[334-88-3]  · CH2N2  · Diazomethane  · (MW 42.04)

(methylating agent for various functional groups including carboxylic acids, alcohols, phenols, and amides; reagent for the synthesis of a-diazo ketones from acid chlorides, and the cyclopropanation of alkenes1)

Physical Data: mp -145 °C; bp -23 °C.

Solubility: diazomethane is most often used as prepared in ether, or in ether containing a small amount of ethanol. It is less frequently prepared and used in other solvents such as dichloromethane.

Analysis of Reagent Purity: diazomethane is titrated2 by adding a known quantity of benzoic acid to an aliquot of the solution such that the solution is colorless and excess benzoic acid remains. Water is then added, and the amount of benzoic acid remaining is back-titrated with NaOH solution. The difference between the amount of acid added and the amount remaining reveals the amount of active diazomethane present in the aliquot.

Preparative Methods: diazomethane is usually prepared by the decomposition of various derivatives of N-methyl-N-nitrosoamines. Numerous methods of preparation have been described,3 but the most common and most frequently employed are those which utilize N-Methyl-N-nitroso-p-toluenesulfonamide (Diazald®; 1),4 1-Methyl-3-nitro-1-nitrosoguanidine (MNNG, 2),5 or N-methyl-N-nitrosourea (3).2

The various reagents each have their advantages and disadvantages, as discussed below. The original procedure6 for the synthesis of diazomethane involved the use of N-methyl-N-nitrosourea, and similar procedures are still in use today. An advantage of using this reagent is that solutions of diazomethane can be prepared without distillation,7 thus avoiding the most dangerous operation in other preparations of diazomethane. For small scale preparations (1 mmol or less) which do not contain any alcohol, a kit is available utilizing MNNG which produces distilled diazomethane in a closed environment. Furthermore, MNNG is a stable compound and has a shelf life of many years. For larger scale preparations, kits are available for the synthesis of up to 300 mmol of diazomethane using Diazald as the precursor. The shelf life of Diazald (about 1-2 years), however, is shorter than that of MNNG. Furthermore, the common procedure using Diazald produces an ethereal solution of diazomethane which contains ethanol; however, it can be modified to produce an alcohol-free solution. Typical preparations of diazomethane involve the slow addition of base to a heterogeneous aqueous ether mixture containing the precursor. The precursor reacts with the base to liberate diazomethane which partitions into the ether layer and is concomitantly distilled with the ether to provide an ethereal solution of diazomethane. Due to the potentially explosive nature of diazomethane, the chemist is advised to carefully follow the exact procedure given for a particular preparation. Furthermore, since diazomethane has been reported to explode upon contact with ground glass, apparatus which do not contain ground glass should be used. All of the kits previously mentioned avoid the use of ground glass.

Handling, Storage, and Precautions: diazomethane as well as the precursors for its synthesis can present several safety hazards, and must be used with great care.8 The reagent itself is highly toxic and irritating. It is a sensitizer, and long term exposure can lead to symptoms similar to asthma. It can also detonate unexpectedly, especially when in contact with rough surfaces, or on crystallization. It is therefore essential that any glassware used in handling diazomethane be fire polished and not contain any scratches or ground glass joints. Furthermore, contact with certain metal ions can also cause explosions. Therefore metal salts such as calcium chloride, sodium sulfate, or magnesium sulfate must not be used to dry solutions of the reagent. The recommended drying agent is potassium hydroxide. Strong light is also known to initiate detonation. The reagent is usually generated immediately prior to use and is not stored for extended periods of time. Of course, the reagent must be prepared and used in a well-ventilated hood, preferably behind a blast shield. The precursors used to generate diazomethane are irritants and in some cases mutagens and suspected carcinogens, and care should be exercised in their handling as well.

Methylation of Heteroatoms.

The most widely used feature of the chemistry of diazomethane is the methylation of carboxylic acids. Carboxylic acids are good substrates for reaction with diazomethane because the acid is capable of protonating the diazomethane on carbon to form a diazonium carboxylate. The carboxylate can then attack the diazonium salt in what is most likely an SN2 reaction to provide the ester. Species which are not acidic enough to protonate diazomethane, such as alcohols, require an additional catalyst, such as Boron Trifluoride Etherate, to increase their acidity and facilitate the reaction. The methylation reaction proceeds under mild conditions and is highly reliable and very selective for carboxylic acids. A typical procedure is to add a yellow solution of diazomethane to the carboxylic acid in portions. When the yellow color persists and no more gas is evolved, the reaction is deemed complete. Excess reagent can be destroyed by the addition of a few drops of acetic acid and the entire solution concentrated to provide the methyl ester.

