Pd catalyst, the nature of the solvent
system (aqueous or organic), the presence of byprod-
ucts or unreacted reagents in solution and whether
the scavenger will be applied in a batch process or
continuous flow system. Some examples of Smopex®
fibres that can be applied under different conditions
are shown in Figure 2.
Process ScreeningPrior to using a scavenger in a particular process, it is
common practice to screen a selection of scavengers
to determine the most selective individual or combi-
nation of scavengers. Properties including the type of
scavenger used (based on metal species), amount of
scavenger used (based on concentration),and effects
of solvent and permitted temperature will be investi-
gated and optimised, as well as the kinetics and flow
system requirements. Data is also available on the
scavengers which are known to perform best for spe-
cific reactions (4),and this can be used to make a rec-
ommendation on the scavenger that is likely to offer
the best recovery in each case.
Two examples to illustrate the screening process
follow.
FINAL ANALYSIS
Fig. 1. (a) Smopex®, a fibrous material with a polypropyleneor viscose backbone; (b) Schematic representation of thefunctional groups (red) located on the surface of theSmopex® fibres (3)
(a)
(b)
Case Study 1: Suzuki ReactionThe process stream from a Suzuki coupling reaction
using the catalyst trans-dichlorobis(triphenylphos-
phine)palladium(II) (PdCl2(PPh3)2) in toluene was
analysed and found to contain 100 parts per million
(ppm) of Pd as well as triphenylphosphine and inor-
ganic salts. For Pd present following a reaction using
PdCl2(PPh3)2, thiol-based scavengers are known to be
the most suitable as they are able to break down any
Pd complexes in the solution and bind strongly to the
metal.An excess of Smopex® was applied for the ini-
tial screening process at a rate of 1 wt% Smopex® for
100 ppm Pd.
In this case toluene was used as the process sol-
vent, therefore hydrophobic fibres were recommend-
ed. A process temperature of 80ºC was used in the
coupling step, but the preferred stage for Pd recovery
was after the washing step, at a slightly lower temper-
ature of 60ºC. Screening was carried out using
Smopex®-111 and Smopex®-234, both thiol-based
scavengers (see Figure 2). In both cases, 1 wt% of
Smopex® was stirred at 60ºC for 1 hour, the liquor was
then filtered off and the filtrate was found to contain
<2 ppm Pd when Smopex®-111 was used,and <5 ppm
with Smopex®-234. After further optimisation it was
determined that the amount of Smopex® could be
reduced by half if 3 hours’ contact time was applied.
Case Study 2: Multiple Palladium SpeciesA process stream from a tetrakis(triphenylphos-
phine)palladium(0) (Pd(PPh3)4)-catalysed coupling
reaction with tetrahydrofuran as the solvent was
analysed and found to contain 30 ppm of Pd. In this
case,the Pd was present as both Pd(II) and Pd(0) and
therefore two different scavengers were tested.
Scavenging conditions of 60ºC for 1 hour were again
applied, and a first pass with Smopex®-105 (an anion
exchanger) gave 85% Pd recovery. A further treatment
with Smopex®-101 (a cation exchanger) recovered
the additional 15%, giving an overall recovery of
100%. In some similar cases a thiol fibre such as
Smopex®-111 can give total recovery on its own, but
where this is not achievable, a mixture offers another
way to achieve full recovery of the Pd.
In ConclusionThe widespread use of Pd catalysts for coupling reac-
tions continues to precipitate a requirement for Pd
scavenging of the product solution. Metal scavengers
such as Smopex® fibres can be used with a wide vari-
ety of processes to recover Pd, other pgms or base
metals down to ppb levels, and offer a viable alterna-
tive to traditional procedures such as product recrys-
tallisation.
STEPHANIE PHILLIPS and PASI KAUPPINEN
References1 C. Barnard, Platinum Metals Rev., 2008, 52, (1), 38
2 T. J. Colacot, Platinum Metals Rev., 2009, 53, (4), 183
3 Smopex® Metal Scavengers, A powerful and effectiveway to recover metal from solution:http://www.smopex.com/ (Accessed on 30th October2009)
4 Smopex® Metal Scavengers, ‘Fibre Selection Guide’:http://www.smopex.com/userfiles/file/Smopex%20selection%20guide2.pdf (Accessed on 1st December 2009)
The Authors
Stephanie Phillips is the Product Specialist for Smopex® working forJohnson Matthey’s Chemical Products and Refining Technologies atRoyston, UK. Stephanie has worked in Sales and Marketing since2001 and has been involved with the development and marketingof the Smopex® range of products since that time. Stephanie has aBSc in Chemistry and an MSc in Analytical Chemistry.
Dr Pasi Kauppinen works as Smopex® Development Manager at theJohnson Matthey plant in Turku, Finland. He has expertise in therecovery of platinum group metals and catalysts from solution, polymer absorbents, catalysis and the Smopex® product range.
70 © 2010 Johnson Matthey
doi:10.1595/147106709X481093 •Platinum Metals Rev., 2010, 54, (1)•
SO3–H+
SH
SH
Smopex®-101Styryl sulfonic acidgrafted fibre
Smopex®-105Vinyl pyridine graftedfibre
NH+Cl–
Smopex®-111Styryl thiol graftedfibre
Smopex®-234Mercaptoethylacrylategrafted fibre
O
O
Fig. 2. Examples of Smopex® functional groups graftedonto polypropylene fibres (3)
Platinum Metals Rev., 2008, 52, (2), 64–70 64
Microwave heating has developed as an impor-tant tool for research chemists, enabling reactionsto be carried out and optimised more quickly thanusing traditional heating methods (1–3). Directirradiation of the reaction mixture produces amore uniform and homogeneous heating profilethan does, for example, an oil bath. In most casesthe observed increase in rate can be explained bythe extremely efficient energy transfer and homo-geneous heating effect. This can lead tosuperheating of the reaction mixture (4): indeed,even microwave heating of an open vessel canachieve temperatures several degrees higher thanthe boiling point of the solvent (5).
In certain cases the presence of elements thatstrongly absorb microwave energy and release itefficiently as heat can cause localised ‘hotspots’tens of degrees higher than the bulk temperature,generating significant rate enhancements (6–8).This effect can be exploited to heat materials oflow microwave absorbance by the use of ‘passiveheating elements’ (9). Non-polar and poorlyabsorbing solvents can also be superheated byadding small amounts of a strongly absorbingcosolvent such as an ionic liquid (10–13). Theapplication of this selective heating can be particu-larly striking when the element is a heterogeneous
catalyst (14–16). A localised increase in tempera-ture at a catalyst surface over the bulk temperature,or a selective absorption of microwave energy bycatalytic species or organometallic intermediateson a reaction pathway, can lead to increased selec-tivity for the catalytic process while unwanted(thermally driven) side reactions are minimised bya relatively low bulk temperature (17). A synergis-tic advantage between microwave heating andplatinum group metal catalysis can therefore bedemonstrated (18).
The use of commercially available focused(monomode) microwave units (19–21) enhancesthe safety and reproducibility of reactions. Thestandard integration of monomode units intomany laboratory environments has expanded thearmoury of techniques available to chemists, allow-ing ready access to previously difficult-to-achievechemistries. These include high-temperature reac-tions such as Ullmann couplings (22); someheterocycle preparations previously requiringmetal baths (23, 24); the use of near-critical wateras solvent (25–29); and shortening the reactiontime on slow processes such as cycloadditions (30)to practically useful timescales, including replacingthe need for autoclaves (31); and automated pep-tide synthesis (32, 33).
Safer, Faster and Cleaner Reactions UsingEncapsulated Metal Catalysts andMicrowave HeatingPERFORMANCE ENHANCEMENT OF PALLADIUM, PLATINUM AND OSMIUM CATALYSTS
By M. R. Pitts*Reaxa Ltd., Hexagon Tower, Blackley, Manchester M9 8ZS, U.K.; E-mail: [email protected]
The combination of focused microwave heating and encapsulated metal promoters (EnCatTM)offers a safer, cleaner and more cost-effective solution to a wide range of catalyst-mediatedreactions, some of which are not widely accessible to the bench chemist due to high hazardratings. These include the palladium-catalysed Sonogashira cross-coupling, palladium-catalysed transfer hydrogenation, platinum-mediated hydrogenation and osmium tetroxide-catalysed dihydroxylation.
*Present address: Chemistry Innovation KTN, The Heath, Runcorn WA7 4QZ, U.K.; E-mail: [email protected]
DOI: 10.1595/147106708X292526
For the reasons discussed, metal-catalysedreactions work particularly well under microwave irra-diation; however safety and isolation issues still arisefrom their use. Elemental metal can deposit fromreaction mixtures onto the side of the glass tube,causing localised superheating of the glass and explo-sive rupture of the vessel (34). This can occur withboth homogeneous and heterogeneous catalysts. Itcan also be difficult to remove metal species selective-ly from the product on completion of the reaction.
The EnCatTM range of encapsulated metal cata-lysts were designed to address these issues ofpurification and reuse. Unlike other immobilisedhomogeneous catalysts such as FibreCatTM, wherephosphine ligands are attached to polyethylene fibres(35), the homogenous catalyst in EnCat is containedwithin a resin microcapsule. The use of such support-ed or ‘heterogenised’ catalysts industrially is beingdriven by regulatory pressures towards lower residuallevels of metal catalysts within active pharmaceuticalintermediates (APIs) (36, 37).
EnCats are prepared by an interfacial micropoly-merisation of an organic solution containing thehomogeneous metal catalyst, monomers (function-alised isocyanates) and additives, dispersed as asuspension in an aqueous phase. Reactive groupsgenerated at the interface combine to form polymerwalls and, as the surrounding matrix forms, the cata-lyst is entrapped to give spherical microcapsules (38).The individual catalytic species gain additional stabil-isation through interaction with the amidefunctionality of the polyurea matrix, resulting in verylow levels of metal leaching. Consequently the cata-lyst can be recovered efficiently by simple filtrationand reused.
Examples of catalysts already encapsulated thisway include palladium(II) acetate (39, 40) with andwithout various phosphine ligands (41), palladium(0)nanoparticles (42), platinum(0) (43) and osmiumtetroxide (44). Here we describe how EnCats providea homogeneous catalyst in a more effective form foruse with microwave heating.
EnCats in Microwave HeatedReactions
EnCats have been shown to be highly compatiblewith microwave heating (45, 46). Following the excel-
lent work by Ley and coworkers in demonstratingmicrowave-enhanced palladium EnCat-catalysedSuzuki couplings in both batch and flow modes (47),we were keen to understand the role of EnCat inheating bulk solution. Ley found that cooling reac-tions while providing a fixed microwave powerequivalent to that required for good conversion in thenon-cooled method resulted in cleaner products atsimilar or better conversions. The lower bulk temper-ature in the case of cooling may explain the reductionin side reactions, with the temperature ‘inside’ theEnCat beads potentially much higher. It is knownthat Pd/C preferentially absorbs microwave energywhen suspended in a virtually microwave-transparentsolvent, and ‘passively’ heats the surroundings (48).To investigate whether EnCat acts in the same way, a5 cm3 sample of anhydrous toluene, with variousadditives, was irradiated at a constant power of 200W for 5 minutes and the temperature recorded(Figure 1). Adding 250 mg of Pd EnCat had a negli-gible effect on the heating profile, as did the additionof ‘blank’ EnCat beads containing no metal. Additionof an equivalent amount of homogeneous palladiumacetate (27 mg) also had no effect on the heatingbehaviour, whereas 50 mg of palladium (5%) on car-bon caused a significantly increased rate of heating.
These results suggest Pd EnCat does not causesuperheating of the bulk solution, and behaves morelike homogeneous palladium acetate than palladiumon carbon.
Palladium(II) for Cross-CouplingReactions
Considerable effort has been focused on the useof Pd EnCat to facilitate cross-coupling reactions(41). The extremely low leaching of metal species andease of handling of EnCat beads greatly simplifypurification of these reactions. Many examples havebeen published regarding the use of EnCats withmicrowave heating for the acceleration of specificreactions (49–52). An important advantage, often notconsidered, is improved safety when using EnCats ina microwave reactor. Deposition of a film of elemen-tal metal on the glass walls of microwave tubes byprecipitation from solution is a common problemwith conventional metal catalysts. This has beenshown not to occur with Pd EnCat (53). Where a
Platinum Metals Rev., 2008, 52, (2) 65
film is deposited, it absorbs microwave energystrongly, and hotspots can form, resulting in vesselfailure. With modern microwave reactor designssuch ruptures are well contained; however therelease of vapours and subsequent decontamina-tion pose serious issues. These can lead torestrictions on the use of particularly hazardousreagents.
By way of example, a useful palladium-mediatedmicrowave process is the carbonylation of arylhalides with solid sources of carbon monoxide(54). Molybdenum hexacarbonyl has been shownto be an effective carbon monoxide releasing agent(55, 56), however it is a very toxic substance withrelatively high volatility (57). The risk of vessel rup-ture in such procedures can be greatly reduced bysubstituting Pd EnCat for the traditional palladiumcatalyst. The reaction proceeds with quantitativeconversion as shown in Scheme I.
EnCats have been applied in flow chemistrywith the beads packed in simple columns and
reagents passed over them. The initial work inthis area is extremely promising for the process-intensification of homogeneous catalytic reactions(47, 58–60).
A low degree of leaching of the catalytic speciesis vital in a continuous process, in order to avoidrapid deactivation and resulting contamination ofthe product flow stream. Certain substrates areknown to induce leaching of palladium fromEnCat resins, with aryl iodides and alkynes show-ing a high propensity. Indeed, running themicrowave-assisted Sonogashira reaction inScheme II with Pd EnCat 30 resulted in productwith a palladium content of 83 ppm. The triph-enylphosphine-entrapped Pd EnCat (polyTPP30)resin demonstrates an extremely high retention ofboth the palladium and phosphorus ligand, and hasbeen used to great effect in the same reaction(Scheme II). Using Pd EnCat polyTPP30 as thecatalyst, the residual palladium concentration in theproduct was only 14 ppm.
Platinum Metals Rev., 2008, 52, (2) 66
0
20
40
60
80
100
120
140
160
180
0 62000 124000 186000 248000 310000 372000 434000
time (data points)
tem
pera
ture
(C)
tolueneblank beads0.48 mmol/g Pd EnCatpalladium acetate5% Pd/C
Time, 1000 data points
0 62 124 186 248 310 372 434
Tem
pera
ture
, ºC 5%Pd/C
PdEnCat(0.48mmol Pd g–1 )BlankbeadsToluenePalladiumacetate
Fig. 1 Rate of heating of toluene containing various dopants under microwave irradiation
Pd EnCat 30Mo(CO)6
DBU, THFMicrowave
120ºC30 min
Me
I
Ph+ H2N
Yield 98%
PhN
H
NH
Me
O
DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene
Scheme I
Platinum Metals Rev., 2008, 52, (2) 67
Palladium(0) for HydrogenationReactions
The nanoparticulate palladium(0) EnCatcatalyst has been demonstrated as a highlychemoselective hydrogenation and transferhydrogenation catalyst (61, 62). In additionto the improved selectivity shown by PdEnCat NP30, a superior safety profile andease of handling make it a powerful alterna-tive to palladium on charcoal.
Transfer hydrogenation with Pd EnCatNP30 is easily performed in the microwave,allowing reactions in minutes rather thanhours. A recent paper by Quai and coworkersdemonstrated the efficiency of microwave-assisted transfer hydrogenation for O-benzyldeprotection (Scheme III) (63). The use ofEnCat was recommended to improve thesafety of the process and reduce palladiumcontamination of the products.
Scheme IV shows a representative exam-ple of an aromatic nitro reduction. Thesereactions are conventionally carried out atambient temperature overnight (64). How-ever, the microwave transfer hydrogenationprocedure gave a quantitative conversion tothe final product in only 5 minutes.
Platinum(0) for Hydrogenation andReduction Reactions
To complement the palladium(0) EnCatrange, a platinum(0) EnCat has recently beendeveloped, offering the same benefits over itscarbon-supported equivalents as the palladiumversion: improved safety profile, ease of handlingand low metal leaching. Pt(0) EnCat 40 performssimilarly to Pt/C in hydrogenation reactions, andis particularly useful in selective reductions in thepresence of aryl chlorides. The reaction shown inScheme V gave 3-chloroaniline with > 98%selectivity at room temperature under an atmos-phere of hydrogen after one hour (65).Microwave-assisted hydrogenations have recent-ly been investigated (66), and equipment to runthem in the laboratory is becoming commerciallyavailable (67, 68). With microwave reactorsdesigned to meter pressures up to 15 bar and runat them, such technology offers the benchchemist simple, safe access to hydrogenation.
The microwave-assisted hydrogenation of 3-chloronitrobenzene shown in Scheme V was runusing a standard microwave vial. A hydrogenatmosphere (at slight positive pressure) wasintroduced via a needle and manifold cycledbetween vacuum and hydrogen from a lecture
Pd EnCat 30or polyTPP30
CuI, Et3N, THFMicrowave
140ºC20 min Yield 99%
Ph
Me
O
Ph
Me
O
I
+ Scheme II
Pd(0) EnCat NP30HCOONH4, DMF
Microwave (cooled)80ºC
10 minOPh
R
R = NH2, NHMe, COOH, CN, COR, heterocycle, etc.
HO
R
Scheme III
Yield > 99%
Pd(0) EnCat NP30HCOONH4, EtOH
Microwave80ºC5 min
HO HO
NH2NO2
Scheme IV
Platinum Metals Rev., 2008, 52, (2) 68
bottle. Following irradiation at a constant power(30 W) for 13 minutes all the starting materialwas consumed, giving 3-chloroaniline in 85%yield. With equipment designed to charge gas to agiven pressure and monitor the pressure drop, it isto be expected that this reaction could be opti-mised to higher selectivities.
Encapsulated Osmium Tetroxidefor Dihydroxylation Reactions
The osmium tetroxide-catalysed dihydroxyla-tion reaction is Nobel Prize-winning chemistry(69); however the routine use of osmium in thelaboratory is avoided where possible due to its tox-icity, the likelihood of contact due to its volatilityand its propensity to cause burns (70). Os EnCat40 is an encapsulated osmium tetroxide that issafer to handle because no osmium tetroxidevapour can escape the polymer matrix (44). TheEnCat acts as a reservoir of osmium tetroxide,releasing catalytic amounts under oxidation reac-tion conditions, but retaining sufficient activity forrecycling (71). Following the reaction only verylow levels of residual osmium are detectable in thereaction media. Os EnCat 40 has been successful-ly applied to asymmetric dihydroxylation reactions(72). To demonstrate the application of Os EnCat40 under microwave conditions, the simple dihy-droxylation in Scheme VI was carried out at 80ºCand was complete in 20 minutes. The correspond-ing reaction at ambient temperature, when allowedto proceed overnight, gave the product in 86%yield (73). With the reaction performed in a sealedmicrowave tube, the contents could be removed
via syringe with a fine filter fitting, minimising con-tact and potential hazards, and allowing routine,safe use of such chemistry.
ConclusionsMicrowave heating has expanded the arsenal of
synthetic methods available to the bench chemist.The use of encapsulated platinum group metal cat-alysts coupled with the inherently safe design ofmodern microwave apparatus enables safe accessto an even greater range of useful transformations.Such a synergistic combination of technologiesenables reactions to be performed that furnishclean products with very low levels of residualmetal, thus simplifying the preparation of complexmolecules.
Pt(0) EnCat 40H2, EtOH
Microwave 30 W13 min
Yield 85%
Cl NO2 Cl NH2
Scheme V
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Ph
Os EnCatNMO
H2O/acetone
Microwave80ºC
20 min
Ph
OH
Ph
OH
PhScheme VI
Yield 91%NMO = N-methylmorpholine N-oxide
Platinum Metals Rev., 2008, 52, (2) 69
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Platinum Metals Rev., 2008, 52, (2) 70
The AuthorMike Pitts obtained his first degree at LoughboroughUniversity, U.K., in 1997. Zeneca sponsored a project ondioxirane chemistry in his final year, following a successfulindustrial placement year as part of the degree. He then movedto the University of Exeter, U.K., to obtain a Ph.D. withProfessor Chris Moody on ‘Selective Reductions with IndiumMetal’. A postdoctoral stay with Professor Johann Mulzer at theUniversity of Vienna, Austria, followed, where he completed aformal total synthesis of laulimalide as part of a European
Network focused on antitumour natural products. Mike returned to the U.K. in 2002to work for StylaCats Ltd., a start-up company from the University of Liverpool,where he initiated and developed a microwave research platform. In September 2005he moved to Reaxa Ltd. in Manchester, a technology spin-out from Avecia, to developmicrowave processes with their proprietary catalysts. In August 2007 he took up hiscurrent position managing Sustainable Technologies at the Chemistry InnovationKnowledge Transfer Network.
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58 C. K. Y. Lee, A. B. Holmes, S. V. Ley, I. F.McConvey, B. Al-Duri, G. A. Leeke, R. C. D. Santosand J. P. K. Seville, Chem. Commun., 2005, 2175
59 G. A. Leeke, R. C. D. Santos, B. Al-Duri, J. P. K.Seville, C. J. Smith, C. K. Y. Lee, A. B. Holmes andI. F. McConvey, Org. Process Res. Dev., 2007, 11, (1),144
60 I. R. Baxendale and M. R. Pitts, Chem. Today, 2006,24, (3), 41
61 S. V. Ley, C. Mitchell, D. Pears, C. Ramarao, J.-Q.Yu and W. Zhou, Org. Lett., 2003, 5, (24), 4665
62 S. V. Ley, A. J. P. Stewart-Liddon, D. Pears, R. H.Perni and K. Treacher, Beilstein J. Org. Chem., 2006,2:15
63 M. Quai, C. Repetto, W. Barbaglia and E. Cereda,Tetrahedron Lett., 2007, 48, (7), 1241
64 Results from Reaxa laboratories are available in‘Pd(0) EnCatTM NP30 Hydrogenation & TransferHydrogenation User Guide’, Reaxa Ltd., April 2006:http://www.reaxa.com/images/stories/reaxa_pd0_encat_30np_user_guide_2006.pdf
65 Results from Reaxa laboratories are available in
‘Pt(0) EnCatTM 40 User Guide’, Reaxa Ltd., March2007:http://www.reaxa.com/images/stories/Reaxa%20Pt(0)%20EnCatT%20User%20Guide_mar_07.pdf
66 G. S. Vanier, Synlett, 2007, 13167 C. M. Kormos and N. E. Leadbeater, Synlett, 2006,
166368 E. Heller, W. Lautenschläger and U. Holzgrabe,
Tetrahedron Lett., 2005, 46, (8), 124769 K. B. Sharpless, Angew. Chem. Int. Ed., 2002, 41, (12),
202470 Material Safety Data Sheet, Osmium(VIII) Oxide,
Alfa Aesar GmbH & Co. KG, 08.02.2008:http://www.avocadochem.com/daten_msds/GB/12103_-_GB.pdf
71 D. C. Whitehead, B. R. Travis and B. Borhan,Tetrahedron Lett., 2006, 47, (22), 3797
72 A.-L. Lee and S. V. Ley, Org. Biomol. Chem., 2003, 1,3957
73 Results from Reaxa laboratories are available in‘User Guide – Catalytic Oxidations with OsEnCatTM Microencapsulated Osmium TetroxideCatalysts’, Reaxa Ltd.:http://www.reaxa.com/images/stories/reaxaosencatuserguide.pdf
•Platinum Metals Rev., 2012, 56, (2), 62–74•
62 © 2012 Johnson Matthey
http://dx.doi.org/10.1595/147106712X629761 http://www.platinummetalsreview.com/
By Bruce H. Lipshutz*, Benjamin R. Taft and Alexander R. Abela
Department of Chemistry, University of California, Santa Barbara, CA 93106, USA
*Email: [email protected]
Subir Ghorai
New Product Research & Development, Sigma-Aldrich Chemical Company, Sheboygan Falls, WI 53085, USA
Email: [email protected]
Arkady Krasovskiy
Dow Chemical Company, 1776 Building, E-10C, Midland, MI 48674, USA
Email: [email protected]
Christophe Duplais
UMR-CNRS Ecofog, Institut Pasteur de la Guyane, 23 Avenue Pasteur, 97306 Cayenne, French Guyana
Email: [email protected]
Palladium-catalysed cross-couplings, in particular Heck,
Suzuki-Miyaura and Negishi reactions developed over
three decades ago, are routinely carried out in organic
solvents. However, alternative media are currently of
considerable interest given an increasing emphasis
on making organic processes ‘greener’; for example,
by minimising organic waste in the form of organic
solvents. Water is the obvious leading candidate in this
regard. Hence, this review focuses on the application
of micellar catalysis, in which a ‘designer’ surfactant
enables these award-winning coupling reactions to be
run in water at room temperature.
1. IntroductionDecades ago, before palladium-catalysed cross-
couplings arrived, copper was the transition metal of
choice for mediating carbon–carbon bond formation,
regardless of which organometallic complex was used
as the precursor to arrive at various Cu(I) reagents.
However, palladium eventually gained in popularity,
and in 2010 with the recognition of Heck, Suzuki and
Negishi as Nobel Prize recipients (1), the importance of
Pd-catalysed carbon-carbon bond-forming reactions
in organic synthesis was confi rmed.
Each modern organic synthetic reaction was
developed along traditional lines; that is, the chemistry
was matched, not surprisingly, to an organic solvent in
which the coupling best took place (Scheme I). And
while the presence of varying percentages of water
is not an issue for Heck reactions that lead (2–4) to
products such as cinnamates, and Suzuki-Miyaura
reactions that afford (5–7), for example, arylated
aromatics, the far more basic nature of organozinc
halides (RZnX; R = alkyl) (8–11) in Negishi couplings
(12, 13) that give products such as alkylated aromatics
Heck, Suzuki-Miyaura and Negishi reactions carried out in the absence of organic solvents, enabled by micellar catalysis
Catalysis in the Service of Green Chemistry: Nobel Prize-Winning Palladium-Catalysed Cross-Couplings, Run in Water at Room Temperature
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63 © 2012 Johnson Matthey
precludes their use under aqueous conditions. None
of these would typically be thought of as amenable to
use in pure water especially at ambient temperatures,
pKa issues aside, if for no other reason than that
organic substrates are not normally soluble in water.
The world is paying increased attention to organic
waste produced by the chemical enterprise, and
organic solvents play a considerable role in this regard
(14).‘Sustainability’ is becoming a guiding principle in
many areas of science and engineering (15), and the
concept of ‘green chemistry’ is gaining in importance
(16–21). Much emphasis, therefore, is being directed
towards ‘alternative media’ (22, 23) in which synthetic
chemistry can be conducted. In this way, our
dependence on organic solvents, whether derived
from petroleum reserves or otherwise, is minimised.
It should be appreciated that green chemistry is an
all-inclusive term, and an evaluation of the full cycle
(a full life cycle assessment (LCA)) of all components
associated with a given process should be considered
in order to fully evaluate the ‘greenness’ of that
process (24–26). Clearly, reductions in major factors
such as the number of steps, the number of changes
in solvent(s), and the number of product isolations
can play a huge role in controlling the generation of
organic waste. Notwithstanding the many virtues of
water as a medium, its use could be costly in terms
of its downstream handling and processing, and if
heating is required either during a reaction or for its
eventual evaporation. But it is also acknowledged that
total LCAs can be both challenging to produce, and
expensive, while on the other hand, solvents, whether
organic or otherwise, are well known entities that can
be readily assessed, quantifi ed, and analysed in terms
of their use in manufacturing and waste disposal.
Scheme I. Traditional cross-coupling reactions going ‘green’
Replace with
water
Product
Organic solvent
Heck Suzuki Negishi
CO2R R–B(OH)2 R–ZnX
Therefore this review considers solvents alone with
regard to ‘greener’ processes.
The most likely alternative among the various
choices available (for example, ionic liquids (27–30),
supercritical carbon dioxide (31–37) etc.), in terms
of potential generality, is water (38–41). To get around
the substrate solubility issue, the leading candidate
technology appears to be micellar catalysis, in which
reactants can be ‘solubilised’ within the surrounding
aqueous phase by the addition of surfactants (42,
43). Although this approach to mixing ‘oil and water’
is decades old, the nature of the surfactants available
to the organic chemist through normal commercial
channels is actually very modest; a handful of each
type (ionic, nonionic and zwitterionic) is all that is
normally seen in the literature. It seems odd, given the
importance of solvent effects in organic chemistry
(24–26), that the choice of amphiphile supplying the
organic medium in which the chemistry is to take
place would be so limited. Moreover, most common
surfactants were created for use in the manufacture of
paint, cosmetics, oil, cleaning fl uids, leather, etc. rather
than for their use in organic synthesis.
To be able to run Heck, Suzuki-Miyaura and Negishi
cross-couplings in water at room temperature, thereby
totally bypassing organic solvents as the reaction
medium, as well as to derive energy savings by
avoiding any need for either heating or cooling reaction
mixtures, the requirements are: (a) identifi cation of an
existing, or possibly newly designed and synthesised
surfactant that leads to results that are as good as or
better than those in organic media; and (b) assurance
that any amphiphile chosen is fully compliant with
‘The 12 Principles of Green Chemistry’ (44).
2. The Amphiphile TPGS-750-MUnlike many surfactants that contain lipophilic, usually
hydrocarbon fragments that have been ‘PEGylated’
(PEG = polyethylene glycol), the newly designed
amphiphile DL--tocopherol methoxypolyethylene
glycol succinate (TPGS-750-M) (1, Figure 1) has three
components (45): non-natural -tocopherol (vitamin
E), a succinic acid linker, and methoxy polyethylene
glycol (‘MPEG-750’). This latter, hydrophilic portion
is monomethylated at one terminus and contains
on average 17 oxyethanyl units (750 divided by 44).
The ‘TPGS’ nomenclature derives originally from
Kodak’s ‘TPGS’, which by analogy is TPGS-1000, and
contains the same -tocopherol (albeit in its natural,
nonracemic form) and succinic acid linker, while the
PEG is PEG-1000 (which has ca. 23 oxyethanyl units
Catalyst LnPdR’
X
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64 © 2012 Johnson Matthey
and a free hydroxyl residue at its terminus) (46).
These look very similar on paper, but their chemistry
is very different, allowing opportunities to fi ne-tune
the nanoreactors formed during micellar catalysis
that serve as an organic solvent-like medium for
homogeneous cross-coupling reactions in water.
In designing TPGS-750-M (45), it was anticipated
that the economics of its synthesis would be quite
favourable, since it is based on racemic vitamin E,
succinic anhydride, and a commercially available
MPEG. It can be prepared in >90% overall yield using
a simple two-step procedure (45). Couplings within
its larger nanomicellar interior should be as fast or
faster than those in other surfactants that form smaller
particles in water, since both size and shape appear
to be signifi cant (for example, TPGS-1000 forms ca. 13
nm spherical micelles, while TPGS-750-M forms ca. 60
nm particles). An important implication was that a Pd
catalyst would be found for each reaction type that
would function well under the high concentrations
typically found in micelles. However, it was far from
obvious whether the ‘rules’ of modern homogeneous
catalysis, in which each process and catalyst is
precisely matched with a particular organic solvent,
would apply to homogeneous catalysis taking place
at much higher concentrations within nanomicelles.
Therefore, a wide range of Pd catalysts, obtained from
Johnson Matthey, were screened for applicability
to transition metal-catalysed couplings under the
infl uence of the hydrophobic effect.
3. Heck ReactionsCinnamate-forming reactions between aryl bromides
and acrylates take place very smoothly at room
temperature within the nanomicellar environment of
TPGS-750-M (5 wt%) (45, 47), akin to those seen earlier
in the fi rst generation surfactant polyoxyethanyl
-tocopheryl sebacate PTS (PTS-600; Figure 2)
(48, 49). The keys to success in this type of coupling
are the use of 3 M sodium chloride solutions in
Fig. 1. Comparison of structures between ‘TPGS’ (TPGS-1000) and newly engineered TPGS-750-M
TPGS-750-M1(ca. 60 nm micelles)
Racemic vitamin E
MPEG-750
Succinic acid
Succinic acid
Nonracemic vitamin E
PEG-1000
TPGS-1000‘TPGS’(ca. 13 nm micelles)
H3C
CH3 CH3 CH3
CH3 CH3
CH3
CH3
O
OO
OO
H23
O
H3C
CH3 CH3 CH3
CH3 CH3
CH3
CH3
O
OO
OO
Me17
O
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65 © 2012 Johnson Matthey
place of water alone, and either of the electron-rich
Johnson Matthey catalysts bis(tri-tert-butylphosphine)-
palladium(0) (Pd(tBu3P)2) or dichloro[1,1’-bis(di-tert-
butylphosphino)]ferrocene palladium(II) (PdCl2(dtbpf))
(Figure 2). Other catalysts, such as those derived
from various Pd(II) salts (for example palladium(II)
acetate (Pd(OAc)2), palladium(II) chloride (PdCl2), or
tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3))
as Pd(0) precursors in the presence of various
bidentate phosphine ligands were all less effective.
The ‘salting out’ effect (50) of the NaCl leads to a
complete alteration from spherical to worm-like
micellar arrays (as seen by cryogenic transmission
electron microscopy (cryo-TEM) analysis) (49) with
presumably greater binding constants of substrates
within the particles and hence, faster rates of reactions.
Triethylamine appears to be the common base for
these Heck couplings. Representative examples, in
general, of (E)-favoured arylated products are shown
in Scheme II.Likewise, (E)-stilbenes constructed from aryl halides
and styrene derivatives can be readily fashioned under
similar micellar conditions (Scheme III) (45, 47).
Reactions with aryl iodides and styrene derivatives
can be performed at room temperature in aqueous
micellar solutions using either deionised water or 3
M NaCl and typically are complete in less than four
hours (global concentration = 0.50 M). The product
stilbenes are obtained in excellent yields with >8:1
E:Z selectivity, and often precipitate directly from
the reaction mixture. As with the case of acrylates
(Scheme II), 3 M NaCl can be used to enhance the
rates of otherwise sluggish reactions.
4. Suzuki-Miyaura Cross-CouplingsBiaryl-forming reactions of arylboronic acids and
aryl or heteroaryl bromides can be effi ciently
catalysed by PdCl2(dtbpf) at room temperature in
aqueous solutions of either PTS or TPGS-750-M. Three
representative cases are illustrated in Scheme IV,
including the cross-coupling of a relatively hindered
2,4,6-triisopropyl-substituted bromide.
The air stable complex, PdCl2(dtbpf), has seen less
extensive use in organic solvents for Suzuki-Miyaura
chemistry than its diphenyl analogue, dichloro-
[1,1'-bis(diphenylphosphino)ferrocene]palladium(II)
(PdCl2(dppf)). Nonetheless, early reports from
Johnson Matthey suggested far greater activity
Fig. 2. Catalysts used in Heck reactions run in water at room temperature
Bis(tri-tert-butylphosphine)palladium(0)
Dichloro[1,1’-bis(di-tert-butylphosphino)]ferrocene palladium(II)
Pd(tBu3P)2
PdCl2(dtbpf)
PTS-600‘PTS’(ca. 25 nm micelles) Sebacic acid
Racemic vitamin E
PEG-600
H3C
CH3 CH3 CH3
CH3 CH3
CH3
CH3
O
OO
O
13O
H
O
P Pd PFe
P
P
PdCl2
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66 © 2012 Johnson Matthey
of PdCl2(dtbpf) in promoting cross-couplings of
aryl chlorides over its more established relative
(51). However, under micellar conditions, with
challenging aryl chlorides, PdCl2(dtbpf) appears
not to be the catalyst of choice (Scheme V). The
Pd(0) catalyst Pd(tBu3P)2 showed little improvement,
despite the tBu3P ligand’s effectiveness at promoting
Suzuki-Miyaura couplings at room temperature in
tetrahydrofuran (THF) (52). And while dichlorobis(p-
methylaminophenyl-di-tert-butylphosphine)palladium(II)
(PdCl2(Amphos)2) showed a marked improvement,
the N-heterocyclic carbene (NHC) bound catalyst
phenylallylchloro[1,3-bis(diisopropylphenyl)imidazole-
2-ylidene]palladium(II) ([(IPr)Pd(cinnamyl)Cl] or
Neolyst CX31), which has been shown to be highly
effi cient in an organic solvent (53), was the most
effective for these reactions being carried out in
nanomicelles.
Interestingly, the scope of Suzuki-Miyaura couplings
in surfactant-water catalysed by this NHC-ligated
catalyst proved to be rather narrow, as PdCl2(Amphos)2
generally provided superior results with heteroaryl
chlorides (Scheme VI). More surprisingly, a large
number of aryl bromide combinations for which
PdCl2(dtbpf) had previously proven effective
(Scheme VII) failed to reach completion under
catalysis with the NHC complex, despite this catalyst’s
demonstrated competence with these substrate
types in organic solvents (53). The effectiveness of
PdCl2(Amphos)2 with heteroaryl coupling partners
was not unexpected given early reports by Amgen
researchers of its high effi ciency with educts of
this type in Suzuki-Miyaura reactions (54, 55).
trans-Dichlorobis(tricyclohexylphosphine)palladium(II)
(PdCl2(Cy3P)2) notably led to very low conversions with
heteroaromatic chlorides under PTS-water conditions,
in spite of previous reports of the Cy3P ligand’s
effectiveness in this role for reactions in dioxane/
water (albeit at elevated temperatures) (56). While an
extensive study comparing specifi c catalysts’ effi cacy
in water vs. organic solvent has not been undertaken,
and notwithstanding the corresponding change of
other parameters (most notably the choice of base),
catalysts PdCl2(dtbpf) and PdCl2(Amphos)2 clearly do
seem especially well-suited to use in water relative to
organic solvents.
5. Negishi-Like Couplings in WaterNegishi couplings today have come to imply a Group 10
metal-catalysed cross-coupling between an organozinc
reagent and an sp2-hybridised electrophilic partner
(12, 13). In fact, there were several other organometallics
Scheme II. Representative Heck couplings in water at room temperature using [Pd(tBu3P)]2
Pd(tBu3P)2 (2 mol%) Et3N (3 equiv.)
PTS or TPGS-750-M (5 wt%) 3 M NaCl, H2O, 4–14 h, RT
86%
90%
82%
84%
76%
O
O
O
OMeO
MeO
OMe
O O
OMe
O
O
O
O O
Cl
Cl
Cl NO2
CO2R’RR
Br+ CO2R’
NH
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67 © 2012 Johnson Matthey
Scheme III. Representative Heck couplings to form stilbenes using PdCl2(dtbpf) in water at room temperature
PdCl2(dtbpf) (2 mol%) Et3N (3 equiv.)
PTS or TPGS-750-M (5 wt%) H2O or 3 M NaCl, 2–4 h, RT
95% 94% 94%
95% 96% 97%
(>8:1 E/Z)
Scheme IV. Representative Suzuki-Miyaura couplings in water at room temperature
PdCl2(dtbpf) (2 mol%) Surfactant-H2O (2 wt%)
Et3N (3.0 equiv.), RT
93% (2 h) (TPGS-750-M)
88% (24 h) (TPGS-750-M)
99% (6 h) (PTS)
that were utilised by the Negishi school before zinc
(for example, aluminium, zirconium and boron)
(57–61). The synthetic potential of zinc reagents, RZnX,
however, is undeniable, as they possess a suitable level
of nucleophilicity to participate in a transmetalation
step to a Pd(II) intermediate, while being especially
IR
BnOOH
OBn
NC
+ Ar RAr
NNN
octyl
NTs
Me
MeOMe
F
MeO
Cl
OMe OMe
EtO2C
ArBr + Ar’B(OH)2 Ar Ar’
OMeN
N
S
N
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68 © 2012 Johnson Matthey
tolerant of most functionality (62). Unfortunately,
however, they are defi nitely not tolerant of water (12,
13). Nonetheless, Negishi couplings can be, and have
been, conducted in pure water (63–65). The secret
to success in this unlikely methodology is avoidance
of the traditional up-front use of stoichiometric Zn
reagents; this is achieved by generating a zinc reagent
over time on the surface of the metal, surrounded
by the hydrophobic pocket of a nanomicelle. The
catalyst must: (a) be readily available while tolerating
exposure to water; and (b) respond favourably to the
hydrophobic effect associated with micellar catalysis.
One species has been identifi ed to date that meets
these criteria: PdCl2(Amphos)2 (54, 55) (2, Figure 3). Other species, including the parent bis-desamino
system PdCl2(tBu2PhP)2 (Figure 3), were screened,
but the rates of conversion were too low to make the
reaction synthetically viable. Interestingly, among the
Scheme V. Comparison of catalysts for Suzuki-Miyaura couplings of aryl chlorides in water at room temperature
Scheme VI. Comparison of NHC-containing catalysts with phosphine-ligand containing catalysts
GC conversion, Catalyst %, 23 h, RT
CX31 68CX32 68PdCl2(Cy3P)2 10PdCl2(Amphos)2 100
Conditions: 2% catalyst, 1 wt% PTS in water, 3.0 equiv. Et3N [(SIPr)Pd(cinnamyl)Cl] (Umicore Neolyst CX32)
Catalyst (2 mol%) PTS-H2O (1 wt%)
Et3N (3.0 equiv.)ArCl + Ar’B(OH)2 Ar Ar’
NF3C
NN
PdCl
Catalyst Time, h Temp., ºC Yield, %
PdCl2(dtbpf) 24 50 28CX31 4 RT 98
GC conversion after 24 h at 50ºC: PdCl2(dtbpf) 38%PdCl2(Amphos)2 83%PdCl2(
tBu3P)2 47%CX31 100%
Catalyst Time, h Temp., ºC Yield, %
PdCl2(dtbpf) 24 50 82CX31 11 RT 99
[(IPr)Pd(cinnamyl)Cl] (Umicore Neolyst CX31)
OMe
NN
PdCl
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69 © 2012 Johnson Matthey
catalysts shown in Figure 3 are selected cases that
are well known to mediate Negishi couplings in THF
(66, 67). Clearly, in a nanomicelle, they are not the
preferred species.
There is a third essential component: the ‘gatekeeper’,
without which there is no coupling whatsoever:
tetramethylethylenediamine (TMEDA). TMEDA likely
plays several important roles in these couplings: (i)
to clean the metal surface for subsequent electron
transfer; (ii) to chelate and thereby stabilise the newly
formed RZnX; and (iii) to enhance the transfer of
RZnX into the nanomicellar interior.
When an alkyl halide (iodide or bromide), an
aryl bromide, excess TMEDA, and PdCl2(Amphos)2
are mixed together in water containing 2 wt% TPGS-
750-M (or PTS), nanomicelles are formed containing
high concentrations of these species. Upon addition
of either Zn powder or dust, chemistry takes place in
water at room temperature. The selective insertion of
Zn into the sp3-carbon-halogen bond via successive
electron transfer steps is presumed to form RZnX
on the metal surface, protected momentarily by the
surrounding micelle. The newly formed organozinc
halide, thought to be chelated by TMEDA, then enters
the hydrophobic interior where a coupling partner
and associated reagents are located.
As illustrated in Scheme VIII, C–C bond formation
takes place smoothly with aryl bromides, including
coupling with a secondary alkylzinc reagent to give
product 3 in good yield (45, 63). It is especially
worthy of note that traditional Negishi couplings
with aryl bromides in THF do not typically occur
at room temperature (Scheme IX; C) (12, 13);
heating at reflux is common, especially for non-
activated substrates. A control experiment using
RZnX (prepared in THF) in an aqueous surfactant
environment gave the expected low level of
conversion due to quenching of the organozinc
halide (A in Scheme IX). Thus, the hydrophobic
effect adds yet another benefit to these reactions
(B in Scheme IX).
Several heteroaromatic halides have also
been studied under micellar catalysis conditions
(Scheme X) (64). Here again, PdCl2(Amphos)2, used
in catalytic amounts (2 mol%), is crucial for success.
Bromides located on each position on a substituted
pyridyl ring lead to good yields of alkylated products,
although the parent 2-, 3- or 4-bromopyridines gave
Scheme VII. Comparison of catalysts for Suzuki-Miyaura couplings of aryl bromidesArBr + Ar’B(OH)2 Ar Ar’
Catalyst (2 mol%) PTS-H2O (2 wt%)
Et3N (3.0 equiv.)
PdCl2(dtbpf): 78% yield CX31: 47% GC conversion
PdCl2(dtbpf): 76% yield CX31: 21% GC conversion
OMe
F OMe
MeO
PdCl2(dtbpf): 100% yield CX31: 39% GC conversion
F
PdCl2(dtbpf): 96% yield CX31: 27% GC conversion
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70 © 2012 Johnson Matthey
Fig. 3. Ligands/catalysts screened for Zn-mediated, Pd-catalysed cross-couplings in water at room temperature
Pd PCy3Cy3PCl
Cl
only traces of substitution. Heteroaromatics including
thiophenes, benzothiophenes, indoles and quinolines
appear to be amenable. As expected for organozinc
reagents, excellent tolerance to functionality in either
partner is observed. Noteworthy is the case of indole
derivative 4, where a secondary centre can be directly
inserted onto the ring in high yield.
In addition to aryl bromides, cross-couplings
involving alkenyl halides are also amenable using
catalyst PdCl2(Amphos)2, although in these cases the
added feature of olefi n geometry is present (Scheme
XI) (65). As anticipated, (E)-alkenyl halides, whether
iodides or bromides, retain their original geometry in
the coupled products. Likewise, (Z)-alkenyl halides
maintain their stereochemical integrity (45) which
was unexpectedly found not to be the case for the
corresponding reactions under traditional Negishi
coupling conditions in THF (66, 67). The positive
stereochemical outcome for these reactions in water is
a fortunate occurrence, since the choice of ligands that
help mediate these couplings (as noted above), at least
to date, is not broad.
[Pd(OAc)2]3 +
PCy2iPr
iPr
iPr Pd(OAc)2 + P(tBu)2Me
PhPh
PPd(dba)2 +
Pd PP OHHOCl
Cl
N
NN
iPr iPr
iPriPrPd ClCl
Cl
FeP
PPd
tButBu
tButBu
ClCl
Pd P(tBu)3(tBu)3P
Br
BrPdPd P(tBu)3(tBu)3P
Pd PPh3Ph3PCl
Cl
Pd PPh3Ph3PPPh3
PPh3
Pd PPCl
Cl
Pd PPCl
ClMe2N NMe2
2, PdCl2(Amphos)2
http://dx.doi.org/10.1595/147106712X629761 •Platinum Metals Rev., 2012, 56, (2)•
71 © 2012 Johnson Matthey
Scheme VIII. Representative Negishi-like couplings between two halides, in water at room temperature
R–X +
(R = primary or secondary alkyl)
Br
R’
PdCl2(Amphos)2 (0.5 mol%) TMEDA (3–5 equiv.)
Zn dust (3 equiv.) Surfactant-H2O (2 wt%), RT
R
R’
EtO2C
C7H15-n
82% (with PTS; X = I) 93% (with PTS; X = I) 74% (with PTS; X = I)MOM = methoxymethyl
3, 75% (with TPGS-750-M; X = Br)
Coupling with a secondary alkyl halide
71% (with TPGS-750-M; X = Br)
EtO2C EtO2C
CO2Et
BocOMOM
C10H21-n
O
N
Scheme IX. Comparison reactions: traditional Negishi coupling conditions vs. micellar conditions
OMe
Br
OMe
C7H15–n
n-C7H15ZnI in THF 2 mol% catalyst 2
2% PTS-H2O, RT, 12 h
n-C7H15I, Zn, TMEDA 2 mol% catalyst 2
2% PTS-H2O, RT, 12 h
n-C7H15ZnI or n-C7H15I, Zn 2 mol% catalyst 2
THF, RT, 12 h
A
C
B
Conversion = 30%
Conversion < 20%
Isolated yield = 90%
http://dx.doi.org/10.1595/147106712X629761 •Platinum Metals Rev., 2012, 56, (2)•
72 © 2012 Johnson Matthey
Scheme X. Cross-couplings of heteroaromatic and alkyl halides using catalyst PdCl2(Amphos)2 in water at room temperature
+
Zn/TMEDAPdCl2(Amphos)2
PTS-H2O, RT
(FG)
X
(FG’)
X
Scheme XI. Representative cross-couplings of alkenyl and alkyl halides, in water at room temperature
6. ConclusionsThe Nobel Prize awarded for the Heck, Negishi and
Suzuki cross-coupling reactions is further recognition
of the importance of the role that catalysis, in
particular by Pd, plays in society. But catalysis is
also a key component of green chemistry, and this
requires ligands on the metal that adjust catalyst
reactivity and selectivity. Catalysts that work well in
traditional organic solvents at modest concentrations
(usually 0.1 to 1 M in substrate) may not be the
species of choice under far higher concentrations in
an alternative medium such as nanomicelles in water.
A completely new set of factors that control catalyst
motion in and out of micelles and result in greater time
spent within nanoreactors (greater binding constants)
may require alternative or even newly devised ligands
for Pd-catalysed cross-couplings. Thus, as an outgrowth
of the hydrophobic effect, some rules for catalysis
may change, giving rise to both new discoveries and
opportunities for new catalysts.
Heteroaromatic
(FG’)
Heteroaromatic-alkyl
(FG)
Alkyl+
FG = functional group
N
OTBS
TIPS86%
N
SOO
S O N
O
CO2EtPh
Cl
CO2Et
Boc
71% 74%
82% 89% 4, 97%
3
n-C7H15BnO
85% (from the iodide; PTS) 87% (from the bromide; TPGS-750-M)
CO2Et4
(Z)-Alkenyl halides give (Z)-alkenyl products
CO2Et
91% (from the bromide; PTS)
http://dx.doi.org/10.1595/147106712X629761 •Platinum Metals Rev., 2012, 56, (2)•
73 © 2012 Johnson Matthey
AcknowledgementsFinancial support provided by the National Institutes
of Health (GM 86485) is warmly acknowledged. We are
indebted to Johnson Matthey for generously providing
the catalysts and ligands that were successfully applied
to the cross-coupling chemistry discussed herein.
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The AuthorsBruce Lipshutz began his career at University of California (UC) Santa Barbara, USA, in 1979, where today he is Professor of Chemistry. His programme has recently shifted towards green chemistry, with the specifi c goal of getting organic solvents out of organic reactions. For this, ‘designer’ surfactants have been introduced that allow for transition metal-catalysed cross-couplings to be carried out in water at room temperature.
Ben Taft received his BS in Chemistry at California State University, Chico, in 2004. He took a PhD from UC Santa Barbara in 2008 with Bruce H. Lipshutz. He then moved to Stanford as an NIH postdoctoral fellow under Barry Trost. He began at Novartis, in Emeryville, in 2011, where he works in the oncology discovery group.
Alexander Abela carried out his graduate work in the Lipshutz group at UC Santa Barbara, focusing on transition metal-catalysed Suzuki-Miyaura cross-coupling reactions in water and C–H activation chemistry. Following completion of his PhD, he joined the Guerrero group at UC San Diego in 2012 to continue his studies as a postdoctoral scholar.
Subir Ghorai took his PhD in 2005 from the Indian Institute of Chemical Biology. After a year of research at UC Riverside, he joined the Lipshutz group at UC Santa Barbara. Currently, he is in the Catalysis and Organometallics group at Sigma-Aldrich in Wisconsin, USA. His research interests are focused on catalysis, organometallics, and green chemistry.
Arkady Krasovskiy holds a PhD in organic chemistry from M. V. Lomonosov Moscow State University, Russia. He has extensive training in synthetic/organometallic chemistry gained during his postdoctoral time in the Knochel (2003–2006), Nicolaou (2006–2008), and Lipshutz (2008–2011) laboratories. Currently he is working in Core Research & Development at the Dow Chemical Company in Midland, MI, USA.
Christophe Duplais took his PhD in 2008 from the University Cergy-Pontoise in France, under the guidance of Gerard Cahiez. He then did a postdoctoral stay in the labs of Bruce Lipshutz at UC Santa Barbara, before accepting a position in 2011 with the CNRS, located in French Guyana.
By Thomas J. Colacot
Johnson Matthey, Catalysis and Chiral Technologies,2001 Nolte Drive, West Deptford, New Jersey 08066,USA;
E-mmail: [email protected]
The 2010 Nobel Prize in Chemistry was awarded joint-
ly to Professor Richard F. Heck (University of Delaware,
USA), Professor Ei-ichi Negishi (Purdue University,
USA) and Professor Akira Suzuki (Hokkaido University,
Japan) for their work on palladium-catalysed cross-
coupling in organic synthesis. This article presents a
brief history of the development of the protocols for
palladium-catalysed coupling in the context of Heck,
Negishi and Suzuki coupling. Further developments in
the area of palladium-catalysed cross-coupling are also
briefly discussed, and the importance of these reac-
tions for real world applications is highlighted.
The 2010 Nobel Prize in chemistry was the third
awarded during the last ten years in the area of plat-
inum group metal (pgm)-based homogeneous cataly-
sis for organic synthesis. Previous prizes had been
awarded to Dr William S. Knowles (Monsanto, USA),
Professor Ryoji Noyori (Nagoya University, Japan) and
Professor K. Barry Sharpless (The Scripps Research
Institute, USA) in 2001, for their development of asym-
metric synthesis reactions catalysed by rhodium,
ruthenium and osmium complexes, and to Dr Yves
Chauvin (Institut Français du Pétrole, France),
Professor Robert H. Grubbs (California Institute of
Technology (Caltech), USA) and Professor Richard
R. Schrock (Massachusetts Institute of Technology
(MIT), USA) in 2005 for the development of the
ruthenium- and molybdenum-catalysed olefin
metathesis method in organic synthesis.
Figure 1 shows some of the researchers who have
made significant contributions in the area of palladi-
um-catalysed cross-coupling, including 2010 Nobel
laureate, Professor Akira Suzuki, during a cross-
coupling conference at the University of Lyon, France,
in 2007 (1).
Palladium-Catalysed ReactionsOrganometallic compounds of pgms are vitally
important as catalysts for real world applications in
84 © 2011 Johnson Matthey
•Platinum Metals Rev., 2011, 55, (2), 84–90•
The 2010 Nobel Prize in Chemistry:Palladium-Catalysed Cross-CouplingThe importance of carbon–carbon coupling for real world applications
doi:10.1595/147106711X558301 http://www.platinummetalsreview.com/
synthetic organic chemistry. Chemists are continually
striving to improve the efficiency of industrial
processes by maximising their yield, selectivity and
safety. Process economics are also important, and
chemists work to minimise the number of steps
required and thereby reduce the potential for waste
and improve the sustainability of the process.
Homogeneous catalysis is a powerful tool which can
help to achieve these goals. Of the three Nobel Prizes
in pgm-based homogeneous catalysis, perhaps the
most impact in practical terms has been made by
palladium-catalysed cross-coupling (2).
In order for an area to be recognised for the Nobel
Prize, its real world application has to be demon-
strated within 20 to 30 years of its discovery. Although
the area of metal-catalysed cross-coupling was initi-
ated in the early 1970s, there were a very limited num-
ber of publications and patents in this area before the
1990s (see Figure 2). However, the area has grown
rapidly from 1990 onwards, especially since 2000.
In terms of the number of scientific publications,
patents and industrial applications, Suzuki coupling
is by far the largest area, followed by Heck,
Sonogashira and Stille coupling (Figure 2). Negishi
coupling is smaller in terms of the number of pub-
lications, but its popularity is growing due to the
functional group tolerance of the zinc reagent in
comparison to magnesium, in addition to its signifi-
cant potential in sp3–sp2 coupling, natural product
synthesis and asymmetric carbon–carbon bond form-
ing reactions (1).
The history and development of the various types
of palladium-catalysed coupling reactions have been
covered in detail elsewhere (3, 4). This short article
will focus on the practical applications of palladium-
catalysed coupling reactions.
Heck CouplingBetween 1968 and
1972, Mizoroki and
coworkers (5, 6) and
Heck and coworkers
(7–9) independently
discovered the use of
Pd(0) catalysts for
coupling of aryl, ben-
zyl and styryl halides
with olefinic com-
85 © 2011 Johnson Matthey
doi:10.1595/147106711X558301 •Platinum Metals Rev., 2011, 55, (2)•
Fig. 1. From left: Professor Kohei Tamao (a significant contributor in Kumada coupling),Professor Gregory C. Fu (a significant contributor in promoting the bulky electron-richtert-butyl phosphine for challenging cross-coupling), Professor Akira Suzuki (2010 NobelPrize in Chemistry Laureate), Dr Thomas J. Colacot (author of this article) and ProfessorTamejiro Hiyama (who first reported Hiyama coupling) in front of a photograph ofProfessor Victor Grignard (who initiated the new method of carbon–carbon coupling) inthe library of the University of Lyon, France
Cop
yrig
ht ©
The
Nob
el F
ound
atio
n.Ph
oto:
Ulla
Mon
tan
pounds, now known as the Heck coupling reaction
(Scheme I) as Heck was the first to uncover the mech-
anism of the reaction.
The applications of this chemistry include the syn-
thesis of hydrocarbons, conducting polymers, light-
emitting electrodes, active pharmaceutical ingredi-
ents and dyes. It can also be used for the enantio-
selective synthesis of natural products.
Heck coupling has a broader range of uses than the
other coupling reactions as it can produce products
of different regio (linear and branched) and stereo
(cis and trans) isomers. Typically, olefins possessing
electron-withdrawing groups favour linear products
while electron-rich groups give a mixture of branched
and linear products.The selectivity is also influenced
by the nature of ligands, halides, additives and sol-
vents, and by the nature of the palladium source. The
reaction has recently been extended to include direct
arylation and hydroarylation, which may have future
potential in terms of practical applications. Heck cou-
pling also has the unique advantage of making chiral
C–C bonds,with the exception of α-arylation reactions.
The Negishi ReactionDuring 1976–1977,
Negishi and co-
workers (10–12) and
Fauvarque and Jutand
(13) reported the use
of zinc reagents in
cross-coupling reac-
tions.During the same
period Kumada et al.
(14–17) and Corriu
et al. (18) independ-
ently reported that nickel–phosphine complexes
were able to catalyse the coupling of aryl and alkenyl
halides with Grignard reagents. Kumada and cowork-
ers later reported (in 1979) the use of dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)
(PdCl2(dppf)) as an effective catalyst for the cross-
coupling of secondary alkyl Grignard reagents with
organic halides (19). One common limitation to both
Ni- and Pd-catalysed Kumada coupling is that cou-
pling partners bearing base sensitive functionalities
86 © 2011 Johnson Matthey
doi:10.1595/147106711X558301 •Platinum Metals Rev., 2011, 55, (2)•
8000
7000
6000
5000
4000
3000
2000
1000
0
Tota
l num
ber
of p
ublic
atio
ns
and
pate
nts
DecadesPre-1990 1991–2000 2001–2010
SuzukiHeckSonogashiraStilleNegishiBuchwald-HartwigKumadaHiyamaAlpha ketone arylation
Fig. 2. Growth in the number of scientific publications and patents on platinumgroup metal-catalysed coupling reactions
RX +R’ H
H H
R’ H
H R
Pd catalyst
Base
R, R’ = aryl, vinyl, alkylX = halide, triflate, etc.
Scheme I. The Heck coupling reaction
Cop
yrig
ht ©
The
Nob
el F
ound
atio
n.Ph
oto:
Ulla
Mon
tan
are not tolerated due to the nature of the organomag-
nesium reagents.
In 1982 Negishi and coworkers therefore carried out
a metal screening in order to identify other possible
organometallic reagents as coupling partners (20).
Several metals were screened in the coupling of an
aryl iodide with an acetylene organometallic reagent,
catalysed by bis(triphenylphosphine)palladium(II)
dichloride (PdCl2(PPh3)2). In this study, the use of
zinc, boron and tin were identified as viable counter-
cations, and provided the desired alkyne product in
good yields. The use of organozinc reagents as cou-
pling partners for palladium-catalysed cross-coupling
to form a C–C single bond is now known as the
Negishi reaction (Scheme II).
The Negishi reaction has been used as an essential
step in the synthesis of natural products and fine
chemicals (21–23).
Suzuki CouplingDuring the same
period as the initial
reports of the use of
palladium–phosphine
complexes in Kumada
couplings, the palla-
dium-catalysed cou-
pling of acetylenes
with aryl or vinyl
halides was concur-
rently disclosed by
three independent research groups, led by
Sonogashira (24), Cassar (25) and Heck (26).
A year after the seminal report on the Stille cou-
pling (27, 28), Suzuki picked up on boron as the last
remaining element out of the three (Zn, Sn and B)
identified by Negishi as suitable countercations in
cross-coupling reactions, and reported the palladium-
catalysed coupling between 1-alkenylboranes and
aryl halides (29) that is now known as Suzuki cou-
pling (Scheme III).
It should be noted that Heck had already demon-
strated in 1975 the transmetallation of a vinyl boronic
acid reagent (30). Perhaps the greatest acomplish-
ment of Suzuki was that he identified PdCl2(PPh3)2 as
an efficient cross-coupling catalyst, thereby demon-
strating the relatively easy reduction of Pd(II) to
Pd(0) during catalysis.
The Suzuki coupling reaction is widely used in
the synthesis of pharmaceutical ingredients such
as losartan. Its use has been extended to include
coupling with alkyl groups and aryl chlorides
through the work of other groups including Fu and
coworkers (31). Subsequent work from Buchwald,
Hartwig, Nolan, Beller and others, including Johnson
Matthey, has expanded the scope of this reaction.
Other Name Reactions in Carbon–CarbonCoupling In 1976, Eaborn et al. published the first palladium-
catalysed reaction of organotin reagents (32), fol-
lowed by Kosugi et al. in 1977 on the use of organotin
reagents (33,34). Stille and Milstein disclosed in 1978
the synthesis of ketones (27) under significantly
milder reaction conditions than Kosugi. At the begin-
ning of the 1980s, Stille further explored and improved
this reaction protocol, to develop it into a highly ver-
satile methodology displaying very broad functional
group compatibility (28).
In 1988, Hiyama and Hatanaka published their work
on the Pd- or Ni-catalysed coupling of organosilanes
with aryl halides or trifluoromethanesulfonates (tri-
flates) (35). Although silicon is less toxic than tin,
a fluoride source, such as tris(dimethylamino)-
sulfonium difluorotrimethylsilicate (TASF) (35) or cae-
sium fluoride (CsF) (36), is required to activate the
organosilane towards transmetallation. Professor S. E.
Denmark has also contributed significantly to this area.
Industrial ApplicationsIn the early 1990s the Merck Corporation was able to
develop two significant drug molecules, losartan, 11,
87 © 2011 Johnson Matthey
doi:10.1595/147106711X558301 •Platinum Metals Rev., 2011, 55, (2)•
RZnY + R’X R–R’Pd catalyst
R, R’ = aryl, vinyl, alkylX = halide, triflate, etc.Y = halide
Scheme II. The Negishi coupling reaction
RBZ2 + R’X R–R’Pd catalyst
Base
R, R’ = aryl, vinyl, alkylX = halide, triflate, etc.Z = OH, OR, etc.
Scheme III. The Suzuki coupling reaction
Cop
yrig
ht ©
The
Nob
el F
ound
atio
n.Ph
oto:
Ulla
Mon
tan
(also known as CozaarTM, for the treatment of hyper-
tension) (37) and montelukast, 22, (also known as
SingulairTM, for the treatment of asthma) (38, 39),
(Figure 3) using Suzuki and Heck coupling processes
respectively. This also increased awareness among
related industries to look into similar processes.
Today, coupling reactions are essential steps in the
preparation of many drugs. Recent reviews by Beller
(40) and by Sigman (41) summarise the applications
of Pd-catalysed coupling in the pharmaceutical,agro-
chemical and fine chemicals industries. Apart from
the major applications in the pharmaceutical and
agrochemical industries (the boscalid process is the
world’s largest commercial Suzuki process), cross-
coupling is also being practiced in the electronics
industry for liquid crystal and organic light-emitting
diode (OLED) applications in display screens (42,
43).
The research and development group at Johnson
Matthey’s Catalysis and Chiral Technologies has devel-
oped commercial processes for preformed catalysts
such as PdCl2(dtbpf) (Pd-118), 33, (44–46), L2Pd(0)
complexes, 44, (47) and precursors to twelve-electron
species such as [Pd(µ-Br)tBu3P]2 (Pd-113), 55, (48)
and LPd(η3-allyl)Cl, 66, (49, 50) (Figure 4). These cata-
lysts are all highly active for various cross-coupling
reactions which are used for real world applications.
More details on the applications of these catalysts
are given elsewhere (48, 51, 52). A special issue of
Accounts of Chemical Research also covered recent
updates of these coupling reactions from academia
in detail (53).
88 © 2011 Johnson Matthey
doi:10.1595/147106711X558301 •Platinum Metals Rev., 2011, 55, (2)•
PdBr
PtBu2
3
Fe
PtBu2
Pd
Cl
ClL L
4
tBu3P–Pd Pd–PtBu3
Br
5Pd
Cl
P
6
4a L = PtBu34b L = PtBu2Np4c L = PCy34d L = Q-Phos4e L = Ata-Phos4f L = P(o-tolyl)34g L = PPhtBu2
Fe
PtBu2
Ph
PhPh
Ph
Q-Phos ligand
Me2N
Ata-Phos ligand
PtBu2
Ph
2 Montelukast 1 Losartan
Fig. 4. Examples of highly active Pd cross-coupling catalysts developed and commercialised by Johnson Matthey
Fig. 3. Structures of losartan and montelukast
In order to address the issue of residual palladium
in the final product, several solid-supported
preformed palladium complexes have been devel-
oped and launched onto the catalyst market
(54–56).
ConclusionsPalladium-catalysed cross-coupling is of great impor-
tance to real world applications in the pharmaceu-
tical, agrochemicals, fine chemicals and electronics
industries. The area has developed quite rapidly
beyond the work of Heck, Negishi and Suzuki,
though all three reactions are widely used. Academic
groups such as those of Beller, Buchwald, Fu, Hartwig
and Nolan as well as industrial groups such as that
at Johnson Matthey, are now developing the field even
further. Buchwald-Hartwig coupling has become par-
ticularly important for developing compounds con-
taining carbon–nitrogen bonds for applications in
industry, as well as α-arylation of carbonyl com-
pounds such as ketones, esters, amides, aldehydes
etc., and nitriles (57). The significant growth of cross-
coupling reactions can be summarised in Professor
K. C. Nicolaou’s words:
“In the last quarter of the 20th century, a new
paradigm for carbon–carbon bond formation has
emerged that has enabled considerably the prowess
of synthetic organic chemists to assemble complex
molecular frameworks and has changed the way
we think about synthesis” (58).
More detailed articles summarising the history of
cross-coupling in the context of the 2010 Nobel Prize
in Chemistry with an outlook on the future of cross-
coupling will be published elsewhere (59, 60).
89 © 2011 Johnson Matthey
doi:10.1595/147106711X558301 •Platinum Metals Rev., 2011, 55, (2)•
Glossary
Ligand Name
Ata-Phos p-dimethylaminophenyl(di-tert-butyl)phosphine
Cy cyclohexyl
dppf 1,1′-bis(diphenylphosphino)ferrocene
dtbpf 1,1′-bis(di-tert-butylphosphino)ferrocene
Np neopentyl
Ph phenyl
Q-Phos 1,2,3,4,5-pentaphenyl-1′-(di-tert-butylphosphino)ferrocenetBu tert-butyl
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The AuthorDr Thomas J. Colacot, FRSC, is aResearch and Development Managerin Homogeneous Catalysis (Global) ofJohnson Matthey’s Catalysis andChiral Technologies business unit.Since 2003 his responsibilities includedeveloping and managing a new cat-alyst development programme, cat-alytic organic chemistry processes,scale up, customer presentations andtechnology transfers of processesglobally. He is a member of PlatinumMetals Review’s Editorial Board,among other responsibilities. He hasco-authored about 100 publicationsand holds several patents.
90 © 2011 Johnson Matthey
doi:10.1595/147106711X558301 •Platinum Metals Rev., 2011, 55, (2)•
•Platinum Metals Rev., 2014, 58, (2), 93–98•
93 © 2014 Johnson Matthey
“Palladium-Catalyzed Coupling Reactions: Practical Aspects and Future Developments”Edited by Árpád Molnár (University of Szeged, Hungary), Wiley-VCH Verlag GmbH & Co KGaA, Weinheim, Germany, 2013, 692 pages, ISBN: 978-3-527-33254-0, £125.00, €150.00, US$190.00
http://dx.doi.org/10.1595/147106714X679458 http://www.platinummetalsreview.com/
Reviewed by Robert Hanley
Johnson Matthey Emission Control Technologies,
Orchard Road, Royston, Hertfordshire SG8 5HE, UK
Email: [email protected]
“Palladium-Catalyzed Coupling Reactions”, published
by Wiley in 2013, is a comprehensive handbook and
guide to modern aspects of this reaction type. The
book focuses on state of the art techniques. The use of
different reaction media, catalyst recycling, supported
catalysts, microwave assisted synthesis and continuous
fl ow reaction systems are all examined, making this
book an excellent resource. The book avoids delving
into the specifi cs of each type of coupling reaction and
instead presents a variety of topics, discussing recent
progress and potential future work in each given area.
It was edited by Árpád Molnár, a Professor of Chemistry
in the University of Szeged, Hungary, who has no less
than 200 publications to his name. Numerous research
papers in the fi eld of catalyst development, coupled
with review papers on many of the subjects covered
in this book, qualify Professor Molnár for his position
of editor.
The content of this book covers fi ve general topics:
an introduction and background to Pd-catalysed
coupling reactions, Pd catalysts on various support
materials, coupling reactions in different reaction
media, reaction conditions for coupling reactions
and industrial applications of Pd catalysed coupling
reactions.
IntroductionThe area of Pd-catalysed coupling reactions has
experienced a huge growth in popularity and has
swiftly increased in maturity in its relatively short
lifetime, having moved from using stoichiometric
amounts of Pd-based reagents to achieving impressively
high turnover numbers (TONs) in just a few decades.
Since the initial Pd-catalysed coupling reactions
described by Heck (1), Negishi (2) and Suzuki (3)
during the 1970s a wide range of coupling reactions,
using different organic halides and organometallic
compounds have been discovered (Figure 1).
http://dx.doi.org/10.1595/147106714X679458 •Platinum Metals Rev., 2014, 58, (2)•
94 © 2014 Johnson Matthey
The fi rst chapter of this book gives a comprehensive
introduction to the area of Pd-catalysed coupling
reactions, covering the history and characteristics
of the reactions and classifi cation of the various
reaction types, which numbered 72 in a recent
review (4). A mechanistic overview is given along
with considerations to be taken with regards to the
effect of the halides and nucleophiles employed, the
nature of the Pd species, ligands employed and other
related topics. The introduction is concluded with a
section on future challenges for Pd-catalysed coupling
reactions. Here aspects relating to practical, real world
applications are discussed along with developments
that will enable these reactions to be brought into
common usage. Even though this introduction is
relatively brief it gives an excellent and comprehensive
overview of Pd-catalysed coupling reactions, explains
why Pd is the catalytic metal of choice and provides a
basis for the following chapters.
Support MaterialsThere are four chapters that discuss the effects of the
support material on the performance of Pd-catalysed
coupling reactions. These are dealuminated ultrastable
Y (USY) zeolites, magnetically separable nanocatalysts,
ordered porous solids and polymers. In the fi rst chapter,
written by Kazu Okumura (Tottori University, Japan)
the high TONs achievable by the use of USY zeolites
is discussed. These materials are widely available due
to their use in alkane cracking and make a suitable
support for Pd due to nanometre sized pores within
the zeolite structure. The preparation of USY zeolites,
the dealumination process of the zeolite framework
and the preparation of Pd/USY zeolite catalysts are
discussed briefl y followed by a number of examples of
coupling reactions performed using these catalysts. As
an introduction to this support type the author describes
a typical Suzuki-Miyaura coupling of bromobenzene
and phenylboronic acid in o-xylene with potassium
carbonate as a base, used by Durgun et al. (5) to
screen activity of Pd salts loaded on USY zeolites.
[Pd(NH3)4]Cl2/USY exhibited high activity and using
0.7 × 10–4 mol% of catalyst for the coupling reaction a
TON of 1.3 × 106 and a 99% yield were obtained. Work
by the same group proved this catalyst type suitable for
Suzuki-Miyaura coupling of heterocyclic compounds.
High TONs and good yields were achieved in the
coupling of 2-bromothiophene and thiophene-2-boronic
acid indicating the possible use of Pd/USY catalyst in
the synthesis of organic semiconductors.
The second chapter in this section, written by Kifah
S. M. Salih and Werner R. Thiel (TU Kaiserslautern,
Germany), concerned magnetically separable
nanocatalysts. Using magnetically separable
supports offers an easy solution to what can be a
diffi cult problem – removing the catalyst from the
reaction mixture. In the introduction the authors
describe the solid state properties required of the
paramagnetic particles, factors affecting the lifetime
of the supported catalyst, some of the characterisation
techniques employed and the types of catalyst
attached to the magnetic particles. For example,
Manorama et al. reported nickel ferrite particles with
a dopamine functionalised surface on which they
grafted Pd nanoparticles (6). This Pd catalyst was
employed in high yielding Suzuki coupling reactions
between aryl chlorides and phenylboronic acid and
also Heck reactions between aryl chlorides and
styrene. Once the reaction was complete the catalyst
was magnetically removed from the reaction mixture
and successive reactions were performed with similar
yields (Figure 2).
Ease of separation of this catalyst type is key to its
functionality. Pd leaching was looked at in several of
the examples described. There was low or negligible
leaching of metal from the nanoparticles after several
uses of the catalyst. In one case, leaching of Pd was
observed during the reaction with reabsorption of
the metal back onto the support occurring after the
reaction mixture had cooled to room temperature.
A number of other magnetically separable catalysts
are described, including catalysts based on Pd
nanoparticles and also Pd complexes supported on
magnetic particles.
The third chapter in this section discussed the
use of ordered porous solids as a support for Pd
Suzuki R X + R’ BY2 R R’
Heck R X + R’ R R’
Sonogashira R X + R’ R R’
Pd cat.Base
Fig. 1. Schematic of the Suzuki, Heck and Sonogashira coupling reactions
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95 © 2014 Johnson Matthey
catalysts and was written by the editor of the book,
Árpád Molnár. The physical properties of ordered
porous solids make them ideal for use in catalysis:
high surface area, uniform pore size and a defi ned,
tunable structure. Materials that fall under the category
of ordered porous solids include zeolites, ordered
porous silica-based materials and metal organic
frameworks amongst others. The chapter opens with
an in-depth look at the synthesis and characterisation
of these materials, focusing on two examples: the
mesoporous silicas MCM and SBA. A background to
the materials, techniques employed to control pore
size and distribution, methods to tailor properties
and functionalisation are all covered extensively. An
Ullmann coupling of iodobenzene using a range of
mesoporous silica-based materials performed by Li et
al. highlighted the catalytic performance and ability
to tailor a catalyst to a reaction (7). Under the selected
reaction conditions a conversion of 27% and a yield of
just 7% were obtained using Pd supported on SiO2. By
altering the ordered porous silica materials to suit the
reaction, with large pores of SBA-15 to accommodate
the biaryl product and aluminium doped MCM-41 to
increase the Lewis acidity, promoting adsorption of
the iodobenzene, much improved conversion and
reaction yields were obtained. The chapter concludes
with a summary of the current state of these materials
together with a discussion of future prospects and
challenges.
Reaction MediaChapters six and seven discuss reaction media
employed for coupling reactions, namely ionic
liquids (ILs) and aqueous media. The solvent
employed as reaction medium has a considerable
effect on the performance, outcome, cost and
environmental impact of a chemical transformation,
so it is appropriate that some consideration is given
to the solvent selection. Traditional solvents used for
Pd-catalysed couplings include dimethylformamide,
N-methylpyrrolidinone and other polar solvents, many
of which have undesirable health implications, and as
with most volatile organic solvents, are fl ammable and
environmentally unfriendly.
Chapter six, written by Michael T. Keßler, Frank
Galbrecht and Martin H. G. Prechtl (Universität zu Köln,
Germany) and Jackson D. Scholten (Universidade
Federal do Rio Grande do Sul, Brazil), is dedicated to
the use of ILs as a reaction medium for Pd-catalysed
coupling reactions. ILs are organic salts with low
melting points, generally below 100ºC. The author cites
a number of reasons for their use: tunable combination
Na[PdCl4]
N2H4, H2ORT
NiFe2O4 NiFe2O4
Pd0HO
HO
NH2
=
Pd@DA/NiFe2O4
Pd@DA/NiFe2O4(50 mg)DMF, 24–36 h
R
R
RX = Cl, Br, IR = H, Me, Ac, OMe, NO2
(1.0 equiv.) (1.2 equiv.)
(1.2 equiv.)
X
K3PO4 (2.0 equiv.), TBAB45–110ºC
(HO)2B
K2CO3 (3.0 equiv.), B45–130ºC
76–98%
72–97%
Fig. 2. Magnetically separable palladium catalyst used for Suzuki and Heck reactions (6) (Image courtesy of Wiley and Sons, Copyright 2013)
http://dx.doi.org/10.1595/147106714X679458 •Platinum Metals Rev., 2014, 58, (2)•
96 © 2014 Johnson Matthey
of anions and cations to suit a particular reaction,
stabilising effect of ILs on ligands and Pd complexes,
solubility of organometallic compounds and ease of
separation of reaction products once the reaction is
complete. Again here, the authors detail a number of
coupling reactions performed in ILs, discussing the use
of both Pd complex-catalysed and Pd nanoparticle-
catalysed reactions. The emphasis is on the advantages
of ILs over more traditional solvents and the authors
use a number of examples to highlight this, often with
very high conversion rates, mild reaction conditions
and excellent catalyst reuse and recycling potential.
In chapter seven, written by Kevin H. Shaughnessy
(The University of Alabama, USA), cross-coupling
reactions in aqueous media is the topic. Water being
a cheap, non-toxic, non-fl ammable, renewable solvent
makes it a sensible solvent choice. However, with
organic compounds, problems of solubility along with
often water labile reaction systems mean that the use
of aqueous media is frequently avoided. The author
discusses the resurgence of aqueous based organic
chemistry, aspects of Pd that lend it to aqueous
reaction systems and developments in water soluble
ligands. The actual need for solubility is also discussed
with effi cient organic reactions being performed
‘on water’, that is, where solubility in the solvent is
not required to achieve chemical transformations. A
range of examples are given: fi rstly in aqueous media,
then in biphasic systems of water and organic solvent
mixtures. An example of a water-only mediated Suzuki
reaction was performed by Basu et al. (8). A ligand free
coupling of tropolone with an aryl trihydroxyborate
allowed Pd(OAc)2 and tetrabutylammonium bromide
to catalyse the reaction at low temperatures and short
reaction times in water (Figure 3).
Reaction Conditions The next section of the book, consisting of three
chapters, covers reaction conditions of coupling
reactions. The topics covered here are microwave
assisted synthesis, catalyst recycling and continuous
fl ow reactions. Despite microwave assisted reactions
and catalyst recycling appearing in numerous
described reactions in previous chapters the editor
considered the exceptional results possible when
employing these techniques worthy of separate
chapters. In the chapters on microwave synthesis and
catalyst recycling the ‘green’ aspects of the subject
are highlighted. In the case of microwave synthesis,
reduced reaction times, minimised side products
and improved yields are cited as reasons for its
consideration.
As in other chapters the authors, Ke-Hu Wang and
Jun-Xian Wang (Northwest Normal University, China),
discuss a range of microwave assisted coupling
reactions, most of which were reported within the
previous decade. In most cases the short reaction
times (with some reactions completing in a matter
of minutes) are emphasised as a unique feature of
microwave assisted synthesis, often coupled with
excellent yields.
In the chapter on catalyst recycling Árpád Molnár
places the focus on some of the shortcomings in
reported recyclable catalysts. In the lengthy introduction,
some common misconceptions with regards to what
is a stable, recyclable catalyst are addressed. Where at
times, effi cacy is maintained while catalytic metal is
being lost, the true recyclable nature of the catalyst is
brought into question. This topic is covered in detail
along with some techniques that can be utilised
to monitor low levels of Pd loss. Nanoparticle,
complex-based and polymer immobilised catalysts
are covered along with a number of other reusable
catalyst types. Here, numerous impressive examples of
robust catalysts are discussed, with some performing
twenty runs of a Heck coupling reaction without loss of
performance (9). The design of reactions is also brought
into question here. Low numbers of repeat runs using
O
O
OTBS
O
O
OTBS
(HO)2B+Br
MeO
O
MeO
O
95%
Pd(OAc)2 (20 mol%)
K2CO3, TBABH2O, 70ºC, 30 min
Fig. 3. A ligand free coupling of tropolone with an aryl trihydroxyborate catalysed by Pd(OAc)2 and tetrabutylammonium bromide using water as reaction solvent (8) (Image courtesy of Wiley and Sons, Copyright 2013)
http://dx.doi.org/10.1595/147106714X679458 •Platinum Metals Rev., 2014, 58, (2)•
97 © 2014 Johnson Matthey
the more reactive halides give impressive results,
whereas for transformations performed with less
reactive compounds, high numbers of test reactions
and adequate characterisation to ensure no loss of
catalyst are required to truly call a catalyst recyclable.
Chapter eleven written by William R. Reynolds and
Christopher G. Frost (University of Bath, UK) covers the
use of continuous fl ow reactors as a reaction system for
coupling reactions. In previous chapters reactions were
performed in batch style fl asks or vessels. Excellent
reaction effi ciencies, both in yield and cost reduction,
have been seen in bulk chemical processes for years. In
recent decades considerable time has been dedicated
to continuous fl ow reactors for organic synthesis and
good reaction effi ciencies have been achieved as a
result. Lower energy requirements, better temperature
control, improved mass transfer, lowered reaction
volume giving greater control over the chemical
reactions and ease of scaling from lab to industrial
scale are cited as some reasons for continuous fl ow
being an attractive alternative to batch type reactions.
An effective example of improved reaction effi ciency
was conducted by Li et al. (10). In this example
effi ciencies of fl ow reactors were compared to batch
reactors in the Suzuki coupling of aryl chlorides with
phenylboronic acids using Pd(OAc)2 as catalyst and
DABCO (1,4-diazabicyclo[2.2.2]octane) as a ligand.
After a 4 h residence time continuous fl ow reactions
of both electron-rich and electron-poor aryl chlorides
had completed with almost quantitative yields. The
batch reacted counterparts had considerably lower
conversions after 4 h and reaction times of 24 h
were required to bring the reactions to completion
(Figure 4). Reactor technology and design is
also discussed, along with catalyst immobilisation
techniques, continuous separation and the use of
microreactors.
All of the chapters so far have presented impressive
results but only in research scale coupling reactions.
The fi nal chapter in the book, by Andreas Dumrath,
Christa Lübbe, and Matthias Beller (Leibniz-Institut
für Katalyse e.V. an der Universität Rostock, Germany)
concerns industrial applications, mainly focusing
on examples from the recent past. The focus of the
introduction differs from the other chapters in that
it includes a discussion based on real life reaction
scale-up along with economic considerations, metal
prices, the cost of the base and reactants employed,
intellectual property implications and toxicity
of catalysts where pharmaceutical products are
concerned. A slightly different approach to examples
is taken in this chapter, often presenting a background
to the desired product, along with different reaction
options and routes taken to catalyst and reaction
selection. A Heck-Mizoroki coupling of benzyl acrylate
with a bromonaphthalene was used in the synthesis
of an oral pharmaceutical by GlaxoSmithKline (11).
By replacing a late stage reaction with this coupling,
the downstream chemistry was simplifi ed resulting
in better scalability along with a large reduction
R1
R1R2
R2Cl B(OH)2 Pd(OAc)2, DABCO+
Conversion, %
Entry Product Flow (4 h) Batch (4 h) Batch (24 h)
1 98 61 98
2 99 35 57OMe
Fig. 4. Comparison of a fl ow vs. batch process for a Suzuki reaction (Image courtesy of Wiley and Sons, Copyright 2013)
http://dx.doi.org/10.1595/147106714X679458 •Platinum Metals Rev., 2014, 58, (2)•
98 © 2014 Johnson Matthey
in raw material cost. Other techniques covered in
other chapters in this book are also used in industry
including microwave assisted synthesis, continuous
fl ow coupling reactions and reusable catalysts. This
chapter exhibits a number of excellent examples
of improvements to reaction rates and conditions
achieved by incorporating Pd catalysed coupling
reactions. Despite the complexity of a number of
these compounds, equivalent or improved yields and
stereocontrol was achieved by using these coupling
reactions, often with an economic benefi t due to fewer
side products, the use of lower quantities of reagents
and a reduced need for purifi cation steps.
SummaryThis book is an excellent, modern summary of the
state of Pd-catalysed coupling reactions. The focus
on highly effi cient reactions and recyclability of the
catalysts is in tune with the ethos being adopted by
many in the chemical industry. Atom effi ciency and
the application of cleaner, less wasteful chemistry is
now very achievable. This book would be an excellent
starting place for an organic chemist who is interested
in reducing costs and increasing effi ciencies of
existing reaction processes or one who is designing
new synthetic routes.
References 1 R. F. Heck and J. P. Nolley, J. Org. Chem., 1972, 37,
(14), 2320
2 A. O. King, N. Okukado and E.-i. Negishi, J. Chem. Soc., Chem. Commun., 1977, (19), 683
3 N. Miyaura, K. Yamada and A. Suzuki, Tetrahedron Lett., 1979, 20, (36), 3437
4 E.-i. Negishi, G. Wang, H. Rao and Z. Xu, J. Org. Chem., 2010, 75, (10), 3151
5 G. Durgun, Ö. Aksın and L. Artok, J. Mol. Catal. A: Chem., 2007, 278, (1–2), 189
6 B. Baruwati, D. Guin and S. V. Manorama, Org. Lett., 2007, 9, (26), 5377
7 H. Li, W. Chai, F. Zhang and J. Chen, Green Chem., 2007, 9, (11), 1223
8 B. Basu, K. Biswas, S. Kundu and S. Ghosh, Green Chem., 2010, 12, (10), 1734
9 Á. Mastalir, B. Rác, Z. Király and Á. Molnár, J. Mol. Catal. A: Chem., 2007, 264, (1–2), 170
10 J. Jin, M.-M. Cai and J.-X. Li, Synlett, 2009, (15), 2534
11 G. Bret, S. J. Harling, K. Herbal, N. Langlade, M. Loft, A. Negus, M. Saganee, S. Shanahan, J. B. Strachan, P. G. Turner and M. P. Whiting, Org. Process Res. Dev., 2011, 15, (1), 112
The ReviewerRobert Hanley obtained a BSc in pharmaceutical science from Cork Institute of Technology, Ireland, and a Master’s degree in green chemistry from Imperial College London, UK. He previously worked for Johnson Matthey Pharmaceutical Materials, Ireland, in the area of prostaglandin synthesis. Currently he is working as a development chemist for Johnson Matthey within the Emission Control Technologies division, his main area of research being diesel oxidation catalysts.
“Palladium-Catalyzed Coupling Reactions: Practical Aspects and Future Developments”
•Platinum Metals Rev., 2013, 57, (4), 234–258•
234 © 2013 Johnson Matthey
The Directed ortho Metallation–Cross-Coupling Fusion: Development and Application in SynthesisPlatinum group metals catalytic synthetic strategy for pharmaceutical, agrochemical and other industrial products
http://dx.doi.org/10.1595/147106713X672311 http://www.platinummetalsreview.com/
By Johnathan Board
Snieckus Innovations, Innovation Park, 945 Princess Street, Kingston, Ontario, K7L 3N6, Canada
Jennifer L. Cosman
Department of Chemistry, Queen’s University, 90 Bader Lane, Kingston, Ontario, K7L 3N6, Canada
Toni Rantanen, Suneel P. Singh and Victor Snieckus*
Snieckus Innovations, Innovation Park, 945 Princess Street, Kingston, Ontario, K7L 3N6, Canada
*Email: [email protected]
This review constitutes a detailed but non-exhaustive
examination of the directed ortho metallation (DoM)–
cross-coupling fusion in its many fl avours. Special
attention is paid to the application of the concept of the
linked reactions and the synthetic utility that it endows,
particularly in the case of one-pot reactions that can
greatly increase the ease and effi ciency of the process.
Personal experience of particular issues that can arise
from these reactions and examples of their solutions
are given, as well as illustrations of the rapid access to
complex molecules that the technique encourages.
IntroductionSince its disclosure, the combination of DoM and
transition metal-catalysed cross-coupling has evolved
into a common strategy in synthesis (1, 2) and,
in particular, has found widespread use in the
preparation of biologically interesting aromatic and
heteroaromatic compounds. A variety of functional
groups such as I, Br, Cl, SiR3, SnR3, B(OR)2 have been
introduced using DoM, followed by different cross-
coupling reactions to form carbon–carbon, carbon–
oxygen, carbon–nitrogen and carbon–sulfur bonds
in order to prepare synthetically and biologically
interesting molecules. Herein we present selected
examples of the use of the DoM–cross-coupling strategy
from the period of 2000 to 2012 in order to demonstrate
its advantages and outline the potential issues that
may be faced in its application. The main focus will
be on cross-couplings involving the platinum group
metals (pgms); however several examples using other
metals such as copper are included for comparison.
In order to make this review more accessible, it is
divided into sections according to the type of bond
being formed and the type of metallation reaction. For
further clarifi cation, a scheme describing the reaction
discussed appears at the beginning of each section.
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235 © 2013 Johnson Matthey
1. DoM–C–C Cross-Coupling Reactions
1.1 Sequential (Multi-Pot) DoM–Cross-Coupling MethodsThe formation of C–C bonds through the sequence
of DoM–halogenation to insert an ortho halide
or pseudohalide, followed by cross-coupling has
been carried out using Ullmann, Heck, Sonogashira,
Negishi, Stille and Suzuki-Miyaura reactions,
among others. As an example, Sanz et al. (3) have
synthesised valuable 4-fl uoro-2-substituted-1H-
indoles 4 through a sequence involving DoM
mediated iodination of 3-fl uorotrifl uoroacetanilide
1, followed by reaction with terminal aromatic
or aliphatic alkynes by a Sonogashira coupling–
cyclisation process (Scheme I). When the DoM
reaction was carried out at temperatures higher
than –60ºC, competitive lithium fl uoride elimination
took place forming a benzyne intermediate 5 which
underwent subsequent intramolecular cyclisation to
provide iodinated benzoxazole 7. This phenomenon
occurring during the directed metallation of
3-fl uoroaniline bearing N-pivaloyl, N-Boc directing
metallation groups (DMGs) or an N-benzoyl group
had been previously observed (4).
The Suzuki-Miyaura cross-coupling is one of the
most popular and widely used reactions in the C–C
DoM–cross couple fusion strategy (for examples, see
(5, 6)). When partnered with DoM, the major advantage
of the Suzuki-Miyaura reaction is that boronation
reagents such as B(OR)3 are often compatible with
lithium bases (usually lithium dialkylamides, but
some boronates are even compatible with s-BuLi )
(7). This allows the boronating agent to be present
in the same reaction vessel as the base in order to
quench the metallated species as it is formed. These
conditions are known in our laboratories as either
Barbier or Martin (8, 9) type conditions according
to the order of addition. (Descriptions of these in
situ quench conditions are as follows: under Barbier
type conditions the base is added to a mixture of
substrate and electrophile; under inverse Barbier
conditions a solution of substrate and electrophile
are added to a solution of the base; under Martin
conditions the substrate is added to a solution of base
and electrophile; under inverse Martin conditions
a solution of base and electrophile are added to a
solution of the substrate. Compatible electrophiles
include, but are not limited to, trimethylsilyl
chloride (TMSCl), Me2SiCl2, B(OMe)3 and B(OiPr)3.)
Halide sources are not usually compatible with
strong bases; for instance, premixing I2 and lithium
DMG DMG
X
DMG
R
DoM Cross-coupling
X = Halide or pseudohalideR = Carbon-based substituent
F
OF3C
NH
1. tBuLi/TMEDA (2.3 equiv.)THF, –78ºC
2. I2 (1.4 equiv.)–78ºC to RT63% yield OLiF3C
N
LiF
OLiF3C
N
>–60ºC–LiF
21
5
3
6
4
7
R1 (1.5 equiv.)PdCl2(PPh3)2 (3 mol%)
CuI (5 mol%)
Et2NH (1.5 equiv.)DMA, 80ºC
R1 = Ph, 87% yieldR1 = nHex, 78% yield
OF3C
NH
IF F
Li IO
NCF3 33% yield
O
NCF3
NH
R1
Scheme I. Sequential DoM and Sonogashira cross-coupling for the synthesis of indoles
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236 © 2013 Johnson Matthey
2,2,6,6-tetramethylpiperidide (LiTMP) before addition
of the metallation substrate has resulted in low yields
of iodinated material in our laboratories. Vedsø et al.
have shown that ester, cyano and halogen substituents
are tolerated when LiTMP/B(OiPr)3 is used for in situ
boronation of unstable ortho metallated species (10).
In our group we have found that the DoM–cross-
coupling strategy fi nds particular utility in the
functionalisation of indoles. Stimulated by work
performed by Iwao et al. (11), we have developed
routes to 3,4-substituted indoles by utilising DoM–
Negishi cross-coupling sequences to afford gramines
8 which undergo useful retro-Mannich fragmentation
to give indoles 9 (12). Similarly, C-7-substituted
indoles 12 have also been synthesised by either
sequential or one-pot C-2 metallation, C-2 silylation,
C-7 metallation and C-7 electrophile treatment of
indoles 10 to provide the boronates or halides 11,
followed by Suzuki-Miyaura cross-coupling to give
12 (13). In addition, 2-aryl/heteroarylindoles 15
have also been synthesised from N-carbamoyl-2-
bromoindoles using either Suzuki-Miyaura (13a) or
one-pot ipso borodesilylation–Suzuki-Miyaura (13b)
reactions to provide indoles 14, followed by a lithium
diisopropylamide (LDA)-induced anionic N–C
carbamoyl migration (Scheme II) (14).
Due to the higher C–H acidity of heteroaromatic
systems, the DoM component of the DoM–cross-
coupling fusion of these systems is dominated by the
use of bases other than butyllithium, such as the lower
N N
N N N
N
N
N
HN
C and Het
DME (refl ux) or DMF (100ºC)6–18 h, 85–92% yields
BCl3 (1.1 equiv.), CH2Cl2, –45ºC, 60 min, then pinacol (4 equiv.) and evaporate, then Ar3Br (0.8 equiv.),
Pd(PPh3)4 (5 mol%), K3PO4 (4 equiv.)
DMF, 100ºC, 12–20 h, 67–89% yields
Ar3B(OH)2 (1.2 equiv.), Pd(PPh3)4 (5 mol%)Na2CO3 (1.5 equiv.) or K3PO4 (3 equiv.)
LDA (4 equiv.), THF0ºC to RT, 1–12 h
R1 = Me, 50–92% yieldsR1 = H, 36%–quant.
yields17 examples
Ar2X (1.1–1.2 equiv.) Pd(PPh3)4
(2–10 mol%)K3PO4 (3 equiv.)
DMF, 80ºC15–20 h
83–99% yields
1. tBuLi (1.1 equiv.) TMSCl (1.05 equiv.)
2. sBuLi/TMEDA (1.5 equiv.)
3. I2, BrCH2CH2Br or B(OiPr)3 (1.5 equiv.), THF, –78ºC to RT, 5 h total
N-bromosuccinimide (1 equiv.)MeOH, RT, 2 min
or1. TBAF (1 equiv.), THF, RT, 10 min
2. N-iodosuccinimide (1 equiv.), MeOH, 0ºC, 5 min3. (Boc)2O (1.5 equiv.), Et3N (1.5 equiv.)
DMAP (cat.), CH2Cl2, RT, 15 min24–81% yields
TIPS
DoM/cross-coupling
NMe2Ar1 Ar1
Ar2
Ar3
PG
X
TMSTMS
TMS
CONEt2 CONEt2 CONEt2
CONEt2 CONEt2
CONEt2CONEt2
CONEt2CONEt2CONEt2
CONEt2
CONEt2
HN
HN
HN
HN
HN
E
Br
Me
Me Me OMe Me
R1 R1
N
SS
8 9
10 11 12
13a
14
13b
15
Select examples:
15a 92% yield from 13 15b 55% yield from 13 15c 56% yield from 13 15d 73% yield from 13 15e 75% yield from 13 using PhB(OH)2 using 2-MeOC6H4B(OH)2 using 3-thienylboronic acid using 3-bromothiophene using 3-bromopyridine
PG = TIPS or Boc; Ar1 = Ph, o-Tol, pyridin-3-yl; X = Br or IE = I, Br, BPin (after pinacolation); Ar2 = 8 examples including Ph, 2-MeOC6H4, pyridin-3-ylR1 = H, MeAr3 = CHCH(4-MeC6H4), Ph, 2-MeOC6H4, 3-MeOC6H4, 4-MeOC6H4, 4-FC6H4, 4-ClC6H4, 4-BrC6H4, furan-3-yl, thiophen-3-yl, pyridin-3-yl, naphthalen-1-yl, isoquinolin-4-yl
Scheme II. Indole functionalisation utilising the DoM and cross-coupling protocol
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237 © 2013 Johnson Matthey
pKa lithio dialkylamides or Grignard bases; the cross-
coupling component has been dominated by Suzuki-
Miyaura and Negishi reactions. The consideration
of which base to choose is heavily infl uenced by
the DMG and by the other functionalities within the
system. For instance, if the DMG is a halogen then
benzyne formation may need to be avoided through
the use of lower temperatures or milder bases
less prone to induce MX elimination. On the other
hand, if the DMG is weak and the system is electron
rich then stronger bases will be required which
may result in nucleophilic attack of the base upon
the heteroaromatic ring, especially in the case of
π-defi cient systems. Usually the accepted wisdom is to
use as mild a base as possible, at a temperature as close
to room temperature as is possible in order to achieve
the greatest degree of functional group compatibility
and experimental simplicity. Certain DMGs are less
tolerant of higher temperatures than others, such as
N,N-diethyl-O-carbamate which may undergo the
anionic ortho Fries rearrangement (1, 15, 16). We have
found also that the variation of solvents can have a
profound effect on the selectivity of the metallation; in
particular the switch between tetrahydrofuran (THF)
and diethyl ether can make the difference between
the success or failure of a reaction.
Although in many cases this type of DoM–cross-
coupling strategy can be performed with relative ease
simply by using conditions precedented for a similar
system, both the DoM and cross-coupling may have
non-trivial problems which should be solved through
methodical application of standard optimisation
techniques, such as variation of solvent, base and
catalyst system. An instructive example concerns work
which eventually led to the discovery of soraprazan
(16, Figure 1), a clinically studied H+/K+-ATPase
inhibitor (17).
Thus, as shown by deuterium quench experiments,
the ortho deprotonation of an N-pivaloyl
imidazo[1,2-a]pyridine 17 gave the highest ratio of
C-5:C-7 (18:19) deprotonation when t-butyllithium was
used in diethyl ether (Scheme III). When this reaction
was performed in THF, products 18 and 19 were
obtained in almost equal conversion. These results
were rationalised by the observed poor solubility of
the kinetically preferred C-7-anion in diethyl ether
which presumably prevented it from undergoing
equilibration with the more thermodynamically
preferred C-5-anion. On the other hand, in THF
the greater solubility of the C-7 anion allowed it to
equilibrate with the C-5 anion thereby eradicating
N
NH
OO
HOPh
Me
Me
MeN
16
Fig. 1. Soraprazan, a H+/K+-ATPase inhibitor (17)
tBuLi (2.8 equiv.)solvent, –78ºC, 15 min
then D2O quenchexamined using 1H NMR
Me
Me
tBu
O
HN
17tBuLi (3 equiv.), TMEDA (3 equiv.)
diethyl ether, –78ºCthen addn. of Bu3SnCl (3 equiv.)–78ºC, 1 h, then RT overnight1:9 ratio, 20:21 obtained in
41% yield
Me
Me
tBu
O
HN
18
Me
Me
tBu
O
HN
19
Me
Me
tBu
O
HN
20
Me
Me
tBu
O
HN
21
D
D
SnBu3
Bu3Sn
++
others, mainly bis-deuterated products
+
Solvent Conversion, %THF 23 25 53Ether 18 82 <3N
N
N
N
N
N
N
N
N
N
Scheme III. DoM studies of the N-pivaloyl-imidazo[1,2-a]pyridine 17 (17)
http://dx.doi.org/10.1595/147106713X672311 •Platinum Metals Rev., 2013, 57, (4)•
238 © 2013 Johnson Matthey
the selectivity. When the reaction was performed
using the weaker n-butyllithium, no selectivity
between C-5 and C-7 metallation was achieved, and
a large amount of starting material was recovered
even when the reaction was conducted over longer
periods of time or at higher temperatures. This is
presumably due to the moderate ortho-directing
ability of the N-pivaloyl group. Use of the optimised
deprotonation conditions followed by stannylation
afforded the desired C-7 product 21 in acceptable
yield in a 1:9 ratio together with the undesired C-5
regioisomer 20.
The derived compound 21 was used in acylative
Stille cross-couplings with cinnamoyl chlorides to
give compounds 23, which by straightforward acid-
mediated Michael cyclisation-depivaloylation afforded
compounds 24, which are intermediates for sorapazan
(16) and its analogues (Scheme IV). The execution
of the Stille cross-coupling was far from trivial and
therefore deserves comment. Experiments with a
variety of palladium sources were unsuccessful and
only the combination of PdCl2(MeCN)2 and a three-fold
excess of the cinnamoyl chloride led to cross-coupled
products 23, in poor yields, which precipitated from
the reaction mixture as the hydrochloride salts. The
known advantages of using halide salts in Stille cross-
couplings of aryl trifl ates (18–20) led to speculation
about the role of halide salts in the reaction. Thus,
on addition of one equivalent of lithium chloride to
the reaction mixture, conversion to products 23 was
achieved in moderate yield.
Despite the demonstration in our laboratories
of the advantages of performing a DoM–Suzuki
Miyaura cross-coupling in a one-pot fashion (such
as fewer chemicals used, eradication of at least one
workup step, higher effi ciency and convenience),
most reported reactions are performed with isolation
of the DoM products. Schemes V and VI (21, 22)
N
N
Me
Me Me
Me
Me
Me
tBu
O
HN tBu
O
HNBu3Sn
ArAr Ar
OO O
Cl
21 2223 24(1–1.28 equiv.)
Pd2(dba)3•CHCl3 (1 mol%)LiCl (1–1.28 equiv.)
THF, 60ºC, 2.5 hthen RT overnight
NH
N
NN
N
Conc. HClor 50% H2SO4
100ºC
3–4 h
Ar Yield, % Yield, %Ph 66 692-ClC6H4 4 732,6-Cl2C6H3 50 412-F3CC6H4 50 41
Scheme IV. Acylative Stille cross-coupling of 21 to provide products 23 and thence sorapazan precursors 24
N
25
NOMe
Ar1
NNOMe
Ar1
NNOMe
Ar1
1. nBuLi (2 equiv.)iPr2NH (2 equiv.)
Et2O, 30 min, 0ºC to –78ºC then 25 (1 equiv.)/Et2O, 1 h, then B(OiPr)3 (3 equiv.)
1.5 h, –78ºC to RT
2. Acidic workup 61–69% yields
B(OH)2
26
28
NNOMe
Ar1
27
BPinPinacol (1 equiv.)MgSO4, toluene
12–19 h, RT73–90% yields
Ar2
Ar2Br, Pd2(dba)3 (1 mol%)PCy3 (2.4 mol%)K3PO4 (aq. 1.3 M, 1.7 equiv.)1,4-dioxane, refl ux, 24 h18–76% yields
Ar1 = Ph, 4-MeOC6H4, 2-MeO-pyridin-5-yl, 2-F-pyridin-5-ylAr2 = pyridin-2-yl, 5-O2N-6-H2N-pyridin-2-yl, pyrimidin-5-yl
Scheme V. Sequential DoM–Suzuki Miyaura synthesis of arylpyridazines 28 (21)
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239 © 2013 Johnson Matthey
depict cases in which the boronic acids 26 and 30, generated from DoM reactions, are isolated prior to
cross-coupling. Of particular note is the low yield of
boronic acid 30, which is likely attributable in part to
the instability of this heterocyclic boronic acid.
1.2 One-Pot DoM–Cross-Coupling MethodsA more effi cient process than shown so far is a DoM–
cross-coupling protocol carried out without isolation
of the intermediate species (boronic acid, zincate for
instance) which is most often accomplished using
Suzuki-Miyaura or Negishi cross-coupling reactions.
For instance, as part of a campaign towards the
synthesis of the antimicrobial agent GSK966587 (32,
Figure 2), a ‘one-pot’ DoM–cross-coupling method
was developed (23).
Thus, the DoM–iodination reaction of 33 was
investigated (Scheme VII) in preparation for Heck
coupling chemistry (Scheme VIII). The use of the
more traditional alkyllithium and lithium amide
bases was complicated by the formation of dianions
and by competitive fl uoride displacement. The use of
LDA at low temperatures under short reaction times
was promising but gave mixtures of both mono-
iodides 34 and 35 and bis-iodide 36. Although the
Uchiyama zincate mixed metal base TMPZn(tBu)2Li
gave predominantly the undesired mono-iodide 35,
the analogous (iPr)2NZn(tBu)2Li gave an encouraging
result. A further shift to (iPr)2NZnEt2Li (prepared by
mixing Et2Zn and LDA) gave excellent selectivity
for the desired iodide 34 which was eventually
isolated in 85% yield (74% from starting material 39, Scheme VIII).
After extensive screening, Heck coupling of iodide
34 with allyl alcohol was achieved to give the
-coupled product 37 in 77% yield (57% yield from
39, Scheme VIII). As a more effi cient alternative to this
sequential procedure, the Negishi cross-coupling of
the zincate intermediate 38 (the presumed metallated
species from the DoM reaction of 33) was realised and
gave a comparable yield of 37 (68% yield from 39)
but required no iodine and fewer purifi cation steps.
N29
ClR1O N30
ClR1O N31
ClR1O
(HO)2B Ar1. LDA (1.1 equiv.)2. B(OiPr)3 (1.2 equiv.)
THF, –78ºC to RTacidic workup, 13% yield
ArX (0.9 equiv.) Pd(PPh3)2Cl2 (5 mol%)
Na2CO3 (aq. 1 M)
1,4-dioxane, refl ux, 24 h, 29–98% yields
R1 = Me, EtAr2 = 2-MeO-pyridin-5-yl, 2-MeO-pyridin-6-yl, pyrimidin-5-yl, 2-MeO-pyrimidin-5-yl
Scheme VI. Sequential DoM–Suzuki Miyaura synthesis of aryl-2-chloropyridines 31 (22)
N
NHO
FO
NHO
ON
32
N
Fig. 2. Antimicrobial agent GSK966587
N
NMeO F
33N
NMeO F
34N
NMeO F
35N
NMeO F
36
++
I I
II
Base Equiv. Time, min Temp., ºC Area, %, by HPLC analysisLDA 1.5 15 –70 42 8 40LDA 1.1 5 –60 83 8 1.5TMPZn(tBu)2Li 1.1 30 23 26 34 23(iPr)2NZn(tBu)2Li 1.0 120 23 45 5 0(iPr)2NZnEt2Li 1.2 30 –10 96a 4 0a85% isolated yield
Scheme VII. DoM route to 7-fl uoro-8-iodo-2-methoxynaphthyridine 34 (23)
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240 © 2013 Johnson Matthey
By its nature, the DoM–Negishi cross-coupling
protocol lends itself to a one-pot procedure whereby
the deprotonation, transmetallation (if necessary)
to a zincate and transition metal-catalysed cross-
coupling occur sequentially in the same reaction
vessel. Among the cases illustrated in Schemes IX–XI (24–26), of note is the use of the oxazole DMG which
by hydrolysis provides the desired carboxylic acid
in the target molecule 43 (Scheme IX). This is a
further demonstration of the use of tetrazole as a DMG
in the synthesis of the ‘sartan’ pharmaceutical 46
(Scheme X) and the use of catalytic zinc chloride and
of the pyridine N-oxide as a DMG in the preparation of
azabiaryl 49 (Scheme XI).
Recently, a one-pot DoM–Negishi cross-
coupling strategy that can utilise esters as DMGs
N
NMeO F
34
N
NMeO F
33N
HNO F
39N
NMeO F
N
NMeO F
37
I HO
Li+ –ZnEt2
38
1. SOCl2(nBu)2NCHO
toluene
2. MeOHno yield given
1. (iPr)2NZnEt2Li (1.1 equiv.)2. I2 (3.9 equiv.)
THF, –10ºC to RT, 85% yield74% yield from 39
HOBr (2.2 equiv.)
LDA (2.2 equiv., addn. at –30ºC)Tri(2-furyl)phosphine (8 mol%)Pd2(dba)3•CHCl3 (2 mol%)
THF, 45ºC, 60 min, 68% yield from 39
(iPr)2NZnEt2Li(1.1 equiv.)
THF, –10ºC to RT
Allyl alcohol (15 equiv.)Pd(OAc)2 (2.5 mol%)
dppf (5.5 mol%)NH4OAc (2 equiv.)
ethylene glycol130ºC, 7–8 h, 77% yield
57% yield from 39
Scheme VIII. Sequential and ‘one-pot’ DoM–Heck coupling synthesis of naphthyridine 37 (Note: The authors provide the yields for the optimisation, but also for a process whereby all of the batch is taken through the whole process with only minimal purifi cation. Hence overall yields comparing the two processes are given even though no yield is given for the conversion of 39 to 33)
N
O
Me
Me40
O
N
N
Me
Me
NnPr
N
OH
N
N
Me
Me
NnPr
N
Br
N
O
Me
Me
N
N
Me
Me
NnPr
N
42
41
43
nBuLi (1.2 equiv.)ZnCl2 (1.8 equiv.)0ºC, THF, 120 min
then Pd(PPh3)4 (1 mol%)41 (1 equiv.)
55ºC, 24 h, 55% yield
HCl, refl ux
30 min, 85% yield
Scheme IX. One-pot DoM–Negishi cross-coupling strategy for the synthesis of telmisartan 43 angiotensin II receptor antagonist (24)
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has been developed by Knochel and coworkers
involving the amide bases tmpMgCl·LiCl (tmp =
2,2,6,6-tetramethylpiperidyl), tmp2Mg·2LiCl and
tmp2Zn·2MgCl2·2LiCl (27). These bases are used
in stoichiometric amounts (no extreme excess is
required), facilitated by LiCl which complexes and
solubilises the bases and leads to monomeric metallic
amides. Due to its stability (at least 6 months at 25ºC
under inert atmosphere) (28, 29) tmpMgCl·LiCl is
commercially available and is capable of metallating
moderately C–H acidic aromatic compounds. For
more demanding aromatic cases tmp2Mg·2LiCl (30)
may be used and for systems that contain sensitive
functional groups tmp2Zn·2MgCl2·2LiCl (31) has
proven to be effective. Unfortunately the latter two
bases are not as stable as tmpMgCl·LiCl; for instance
tmp2Mg·2LiCl is stable only for 24 h at 25ºC (27).
These reagents are usually prepared fresh for each
reaction, or set of reactions, from tmpMgCl·LiCl by
the addition of LiTMP or ZnCl2, respectively. The
use of these bases for combined metallation–cross-
coupling reactions greatly increases the potential
substrate scope of this strategy, as illustrated by
the synthesis of aromatic esters 51, 53 and 55
(Schemes XII–XIV). Noteworthy is the last case
since nitrile groups are not normally compatible
with the use of Grignard reagents. In addition, only
0.5 equivalents of tmp2Zn·2MgCl·2LiCl are required
(i.e. both potential TMP anions are available) and
transmetallation is unnecessary as this reagent
N NN NPh3C
44
N NN NPh3C
46
O
N
nBu
CO2Me
nBuLi (1.2 equiv.)ZnCl2 (1.8 equiv.)
–20ºC to RT, THF, 90 minthen
Pd(OAc)2 (5 mol%)QPhos (5 mol%)
45 (1 equiv.)75ºC, 2 h, 80% yield
O
N
nBu
CO2Me
45Br
Scheme X. One-pot DoM–Negishi cross-coupling strategy to synthesise valsartan 46 angiotensin II receptor agonist (25)
I+
–OTf
48
47 49
N+
O–
MeMe
N+
O–
MeMeiPrMgCl (1.2 equiv.)
–78ºC, 60 minthen
ZnCl2 (5 mol%)Pd(PPh3)4 (5 mol%)
48 (1.5 equiv.)70ºC, 10 min, 51% yield
Scheme XI. One-pot DoM–Negishi cross-coupling strategy using catalytic zinc chloride for the synthesis of azabiaryl N-oxide 49 (26)
1. TMPMgCl•LiCl (1.1 equiv.)0ºC, 6 h
2. Benzoyl chloride (1.0 equiv.)CuCN•2LiCl (10 mol%)
–40ºC to 25ºC, 3 h86% yield
50 51
Cl CO2Et Cl CO2Et
O PhScheme XII. One-pot DoM–Negishi cross-coupling protocol using commercially available tmpMgCl·LiCl
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242 © 2013 Johnson Matthey
directly provides a zincate suitable for Negishi
cross-coupling under relatively standard conditions.
Although these reactions were developed and
optimised on 1–2 mmol scale, all of these examples
were performed on 80–100 mmol scale in order to
demonstrate good scale up potential.
The combined DoM–Suzuki-Miyaura cross-
coupling also lends itself to a one-pot procedure. An
illustration of this is our recent extension of previous
work on one-pot DoM–Suzuki-Miyaura reactions (32),
in which the synthesis of heterobiaryl sulfonamides
was developed with the aim of increasing the
available methodology for the construction of
bioactive molecules bearing the popular sulfonamide
pharmacophore (Scheme XV) (7).
This one-pot metallation-boronation–cross-coupling
procedure was generalised for tertiary and secondary
sulfonamides 56 in couplings with electron-rich and
-poor aryl and heteroaryl bromides and chlorides to
furnish biaryl sulfonamides 57. A change to a bulkier
catalyst was needed when meta or ortho substituted
sulfonamides were used as shown by example 57c.
1.3. Iridium-Catalysed Boronation–Suzuki-Miyaura Cross-Coupling: A Complementary MethodThe knowledge that iridium-catalysed boronation of
aromatics is qualitatively determined by steric effects
(33–37) led us to explore this reaction in DMG-bearing
substrates in order to establish complementarity with
52
CO2Et
53
CO2Et
Me
1. TMPMg•2LiCl (1.1 equiv.)25ºC, 45 h
2. ZnCl2 (1.1 equiv.)–40ºC, 15 min
3. 4-Bromotoluene (1.05 equiv.)Pd(OAc)2 (0.5 mol%)RuPHOS (1.0 mol%)–40ºC to 25ºC, 12 h
71% yield
Scheme XIII. One-pot DoM–Negishi cross-coupling protocol using tmp2Mg·2LiCl
54
CO2Et
55
CO2Et1. TMP2Zn•2MgCl•2LiCl (0.5 equiv.)25ºC, 48 h
2. Iodobenzene (1.0 equiv.)Pd(dba)2 (0.5 mol%)(o-Fur3)P (1.0 mol%)
25ºC, 6 h84% yield
PhNCNC
Scheme XIV. One-pot DoM–Negishi cross-coupling protocol using 0.5 equivalents tmp2Zn·2MgCl·2LiCl
1. nBuLi or LDA (1.3 equiv. or 2.3 equiv.)2. MeOBpin or iPrOBpin (3.5–4.0 equiv.)
THF, –78ºC to RT, 13 h
3. Pd(dppf)Cl2•CH2Cl2 (8 mol%)Na2CO3 (4 equiv.), DME:H2O (4:1), 80ºC, 12 h
15–74% yields
ArHetAr
H
SO2NRR1
56
ArHetAr
SO2NRR1
57
ArHetAr
57a (71%) 57b (65%) 57c (15%) [Pd(dppf)Cl2•CH2Cl2] (60%) [Pd(DtBPF)Cl2]
SO2NEt2
SO2PhN
SO2NEt2
SO2PhN
N
N
SO2NEt2
MOM
Scheme XV. One-pot DoM–Suzuki-Miyaura cross-coupling route to heterobiaryl sulfonamides 57 (7)
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the DoM–Suzuki-Miyaura cross-coupling process
(Scheme XVI) (38). Thus, complementary methods
of considerable scope for the synthesis of biaryls and
heterobiaryls were demonstrated by C–H activation at C-2
(DoM) and at C-3 (Ir-catalysed boronation) of 58 which
offer new routes for the regioselective construction of
substituted biaryls 60 and 59 respectively.
1.4 The Use Of DoM–Cross-Coupling Strategies in Total SynthesisWe have also employed the DoM–cross-coupling
strategy as part of syntheses of targeted drugs and
natural product intermediates. In 2004, we reported
a synthesis of the tetracyclic A/B/C/D ring core 66 of
the antitumour agent camptothecin (Scheme XVII) (39).
This route is highlighted by an anionic ortho-Fries
rearrangement of O-carbamate 61 to give the
quinolone 62, a Negishi cross-coupling of trifl ate 63
to give biaryl 65, and a modifi ed Rosenmund–von
Braun reaction to provide the tetracyclic core 66 of
the antitumour alkaloid camptothecin in seven steps
with an overall 11% yield.
Most recently, we have completed a total synthesis
of schumanniophytine 72 (Scheme XVIII) (40), a
natural product which had been prepared only once
previously (41). Starting with DoM chemistry to obtain
the cross-coupling partners 68 from 67, our route
takes advantage of a combined DoM–cross-coupling
strategy using Stille or Suzuki-Miyaura reactions to
synthesise biaryl 69, and also incorporates a key ortho-
silicon-induced O-carbamate remote anionic Fries
rearrangement of carbamates 70 to provide amides 71.
ArHetAr
DMG
H
R
60
DMGR
DMGR
H HH
ArHetAr
5859
1. DoM
2. Suzuki-Miyaura
C2–H activation
1. Ir/B2Pin2
2. Suzuki-Miyaura
C3–H activation
DMG = CONEt2, OCONEt2, OMOM, SO2NEt2
Scheme XVI. Complementary ortho and meta boronation/Suzuki–Miyaura cross-coupling reactions of DMG bearing aromatics (38)
N OCONEt2
61 62 63
NH
CONEt2
O N
CONEt2
OTf
1. LDA (1.3 equiv.)THF, –78ºC, 1 h
2. MeOH61% yield
Tf2O (1 equiv.)NEt3 (1.8 equiv.)
CH2Cl2, 0ºC, 1 h70% yield
NBr OMe
N
CONEt2
N OMe
64 65
Steps
NN
O
66
1. tBuLi (2.0 equiv.)THF, –78ºC, 15 min
2. Anhyd. ZnBr2 (1.1 equiv.)–78ºC, 1 h
3. 63/Pd(PPh3)4 (3 mol%) THF/refl ux, 60 h
57% yield
Scheme XVII. Key reactions in the synthesis of the tetracyclic core 66 of camptothecin: anionic ortho-Fries rearrangement 61–62 and Negishi cross-coupling 64–65 (39)
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2. DoM–C–Heteroatom (N, S, O) Cross-Coupling Reactions
With the advent of transition metal-catalysed C–N,
C–O and C–S cross-coupling technologies, these
reactions have also been fused with DoM and
the combined DoM–heteroatom cross-coupling
methodology has become viable for the construction
of biologically interesting molecules and natural
products. Thus the naphthyldihydroisoquinoline
alkaloid ancistrocladinium B 76 (Scheme XIX),
which shows high in vitro antileishmanial activities,
has been synthesised from 73 via methoxymethyl
(MOM) directed metallation-bromination to provide
bromide 74, followed by Buchwald-Hartwig amination
to furnish the key intermediate 75. The synthesis of
ancistrocladinium C (77) was also achieved using a
similar strategy (42).
Similarly, the construction of a C–O bond has been
accomplished using DoM–cross-coupling strategies.
Although copper catalysis is the preferred choice for
C–O bond formation (43–45), it is also possible to use
pgm catalysis as an alternative (46–48).
Among the DoM–C–heteroatom cross-coupling
strategies, the DoM–C–S regimen is far less evident in
the literature. In an instructive study which shows the
utility of inverting the coupling partners, substituted
2-iodo-anisoles 79 (Scheme XX) were synthesised
using DoM chemistry and subjected to Buchwald-
Hartwig coupling with 3-fl uorobenzenethiol 81,
to afford biaryl sulfi de derivatives 83 which were
further modifi ed to give the desired compounds 84.
Alternatively, 3-chloro-2-methoxyphenyl thiol 80
was coupled with 3-fl uoroiodobenzene 82 to furnish
similar analogues 83. These were demonstrated
to possess in vitro potency for blocking glycine
transporter-1 (GlyT-1), which has been recognised
as a potential strategy for the treatment of
schizophrenia (49).
OMeMeO
OCONEt2
OMeMeO
OCONEt2
OMeMeO
Et2NOCOR1
N
67 69
OMeMeO
Et2NOCO N
Yield, %R = Me 70a 94R = Et 70b 91
R3Si
OMeMeO
R2OR3Si
HO
72
N
OEt2N Me
O
OOSteps
TMEDA (1.3 equiv.)sBuLi (1.3 equiv.)
THF, <–72ºC, 10 min thenI2 (1.5 equiv.), <–72ºC to RT
or
1. B(OiPr)3 (2.6 equiv.), THFLDA (1.2 equiv.)
–78ºC, 1 h–78ºC to RT, 1 M HCl
2. Pinacol (1.05 equiv.), EtOAc
68a, PdCl2(PPh3)2 (10 mol%)4-tributylstannylpyridine (1.5 equiv.)
DMF, refl ux, 1 h, 73% yieldor
68b, Pd(PPh3)4 (4 mol%)4-bromopyridine hydrochloride (1.0 equiv.)/Na2CO3 (2 equiv.)
DME/Na2CO3 (2 M)90ºC, 20 h, 99% yield
LDA (3.5 equiv.), Me3SiCl(4.5 equiv.), THF
–78ºC to RT, 10 hor
nBuLi (1.2 equiv.), THF –100ºC, 5 min, then
Et3SiCl (2.5 equiv.)–100ºC, 1.5 h
LDA (4 equiv.)THF, 0ºC to RT, 1 h
then
Ac2O or BzCl (5 equiv.)0ºC to RT
Yield, %R2 = Ac 71a 75R2 = Bz 71b 65
Yield, %R1 = I 68a 86R1 = Bpin 68b 95
NO
Scheme XVIII. Key reactions in the total synthesis of schumanniophytine 72 (40)
DMG DMG
X
DMG
Y
DoM Cross-coupling
X = Halide or pseudohalideY = NR2, SR, OR
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245 © 2013 Johnson Matthey
OMe
OMe
Me
O
73
OMe
OMe
Me
O
74
BrOMe
Me
OMe
O
MeO
OMe
NH2
Me
(1.2 equiv.)
1. nBuLi (1.9 equiv.)TMEDA (1.9 equiv.)
THF, –10ºC, 1 h
2. (CBrCl2)2 (1.5 equiv.)–10ºC to RT
74% yieldPd2(dba)3 (1 mol%)rac-BINAP (2 mol%)KOtBu (1.4 equiv.)toluene, refl ux, 2 d
49% yield
MeO
OMe
HN
Me
75
OMe
Me
OHN
Me
76
1. AcCl (3 equiv.)DMAP (3 equiv.)
toluene, refl ux, 1 h86% yield
2. POCl3 (5 equiv.) CH3CN, refl ux, 1 h
95% yield
+
MeOMe
MeOTFA–
OMeOHN
Me
77
+
MeOMe
MeOTFA–
Me
Scheme XIX. Synthesis of ancistrocladinium B 76 as atropo-diasteromers (P/M) 46/54 and ancistrocladinium C 77 as atropo-diasteromers (P/M) 3/2 using a DoM–C–N cross-coupling strategy (42)
OMe
R1
OMe
R1
OMe
R1O
R2
F
F
F
F
IHS
+
IOMeSHCl
+
S
S
N
O
HO
78 79 81
80 82
83
84
For R1 = 3-Cl:1. sBuLi, TMEDA THF, –95ºC, 1 h
2. I2, –95ºC to RT 16 h
Pd2(dba)3, KOtBu, toluene
Pd2(dba)3 DPEPhos, KOtBu
toluene, 100ºC, 90 min 55% yield
R1 = 3-Cl, 4-Cl, 5-Cl, 6-Cl, 4-Br, 5-BrR2 = 3-Cl, 4-Cl, 5-Cl, 6-Cl, 4-Ph, 4-thiophen-3-yl, 3-MeOC6H4-4-yl, 4-MeOC6H4-4-yl, 4-ClC6H4-4-yl, 5-Ph
Scheme XX. DoM–C–S cross-coupling route to diaryl sulfi des 84
3. DoM–Halogen Dance–Cross-Coupling Reactions
The DoM reaction on halogenated aromatic and
heteroaromatic compounds may be accompanied
by halogen dance reactions in which halogens, most
notably iodine, undergo migration to the incipient
DMG DMG
X
DMGDoMHalogen dance
X = Br, IR = Substituent inserted through cross-coupling
(Het) (Het) (Het)
R
X
R R
Cross-coupling DMG(Het)
R
R
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246 © 2013 Johnson Matthey
anion and provide, generally but not invariably,
the most thermodynamically stable anion (50).
This not only provides an option to halogenate
positions which are otherwise diffi cult to access,
but also enables the introduction of an external
electrophile at the site bearing the newly formed
anion. In this context, we have developed routes
to polyfunctionalised pyridines (51) and others
have utilised halogen dance in the formation of
heterobiaryls (Scheme XXI) to provide substituted
2-arylquinolines as novel CRF1 receptor antagonists
(52). Thus, metallation-iodination of quinoline 85
afforded iodoquinoline 86 which, when subjected
to a second metallation-protonation, gave the
halogen dance product 87. Suzuki-Miyaura cross-
coupling and subsequent steps led to the substituted
arylquinolines 88. We have found that it is important
to be vigilant for potential undesired halogen dance
reactions which may arise in many metallation
reactions of halogenated heterocycles.
N
Cl
N
Cl
N
Cl
N
Cl
I
I
OMeMeO
OMe
Me
NEt2
LDA, THF, –78ºCI2
Metallation
LDA, THF, –78ºC
Halogen dance
85 86 (49% yield) 87 (56% yield)
88
Scheme XXI. Metallation–halogen dance–Suzuki-Miyaura route to 2-arylquinoline 88 CRF1 receptor antagonist
DMG DMG
X
DMGDoM Cross-coupling
R
O
( )nDreM
X = Halide or pseudohalideR = H, Men = 0, 1
4. DoM–Cross-Coupling–DreM Reactions
The synthesis of interesting polycyclic aromatic and
heteroaromatic molecules has a long history in the
Snieckus laboratories (a recent example uses the
Suzuki-Miyaura cross-coupling (53)). To construct
these systems, the directed remote metallation (DreM)
reaction (54, 55) on specifi cally designed 2-DMG
biaryls is the key reaction to forge the central aromatic
bridging ring. Generally this method complements
already established methods for their synthesis
and allows easy access to previously unreported
compounds. The standard conditions for a DreM
reaction are formation of the anion by treatment with
LDA at –20ºC or 0ºC, followed by warming to room
temperature to ensure completion of the anionic
cyclisation. Depending on the type of substituents
in the biaryl starting material, often a minimum of 2
equivalents of LDA is required, proposed to be due to
‘losing’ one or more equivalents to coordination with
these substituents.
4.1 Synthesis of Biaryls Using DoM–Cross-Coupling ReactionsFor the construction of requisite biaryls, the
DoM–Suzuki-Miyaura protocol is frequently
practiced, although other cross-coupling strategies
such as DoM–Negishi are also used. Thus, in
general (Scheme XXII), cross-coupling partners
2-halodiethylbenzamides 91 and boronic acids 92
are synthesised using standard DoM conditions
from diethylbenzamides 89 and by metal halogen
exchange on bromobenzenes 90 respectively,
although currently many of the boronic acids may be
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247 © 2013 Johnson Matthey
purchased. Alternatively, the cross-coupling partners
may be inverted so that DoM derived boronic
acids 91 (X = B(OH)2) may be directly coupled with
aromatic trifl ates or with bromobenzenes 90 without
the need for metal halogen exchange. We have found
that the Suzuki-Miyaura reaction usually requires
only minimal development using standard palladium
sources and ligands, although the reactions are still
substrate dependent. On the other hand, certain
boronic acids, especially heteroaromatic cases,
can be diffi cult to handle and unstable due to their
propensity for protodeboronation. As a notable
example, we have learned from experience that
3-methoxy-N,N -diethylbenzamide-2-boronic acid
is diffi cult to isolate, and is reliably synthesised
only if the aqueous quench of the reaction mixture
is performed at –40ºC slowly by the addition of a
CH2Cl2/H2O mixture. Others have reported similar
problems regarding this boronic acid (56).
The absence of reports concerning aryl sulfonamide
ortho-boronic acids prompted a study in which the
problems associated with the synthesis of this class
of unstable boronic acids was solved, at least in this
particular case (7). Although it was determined
that metallation of aryl sulfonamides proceeds
uneventfully, as evidenced by deuterium quench
experiments, quenching the metallated species
with B(OR)3 reagents followed by aqueous workup
provided boronic acids in low yields, accompanied
by recovery of starting material, which suggested
instability of the ortho-boronic acids. This problem
was circumvented by utilising an in situ quench with
MeOBpin or iPrOBpin as electrophiles, leading directly
to the boropinacolate derivatives which are known to
be more stable than the corresponding boronic acids.
Similarly in the even more unstable pyridine boronic
acid series, in situ formation of boropinacolates was
advantageous in isolation of compounds useful for
Suzuki-Miyaura cross-coupling reactions (32).
Another solution for the synthesis of problematic
arylboronic acids stemming from our laboratories
is the ipso-borodesilylation reaction of trimethylsilyl
arenes (57). The silylated starting materials are
readily obtained in high yields using DoM chemistry,
and are quite stable with the exception of certain
heteroaromatic silanes. Treatment with BCl3 or BBr3
affords the Ar-BX2 species which, without isolation, may
be converted into the corresponding boropinacolates
by stirring with pinacol, or otherwise may be used
directly in a one-pot cross-coupling process.
4.2 Combined DoM–Suzuki-Miyaura–DreM Synthesis of FluorenonesTreatment of biaryl-2-amides 93a, derived from
DoM–cross-coupling reactions, under standard DreM
conditions results in alternate ring deprotonation
followed by cyclisation to provide fl uorenones 94
in good yields (Scheme XXIII). As ourselves and
others (58, 59) have demonstrated, various substituted
fl uorenones, azafl uorenones and two natural products
dengibsinin 95 and dengibsin 96 may be synthesised
using this strategy (60, 61).
Generally the highest yields are obtained for
biaryl cases bearing an additional 3-DMG which
promotes synergistic metallation, thereby leading
to regioselective cyclisation. In the synthesis of
azafl uorenones 99 using this strategy (Scheme XXIV),
the use of a one-pot DoM–Suzuki-Miyaura protocol was
CONEt2
R1DoM
Metal-halogen exchange
–
–R3
R2Br
CONEt2
R1
R2
R3
B(OH)2
X
Et2NOC
R1
R2
R3
Cross-coupling
1. sBuLi/TMEDA THF, –78ºC
2. Electrophile
1. nBuLi THF, –78ºC
2. Electrophile
X = halogen (or B(OH)2 when coupled with 90)R3 = H 93a Me 93b
89 91
90 92
93
Scheme XXII. DoM–Suzuki-Miyaura cross-coupling synthesis of biaryls 93
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248 © 2013 Johnson Matthey
essential due to the instability of the pyridyl boronates
towards protodeboronation (32).
This method proved useful for the construction of
diverse azafl uorenones with electron-donating and
electron-withdrawing substituents. This sequential
DoM–cross-coupling–DreM strategy allows the
construction of azafl uorenones which are inaccessible
or afford isomeric mixtures by the traditional Friedel-
Crafts reactions.
4.3 Combined DoM–Suzuki-Miyaura–DreM Synthesis of Phenanthrols and PhenanthrenesTreatment of biaryls exhibiting 2-methyl substituents
93b under standard DreM conditions affords
9-phenanthrol derivatives 100 (Scheme XXV). The
deprotonation is often – but not always – indicated
by a deep red colour attributed to the generated tolyl
anion. Conversion of the resulting phenanthrols 100 to
phenanthrenes 101 is readily achieved using trifl ation
followed by palladium-catalysed hydrogenolysis. Often
no purifi cation is required for the intermediate steps,
and the fi nal phenanthrenes may be obtained in good
yield and high purity after a simple recrystallisation.
This route is scalable and reliably provides
substituted phenanthrenes in high purity which have
been used successfully in our collaborative projects
to conduct toxicity studies concerning the effects of
substituted polyaromatic hydrocarbons on fi sh (62).
R1
Et2NOCR2
R1 R2
OLDA (2.5 equiv.), THF –20ºC or 0ºC
93a 94O
OMeOH
OHO
OMeOH
OH
OMe
95 96
Scheme XXIII. Synthesis of fl uorenones using the combined DoM–cross-coupling–DreM strategy for dengibsinin 95 and dengibsin 96
DMGN DMG
N
RR
N
O
97 98 99
1. B(OiPr)3 (1.1 equiv.)THF, –78ºC to –10ºC
2. LDA (1.1 equiv.), 0ºC, 45 min3. Pinacol (1.2 equiv.), RT, 1 hor N-methyldiethanolamine
(1.1 equiv.), 0ºC, 2 h
3. ArBr (1.1 equiv.)Na2CO3 (aq., 2 M, 5 equiv.)
Pd(PPh3)4 (5 mol%)PhMe, refl ux, 12 h
30–76% yields
DMG = CONEt2
LDA (1.2–3.0 equiv.)THF, –78ºC to 10ºC
55–81% yields
DMG = 2-CONEt2, 3-CONEt2, 4-CONEt2, 4-Cl, 2-F, 3-OCONEt2ArBr = various, containing R = MeO, CN, NO2, CONEt2, Cl groups
Scheme XXIV. One-pot DoM–Suzuki-Miyaura–DreM synthesis of azafl uorenones 99 (32)
R1
Et2NOCR2
93bMe
R1
R2HO
100 101
R1
R2LDA, THF, –20ºC or 0ºC 1. Tf2O, pyridine, CH2Cl2 2. Pd(OAc)2, PPh3, Et3N
HCO2H, DMF
Scheme XXV. Synthesis of phenanthrenes 101 by the combined DoM–Suzuki-Miyaura–DreM strategy
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249 © 2013 Johnson Matthey
4.4 Combined DoM–Suzuki-Miyaura–DreM Synthesis of Acridones and BenzazepinonesA DreM process analogous to that shown in
Scheme XXV may also be achieved on diarylamines
103, which are prepared using palladium-catalysed
Buchwald-Hartwig cross-coupling of anilines 102 with
DoM derived halo or pseudohalo diethylbenzamides
91, followed by N-alkylation. Thus treatment of
diarylamine 103a (R2 = H), under standard DreM
conditions provides acridones 104a (n = 0) in
good to excellent yields. In an analogous fashion to
the formation of phenanthrenes (Scheme XXV),
subjection of the diarylamine 103b (R2 = Me) to
standard DreM conditions affords dibenzazepinones
104b (n = 1), also in good to excellent yields
(Scheme XXVI) (63).
These protocols constitute anionic equivalents of
Friedel-Crafts type cyclisations affording acridones, and
complement existing syntheses of dibenzoazepinones,
compound classes which both exhibit signifi cant
bioactivities. For instance, acridone derivatives possess
antimalarial properties (64), and dibenzoazepinone
derivative trileptal is an antiepileptic drug (65).
In a collaborative study, we investigated the multi-
nitrogen-containing imidazo[1,5-a]pyrazine 105 for
use as a scaffold for the preparation of potentially
bioactive molecules. Without prediction based
on available precedent, the metallation of 105a and 105b followed by iodination afforded C-5
iodinated compounds 106a and 106b in high yields.
Subsequent Suzuki-Miyaura cross-coupling with
2-(diethylcarbamoyl)phenylboronic acid (synthesised
from N,N-diethylbenzamide using a DoM protocol)
provided biaryls 107a and 107b. Treatment of 107b
with LiTMP at cryogenic temperatures furnished
the previously unknown triazadibenzo[cd,f]azulen-
7(6H)-one 108b (Scheme XXVII) (66). To the
best of our knowledge, DreM processes of complex
heterocycles such as 107 had not been previously
reported.
91
R1
OEt2N
X
R3
R2
HN+
R2 = H 102a Me 102b
1. [Pd]
2. MeI
R2 = H 103a Me 103b
R1
OEt2N
R3
R2Me
NLDA (2–4 equiv.)
n = 0 104a 1 104b
R1 R3
( )n
O
NMe
Scheme XXVI. Synthesis of acridones and dibenzazepinones using DoM–C–N cross-coupling–DreM strategy
N
Me
X
X = Cl 105a OMe 105b
X = Cl (quant.) 106a OMe (79%) 106b
N
Me
X
I
B(OH)2CONEt2
(1.1–1.2 equiv.)Pd(PPh3)4 (5 mol%)
K2CO3 (3 equiv.)
DME:H2O (50:7) refl ux, 4 h
1. nBuLi (1.0–1.2 equiv.)15 min, THF, –78ºC
2. I2 (1.2–1.3 equiv.), 15 min THF, –78ºC
NN N
N
N
Me
X
NN
CONEt2
X = Cl (79%) 107a OMe (61%) 107b
N
OMe
NN
O
X = OMe (45%) 108
HTMP (3 equiv.), nBuLi (3 equiv.), THF, –78ºC, 90 min
107b
Scheme XXVII. DoM–Suzuki–DreM–cyclisation route to triazadibenzo[cd,f]azulen-7(6H)-one 108b (64)
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250 © 2013 Johnson Matthey
5. Scale-Up and Industrial use of DoM–Cross-Coupling–DreM ReactionsIf proper safety protocols are followed and
temperature and stirring of the reaction mixture are
controlled and maintained, metallation chemistry
may be effectively used for large scale synthesis. In
fact, there is often no viable alternative to the use of
a DoM–cross-coupling sequence at multi-kilogram
scale in the pharmaceutical and fi ne chemical
industry (67–69). For instance, Merck has recently
demonstrated a practical, effi cient and multi-hundred
gram synthesis of 3-bromo-6-chloro-phenanthrene-
9,10-dione 113 using a DoM–cross-coupling–DreM
sequence (Scheme XXVIII) (70). Compound 113
is a useful building block for the preparation of
pharmaceutically important phenanthrenequinones
and phenanthreneimidazoles.
Similarly, as further evidence of utility, Merck
has achieved a kilogram-scale chromatography-
free synthesis of mPGE synthase I inhibitor
MK-7285 119 (Scheme XXIX) (71). Thus DoM–
boronation of 114 provided the lithioborate 115
Cl
CONEt2
Cl
CONEt2
Cl
Et2NOCB(OH)2
Me
HO
Cl Cl
O
O
Br
109 110 111(89% yield over 2 steps)
112 113
1. B(OiPr)3 (1.6 equiv.)DME
2. LDA (1.6 equiv.)–35ºC to 25ºC
3. H2O(regioselectivity 97>1)
2-Iodotoluene (0.93 equiv.) Pd(OAc)2 (0.5 mol%)
PPh3 (1 mol%)K2CO3 (2.5 equiv.)
DME/THF/H2O, 8 h, 70ºC
1. LiNEt2 (1.3 equiv.), DME, –45ºC, 2 h2. HCl (4 equiv.), 0ºC to 5ºC
85% yield
Scheme XXVIII. Large scale synthesis of phenanthrene-9,10-diones 113 using a combined DoM–cross-coupling–DreM strategy. 109 was used at a scale of 245.7 g, 111 was produced at a scale of 311.5 g and 112 at 200 g (68)
O O
CONEt2
MeBr
OH
MeMe
O
Li+ –B(OiPr)3CONEt2CONEt2
1. B(OiPr)3 (2 equiv.)THF, –25ºC
2. LDA (2 equiv.)<–20ºC, 2 h 3. H2O, 20ºC
quantitative conversion
(0.7 equiv.)
PdCl2•dppf (2.5 mol%)H2O, refl ux, 12 h
88–98% yield
114115
116
117
MeOH
MeMe
O
OH
OH
MeMe
118O
OH
MeMe
119
NC
NC
FN
NH
Et2NLi (3.5 equiv.)THF (<0.24 M)
0ºC to –5ºC, 14 h63% yield
Scheme XXIX. Large scale synthesis of mPGE synthase I inhibitor 119 using the combined DoM–cross-coupling–DreM strategy. 114 was used at a scale of 3.75 kg, 117 was produced at a scale of 7.69 kg (69)
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251 © 2013 Johnson Matthey
which, without isolation, was subjected to Suzuki-
Miyaura cross-coupling with bromobenzene 116
to afford biaryl 117. In the key step, treatment of
biaryl 117 with lithium diethylamide resulted in
a DreM cyclisation to provide the phenanthrol
118 in acceptable yield. A significant observation
was that in the DreM reaction, at concentrations
greater than 0.24 M, competitive intermolecular
condensation provided 5–10% of an undesired
product.
6. Diversifi cation of the DoM–Cross-Coupling Strategy
The unique power and considerable synthetic
advantage of DoM chemistry is the regioselective ortho
introduction of only one functional group per DMG.
Furthermore, synthetic strategies may be devised
to use the same DMG to achieve 2,6-disubstitution
and thus to construct 1,2,3-trisubstituted aromatic
systems (72). Using the N-cumylsulfonamide DMG,
this strategy has been adapted for the synthesis of
7-substituted saccharins (Scheme XXX) (73). Thus,
as conceptually illustrated below, the straightforward
DMG DMG
R1
DMGFirst DoM
Cross-coupling R1
R1, R2 = Substituent introduced through cross-couplingR3 = Substituent introduced through DoM
Second DoM
Cross-coupling
Cross-coupling
DMG
R3
R2
DMG
R3
R1
First DoM
Second DoM
First DoM (E+ = halide source)
Second DoM (E+ = ClCONEt2)
SO2NHCumylFirst DoM
Cross-couplingSecond DoM
SO2NHCumyl
CONEt2
Ar
TFAAcOH
O
Ar
SO2
NH
SO2NHCumyl
120
SO2NHCumyl
SO2NHCumyl SO2NHCumyl
I
ArAr
CONEt2
121
122 123 124
O
Ar
S O2
NH
ArB(OH)2 (1.1–2.0 equiv.)Pd(PPh3)4 (5 mol%), A or B or C or D, 24 h
A. K3PO4 (3 equiv.), DMF, 100ºC B. Na2CO3 (8–10 equiv.), THF, 70ºCC. Cs2CO3 (2–8 equiv.), THF, 70ºCD. Na2CO3 (10 equiv.), DME, 90ºC
57–99% yields
1. sBuLi (2.2 equiv.)TMEDA (2.2 equiv.)
THF, –78ºC
2. I2 (1.2 equiv.)–78ºC to RT
3. NH4Cl (aq.)88% yield
1. nBuLi (2.2 equiv.)TMEDA (2.2 equiv.)
THF, 0ºC, 1 h
2. ClCONEt2 (1.2 equiv.)0ºC to RT
3. NH4Cl (aq.)78–99% yieldsa
1. TFA, RT, 10 min2. AcOH, refl ux, 12 h
3. HCl
42–89% yields (over two steps)
Ar = C6H5, 2,3-di-MeC6H3, 3,5-di-ClC6H3, 2-Et2NC(O)C6H4, naphthalen-2-yl, thiophen-3-yla Some of the products were taken to the next steps without purifi cation
–
–
Scheme XXX. Double use of the N-cumylsulfonamide DMG in the synthesis of substituted saccharins 124
122
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252 © 2013 Johnson Matthey
DoM–halogenation–Suzuki-Miyaura coupling of
N-cumylbenzenesulfonamides 120 provided,
via iodide 121, the biaryls 122. Then the same
N-cumyl sulfonamide DMG served for a second
DoM–carbamoylation to furnish the biaryl amide
sulfonamide 123. Decumylation of 123 using TFA,
followed by acid-mediated cyclisation gave rapid
access to saccharins 124 in good overall yield.
Aside from interesting pharmaceutical properties
and use in the fi elds of fl avour, polymer and
coordination chemistry, the saccharin core has
played a role in the discovery of a human leukocyte
elastase inhibitor, KAN400473 (125, Figure 3), used
for the treatment of emphysema (74). It also features
in the Merck carbapenem antibacterial agents (126,
Figure 3) (75).
Double DoM–double cross-coupling reactions
involving multiple DMGs are also useful synthetic
tactics. Thus the fi rst total syntheses of natural,
unsymmetrical 2,3-diacyloxy-p-terphenyls, thelephantin
O 131a (Scheme XXXI) and terrestrins C and D
(131b and 131c, respectively), were achieved using
double DoM and bromination of 127 to give the
hexasubstituted benzene 128 which, after Suzuki-
Miyaura cross-coupling with 129, afforded the key
intermediate teraryl 130. Synthesis of the symmetrical
diesters vialinin A/terrestrin A 131d and terrestrin B
131e was also achieved using the same sequence (76).
O
O
O
NR3+
O
CO2–
HO Me
Me N
NSO2
126
NNN
N
NSS
O2
125
Fig. 3. Biologically active saccharins KAN400473 125 and Merck antibacterial agents 126
MeMe
OMOMMOMO
O O
MeMe
OMOMMOMO
O O
MeMe
OMOMMOMO
O O HO OH
O OO O
OHHO
R1 R2
Br Br
TBSO OTBS
127
130
128
131a–e
129
TBSOOB
(1.5 equiv.)3
1. nBuLi (3 equiv.)THF, 0ºC, 1 h
2. BrCF2CF2Br (3 equiv.)0ºC, 1 h3. H2O
94% yield
Pd(PPh3)4 (5 mol%)K2CO3 (6 equiv.)
1,4-dioxane:H2O (3:1) 2 h, refl ux78% yield
R1 R2
131a Ph CH2Ph131b Pr CH2Ph131c Me CH2Ph131d CH2Ph CH2Ph131e Pr Pr
Scheme XXXI. Synthesis of teraryl natural products using double DoM–Suzuki-Miyaura cross-coupling sequence
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253 © 2013 Johnson Matthey
7. The DMG as a Pseudohalide in Cross-Coupling Reactions
As documented in this review, cross-coupling of DoM
derived species such as B, Zn, Sn and Mg has become
a highly useful synthetic strategy. The development of
DMGs that themselves act as cross-coupling partners
was fi rst achieved in our group with O -carbamates
(77) and subsequently with sulfonamides (78) under
Ni(acac)2 conditions. Furthermore, these DMGs may
be excised from the aromatic framework using the
-hydride donor properties of iPrMgCl and iPr2Mg
respectively, thus establishing the latency concept
of DMGs (77, 78). Recently additional DMGs such as
ethers, esters, O-carbamates under Suzuki-Miyaura
conditions (79, 80) and O -sulfamates (79) have
been established as cross-coupling partners (81).
The non-reactive nature of some of these groups in
palladium-catalysed coupling reactions allows the
establishment of orthogonal processes (82, 83). For
example, subsequent to work in our laboratories
(80), Garg et al. (84) recently explored regioselective
construction of biaryls based on differential reactivity
of bromide, O-carbamate and O-sulfamate groups
toward Pd and Ni catalysts (Scheme XXXII). Thus,
DoM–bromination of 132 furnishes aromatic bromide
133, which undergoes sequential and selective
palladium-catalysed Stille, nickel-catalysed Suzuki-
Miyaura and nickel-catalysed C–N cross-coupling
to rapidly provide biaryl 136 in good yield. Recent
efforts on transition metal-catalysed cross-coupling
reactions of new O-based electrophiles via C–O bond
activation have focused on nickel and iron based
catalysis (85–87).
Authors’ note added in proof: after the submission
of this review, Feringa and co-workers established the
palladium-catalysed cross-coupling of alkyl, alkenyl
and aromatic lithiates (some derived using DoM) with
aromatic bromides (88).
132
1. TMEDA (1.1 equiv.) sBuLi (1.1 equiv.)
THF, –93ºC, 45 min 2. BrCF2CF2Br (1.4 equiv.)
–93ºC to RT
3. NH4Cl (aq.)78% yield
LiCl (5 equiv.) PdCl2(PPh3)2Me4Sn, DMF100ºC, 16 h
74% yield
p-MeOArB(OH)2 (5 equiv.) NiCl2(PCy3)2 (20 mol%)
K3PO4 (7.2 equiv.)
toluene, 130ºC, 8 h52% yield
Morpholine (2.4 equiv.) Ni(cod)2 (10 mol%)SIPr4•HCl (20 mol%) NaOtBu (2.2 equiv.)
dioxane, 80ºC, 3 h64% yield
OCONEt2
OSO2NMe2
OCONEt2 OCONEt2
OCONEt2
133 134
135 136
Br Me
Me Me
OMeOMe
O
N
OSO2NMe2 OSO2NMe2
Scheme XXXII. Use of O-carbamate and O-sulfamate DMGs as cross-coupling partners
DMG DMG
R1
DoM
R1
Cross-coupling R2
R1 = Substituent introduced through DoMR2 = Substituent introduced through cross-coupling
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254 © 2013 Johnson Matthey
Conclusions This brief review has demonstrated that the combined
DoM–cross-coupling strategy, fi rst developed in our
laboratories in the mid-1980s, has considerable value
in organic synthesis. In this aim, we have attempted
fi rstly to provide supportive evidence using selected
recent examples derived from industrial and
academic laboratories, including many from our own
work. Emphasis has been placed on heterocycles,
which constitute 80% of current marketed drugs,
with synthetic case studies on a variety of bioactive
molecules in early, clinical or process stages of
development, including soraprazan (Figure 1),
GSK966587 (Figure 2), ancistrocladinium B and
C (Scheme XIX) and CRF1 receptor antagonist
(Scheme XXI). As will be recognised, the
heterocycles range from recognisable to more
unusual and complex frameworks (for example
Scheme XXVII). The pgms, particularly palladium,
catalyse many of the processes, contributing to the
enormous versatility of this strategy.
The second aim of the review has been to offer,
in various described processes, practical from-the-
bench tips based on our experience, at least in
small-scale reactions. These include the advantage
of deuterium-quench experiments to establish the
extent of the DoM step before taking the road to
scale-up (for example Scheme III), and the caveat
regarding purity of starting materials and their
instability.
Prognosis for the DoM–Cross Coupling StrategyEmerging from the content of this review are the
following features:
1. DoM–C–C Cross-Coupling Reactions This section suggests that among the cross-
coupling reactions used in combination
with DoM: Ullmann, Heck, Sonogashira,
Negishi, Stille and Suzuki-Miyaura, the latter
dominates the synthetic landscape with
increasing presence of the Negishi protocol.
The advent of new nontraditional lithium
bases such as the commercial Knochel
type tmpMgCl·LiCl combined with zinc
transmetallation and Negishi coupling
(Scheme XII) are beginning to provide more
convenient conditions for the DoM–cross-
coupling strategy.
Iridium-catalysed boronation offers a
complementary method for meta boronation
compared to the DoM–Suzuki-Miyaura
coupling process (Scheme XVI).
Only an inkling has been given of the
potential for DoM–cross-coupling in natural
product synthesis (Schemes XVII and XVIII)
and this can only be expected to grow in
importance.
2. DoM–C–Heteroatom (N, S, O) Cross-Coupling Reactions Based on our literature review, this motif has
considerable use in combined DoM–Hartwig-
Buchwald C–N and C–O cross-coupling
processes and is as yet underdeveloped for
C–S fusion reactions.
3. DoM–Halogen Dance–Cross-Coupling Reactions Although the agreeably named halogen
dance is of some vintage, its application in
the construction of substituted aromatics
and heteroaromatics has considerable, as yet
unfulfi lled, promise.
Among the practical tips is the caveat that, to
eventual regret, it may be easy to overlook the
occurrence of the halogen dance in the dash
to publication.
4. DoM–Cross-Coupling–DreM Reactions The DoM–cross-coupling sequence fi nds
additional advantage in synthesis when
combined with the DreM process.
Thus, the regioselective synthesis of
substituted fl uorenones (Schemes XXIII and
XXIV), phenanthrenes (Scheme XXV) and
acridones and dibenzazepinones (Scheme XXVI) become feasible in practical, effi cient
and environmentally friendly ways compared
with, for example, traditional electrophilic
substitution methods. Specifi cally, the DreM
approach to fl uorenones and azafl uorenones
(Scheme XXIV) demonstrates the
complementarity between Friedel-Crafts and
DreM tactics.
5. Scale-Up and Industrial use of DoM–Cross-Coupling–DreM Reactions As in the case of DoM chemistry which
was dormant for about a decade after
developments in our laboratories in the late
1970s, the DreM concept has been nurtured
in industry and is now appearing in the
open literature. It is encouraging to see the
application of the combined DoM–cross-
coupling technology (Scheme XXVIII),
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255 © 2013 Johnson Matthey
including DreM (Scheme XXIX) methods,
on a multi-kilogram scale.
6. Diversifi cation of the DoM–Cross-Coupling Strategy While DoM reactions constitute one
functional group per DMG for synthetic
considerations, signifi cant advantage is
gained in diversifi cation, with or without
protection requirements, to the creation of
2,6-disubstituted DMG-bearing aromatics.
Perhaps insuffi ciently appreciated and
adapted as yet, such a sequence is shown in
Scheme XXX.
Another conceptual element, a double DoM
process (Scheme XXXI), may also be the tip
of the iceberg in synthesis.
7. The DMG as a Pseudohalide in Cross-Coupling Reactions Adaption of methodology which uses the
DMG aromatic as a pseudohalide coupling
partner, already demonstrated in our Corriu-
Kumada reaction of aryl O-carbamates
in the early 1990s, has taken on new
possibilities in O-carbamate, O-sulfamate
and sulfonamide Corriu-Kumada and
Suzuki-Miyaura reactions (Scheme XXXII)
in our laboratories as well as others. The
potential of this chemistry, including the
excision of the DMG by transition metal-
catalysed -hydride elimination processes,
is only now surfacing in the literature.
We hope the aims of this review have been met and
will be valuable to synthetic chemists. The prognostic
views expressed throughout this fi nal section are, as
many times experienced by all, dangerous to place, as
we do, into the literature.
AcknowledgementsThis review is dedicated to Alfred Bader, benefactor
of Snieckus Innovations, for giving us the opportunity
to impel our basic knowledge of chemistry to reach
practical ends.
Victor Snieckus thanks the Natural Sciences and
Engineering Research Council of Canada (NSERC)
for support by the Discovery Grant program. Suneel
Singh is grateful to NSERC for an industrial post
doctoral fellowship award.
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DMG directed metallation group
Het heterocycle
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257 © 2013 Johnson Matthey
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http://dx.doi.org/10.1595/147106713X672311 •Platinum Metals Rev., 2013, 57, (4)•
258 © 2013 Johnson Matthey
The Authors
Victor Snieckus was born in Kaunas, Lithuania and spent his childhood in Germany during World War II. His training was at the University of Alberta, Canada, (BSc Honors), strongly infl uenced by the iconoclastic teacher, Rube Sandin; the University of California, Berkeley, USA, (MSc), where he gained an appreciation of physical organic principles under D. S. Noyce; the University of Oregon, USA, (PhD), discovering his passion for organic synthesis under the excellent mentor, Virgil Boekelheide; and at the National Research Council, Ottawa, Canada, where he completed a postdoctoral tenure with the ardent Ted Edwards. His appointments have been at the University of Waterloo, USA, (Assistant Professor, 1966); Monsanto (NRC Industrial Research Chair, 1992–1998); and Queen’s University, Canada, (Inaugural Bader Chair in Organic Chemistry, 1998–2009). Some of his awards include A. C. Cope Scholar (2001, one of 4 Canadians); Order of the Grand Duke Gediminas (2002, from the President of Lithuania); Arfedson-Schlenk (2003, Geselschaft Deutscher Chemiker); Bernard Belleau (2005, Canadian Society for Chemistry); Givaudan-Karrer Medal (2008, University of Zurich, Switzerland); Honoris causa (2009, Technical University Tallinn, Estonia); and Global Lithuanian Leader in the Sciences (2012). In research, the Snieckus group has contributed to the development and application of the directed ortho metallation reaction
(DoM) and used it as a conceptual platform for the discovery of new effi cient methods for the regioselective synthesis of polysubstituted aromatics and heteroaromatics. The directed remote metallation (DreM) reaction and DoM–linked transition metal catalysed cross-coupling reactions (especially Suzuki-Miyaura) were fi rst uncovered in his laboratories. These have found broad application in the agrochemical and pharmaceutical industries, e.g. the fungicide silthiofam (Monsanto), the anti-AIDS medication efavirenz and the anti-infl ammatory losartan (Bristol-Myers Squibb). He continues fundamental research as Bader Chair Emeritus as well as Director of Snieckus Innovations, an academic unit that undertakes synthesis of small molecules for the pharmaceutical and agrochemical industries.
Johnathan Board received his MChem from the University of Sussex, UK, and subsequently undertook his PhD with Professor Philip J. Parsons, also at the University of Sussex, working towards the synthesis of the backbone of lactonamycin. He joined the Snieckus group at Queen’s University Kingston, Ontario, Canada in 2007 as a postdoctoral fellow and worked on projects with industrial partners. In 2010 he helped set up Snieckus Innovations in which organisation he is currently a laboratory and research manager.
Jennifer Cosman received her BScH in Chemistry at Queen’s University Kingston in 2010. She joined Snieckus Innovations in early 2011, working on the custom synthesis of small molecules. In 2013 she began her MSc degree under the co-supervision of Professors P. Andrew Evans and Victor Snieckus, and is currently at Queen’s University completing this programme.
Suneel Pratap Singh was born in India, where he obtained his PhD degree (Organic Chemistry) in 2008 from the Indian Institute of Technology, New Delhi, under the supervision of Professor H. M. Chawla. After postdoctoral training on synthetic aspects of organosulfur chemistry with Professor Adrian Schwan at University of Guelph, Guelph, Ontario, Canada, he joined Snieckus Innovations in 2011. His research interests include directed ortho metallation and development of new synthetic methodologies for heterocycles.
Toni Rantanen received his PhD from RWTH Aachen University, Germany, where he studied under the supervision of Professor Carsten Bolm on the topics of organocatalysis, microwave chemistry and ball milling. In 2007 he joined the Snieckus group fi rst as an industrial postdoctoral fellow followed by academic research on the synthesis and functionalisation of heterocycles. In 2010, he helped to inaugurate Snieckus Innovations at which he is currently utilising his formidable experience as a laboratory and research manager.
IntroductionThe palladium(I) dimer, di-μ-bromobis(tri-tert-
butylphosphine)dipalladium(I), [Pd(μ-Br)( tBu3P)]2,was synthesised and fully characterised by Mingos(1, 2). However, its potential as a unique C–C andC–N coupling catalyst (3) was first explored byHartwig (6). It has emerged as one of the bestthird-generation coupling catalysts for cross-cou-pling reactions, including C–heteroatom couplingand α-arylations. In this review, the physical andchemical characteristics of the Pd(I) dimer as a cat-alyst material are discussed from a practicalviewpoint, and up to date information on its appli-cations in coupling catalysis is provided.
Characteristics and HandlingThe Pd(I) dimer is a dark greenish-blue
crystalline material, which gives a single peak in the31P NMR spectrum at (δ) 87.0 ppm. The 1H NMRspectrum gives a peak at (δ) 1.33 ppm (singlet; onexpansion it appears as a distorted triplet) in deuter-ated benzene (1, 2). The compound decomposes in
chlorinated solvents, especially in deuterated chlo-roform. The X-ray crystal structure is reported inthe literature as a dimer with Pd–Pd bonding, stabilised by bromine atoms via bridge formation(1, 2). It can be handled in air as a solid for a shortperiod of time, allowing the user to place it into areactor in the absence of a solvent, degas and thencarry out catalysis under inert conditions. However,this compound is highly sensitive to air and mois-ture in the solution phase. It can also decompose inthe solid phase if not stored under strictly inert conditions. The solid state decomposition patternover time was monitored in our laboratory at 0, 48and 112 hours (Figure 1) (4). Its sensitivity towardsoxygen is well understood, and is based on the formation of an oxygen-inserted product with theelimination of hydrogen (Scheme I) (5). Figure 2shows the oxygen sensitivity of the Pd(I) dimer ona proton-decoupled 31P NMR spectrum recordedusing a solvent which was not degassed. The peakat 107 ppm indicates the presence of the oxygen-inserted decomposition product.
183Platinum Metals Rev., 2009, 53, (4), 183–188
A Highly Active Palladium(I) Dimer forPharmaceutical Applications[Pd(μ-Br)(tBu3P)]2 AS A PRACTICAL CROSS-COUPLING CATALYST
By Thomas J. ColacotJohnson Matthey, Catalysis and Chiral Technologies, West Deptford, New Jersey 08066, U.S.A.; E-mail: [email protected]
The Pd(I) dimer [Pd(μ-Br)( tBu3P)]2 is one of the best third-generation cross-coupling catalystsfor carbon–carbon and carbon–heteroatom coupling reactions. Information on itscharacterisation and handling are presented, including its decomposition mechanism in thepresence of oxygen. The catalytic activity of [Pd(μ-Br)( tBu3P)]2 is higher than either( tBu3P)Pd(0) or the in situ generated catalyst system based on Pd2(dba)3 with tBu3P. Examplesof suitable reactions for which the Pd(I) dimer offers superior performance are given.
DOI: 10.1595/147106709X472147
0 h 48 h 112 h
Fig. 1 The solid stateoxygen sensitivity of purePd(I) dimer, [Pd(μ-Br)( tBu3P)]2, withtime (4)
Applications in Coupling CatalysisThe high catalytic activity of the Pd(I) dimer
[Pd(μ-Br)(tBu3P)]2 is due to its ease of activation,presumably to a highly active, coordinatively unsat-urated and kinetically favoured ‘12-electron’catalyst species, (tBu3P)Pd(0) (Scheme II). Thisrenders the Pd(I) dimer more active than either theknown ‘14-electron Pd(0)’ catalyst, (tBu3P)2Pd(0),or the Pd(0) catalyst generated in situ by mixingPd2(dba)3 with two molar equivalents of tBu3P. Theapplications of the Pd(I) dimer in organic synthesisare described below.
Carbon–Heteroatom CouplingHartwig identified the potential of the Pd(I)
dimer as a highly active catalyst for C–N coupling
using aryl chlorides as substrates with variousamines at room temperature. A few examples areshown in Scheme III (6). Typically, aryl chloridecoupling requires higher temperatures and longerreaction times when using the in situ generatedPd(0) catalyst, or even the (tBu3P)2Pd(0) complex(7). Around the same time, Prashad and cowork-ers at Novartis reported an amination reactionusing [Pd(μ-Br)(tBu3P)]2 with challenging sub-strates such as hindered anilines (8). Scheme IVshows the coupling of N-cyclohexylaniline withbromobenzene, comparing the performance ofthe Pd(I) dimer with those of in situ generated cat-alysts derived from Pd(OAc)2 with tBu3P, BINAP,Xantphos or DPEphos. The performance of[Pd(μ-Br)(tBu3P)]2 is superior in each case.
Platinum Metals Rev., 2009, 53, (4) 184
180 140160 120 100 80 60 40 20 0 ppm
Fig. 2 The oxygensensitivity of Pd(I)dimer, [Pd(μ-Br)( tBu3P)]2, as observed in the 31P NMR (ppm)spectrum recordedusing non-degassedC6D6
P P B r
P d B r
P d O 2
-2 H
O P d
O P d
C H 2
C H 2
P
B r P
B r
3 1 P N M R : 8 7 P P M 3 1 P N M R : 1 0 7 P P M P d ( I ) d i m e r
31P NMR: 107 ppm
–2H
P P
Br
Pd
Br
Pd P Pd
Highly active 12-electron species
Scheme I Theoxygen sensitivityof Pd(I) dimer,[Pd(μ-Br)( tBu3P)]2,with the formationof an inactive Pd-Ospecies (5)
Scheme II The activationof Pd(I) dimer to a 12-electron catalystspecies during couplingcatalysis
Pd(I) dimer
31P NMR: 87 ppm
Hartwig’s group subsequently conducted adetailed study to understand the activity and scopeof [Pd(μ-Br)(tBu3P)]2 in the amination of five-membered heterocyclic halides. Variouscombinations of Pd precursors with tBu3P werestudied for a model system, the reaction of N-methylaniline with 3-bromothiophene. Thefastest reaction occurred with the Pd(I) dimer (9).
More recently, Eichman and Stambuli reporteda very interesting zinc-mediated Pd(I) dimer-catalysed C–S coupling, which should generatemuch interest in the area of C–S coupling(Scheme V) (10). For the reactions of alkyl thiolswith aryl bromides and iodides, potassium hydridewas the best base, as illustrated in Scheme V. Forthe Pd-catalysed cross-coupling reactions of aryl
bromides and benzenethiol using zinc chloride incatalytic amounts, with sodium tert-butoxide asthe base, most of the reactions were sluggish andgave low yields. However, the addition of stoi-chiometric amounts of lithium iodide increasedthe rate of the reaction significantly, which isspeculated to be due to the anionic effects pro-posed by Amatore and Jutand (11).
Carbon–Carbon Bond FormationHartwig’s group also studied the Suzuki cou-
pling of sterically hindered tri-substituted arylbromides. A Pd(I) dimer loading of 0.5 mol%, inthe presence of alkali metal hydroxide base, gavegood yields at room temperature within minutes(Scheme VI) (6).
Platinum Metals Rev., 2009, 53, (4) 185
0.5 mol% Pd(I) dimer
NaOtBu, RT
15 min–1 h
R = Bu, Ph
or R2NH = morpholine
R
Yield 88–99%
Cl R
R NH +
R
N
Scheme III Arylchloride coupling atroom temperature (6)
Pd catalysts
NaOtBu, Toluene, 110°C
Catalyst loading Yield
[Pd(μ-Br)(tBu3P)]2 0.25 mol% 93%
Pd(OAc)2 + tBu3P 0.5 mol% 86%
Pd(OAc)2 + BINAP 0.5 mol% 27%
Pd(OAc)2 + Xantphos 0.5 mol% 27%
Pd(OAc)2 + DPEphos 0.5 mol% none
Br
+
HN N
Scheme IV Pd(I) dimer-catalysed C–N coupling of N-cyclohexylaniline (8)
0.5–2.0 mol% Pd(I) dimer
THF
ZnCl2 (catalyst)
KH (1.1 equiv.)
X = Br, I
Ar-X + RSH Ar-S-R
Yield 46–99%
R = tBu,
nBu, PhCH2
Scheme V Zinc-mediatedPd(I) dimer-catalysed C–Scoupling (10)
Research work from Ryberg at Astra Zeneca(12) demonstrated a very practical, clean methodfor C–CN coupling using the Pd(I) dimer [Pd(μ-Br)(tBu3P)]2 to produce 3 kg to 7 kg ofproduct routinely (Scheme VII). During the initialin situ studies, Pd2(dba)3 in combination withcommercial ligands such as Q-Phos, tBu2P-biphenyl or Cy2P-biphenyl gave poor results,although with proper process tweaking improve-ments were made. The conventional ligands, suchas Ph3P and dppf, were not useful. However, theP(o-tol)3/Pd2(dba)3 system behaved somewhatwell with the formation of some byproducts. The
Pd loading was as high as 5 mol% (12).For the α-arylation (13) of fairly challenging
carbonyl compounds, Hartwig identified thePd(I) dimer [Pd(μ-Br)(tBu3P)]2 as one of the bestcatalysts, especially for amides and esters. Thework from Hartwig’s group provided generalconditions for α-arylations of esters and amides(14–16). The coupling reactions of aryl halideswith esters are summarised in Scheme VIII (17).For aryl bromides, lithium dicyclohexylamide(LiNCy2) was the best base, while sodium hexa-methyldisilazide (NaHMDS) was required for arylchloride substrates. Intermolecular α-arylation of
Platinum Metals Rev., 2009, 53, (4) 186
Yield 84–95%
0.5 mol% Pd(I) dimer
KOH, THF
15 min, RT
Ph
R1R2
R3
PhB(OH)2
X
R1R2
R3
+
Scheme VI Roomtemperature Suzukicoupling of stericallybulky aryl bromides (6)
Pd(I) dimer, Zn(CN)2
Zn, DMF
50ºC, 1–3 hN
HN
Br
OH
N
O
N
HN
NC
OH
N
O
Yield 71–88%R1, R2 = Me, H; R = Me,
tBu
X = Br, Cl; R3 = Me, MeO, F
(i) LiNCy2 (X = Br) or
NaHMDS (X = Cl)
Toluene, RT, 10 min
(ii) Pd(I) dimer
RT–100ºC, 4 hR2
R1
R3O
OR
+
X
R3
OR1
OR
R2
Scheme VIII α-Arylation of esters under milder conditions using the Pd(I) dimer catalyst (17)
Scheme VIIThe Pd(I)dimer-catalysedcyanationreaction, whichmay be carriedout on akilogram scale(12)
X = Br;
R1 = H, CN, CF3, OCH3 or CH3; R2, R3 = H or CH3
in situ generated zinc enolates of amides was alsoreported in excellent yield under Reformatskyconditions using the Pd(I) dimer, (Scheme IX)(18). The appropriate choice of base for the sub-strate is critical for this reaction.
The α-vinylation of carbonyl compounds hasbeen reported recently by Huang and coworkersat Amgen, catalysed by the Pd(I) dimer in con-junction with lithium hexamethyldisilazide(LiHMDS) base (Scheme X) (19). The same cat-alytic system can be extended to the α-vinylation
of ketones and esters. The combination ofPd2(dba)3 with Buchwald ligands such as X-Phosand S-Phos gave inferior results, as did in situcatalysis with ligands such as Xantphos, (S)-MOP,BINAP and IPr-HCl (carbene) in the presence ofPd2(dba)3. Amgen researchers also reported astereoselective α-arylation of 4-substituted cyclo-hexyl esters using the Pd(I) dimer at roomtemperature, with lithium diisopropylamide(LDA) as the base. Diastereomeric ratios, dr, ofup to 37:1 were achieved (Scheme XI) (20).
Platinum Metals Rev., 2009, 53, (4) 187
Glossary
Ligand Full name
BINAP 2,2' -bis(diphenylphosphino)-1,1' -binaphthyltBu2P-biphenyl 2-(di-tert-butylphosphino)biphenyltBu3 tri-tert-butylphosphine
Cy2P-biphenyl 2-(dicyclohexylphosphino)biphenyl
dba dibenzylideneacetone
DPEphos bis(2-diphenylphosphinophenyl)ether
dppf 1,1' -bis(diphenylphosphino)ferrocene
IPr-HCl (carbene) 1,3-bis-(2,6-diisopropylphenyl)imidazolium chloride
(S)-MOP 2-(diphenylphosphino)-2' -methoxy-1,1' -binaphthyl
OAc acetate
P(o-tol)3 tri(o-tolyl)phosphine
Ph3P triphenylphosphine
Q-Phos 1,2,3,4,5-pentaphenyl-1' -(di-tert-butylphosphino)ferrocene
S-Phos 2-dicyclohexylphosphanyl-2' ,6' -dimethoxybiphenyl
Xantphos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene
X-Phos 2-dicyclohexylphosphino-2' ,4' ,6' -triisopropylbiphenyl
(i) 1.5 equiv. Zn*
THF, RT, 30 min
(ii) 2.5 mol% Pd(I) dimer
Yield
94%
O
X
NMe2
Br
N
O
NMe2
N
Yield 48–95%
Toluene, 80ºC, 24 h
Pd(I) dimer, LiHMDS
X = Br, OTf, OTs
R1
R3
X
R2
R'''R''R'
OR
1
R2
R3
R'''
R''R'
O
+
Scheme IX α-Arylation ofamides underReformatskyconditions (18);Zn* = activatedzinc species
Scheme X α-Vinylationreaction usingPd(I) dimercatalyst (19);OTf =trifluoromethanesulfonate; OTs = tosylate
ConclusionsThe Pd(I) dimer [Pd(μ-Br)(tBu3P)]2 stands out
as unique among the third generation catalysts forcross-coupling. It has a higher activity than othercatalysts, a fact which can be attributed to its abili-ty to form a 12-electron ‘ligand-Pd(0)’ speciesduring the activation step in the catalytic cycle. Itsapplication to a wide variety of C–C, C–N and C–S
cross-coupling reactions will enable higher yieldsand better product selectivities under relativelymild conditions.
AcknowledgementsFred Hancock and Gerard Compagnoni of
Johnson Matthey’s Catalysis and Chiral Technologiesare acknowledged for their support of this work.
Platinum Metals Rev., 2009, 53, (4) 188
The AuthorDr Thomas J. Colacot is a Research and DevelopmentManager in Homogeneous Catalysis (Global) ofJohnson Matthey’s Catalysis and Chiral Technologiesbusiness unit. Since 2003 his responsibilities includedeveloping and managing a new catalyst developmentprogramme, catalytic organic chemistry processes,scale up, customer presentations and technologytransfers of processes globally.
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Pd(I) dimer, LDA
Toluene, RT, 3–24 h
Yield 37–85%
Up to 37:1 dr
R1 R
1
CO2Et
R–X+
CO2Et
R
Scheme XI Roomtemperaturediasteroselectiveα-arylation of 4-substitutedcyclohexyl estersusing Pd(I) dimer(20)
References
212 © 2011 Johnson Matthey
doi:10.1595/147106711X579128 •Platinum Metals Rev., 2011, 55, (3) 212–214•
In the last decade gold has emerged as a kind of
“philosopher’s stone” in catalysis, being able to promote
a bewildering variety of transformations, including
cross-coupling reactions for the formation of carbon–
carbon bonds. These highly useful transformations
were developed in part by the 2010 Nobel Prize
awardees Richard Heck, Ei-ichi Negishi and Akira
Suzuki (1) and with contributions from many other
research groups. Recently, there has been some ques-
tion over whether gold can catalyse these reactions
which have been traditionally catalysed by palladium
complexes.
In 2007, Corma’s research group published a paper
with the suggestive title ‘Catalysis by Gold(I) and
Gold(III): A Parallelism between Homo- and Hetero-
geneous Catalysts for Copper-Free Sonogashira Cross-
Coupling Reactions’ (2). This work stressed the similar
behaviour of well-known homogeneous gold(I) com-
plexes such as AuCl(PPh3) with that of heterogeneous
gold on ceria (Au/CeO2) as catalysts for the Sonogashira
coupling reaction. In addition to AuCl(PPh3), a tri-
nuclear Au(I) complex was also claimed to be a cata-
lyst for this reaction (Scheme I) (2–6). These homo-
geneous gold(I) catalysts were also reported to
catalyse the Suzuki coupling of iodobenzenes with
arylboronic acids (5, 6).
Traces of PalladiumNevertheless, from a practical perspective, it is impor-
tant to note that all these reactions proceeded only
under much harsher conditions (130°C in o-xylene)
(2–6) than those required with palladium catalysts.
Moreover, only the most reactive iodobenzenes were
used as the coupling partners. Another group reported
that gold(I) iodide in the presence of mono- or diphos-
phines as ligands acted as a catalyst for the Sonoga-
shira coupling of iodo- and activated bromobenzenes
under similar conditions (130°C in toluene) (7).
A central argument behind the development of gold
catalysts for cross-coupling chemistry was that “Au(I),
having the same d10 confi guration as Pd(0) can cata-
lyse reactions typically catalysed by palladium” (2–6).
However, this is a rather simplistic argument, since
even elements within the same group often behave
very differently in catalysis.
The fi rst step in the catalytic cycle of haloarene cou-
pling reactions is the oxidative addition of aryl halides
(ArX) to the metal catalyst. Thus, for a gold-catalysed
reaction of ArX with a catalyst AuX(L) (L = ligand),
a square planar Au(III) complex AuArX2(L) would be
formed. There is no report for such oxidative addition.
In fact, our preliminary results are pointing towards
high activation barriers for these types of transforma-
tions and all our attempts to carry out the oxidative
addition of a variety of iodobenzenes to AuCl(PPh3)
and other Au(I) complexes in a variety of solvents
led to complete recovery of the staring materials (8).
This is in sharp contrast to the behaviour of PdL4 or
Pd2(dba)
3 L systems, which react readily with aryl
halides to give complexes PdArX(L)2. Furthermore,
we failed to observe any coupling reaction between
iodobenzene and phenylacetylene catalysed by gold
iodide and 1,2-(diphenylphosphino)ethane. Finally,
we examined a possible Sonogashira coupling
FINAL ANALYSIS
Is Gold a Catalyst in Cross-Coupling Reactions in the Absence of Palladium?
Homogeneous Au(I) catalyst
Scheme I. Can a homogeneous gold(I) complex catalyse the Sonogashira coupling reaction?
doi:10.1595/147106711X579128 •Platinum Metals Rev., 2011, 55, (3)•
213 © 2011 Johnson Matthey
proceeding via a gold(I) acetylide (Scheme II), which
also met with failure.
It has been reported that as little as 50 ppb Pd
present in commercially available sodium carbonate
is able to catalyse the Suzuki coupling reaction (9).
Since high purity gold often contains traces of palla-
dium, we suspected that palladium was actually
responsible for the success of the Au(I)-catalysed
‘Pd-free Sonogashira reaction’. Indeed, low loadings
of palladium(0) were enough to carry out the couplings
in Schemes I and II (8). Therefore, we concluded that
it was very unlikely that gold(I) complexes alone
could act as homogeneous catalysts for cross-coupling
reactions of aryl halides and closely related organic
substrates (Csp2–X containing electrophiles) (8).
Gold NanoparticlesAll of the previous discussion here pertains to cou-
pling reactions catalysed under homogeneous condi-
tions. However, we should also consider the possibility
that the reaction proceeds via heterogeneous rather
than homogeneous catalysis. We have previously
shown that heterogeneous and homogeneous gold
catalysts activate small molecules such as alkynes
and alkenes by totally different mechanisms (10).
Accordingly, it is not entirely surprising to fi nd that
gold nanoparticles are effi cient catalysts for the Suzuki
coupling reaction (11). The reaction catalysed by
gold nanoparticles prepared from hydrogen tetra-
chloroaurate and 2-aminothiophenol proceeded sat-
isfactorily using chlorobenzenes as substrates, which
are less reactive than iodobenzene, under conditions
(80°C, 4 h) much milder that those required with Au/
CeO2 (150°C, 24 h) in o-xylene (2–6).
In addition to contamination by palladium, which
will depend on the particular source of gold used for
the preparation of the gold complexes, is there any
other way by which complexes like AuCl(PPh3) could
lead to species catalytically active in cross-coupling
reactions? This issue was addressed last year by
Lambert’s group, which demonstrated that gold
nanoparticles were formed as the active catalysts by
the slow decomposition of the AuCl(PPh3) complex
(12–14). Thus, in the reaction between iodobenzene
and phenylacetylene, long induction periods (145°C,
100 h) were required to detect the Sonogashira cou-
pling product in low yield.
Corma’s group has recently published results that
further confi rm the active role of gold nanoparticles
in cross-coupling reactions, along with theoretical
calculations that support the unlikeliness of a homo-
geneous Au(I)-catalysed Sonogashira coupling reac-
tion (15), in line with our own conclusions (8).
ConclusionsTaken together, all these results show that fundamen-
tal differences exist between heterogeneous and
homogeneous catalysts (10). In order to bridge the
gap between these two fi elds, a deeper understand-
ing of catalytic systems and their active species is
required.
Thus, while gold nanoparticles may play a role in
catalysing cross-coupling reactions, homogeneous
gold(I) complexes are unlikely to act as catalysts for
these reactions in the absence of palladium.
MADELEINE LIVENDAHL1, PABLO ESPINET2 ANDANTONIO M. ECHAVARREN1*
1Institute of Chemical Research of Catalonia (ICIQ),Av. Països Catalans 16, E-43007 Tarragona, Spain;
2IU CINQUIMA/Química Inorgánica, Facultad de Ciencias, Universidad de Valladolid, E-47071 Valladolid, Spain
*Email: [email protected]
References 1 ‘Scientifi c Background on the Nobel Prize in Chemistry
2010: Palladium-Catalyzed Cross Couplings in Organic Synthesis’, The Royal Swedish Academy of Sciences, Stockholm, Sweden, 6th October, 2010: http://nobelprize.org/nobel_prizes/chemistry/laureates/2010/sci. html (Accessed on 18th May 2011)
2 C. González-Arellano, A. Abad, A. Corma, H. García,M. Iglesias and F. Sánchez, Angew. Chem. Int. Ed., 2007, 46, (9), 1536
3 C. González-Arellano, A. Corma, M. Iglesias and F. Sánchez, Eur. J. Inorg. Chem., 2008, (7), 1107
4 A. Corma, C. González-Arellano, M. Iglesias, S. Pérez-Ferreras and F. Sánchez, Synlett, 2007, (11), 1771
Scheme II. A gold(I) acetylide complex does not catalyse Sonogashira coupling
doi:10.1595/147106711X579128 •Platinum Metals Rev., 2011, 55, (3)•
214 © 2011 Johnson Matthey
5 C. González-Arellano, A. Corma, M. Iglesias and F. Sánchez, J. Catal., 2006, 238, (2), 497
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11 J. Han, Y. Liu and R. Guo, J. Am. Chem. Soc., 2009, 131, (6), 2060
12 G. Kyriakou, S. K. Beaumont, S. M. Humphrey,C. Antonetti and R. M. Lambert, ChemCatChem, 2010, 2, (11), 1444
13 V. K. Kanuru, G. Kyriakou, S. K. Beaumont, A. C. Papageorgiou, D. J. Watson and R. M. Lambert, J. Am. Chem. Soc., 2010, 132, (23), 8081
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The Authors
Madeleine Livendahl was born in Stockholm, Sweden, in 1983. She obtained her Master of Science in Chemistry from Stockholm University. In 2009 she joined the research group of Professor Antonio M. Echavarren at the Institute of Chemical Research of Catalonia (ICIQ) in Tarragona, Spain, with a predoctoral ICIQ fellowship. Her research interests are the discovery of new transition metal-catalysed reactions.
Pablo Espinet, born in Borja (Zaragoza, Spain) is Professor of Inorganic Chemistry in the University of Valladolid, Spain. He is Director of the research institute CINQUIMA (Center for Innovation in Chemistry and Advanced Materials). His research covers the experimental study of reaction mechanisms of palladium-catalysed reactions and the synthesis of functional metal-containing molecules.
Antonio M. Echavarren, born in Bilbao (Basque Country, Spain) is Professor of Organic Chemistry and Group Leader in the Institute of Chemical Research of Catalonia (ICIQ) in Tarragona, Spain. His research interests centre on the development of new catalytic methods based on the organometallic chemistry of transition metals as well as the synthesis of natural products and polyarenes.
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