EXCERPT FROM

THE FIRST STEPS TOWARDS GREEN CYCLOPROPANATION

Krisna Van Dyke

Senior Thesis Project

Submitted in partial fulfillment of the requirements for the degree of Bachelor of Arts

School of Natural Science

Hampshire College

May 2016

Committee Co-Chairs: Dr. Rayane Moreira & Dr. John Castorino

Chapter 3 | Chemical Cyclopropanation

3.1 THE REACTION OF CARBENE AND OLEFIN

Pericyclic reactions are cycloadditions in which two or more unsaturated molecules or

functionalities combine through a bond rearranging conjugated cyclic transition state to form a

cycloadduct with net loss of bond multiplicity.1 Cheletropic reactions are a pericyclic subset in

which the terminal atoms of a conjugated system are those reacting to create two new σ-bonds to

a single atom while losing a π-bond. Cyclopropanations of a singlet carbene by olefin are a

commonly observed [2+1] cycloaddition exemplary of cheletropic reactions. Their cheletropic

nature grants these cyclopropanations a concerted mechanism which ensures stereochemical

preservation of the starting alkene.2 Most introductory level texts describe such reactions with

free carbenes and omit important complexities not only to these reactions,2,3 but

cyclopropanation as a whole. For example; not all cyclopropanations are concerted, not all

carbenes possess a lone pair, and chemical cyclopropanation is mostly done using transition

metal catalysis on the industrial scale.

3.1.1 Basic Structure & Classification of the Carbene

The first two experiments to posit radicals were by Guether and Hermann4 in 1855 and

Nef5 in 1897 but, a radical was not isolated and confirmed until Gomberg’s discovery of

triphenylchloromethylene6 in 1900. Work on ethyldiazoacetate in 1883 by Curtius,7 and in 1911,

work on methylene derivatives such as diazomethane by Staudinger,8,9 marked some of the first

notable research into carbenes. Carbenes are divalent neutral carbon species often classified by

substituents geminal to their carbon lone pair.10 They have geometries ranging from linear, in

which unpaired electrons rest above and below their two bonds, to the more common bent type,

in which the nonbonding electrons are paired.11 These forms can roughly described as ranging

between sp and sp2 hybridization with frontier orbitals determined by this hybridization.

The electrons of triplet carbenes do not occupy the same sub-orbital because they possess

the same spin. Singlet to triplet resonance is forbidden, meaning these two are not resonance

forms of one another, but rather, entirely different species which each possess their own

reactivity.3,12 This is due to an energy barrier between the states whose average is about ~15kcal

mol-1 and often higher in many cases. Despite this quantum forbiddance, the compound

fluorenylidene goes between singlet and triplet states via intersystem crossing due to the low

difference in the energy of its singlet and triplet states.13 Furthered study of these phenomena,

including solvent mediated effects14 could eventually lead to control over the singlet-triplet states

of persistent carbenes. These would then have the synthetic utility of both types of carbene;

which could be selected through the use of specific chemical environments.

Triplet carbenes are readily formed by photolysis of α-diphenyl diazo compounds while

α-dialkyl compounds usually form singlet carbenes.15,16 Triplet carbenes are diradicals which are

extremely reactive and difficult to isolate17–20 and often rearrange or decompose through alkene

dimerization.21 Triplet carbenes can form cyclopropanes via [2+1] cycloaddition but due to

electronics that differ from singlet carbenes, their approach to the alkene is not always

stereospecific.22 Triplet carbenes undergo a variety of other high energy reactions and are

reactive enough for insertion into C-H bonds.23,24 Despite reacting readily, these factors can

make synthesis with them difficult due to selectivity. However, more recent studies have yielded

a triplet carbene which can persist for up to a week!25 Though it is a general rule, triplet carbenes

are not always more reactive than singlet carbons, and unlike them, cannot react with carbon-

halogen bonds.26

Persistent carbenes are those with more than fleeting half-lives. They often exist in

“Wanzlick” equilibrium with alkene dimers formed by their lone pair electrons.27–29

Dimerization of singlet carbenes does not occur by head on collision of the unpaired electrons,

since these would repel each other. Instead, the dimerization mechanism involves the approach

of the lone pair to the empty p-orbital of the adjacent carbon.30 Outside slowing the reaction, this

equilibrium might lead one to believe dimerizing carbenes would always be useful in synthesis

so long as their cyclopropane derivatives were thermodynamically favorable. This is not the

case, as using non-complexed carbenes is often a poor choice in the case of cyclopropanation

because depending on the conditions, not all dimers dissociate.31–33 Even if the carbene can

dissociate from its dimerized form, the conditions under which it does that may be too harsh for

the survival of the cyclopropane.

3.1.2 Singlet Carbenes

Singlet carbenes have a lone pair and six electrons.21 One might think, despite the

presence of a lone pair, that electron deficiency would render singlet carbenes extremely

electrophilic in all cases,2 but depending on the electronics of the carbene, they can be classified

as electrophilic, ambiphilic or nucleophilic.21 The philicity of singlet carbenes has been

researched heavily by Moss,34–37 who created scales of general reactivity based on the

substituents attached to a carbene in reactions with olefins. As one might expect, this is a

spectrum in which EDGs create nucleophilic carbenes and EWGs produce electrophilic carbenes.

The former reacts more readily with electron poor alkenes, and the latter, with electron rich

alkenes. Moss also formulated a more detailed FMO theory to explain singlet carbene reactivity,

similar to the kind used to describe DA cycloadditions, but these were only applicable to ground

state carbenes and thus difficult to test in the lab. Part of the reason so many textbooks give the

simplistic notion that cyclopropanation reactions between olefins and carbenes are [2+1]

cycloadditions preserve the stereochemistry of the starting alkene2,3 is because many, but not all,

of these reactions occur between an electrophilic singlet carbene or carbenoid (i.e. a Fischer

Carbene), and an olefin. Electrophilic singlet carbenes are simply more commonly observed and

their approach to the empty p orbital of an olefin’s π bond has been well characterized. Addition

occurs in a concerted fashion which preserves the stereochemistry of the starting alkene.38–41

One of the simplest methods of producing cyclopropane is by forming a singlet

dichlorocarbene from chloroform in a strongly basic solution.40–42 This can be done with a strong

organic base such as potassium tert-butoxide,42 but can also be accomplished with weaker base,

such as hydroxide ion.3 In these cases, cyclopropanation will occur in poor yield unless a phase

transfer catalyst is employed. Both reactions yield dichlorocyclopropane from an olefin. Though

one would assume the electron withdrawing properties of chlorine would destabilize the

carbene,12 chlorine and other halogens donate electron from their pz orbital into the empty pz

orbital of the carbon. The result is a powerful, but stabilized electrophile. After addition to the

double bond, the halogens can then provide functionality for synthesis afterward or simply be

removed.3

3.1.3 Triplet Carbenes

Stabilizing triplet carbenes is extremely difficult since π-donation and acceptance,

hyperconjugation, and electron withdrawing substituents better stabilize the closed-shell

singlet.20 The philicity of triplet carbenes is not properly understood at this current time, with

minimal study conducted on the matter.42–45 Addition of triplet carbenes to olefins occurs by a

stepwise radical addition.46 Enantiopure mixtures are usually not observed because carbon-

carbon bond rotation is faster than the spin-flip of the biradical intermediate. Despite the lack of

triplet carbene philicity and the shortcomings of the theory for singlet carbenes, theories have

been put forward to explain the overall philicity of both types of carbenes.21 These theories

correlate electron affinity with electrophilicity and ionization potential with nucleophilicity.

3.1.5 Diazo-Derived Carbenes

A common method of carbene creation historically was through photo- or thermolysis of

a diazo compound, an often explosive compound containing the N2 group.2,47,48 Diazo

compounds were not readily available until the discoveries of Nierenstein,49 Arndt50–52 and

Bradley53 in which acylation of diazomethane produced a more synthetically useful and stable

product. Even after increase in the availability of carbenes, synthesis utilizing them was often

difficult to their rampant reactivity. Not only can they react with each other in dimerizations30,

they can undergo a variety of other reactions3,21 including bond insertion into carbon-hydrogen

bonds to yield a variety of products even in mixtures of simple hydrocarbon.48

Though diazo compounds such as diazomethane remain the main source of carbenes,54,55

advances in their use has allowed us to step away from the unselective methods involved with

photo- or thermolysis. In the spirit of high energy approaches to facile syntheses, the diazo

approach makes uses the powerful ability of N2 as a leaving group to generate carbenes. This

method can be completed without catalysis but often undergoes the many unwanted reactions

previously described.30,42,48 Additionally, due to the strength of nitrogen-nitrogen triple bond,2

trapping N2 only for the purpose of using it again as a leaving group is a relatively energetically

wasteful process.

Some of the main important routes of diazo compound as reviewed in 2009 by Maas54

are; (A) diazo transfer onto activated methylene or methane compounds, (B) diazotization of

alpha-acceptor-substituted primary aliphatic amines, (C) base treatment of sulfonylhydrazones,

(D) Alkaline cleavage of N-alkyl-N-nitroso sulfonamides, carboxamides, ureas and urethanes,

(E) triazene fragmentation (rare), (F) electrophilic substitution at diazomethyl compounds, and

(G) substituent modification of an existing diazo compound.

Figure 1. Synthetic routes for diazo compounds as review in 2009 by Maas54

Aside from diazomethane, another very important class of compounds diazo compound is

the α-diazocarbonyls. These are easy to prepare from readily available compounds and can

undergo a large variety of reactions under mild conditions.56 The two most common methods of

creation are, the more widely used acylation of diazomethane with acid chloride, and diazo group

transfer to terminal and nonterminal systems. These α-diazocarbonyls are a much more stable

diazo compound because the dinitrogen functionality can resonate with the carbonyl alpha to it

but still reactive enough to undergo many synthetically useful reactions. The departure of the

diazo group creates an electrophilic carbene which is free to attack an electron-poor alkene or in

some special cases an alkyne.

3.1.7 The Rich Chemistries of Fischer and Schrock Carbenes

Fischer’s 1964 discovery of a tungsten-carbonyl complex,57 and a later discovery by

Schrock,58 marked the beginning of a new age in which stereoselective cyclopropanation

reactions would become widely available. Where heat or light used was once the standard

method of activating diazocompounds for reaction, the method eventually popularized and

exhaustively developed was one that used transition metal catalysts derived from Fischer’s

discovery.59 These catalysts facilitate the loss of the diazo group and form a double bond with

the resultant carbene. The chiral ligands attached to these catalysts facilitate a wide range of

stereoselective reactions, of which the most important to this text is cyclopropanation.

Metal carbene complexes are classified as Fischer or Schrock type based on the carbene’s

substituents, and the involved metal’s type and oxidation state.60 Fischer and Schrock carbenoids

are subsets of a class of compounds called transition metal carbene complexes which have the

common feature of a covalent double bond forming between the involved carbene and the metal

center of the catalyst.

Figure 2. (a) the orbitals of free carbene, (b) the orbitals of a Fischer complex and (c) the orbitals of a Schrock complex60

Fischer type complexes generally involve late transition metals (groups 6 to 8) with low

oxidation states, such as Fe(0), that have π-acceptor ligands and carbenes with at least one π-

donator substituent.21,60 The σ-bond contains electrons from the carbene lone pair while the π-

bond contains two electrons from the metal.60 The dπ orbital is lower in energy than the carbene p

orbital, and as such, clings more strongly to the electrons, causing electron deficiency in the

carbene. This deficiency is stabilized by the π-donator substituent which donates electron density

into the carbene. Donation can, as is the case of the methoxy substituent, result in the existence

of two distinct resonance forms with one being a zwitterion with a triply bonded oxygen. The

resultant Fischer stabilized carbene acts as a singlet.61 To date, Fischer carbenes have seen much

more heavy research and usage overall.55,60,62

Schrock type carbenes generally involve early transition metals (groups 3 to 6) with high

oxidation states like Ta(V) that have non-π-acceptor ligands and carbenes without π-donating

substituents.60 Similar to Fischer type complexes, the σ-bond is also formed by the electrons of

the carbene lone pair. Unlike the Fischer case though, the dπ orbital is higher in energy than the

carbene p orbital which centers electron density on the carbene. Electrons can be thought of

migrating from the metal dπ orbital to the carbenic pz orbital.63 The resultant Schrock stabilized

carbene acts as a triplet.61 Despite the seeming rigidity of these definitions, reactivity can vary

greatly among carbenes within the same class and recently an ambiguous case was discovered.61

This hybrid case was an osmium-based carbene a mixture of Fischer and Schrock characteristics.

In 1966, just as asymmetric catalysis was becoming a major focus of organic chemistry,

Nozaki released the foundations for many studies on asymmetric catalysis of cyclopropanation

reactions to come.64 The widespread approach taken to carbene-based cyclopropanation and

carbene use overall is the previously discussed complexation of a metal catalyst with asymmetric

ligands which acts to stabilize the carbene and ensure it creates stereospecific correct product.65

Many complexed metals have been used for this process, each with their own synthetic utility,

including; ruthenium,66–68 rhodium,59,69–71 palladium,72,73 osmium,61 iron,74–76 copper,77 nickel,78

cobalt,79–81 gold,10 and more. Despite the variety of metals used, the first catalysts reliably used

in cyclopropanation reactions of diazomethane were palladium based, though rhodium and cobalt

quickly followed.82 New metal catalysts are being explored daily and now gold catalysis of

Fischer carbenes, has bloomed in recent years.10,83–85

Figure 3: N2 releasing transition metal complex catalyzed cyclopropanation59

3.2 OTHER IMPORTANT CYCLOPROPANATIONS

It is hard to compete with the powerful asymmetric syntheses techniques developed with

transition metal carbene complexes, but a couple alternative syntheses techniques have found

their niche in fields such as natural product synthesis.86 Below is a sampling of cyclopropanation

techniques, old and new, not described in the previous section. The general lack of atom

economy and promiscuity these reactions display is often apparent.

3.2.1 The Wurtz Reaction

One of the oldest cyclopropanation methods, the Wurtz reaction87 uses the higher affinity

of a metal for a halide to create a radical.88 This radical is then made into a carbanion by

donation of an electron by excess metal. This carbanion completes an SN2 attack on a nearby

alkyl halide, creating a carbon-carbon bond. This method has been used to create cyclopropanes

but requires generous use of metals, creates large amounts of salt byproducts, and only provides

adequate yields in certain highly-specific situations.89

3.2.2 The Simmons-Smith Reaction

Published in 1959 by Simmons and Smith, the Simmons-Smith reaction cyclopropanates

an olefin77. This occurs by means of a butterfly intermediate where a halometal complex,

originally (iodomethyl)zinc iodide, donates its carbon to an electron poor double bond. This is

one of the earlier non-diazo metal carbenoid cyclopropanation reactions and yields are generally

poor to good. However, this is often unacceptable considering, stoichiometrically, that the

reaction creates an entire equivalent of ZnI2 per cyclopropane formed and does not permit a

particularly wide range of substrates. Because of these yield problems and the difficulty of

obtaining certain reagents for the reaction, new techniques and variants have been developed

over time. One such technique creates iodomethylzinc trifluoroacetate from more easily available

diethylzinc, trifluoroacetic acid and diiodomethane at 0°C in dichloromethane.2

3.2.3 The Kulinkovich Reaction

The Kulinkovich reaction, discovered in 1989, relies on an organotitanium complex to

complete catalytic cyclopronations resulting in cyclopropanols.90 The cyclization requires

Titanium isopropoxide, ethylmagnesium bromide, and acid. Two of the titanium ligands are

replaced by ethyl groups, of which one is lost to create a titanocyclopropane. This species is

attacked by a methyl ester which forms a saturated furan ring containing the original titanium.

Rearrangement yields a cyclopropane attached to the titanium which reacts with two more

Grignard reagents. This regenerates the diethyltitanium species and releases the cyclopropane,

which can be converted into an alcohol with an acid workup. The Kulinkovich reaction does not

possess the atom economy offered by diazo-derived metal complexes, especially with the loss of

one ethylene per cyclopropane. However, the Kulinkovich reaction has still seen some recent

use, especially in the synthesis of natural products. It serves as a simple method of preparing

cyclopropanols.

3.3 CYLOPROPANES IN INDUSTRY & CLEANING UP

Owing to its synthetic utility and relatively easy to access reagents it utilizes,

cyclopropane synthesis has found an important place in industrial synthesis. As with any

industrialized process, it now undergoes continual refinement for use on large-scale. Though

these processes have become more efficient and safe as recently as the early 2000s, they have not

necessarily become any greener.91

3.3.1 Industrial Cyclopropanation

Though diazomethane has a reputation of being a dangerous chemical, continuous

improvements of safety have made it safe enough for large scale use on the industrial level,

where it continues to be the most widely used olefin cyclopropanation agent.92 The prevailing

techniques for its use today are continuous flow reactors. This is not to say that other diazo

compounds, such as α-daizo carbonyls, are not used or being researched as well. Generation of

some of these compounds in situ, such as diazo-β-keto ester has been deemed safe enough for

large-scale industrial usage,93 but efforts continue to make these processes safer and more

efficient.92 One of the first pilot plants to utilize diazomethane on an industrial scale had to

complete extensive explosion testing and still could not process the compound in large

volumes.91 It utilized a 181mm tube with an internal volume of 910 cm3 and a full-bore graphite

bursting disk rated at 30 psi which sat over a tank of quenching solution. This plant established

the now most common method of using the hydrolysis of N-methyl-N-nitroso-p-

toluenesulfonamide (diazald) to form diazomethane.91,92,94

Figure 4: Schematic of a diazomethane forming reactor utilizing diazald hydrolysis92

Though we now have a much better understanding of how to complete largescale

cyclopropanation safely, we now have to complete it cleanly. This method requires the

stoichiometric use of potassium hydroxide and diazald which must both be continually prepared

in organic solvents for reactions that will likely involve organic solvent. Even if we cannot

currently complete these reactions enzymatically, options exist to complete specific

cyclopropanation in water without the use of these compounds or a blast-shielded reactor.

3.3.2 Current Options for Aqueous Cyclopropanation

Though metal catalysis in water has been a challenge, considering the reactivity of water

and its frequent ability to completely inactive a catalyst, this area of chemistry is starting to see

serious advancement. Methods of transition metal-catalyed cyclopropanation of olefins in water

have been developed as well as methods of in situ generation of diazo reagents.95,96 The use of a

catalyst assures the diazo compound reacts as desired in water, while the aqueous environment

allows hydrolysis to occur directly. In experiments using a Ru(II) Py-box and Katsuki’s Co(II)

Salen complex, yields of styrene and similar alkenes were roughly 60% and a select few were

better.97 Though this an exciting step in the right direction, these chemistries must have better

yields before industry is able to profitably use them in their syntheses.

CHAPTER 3 REFERENCES

1. Anslyn, E. V. & Dougherty., D. A. Modern Physical Organic Chemistry. Angew. Chemie Int. Ed. 45, (2006).

2. Sorrell, T. N. Organic Chemistry. (University Science Books, 2006).

3. Bruckner, R. Advanced Organic Chemistry. Earth (Elsevier, 2003). doi:10.1021/ed065pA139.2

4. Geuther, A. Ueber die Bereitung des Bleisuperoxyds durch Chlor. Ann. der Chemie und Pharm. 96, 382–383 (1855).

5. Nef, J. U. Ueber das zweiwerthige Kohlenstoffatom. (Vierte Abhandlung.) Die Chemie des Methylens. Justus Liebig’s Ann. der Chemie 298, 202–374 (1897).

6. Gomberg, M. An instance of trivalent carbon: Triphenylmethyl. J. Am. Chem. Soc. 22, 757–771 (1900).

7. Curtius, T. Ueber die Einwirkung von salpetriger Säure auf salzsauren Glycocolläther. Berichte der Dtsch. Chem. Gesellschaft 16, 2230–2231 (1883).

8. Staudinger, H. & Jelagin, S. Über Ketene. XV. Einwirkung von Diphenylketen auf Nitrosoverbindungen. Berichte der Dtsch. Chem. Gesellschaft 44, 365–374 (1911).

9. Staudinger, H. & Kupfer, O. Über Reaktionen des Methylens. III. Diazomethan. Berichte der Dtsch. Chem. Gesellschaft 45, 501–509 (1912).

10. Qian, D. & Zhang, J. Gold-catalyzed cyclopropanation reactions using a carbenoid precursor toolbox. Chem. Soc. Rev. 44, 677–698 (2015).

11. Bourissou, D., Guerret, O., Gabbaï, F. P. & Bertrand, G. Stable Carbenes. Chem. Rev. 100, 39–92 (2000).

12. Skell, P. S. & Woodworth, R. C. Structure of Carbene, Ch 2. J. Am. Chem. Soc. 78, 4496–4497 (1956).

13. Grasse, P. B., Brauer, B. E., Zupancic, J. J., Kaufmann, K. J. & Schuster, G. B. Chemical and

physical properties of fluorenylidene: equilibration of the singlet and triplet carbenes. J. Am. Chem. Soc. 105, 6833–6845 (1983).

14. Sitzmann, E. V., Langan, J. & Eisenthal, K. B. Intermolecular effects on intersystem crossing

studied on the picosecond timescale: the solvent polarity effect on the rate of singlet-to-triplet intersystem crossing of diphenylcarbene. J. Am. Chem. Soc. 106, 1868–1869 (1984).

15. Bally, T., Matzinger, S., Truttmann, L., Platz, M. S. & Morgan, S. Matrix Spectroscopy of 2-

Adamantylidene, a Dialkylcarbene with Singlet Ground State. Angew. Chemie Int. Ed. English 33, 1964–1966 (1994).

16. Ford, F., Yuzawa, T., Platz, M. S., Matzinger, S. & Fülscher, M. Rearrangement of

dimethylcarbene to propene: Study by laser flash photolysis and ab initio molecular orbital

theory. J. Am. Chem. Soc. 120, 4430–4438 (1998).

17. Regitz, M. Stable Carbenes—Illusion or Reality? Angew. Chemie Int. Ed. English 30, 674–

676 (1991).

18. Heinemann, C., Müller, T., Apeloig, Y. & Schwarz, H. On the Question of Stability,

Conjugation, and ‘Aromaticity’ in Imidazol-2-ylidenes and Their Silicon Analogs †. J. Am. Chem. Soc. 118, 2023–2038 (1996).

19. Tomioka, H. Persistent Triplet Carbenes. Acc. Chem. Res. 30, 315–321 (1997).

20. Nemirowski, A. & Schreiner, P. R. Electronic stabilization of ground state triplet carbenes. J. Org. Chem. 72, 9533–9540 (2007).

21. Bertrand, G. Carbene Chemistry: From Fleeting Intermediates to Powerful Reagents. (Marcel Decker, 2002).

22. Eisenthal, K. B., Moss, R. A. & Turro, N. J. Divalent Carbon Intermediates: Laser Photolysis and Spectroscopy. Science (80-. ). 225, 1439–1445 (1984).

23. Tomioka, H., Okada, H., Watanabe, T. & Hirai, K. An Extremely Long-Lived Triplet

Carbene; Reactivity, Optical Absorption Spectrum, and Kinetics of Highly Congested Diarylcarbenes. Angew. Chemie Int. Ed. English 33, 873–875 (1994).

24. Hirai, K., Komatsu, K. & Tomioka, H. Reactions and Kinetics of(2,4,6-Tri-tert-butylphenyl)phenylcarbene. Chem. Lett. 503–506 (1994). doi:10.1246/cl.1994.503

25. Itoh, T., Nakata, Y., Hirai, K. & Tomioka, H. Triplet diphenylcarbenes protected by

trifluoromethyl and bromine groups. A triplet carbene surviving a day in solution at room temperature. J. Am. Chem. Soc. 128, 957–967 (2006).

26. Roth, H. D. Chemically induced nuclear spin polarization in the study of carbene reaction mechanisms. Acc. Chem. Res. 10, 85–91 (1977).

27. Wanzlick, H.-W. & Schikora, E. Ein neuer Zugang zur Carben-Chemie. Angew. Chemie 72, 494–494 (1960).

28. Wanzlick, H.-W. & Schikora, E. Ein nucleophiles Carben. Chem. Ber. 94, 2389–2393 (1961).

29. Wanzlick, H.-W. Nucleophile Carben-Chemie. Angew. Chemie 74, 129–134 (1962).

30. Hoffmann, R., Gleiter, R. & Mallory, F. B. Non-Least-Motion Potential Surfaces. The

Dimerization of Methylenes and Nitroso Compounds. J. Am. Chem. Soc. 92, 1460–1466

(1970).

31. Lemal, D. M., Lovald, R. A. & Kawano, K. I. Tetraaminoethylenes. The Question of Dissociation. J. Am. Chem. Soc. 86, 2518–2519 (1964).

32. Denk, M. K., Hatano, K. & Ma, M. Nucleophilic carbenes and the Wanzlick equilibrium: A reinvestigation. Tetrahedron Lett. 40, 2057–2060 (1999).

33. Liu, Y. & Lemal, D. M. Concerning the ‘Wanzlick equilibrium’. Tetrahedron Lett. 41, 599–602 (2000).

34. Moss, R. A., Mallon, C. B. & Ho, C. The correlation of carbenic reactivity. J. Am. Chem. Soc. 99, 4105–4110 (1977).

35. Moss, R. A. Carbenic selectivity in cyclopropanation reactions. Acc. Chem. Res. 13, 58–64 (1980).

36. Nelson G. Londan, K. N. H. and R. A. M. Transition States and Selectivities. J. Am. Chem.

Soc. 102, 1770–1776 (1980).

37. Moss, R. A. et al. Absolute rate and philicity studies of methoxyphenylcarbene. An extended range for carbenic ambiphilicity. J. Am. Chem. Soc. 109, 4341–4349 (1987).

38. Skell, P. S. & Garner, A. Y. Reactions of bivalent carbon compounds. Reactivities in olefin-dibromocarbene reactions. J. Am. Chem. Soc. 78, 5430–5433 (1956).

39. Skell, P. S. & Garner, A. Y. The Stereochemistry of Carbene-Olefin Reactions. Reactions of Dibromocarbene with the cis- and trans-2-Butenes. J. Am. Chem. Soc. 78, 3409–3411 (1956).

40. von E. Doering, W. The Electron-seeking Demands of Dichlorocarbene in its Addition to

Olefins. J. Am. Chem. Soc. 80, 5274–5277 (1958).

41. Skell, P. S. & Cholod, M. S. Reactions of dichlorocarbene with olefins temperature dependence of relative reactivities. J. Am. Chem. Soc. 91, 7131–7137 (1969).

42. Doering, W. von E. & Hoffman, A. K. The addition of dichlorocarbene to 3-methoxycyclohexene. Tetrahedron Lett. 76, 2703–2706 (1954).

43. Parham, W. E. & Reiff, H. E. Ring Expansion during the Reaction of Indenylsodium and Chloroform. J. Am. Chem. Soc. 77, 1177–1178 (1955).

44. PARHAM, W. E. & TWELVES, R. R. Formation of Naphthalenes from Indenes. III. 1

Substituted Methanes as Carbene Precursors. J. Org. Chem. 22, 730–734 (1957).

45. Skell, P. S. & Sandler, S. R. Reactions of 1,1-Dihalocyclopropanes With Electrophilic

Reagents. Synthetic Route for Inserting a Carbon Atom Between the Atoms of a Double Bond. J. Am. Chem. Soc. 80, 2024–2025 (1958).

46. Su, M. Role of Spin−Orbit Coupling and Symmetry in Triplet Carbenic Addition Chemistry. J. Phys. Chem. 100, 4339–4349 (1996).

47. Steacie, E. W. R. The Thermal Decomposition of Diazomethane. J. Phys. Chem. 35, 1493 (1931).

48. Bonds, C., Herzog, B. M. & Carr, R. W. The Reactivity of Methylene from Diazomethane Photolysis. J. Phys. Chem. 2297, 2688–2693 (1970).

49. Nierenstein, M., Wang, D. G. & Warr, J. C. The Action of Diazomethane on Some Aromatic Acyl Chlorides II. Synthesis of Fisetol. J. Am. Chem. Soc. 46, 2551–2555 (1924).

50. Arndt, F., Eistert, B. & Partale, W. Diazo-methan und o -Nitroverbindungen, II.: N -Oxy-

isatin aus o -Nitro-benzoylchlorid. Berichte der Dtsch. Chem. Gesellschaft (A B Ser. 60, 1364–1370 (1927).

51. Arndt, F. & Amende, J. Synthesen mit Diazo-methan, V.: Über die Reaktion der

Säurechloride mit Diazo-methan. Berichte der Dtsch. Chem. Gesellschaft (A B Ser. 61, 1122–

1124 (1928).

52. Arndt, F., Eistert, B. & Amende, J. Nachträge zu den „Synthesen mit Diazo-methan”. Berichte

der Dtsch. Chem. Gesellschaft (A B Ser. 61, 1949–1953 (1928).

53. Bradley, W. & Robinson, R. CLXXIV.—The interaction of benzoyl chloride and

diazomethane together with a discussion of the reactions of the diazenes. J. Chem. Soc. 1310–

1318 (1928). doi:10.1039/JR9280001310

54. Maas, G. New syntheses of diazo compounds. Angew. Chemie - Int. Ed. 48, 8186–8195 (2009).

55. Dötz, K. H. & Stendel, J. Fischer carbene complexes in organic synthesis: Metal-assisted and metal-templated reactions. Chem. Rev. 109, 3227–3274 (2009).

56. Ye, T. & McKervey, M. A. Organic Synthesis with .alpha.-Diazo Carbonyl Compounds. Chem. Rev. 94, 1091–1160 (1994).

57. Fischer, E. O. & Maasböl, A. On the Existence of a Tungsten Carbonyl Carbene Complex.

Angew. Chemie Int. Ed. English 3, 580–581 (1964).

58. Schrock, R. R. Alkylcarbene complex of tantalum by intramolecular α-hydrogen abstraction. J. Am. Chem. Soc. 96, 6796–6797 (1974).

59. Caballero, A., Prieto, A., Díaz-Requejo, M. M. & Pérez, P. J. Metal-catalyzed olefin

cyclopropanation with ethyl diazoacetate: Control of the diastereoselectivity. Eur. J. Inorg.

Chem. 1137–1144 (2009). doi:10.1002/ejic.200800944

60. Bernasconi, C. F. The Physical Organic chemistry of Fischer Carbene Complexes. Adv. Phys.

Org. Chem. 37, 137–237 (2002).

61. Esteruelas, M. A., González, A. I., López, A. M. & Oñate, E. An osmium-carbene complex

with fischer-schrock ambivalent behavior. Organometallics 22, 414–425 (2003).

62. de Frémont, P., Marion, N. & Nolan, S. P. Carbenes: Synthesis, properties, and organometallic chemistry. Coord. Chem. Rev. 253, 862–892 (2009).

63. Crabtree, R. H. in Encyclopedia of Inorganic and Bioinorganic Chemistry (John Wiley & Sons, Ltd, 2011). doi:10.1002/9781119951438.eibc0270

64. Nozaki, H., Moriuti, S., Takaya, H. & Noyori, R. Asymmetric induction in carbenoid reaction by means of a dissymmetric copper chelate. Tetrahedron Lett. 7, 5239–5244 (1966).

65. Bartoli, G., Bencivenni, G. & Dalpozzo, R. Asymmetric Cyclopropanation Reactions. Synthesis (Stuttg). 46, 979–1029 (2014).

66. Garcia, J. I. et al. QM/MM modeling of enantioselective pybox-ruthenium- and box-copper-

catalyzed cyclopropanation reactions: Scope, performance, and applications to ligand design. Chem. - A Eur. J. 13, 4064–4073 (2007).

67. Maas, G. & Seitz, J. Ruthenium(I)-catalyzed cyclopropanation reactions with

(trimethylsilyl)diazomethane and aryldiazomethanes. Tetrahedron Lett. 42, 6137–6140

(2001).

68. Zhang, J. L., Hong Chan, P. W. & Che, C. M. Ruthenium(II) porphyrin catalyzed

cyclopropanation of alkenes with tosylhydrazones. Tetrahedron Lett. 44, 8733–8737 (2003).

69. Archambeau, A., Miege, F., Meyer, C. & Cossy, J. Intramolecular cyclopropanation and C-H

insertion reactions with metal carbenoids generated from cyclopropenes. Acc. Chem. Res. 48, 1021–1031 (2015).

70. Negretti, S., Cohen, C. M., Chang, J. J., Guptill, D. M. & Davies, H. M. L. Enantioselective

dirhodium(II)-catalyzed cyclopropanations with trimethylsilylethyl and trichloroethyl aryldiazoacetates. Tetrahedron 71, 7415–7420 (2015).

71. Trindade, A. F., Coelho, J. A. S., Afonso, C. A. M., Veiros, L. F. & Gois, P. M. P. Fine tuning of dirhodium(II) complexes: Exploring the axial modification. ACS Catal. 2, 370–383 (2012).

72. Chen, K., Jiang, M., Zhang, Z., Wei, Y. & Shi, M. Palladium(0)-catalyzed reaction of

cyclopropylidenecycloalkanes with carbon dioxide. European J. Org. Chem. 2, 7189–7193

(2011).

73. Zhang, Y. & Wang, J. Recent developments in Pd-catalyzed reactions of diazo compounds.

European J. Org. Chem. 1993, 1015–1026 (2011).

74. Wolf, J. R., Hamaker, C. G., Djukic, J.-P., Kodadek, T. & Woo, L. K. Shape and

stereoselective cyclopropanation of alkenes catalyzed by iron porphyrins. J. Am. Chem. Soc. 117, 9194–9199 (1995).

75. Morandi, B. & Carreira, E. M. Iron-catalyzed cyclopropanation with trifluoroethylamine

hydrochloride and olefins in aqueous media: In situ generation of trifluoromethyl diazomethane. Angew. Chemie - Int. Ed. 49, 938–941 (2010).

76. Zhu, S. F. & Zhou, Q. L. Iron-catalyzed transformations of diazo compounds. Natl. Sci. Rev. 1, 580–603 (2014).

77. H.E. Simmons, R. D. S. A New Synthesis of Cyclopropanes. J. Am. Chem. Soc. 104, 4256

(1947).

78. Künzi, S. A., Sarria Toro, J. M., den Hartog, T. & Chen, P. Nickel-Catalyzed

Cyclopropanation with NMe 4 OTf and n BuLi. Angew. Chemie Int. Ed. 54, 10670–10674

(2015).

79. Nakamura, A., Konishi, A., Tatsuno, Y. & Otsuka, S. A Highly Enantioselective Synthesis of

Cyclopropane Derivatives through Chiral Cobalt(II)Complex. J. Am. Chem. Soc. 100, 3443–3448 (1978).

80. Chen, Y., Ruppel, J. V. & Zhang, X. P. Cobalt-catalyzed asymmetric cyclopropanation of electron-deficient olefins. J. Am. Chem. Soc. 129, 12074–12075 (2007).

81. Zhu, S., Xu, X., Perman, J. A. & Zhang, X. P. A general and efficient cobalt(II)-based

catalytic system for highly stereoselective cyclopropanation of alkenes with alpha-cyanodiazoacetates. J. Am. Chem. Soc. 132, 12796–12799 (2010).

82. Denmark, S. E., Stavenger, R. a, Faucher, A. & Edwards, J. P. Cyclopropanation with

Diazomethane and Bis ( oxazoline ) palladium ( II ) Complexes The design , evaluation , and understanding of catalysts. Organometallics 3263, 3375–3389 (1997).

83. Seidel, G. & Furstner, A. Structure of a reactive gold carbenoid. Angew. Chemie - Int. Ed. 53, 4807–4811 (2014).

84. Schädlich, J., Lauterbach, T., Rudolph, M., Rominger, F. & Hashmi, A. S. K. Gold-catalyzed

cyclization of propargylic diynes: Ethers vs acetates – Related products but different

pathways. J. Organomet. Chem. 795, 71–77 (2015).

85. Oxidation, G. A. A Non-Diazo Approach to r ‑ Oxo Gold Carbenes. 47, 877–888 (2015).

86. Haym, I. & Brimble, M. A. The Kulinkovich hydroxycyclopropanation reaction in natural product synthesis. Org. Biomol. Chem. 10, 7649–7665 (2012).

87. Wurtz, A. Ueber eine neue Klasse organischer Radicale. Ann. der Chemie und Pharm. 96, 364–375 (1855).

88. Wooster, C. B. Organo-Alkali Compounds. Chem. Rev. 11, 1–91 (1932).

89. Whitmore, F. C. & Zook, H. D. The Formation of Cyclopropanes from Monohalides. III.

Action of Sodium Alkyls on Aliphatic Chlorides. Relation to the Wurtz Reaction. J. Am. Chem. Soc. 64, 1783–1785 (1942).

90. Faler, C. A. & Joullié, M. M. The kulinkovich reaction in the synthesis of constrained N,N-dialkyl neurotransmitter analogues. Org. Lett. 9, 1987–1990 (2007).

91. Proctor, L. D. & Warr, A. J. Development of a Continuous Process for the Industrial

Generation of Diazomethane 1. Org. Process Res. Dev. 6, 884–892 (2002).

92. Deadman, B. J., Collins, S. G. & Maguire, A. R. Taming hazardous chemistry in flow: the

continuous processing of diazo and diazonium compounds. Chemistry 21, 2298–2308 (2015).

93. Clark, J. D., Shah, A. S. & Peterson, J. C. Understanding the large-scale chemistry of ethyl

diazoacetate via reaction calorimetry. Thermochim. Acta 392-393, 177–186 (2002).

94. Castano, B. et al. Continuous Flow Asymmetric Cyclopropanation Reactions Using Cu(I)

Complexes of Pc-L* Ligands Supported on Silica as Catalysts with Carbon Dioxide as Carrier. Green Chem. 3202–3209 (2014). doi:10.1039/c4gc00119b

95. Wurz, R. P. & Charette, A. B. Transition Metal-Catalyzed Cyclopropanation of Alkenes in

Water: Catalyst Efficiency and in Situ Generation of the Diazo Reagent. Org. Lett. 4, 4531–4533 (2002).

96. Ikeno, T., Nishizuka, A., Sato, M. & Yamada, T. Highly Enantioselective Cyclopropanation in

Alcoholic and Aqueous Solvents Catalyzed by Optically Active β-Ketoiminato Cobalt(II) Complex. Synlett 406–408 (2001). doi:10.1055/s-2001-11416

97. Niimi, T., Uchida, T., Irie, R. & Katsuki, T. Co(II)-salen-catalyzed highly cis- and

enantioselective cyclopropanation. Tetrahedron Lett. 41, 3647–3651 (2000).