Esterification of Carboxylic Acids and Other Acidic Functional Groups.

A variety of functional groups will tolerate the esterification of acids with diazomethane. Thus a,b-unsaturated carboxylic acids and alcohols survive the reaction (eq 1),9 as do ketones (eq 2),10 isolated alkenes (eq 3),11 and amines (eq 4).12

Other acidic functional groups will also undergo reaction with diazomethane. Thus phosphonic acids (eq 5)13 and phenols (eq 6)14 are methylated in high yields, as are hydroxytropolones (eq 7)15 and vinylogous carboxylic acids (eq 8).16 The origin of the selectivity in eq 6 is due to the greater acidity of the A-ring phenol.

Selective monomethylation of dicarboxylic acids has been reported using Alumina as an additive (eq 9).17 It is thought that one of the two carboxylic acid groups is bound to the surface of the alumina and is therefore not available for reaction. Carboxylic acids that are engaged as lactols will also undergo methylation with diazomethane to provide the methyl ester and aldehyde (eq 10).18

Methylation of Alcohols and Other Less Acidic Functional Groups.

As previously mentioned, alcohols require the addition of a catalyst in order to react with diazomethane. The most commonly used is boron trifluoride etherate (eq 11),19 but Tetrafluoroboric Acid has been used as well (eq 12).20 Mineral acids are not effective since they rapidly react with diazomethane to provide the corresponding methyl halides. Acids as mild as silica gel have also been found to be effective (eq 13).21 Monomethylation of 1,2-diols with diazomethane has been reported using various Lewis acids as promoters, the most effective of which is Tin(II) Chloride (eq 14).22

An interesting case of an alcohol reacting with diazomethane at a rate competitive with a carboxylic acid has been reported (eq 15).23 In this case, the tertiary structure of the molecule is thought to place the alcohol and the carboxylic acid in proximity to each other. Protonation of the diazomethane by the carboxylic acid leads to a diazonium ion in proximity to the alcohol as well as the carboxylate. These species then attack the diazonium ion at competitive rates to provide the methyl ether and ester. No reaction is observed upon treatment of the corresponding hydroxy ester with diazomethane, indicating that the acid is required to activate the diazomethane.

Amides can also be methylated with diazomethane in the presence of silica gel; however, the reaction requires a large excess of diazomethane (25-60 equiv, eq 16).24 The reaction primarily provides O-methylated material; however, in one case a mixture of O- and N-methylation was reported. Thioamides are also effectively methylated with this procedure to provide S-methylated compounds. Finally, amines have been methylated with diazomethane in the presence of BF3 etherate, fluoroboric acid,25 or copper(I) salts;26 however, the yields are low to moderate, and the method is not widely used.

The Arndt-Eistert Synthesis.

Diazomethane is a useful reagent for the one-carbon homologation of acid chlorides via a sequence of reactions known as the Arndt-Eistert synthesis. The first step of this sequence takes advantage of the nucleophilicity of diazomethane in its addition to an active ester, typically an acid chloride,27 to give an isolable a-diazo ketone and HCl. The HCl that is liberated from this step can react with diazomethane to produce methyl chloride and nitrogen, and therefore at least 2 equiv of diazomethane are typically used. The a-diazo ketone is then induced to undergo loss of the diazo group and insertion into the adjacent carbon-carbon bond of the ketone to provide a ketene. The ketene is finally attacked by water or an alcohol (or some other nucleophile) to provide the homologated carboxylic acid or ester. This insertion step of the sequence is known as the Wolff rearrangement28 and can be accomplished either thermally (eq 17)29 or, more commonly, by treatment with a metal ion (usually silver salts, eq 18),30 or photochemically (eq 19).31 It has been suggested that the photochemical method is the most efficient of the three.32 As eqs 18 and 19 illustrate, retention of stereochemistry is observed in the migrating group. The obvious limitations of this reaction are that there must not be functional groups present in the molecule which will react with diazomethane more rapidly than it will attack the acid chloride. Thus carboxylic acids will be methylated under these conditions. Furthermore, electron-deficient alkenes will undergo [2,3] dipolar cycloaddition with diazomethane more rapidly than addition to the acid chloride. Thus when the Arndt-Eistert synthesis is attempted on a,b-unsaturated acid chlorides, cycloaddition to the alkene is observed in the product. In order to prevent this, the alkene must first be protected by addition of HBr and then the reaction carried out in the normal way (eq 20).33 Cycloaddition to isolated alkenes, however, is not competitive with addition to acid chlorides.

Other Reactions of a-Diazo Ketones Derived from Diazomethane.

Depending on the conditions employed, the Wolff rearrangement may proceed via a carbene or carbenoid intermediate, or it may proceed by a concerted mechanism where the insertion is concomitant with loss of N2 and no intermediate is formed. In the case where a carbene or carbenoid is involved, other reactions which are characteristic of these species can occur, such as intramolecular cyclopropanation of alkenes. In fact, the reaction conditions can be adjusted to favor cyclopropanation or homologation depending on which is desired. Thus treatment of the dienoic acid chloride shown in eq 21 with diazomethane followed by decomposition of the a-diazo ketone with silver benzoate in the presence of methanol and base provides the homologated methyl ester. However, treatment of the same diazoketone intermediate with CuII salts provides the cyclopropanation products selectively.34 This trend is generally observed; that is, silver salts as well as photochemical conditions (eqs 18 and 19) favor the homologation pathway while copper or rhodium salts favor cyclopropanation.35 Using copper salts to decompose the diazo compounds, hindered alkenes as well as electron-rich aromatics can be cyclopropanated as illustrated in eqs 22 and 23,36,37 respectively.

In addition to these reactions, a-diazo ketones will undergo protonation on carbon in the presence of protic acids38 to provide the corresponding a-diazonium ketone. These species are highly electrophilic and can undergo nucleophilic attack. Thus if the proton source contains a nucleophile such as a halogen then the corresponding a-halo ketone is isolated (eq 24).39 However, if the proton source does not contain a nucleophilic counterion then the diazonium species may react with other nucleophiles that are present in the molecule, such as alkenes (eq 25)40 or aromatic rings (eq 26).41 Note the similarity between the transformations in eqs 26 and 23 which occur using different catalysts and by different pathways. Also, eq 26 illustrates the fact that other active esters will undergo nucleophilic attack by diazomethane.

Lewis acids are also effective in activating a-diazo ketones towards intramolecular nucleophilic attack by alkenes and arenes.42 The reaction has been used effectively for the synthesis of cyclopentenones (eq 27) starting with b,g-unsaturated diazo ketones derived from the corresponding acid chloride and diazomethane. It has also been used to initiate polyalkene cyclizations (eq 28). Typically, boron trifluoride etherate is used as the Lewis acid, and electron-rich alkenes are most effective providing the best yields of annulation products.

The Vinylogous Wolff Rearrangement.

The vinylogous Wolff rearrangement43 is a reaction that occurs when the Arndt-Eistert synthesis is attempted on b,g-unsaturated acid chlorides using copper catalysis. Rather than the usual homologation products, the reaction proceeds to give what is formally the product of a [2,3]-sigmatropic shift, but is mechanistically not derived by this pathway.44 The mechanism is thought to proceed by an initial cyclopropanation of the alkene by the a-diazo ketone to give a bicyclo[2.1.0]pentanone derivative. This compound then undergoes a fragmentation to a ketene alkene before being trapped by the solvent (eq 29). Inspection of the products reveals that they are identical with those derived from the Claisen rearrangement of the corresponding allylic alcohols, and as such this method can be thought of as an alternative to the Claisen procedure. However, the stereoselectivity of the alkene that is formed is not as high as is typically observed in the Claisen rearrangement (eq 30), and in some substrates the reaction proceeds with no selectivity (eq 31).

Insertions into Aldehyde C-H Bonds.

The a-diazo ketones (and esters) derived from diazomethane and an acid chloride (or chloroformate) will also insert into the C-H bond of aldehydes to give 1,3-dicarbonyl derivatives.45 The reaction is catalyzed by SnCl2, but some simple Lewis acids, such as BF3 etherate, also work. The reaction works well for aliphatic aldehydes, but gives variable results with aromatic aldehydes, at times giving none of the desired diketone (eq 32). Sterically hindered aldehydes will also participate in this reaction, as illustrated in eq 33 with the reaction of ethyl a-diazoacetate and pivaldehyde. In a related reaction, a-diazo phosphonates and sulfonates will react with aldehydes in the presence of SnCl2 to give the corresponding b-keto phosphonates and sulfonates.46 This reaction is a practical alternative to the Arbuzov reaction for the synthesis of these species.

Additions to Ketones.

The addition of diazomethane to ketones47 is also a preparatively useful method for one-carbon homologation. This reaction is a one-step alternative to the Tiffeneau-Demjanow rearrangement48 and proceeds by the mechanism shown in eq 34. It can lead to either homologation or epoxidation depending on the substrate and reaction conditions. The addition of Lewis acids, such as BF3 etherate, or alcoholic cosolvents tend to favor formation of the homologation products over epoxidation.

However, the reaction is limited by the poor regioselectivity observed in the insertion when the groups R1 and R2 in the starting ketone are different alkyl groups. What selectivity is observed tends to favor migration of the less substituted carbon,49 a trend which is opposite to that typically observed in rearrangements of electron-deficient species such as in the Baeyer-Villiger reaction. Furthermore, the product of the reaction is a ketone and is therefore capable of undergoing further reaction with diazomethane. Thus, ideally, the product ketone should be less reactive than the starting ketone. Strained ketones tend to react more rapidly and are therefore good substrates for this reaction (eq 35).50 This method has also found extensive use in cyclopentane annulation reactions starting with an alkene. The overall process begins with dichloroketene addition to the alkene to produce an a-dichlorocyclobutanone. These species are ideally suited for reaction with diazomethane because the reactivity of the starting ketone is enhanced due to the strain in the cyclobutanone as well as the a-dichloro substitution. Furthermore, the presence of the a-dichloro substituents hinders migration of that group and leads to almost exclusive migration of the methylene group. Thus treatment with diazomethane and methanol leads to a rapid evolution of nitrogen, and produces the corresponding a-dichlorocyclopentanone, which can be readily dehalogenated to the hydrocarbon (eq 36).51 Aldehydes will also react with diazomethane, but in this case homologation is not observed. Rather, the corresponding methyl ketone derived from migration of the hydrogen is produced (eq 37).

Cycloadditions with Diazomethane.

Diazomethane will undergo [3 + 2] dipolar cycloadditions with alkenes and alkynes to give pyrazolines and pyrazoles, respectively.52 The reaction proceeds more rapidly with electron-deficient alkenes and strained alkenes and is controlled by FMO considerations with the HOMO of the diazomethane and the LUMO of the alkene serving as the predominant interaction.53 In the case of additions to electron-deficient alkenes, the carbon atom of the diazomethane behaves as the negatively charged end of the dipole, and therefore the regiochemistry observed is as shown in eq 38. With conjugated alkenes, such as styrene, the terminal carbon has the larger lobe in the LUMO, and as such the reaction proceeds to give the product shown in eq 39. Pyrazolines are most often used as precursors to cyclopropanes by either thermal or photochemical extrusion of N2. In both cases the reaction may proceed by a stepwise mechanism with loss of stereospecificity. As shown in eq 40, the thermal reaction provides an almost random product distribution, while the photochemical reaction provides variable results ranging from 20:1 to stereospecific extrusion of nitrogen.54

Cyclopropanes can also be directly synthesized from alkenes and diazomethane, either photochemically or by using transition metal salts, usually Copper(II) Chloride or Palladium(II) Acetate, as promoters. The metal-mediated reactions are more commonly used than the photochemical ones, but they are not as popular as the Simmons-Smith procedure. However, they do occasionally offer advantages. Of the two processes, the Cu-catalyzed reaction produces a more active reagent55 which will cyclopropanate a variety of alkenes, including enamines as shown in eq 41.56 These products can then be converted to a-methyl ketones by thermolysis. The cyclopropanation of the norbornenol derivative shown in eq 42 was problematic using the Simmons-Smith procedure and provided low yields, but occurred smoothly using the CuCl2/diazomethane method.57

The Pd(OAc)2-mediated reaction can be used to cyclopropanate electron-deficient alkenes as well as terminal alkenes. Thus selective reaction at a monosubstituted alkene in the presence of others is readily achieved using this method (eq 43).58 The example shown in eq 44 is one in which the Simmons-Smith procedure failed to provide any of the desired product, whereas the current method provided a 92% yield of cyclopropane.59

In the case of the photochemical reaction, irradiation of diazomethane in the presence of cis-2-butene provides cis-1,2-dimethylcyclopropane with no detectable amount of the trans isomer (eq 45).60 This reaction is thought to proceed via a singlet carbene. However, if the same reaction is carried out via a triplet carbene, generated via triplet sensitization, then a 1.3:1 mixture of trans to cis dimethylcyclopropane is observed (eq 46).61 The yields in the photochemical reaction are typically lower than the metal-mediated processes, and are usually accompanied by more side products.

Additions to Electron-Deficient Species.

Diazomethane will also add to highly electrophilic species such as sulfenes or imminium salts to give the corresponding three-membered ring heterocycles. When the reaction is performed on sulfenes, the products are episulfones which are intermediates in the Ramberg-Backlund rearrangement, and are therefore precursors for the synthesis of alkenes via chelotropic extrusion of SO2. The sulfenes are typically prepared in situ by treatment of a sulfonyl chloride with a mild base, such as Triethylamine (eq 47).62 Similarly, the addition of diazomethane to imminium salts has been used to methylenate carbonyls.63 In this case, the intermediate aziridinium salt is treated with a strong base, such as n-Butyllithium, in order to induce elimination (eq 48).

Miscellaneous Reactions.

Diazomethane has been shown to react with vinylsilanes derived from a,b-unsaturated esters to provide the corresponding allylsilane by insertion of CH2 into the C-Si bond (eq 49).64 The reaction has been shown to be stereospecific, with cis-vinylsilane providing cis-allylsilanes; however, the mechanism of the reaction has not been defined. Diazomethane has also been used in the preparation of trimethyloxonium salts. Treatment of a solution of dimethyl ether and trinitrobenzenesulfonic acid with diazomethane provides trimethyloxonium trinitrobenzenesulfonate, which is more stable than the fluoroborate salt.65

Related Reagents.

2-Diazopropane; Diphenyldiazomethane; Phenyldiazomethane; 1-Diazo-2-propene.

1. (a) Regitz, M.; Maas, G. Diazo Compounds, Properties and Synthesis; Academic: Orlando, 1986. (b) Black, T. H. Aldrichim. acta 1983, 16, 3. (c) Pizey, J. S. Synthetic Reagents; Wiley: New York, 1974; Vol. 2, pp 65-142.
2. Arndt, F. OSC 1943, 2, 165.
3. Moore, J. A.; Reed, D. E. OSC 1973, 5, 351. Redemann, C. E.; Rice, F. O.; Roberts, R.; Ward, H. P. OSC 1955, 3, 244. McPhee, W. D.; Klingsberg, E. OSC 1955, 3, 119.
4. De Boer, Th. J.; Backer, H. J. OSC 1963, 4, 250. Hudlicky, M. JOC 1980, 45, 5377. See also Aldrich Chemical Company Technical Bulletins Number AL-121 and AL-131. Note that the preparation described in FF, 1967, 1, 191 is flawed and neglects to mention the addition of ethanol. Failure to add ethanol can result in a buildup of diazomethane and a subsequent explosion.
5. McKay, A. F. JACS 1948, 70, 1974. See also Aldrich Chemical Company Technical Bulletin Number AL-132.
6. von Pechman, A. CB 1894, 27, 1888.
7. Ref. 2, note 3.
8. For a description of the safety hazards associated with diazomethane, see: Gutsche, C. D. OR 1954, 8, 391.
9. Fujisawa, T.; Sato, T.; Itoh, T. CL 1982, 219.
10. Nicolaou, K. C.; Paphatjis, D. P.; Claremon, D. A.; Dole, R. E. JACS 1981, 103, 6967.
11. Fujisawa, T.; Sato, T.; Kawashima, M.; Naruse, K.; Tamai, K. TL 1982, 23, 3583.
12. Kozikowski, A. P.; Sugiyama, K.; Springer, J. P. JOC 1981, 46, 2426.
13. De, B.; Corey, E. J. TL 1990, 31, 4831. Macomber, R. S. SC 1977, 7, 405.
14. Blade, R. J.; Hodge, P. CC 1979, 85.
15. Kawamata, A.; Fukuzawa, Y.; Fujise, Y.; Ito, S. TL 1982, 23, 1083.
16. Ray, J. A.; Harris, T. M. TL 1982, 23, 1971.
17. Ogawa, H.; Chihara, T.; Taya, K. JACS 1985, 107, 1365.
18. Frimer, A. A.; Gilinsky-Sharon, P.; Aljadef, G. TL 1982, 23, 1301.
19. Chavis, C.; Dumont, F.; Wightman, R. H.; Ziegler, J. C.; Imbach, J. L. JOC 1982, 47, 202.
20. Neeman, M.; Johnson, W. S. OSC 1973, 5, 245.
21. Ohno, K.; Nishiyama, H.; Nagase, H. TL 1979, 20, 4405.
22. Robins, M. J.; Lee, A. S. K.; Norris, F. A. Carbohydr. Res. 1975, 41, 304.
23. Evans, D. S.; Bender, S. L.; Morris, J. JACS 1988, 110, 2506. For a similar example with the antibiotic lasalocid, see: Westly, J. W.; Oliveto, E. P.; Berger, J.; Evans, R. H.; