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MicrowaveMicrowaveMicrowave---promoted synthesis in waterpromoted synthesis in waterpromoted synthesis in water
Nicholas E. Leadbeater
nicholas.leadbeater@uconn.edu
Outline of what we do
Synthesis / Methodology / New techniques
Pure organic synthesiseg. Baylis-Hillman Reaction
Organometallic and inorganic chemistryfocused towards organic synthesis
Pure organometallic synthesiseg. Making organometallic polymersand other functional materials
• Growing interest in microwave synthesisMany papers and reviews coming out in 2002, 2003 and now 2004
• Enhanced reaction times and product yieldsMinutes instead of hours
• New avenues for chemistryUsing microwaves, chemists are finding that they can do new chemistry
Microwave-promoted synthesis
Microwave reactions using aryl halides
• Aryl halides are widely used to form new carbon-carbonand carbon-heteroatom bonds
• Also useful in nucleophilic displacement reactions
• I and Br substituted aryl halides are most reactive, howeverCl analogues are cheaper and more readily available
Halogen exchange reactions in aryl halides
DMFCl Br+
µw, x min, y °C
Optimum microwave power = 100 W
Optimum quantity of NiBr2 = 2 equiv.Best solvent = DMFOptimum volume = 0.5 mL
Use of 1 equiv has the effect of lowering product yield considerably
Optimum temperature = 170 °C
Lower temperature means longer reaction timeand lower product yields
Optimum reaction time = 5 min
Shorter times mean starting material remains
44 % isolated yieldNiBr2
Halogen exchange reactions in aryl halides
• Methodology is suitable for a range of halide exchanges
Br
MeO
Br
NiBr2Cl
R
Br
R
NiBr2I
R
Br
R
Cl
Cl
COMe
Cl
OMe
Cl
CHO
44
43
45
41
I
I
COMe
I
OMe
I
NO2
72
70
68
72
NiCl2Br
R
Cl
R
Br
Br
COMe
Br
OMe
94
99
99
NiCl2I
R
Cl
R
I
I
COMe
I
OMe
I
CO2H
92
97
95
94
99
94
yield (%) yield (%) yield (%) yield (%)
Latest developments
Tetrabutylammonium halides can be used as halogen sources
+µw, DMF
ITBAB
O
10 mol % NiBr2 Br
O
72% yield
+µw, DMF
ClTBACl
O
10 mol % NiBr2 Cl
O
50% yield
Cyanation of aryl halides
• Aryl nitriles are valuable intermediates in organic chemistry
Form integral parts of of dyes, herbicides, natural productsand pharmaceuticals
• Many methodologies have been developed over the years
Most direct and versatile method found so far is transition-metalcatalyzed cyanation of aryl halides
Microwave promotion has been used as a tool for the Pd-mediatedcyanation of aryl bromides (J. Org. Chem. 2000, 65, 7984)
Cyanation of aryl halides
• Use of nickel cyanide
We have developed a fast, easy methodology using nickel cyanideas a reagent
R. K. Arvela and N. E. Leadbeater, J. Org. Chem., 2003, 68, 9122
X CNR R
X = Cl, Br, I
Ni(CN)2or
NiBr2 + NaCN
Cyanation of aryl halides
NMPBr CN+
µw, x min, y °C
Optimum microwave power = 100 W
Optimum quantity of Ni(CN)2 = 0.6 equiv.Best solvent = NMPOptimum volume = 1 mL
Use of 0.5 equiv has the effect of lowering product yield considerably
Optimum temperature = 200 °C
Lower temperature means longer reaction timeand lower product yields
Optimum reaction time = 10 min
Shorter times mean starting material remains
99 % isolated yieldNi(CN)2
Cyanation of aryl halides
• Using Ni(CN)2
Conditions suitable for a wide range of substrates
Br NO2
Br
COMe
BrBr
Br Br
MeO
Br
OMe
Br
CO2H
Br
CHO
Br
NH2
99 48 9899
99 86
99
33 6096 95
86
N Br S Br
+BrR
CNR
µw
NMPISOLATED YIELDS (%)Ni(CN)2
Cyanation of aryl halides
• Using NiBr2 and NaCN
Form Ni(CN)2 in-situ
Can effect a tandem halide exchange / cyanation of aryl chlorides
+Br CNµw
NMPNiBr2 + NaCN 93% yield
+ClR
CNR
µw
NMPISOLATED YIELDS (%)NiBr2 + NaCN
Cl CO2H
Cl
COMe
ClCl Cl
OMe
Cl
OH
80 99 9985 78 61 24
N Cl
Water as a solvent for microwave chemistry
• In principle, water is a good solvent for use in synthesis
CheapReadily availableNon-toxic Non-flammableSuitable for scale-upMicrowaves interact well with it
• There are however problems
Solubility of reagents and catalystsUnwanted side reactions
The Suzuki reaction• Suzuki couplings are used on a small and multi-ton scale and
are big business
• Millions of $ / £ / € spent every year on Pd catalysts and rangesof ligands for performing this reaction
• Biaryl units are found in:
Pharmaceuticals
Herbicides
Conducting materials
Liquid crystals
Water as a solvent for the Suzuki reaction
• Water has been used as a solvent with ‘ligandless’palladium catalysts
One of the first examples was with water-soluble aryl iodides(Tetrahedron 1997, 53, 14437)
B(OH)2
R = OH, COOH
+IPdCl2, Na2CO3
H2OR R
Water as a solvent for the Suzuki reaction
• Tetrabutylammonium bromide (TBAB) has been used as anadditive for couplings in water using conventional heating(J. Org. Chem., 1997, 62, 7170)
Acts as a phase-transfer agent to aid substrate solubilityActivates boronic acid to reaction
Pd(OAc)2, Na2CO3, TBAB
H2OB(OH)2+Br
R R
Generally, activated aryl bromides used
Water as a solvent for the Suzuki reaction
• Microwaves have been used for Suzuki couplings
Using water / organic solvent mixtures (J. Org. Chem., 1996, 61, 9582)
Using water soluble aryl iodides (J. Org. Chem., 1999, 64, 3885)
B(OH)2
R = COOMe or PEG-based polymer support
+IR
Rxn time = 2 - 5 minRPd(OAc)2, Na2CO3
H2O or PEG
µw
B(OH)2+IPd(PPh3)4, µw
EtOH, DMF, H2O
Rxn time with microwave = 3.6 minProduct yield = 55%
Rxn time conventionally = 6 hProduct yield = 88%
Water as a solvent for the Suzuki reaction
• We wanted to couple the advantages of microwaves andTBAB
Can we form biaryls rapidly in neat water and activate aryl iodides,bromide and chlorides?
B(OH)2
X = Cl, Br, I
+XR R
µw
Pd(OAc)2, Na2CO3TBAB, H2O
N. E. Leadbeater and M. Marco, Org. Lett., 2002, 4, 2973
Water as a solvent for the Suzuki reaction
• Conditions suitable for a wide range of substrates
Br NO2
Br
COMe
Br
Br Br Br
Br
OMe
Br
CHO
Br
CO2Me
Br
OH
I Cl
Cl Cl
OMe
Br
COOH
I
OH
I
COOH
84 92 6879 91 73
91 86 8391 8790
80 89 87 45 62 50
MeO Br
B(OH)2+XR R
µw
Pd(OAc)2, Na2CO3TBAB, H2O
ISOLATED YIELDS (%)
Using water as a solvent in other reactions
• Sonogashira coupling reactions
Like the Suzuki reaction, the Sonogashira coupling finds used in arange of applications
Usually a catalyst mixture of a Pd complex and CuI is used
X = Cl, Br, I
+Catalyst
BaseX R H R
Sonogashira coupling reactions
• We have developed a rapid, copper-free methodology
PdCl2(PPh3)2, baseTBAB, H2O
Br +µw, x min, y °C
Optimum microwave power = 60 W
Optimum catalyst loading = 4 mol %
Optimum quantity of TBAB = 1 equiv.
Optimum volume of water = 2 mL
Best base = piperidine
Temperature = 140-150 °C
Reaction time = 5 min or shorter
99 % isolated yield
H
Sonogashira coupling reactions
• Reaction times are very fast with a range of substratesReaction needs only 20 sec microwave irradiation
Conventional heating can be used with reactions taking 5 min
Good yields of product are obtained with aryl bromides
Aryl iodides give slightly lower yields (like Suzuki couplings)
OMeO
Br
99%
99%
99%
BrBr
Br
94%
92%
93%
61%
-
62%
90%
88%
77%
µw, 60W, 5 min then 5 min cool
µw, 60W, 20 sec then 5 min cool
oil bath, 140°C, 5 min then 5 min cool
Sonogashira coupling reactions
• Not the first methodology using water but the fastest, most versatile and easiest
• Not the first copper free methodology
PPh2O N
H
O
PdCl
Heterocycles 2003, 59, 71
Tetrahedron Lett., 1997, 38, 7843
P
SO3
SO3O3Sn
J. Org. Chem., 1995, 60, 6829
Tetrahedron Lett., 1998, 39, 525
-
--
PdN
C6H4-p-Cl
OH
ClCl2
NNBu+ PF6
-
Tetrahedron Lett., 2002, 43, 9365 Org. Lett., 2002, 4, 1691
New Suzuki-type couplings
• Whilst probing the microwave-promoted coupling protocol we have found that it is possible to perform Suzuki-typecouplings
without the need for addition of atransition-metal catalyst
No catalyst added Suzuki couplings
B(OH)2+XR R
µw
Na2CO3TBAB, H2O
N. E. Leadbeater and M. Marco, Angew. Chem. Int. Ed., 2003, 42, 1407
Latest developments
Vinylboronic acids can be used in the no added catalyst protocol
+Brµw, H2OB(OH)2
R R
+Brµw, H2O
B(OH)2
R
Latest developments
Vinylboronic acids can be used in the no catalyst added protocol
+µw, H2OB(OH)2
R
Br
R
Synthesis of losartan• Anti-hypertensive drug also known as ‘Cozaar’
Nonpeptide angiotensin II receptor antagonist
A number of syntheses have been patented and published(eg: J. Med. Chem. 1994, 37, 542; J. Org. Chem., 1994, 59, 6391)
NNH
NN
NN
Cl
OH
Synthesis of losartan• Develop a rapid synthesis with scope for diversity
Bring together several microwave steps
NNH
NN
NN
Cl
OH
NNH
NN
NN
Cl
OH
NN
Cl
OH
B(OH)2N
NHN
NBr
NNH
NN
Br
NN
Cl
OH
B(OH)2
NN
Cl
OH
HBr
B(OH)2
Br CNNaN3
Br CNBr ICuCN
Br II INiBr2
NaN3
CuCN
Synthesis of losartan• Putting the synthesis together
(HO)2B
Br
NN
Cl OH
H B(OH)2
NN
Cl
OH
1
BrI µw
CuCN, TBAB,H2O
BrCN µw
NaN3, ZnBr2,H2O
Br
NNH
NN
µw, 1N
NHN
N
NN
Cl
OH
Losartan
DMA
Pd(OAc)2TBAB, Na2CO3, H2O
Acknowledgements
I acknowledge the hard work and dedication of the students who have been involved in the work presented here:Riina ArvelaEmilie JoliboisMaria Marco Sharon PillsworthErik ShanahanBonnie TominackVicki Willams
I thank Hoffmann La Roche, EvotecOAI and CEM Microwave Technology for financial support of our work
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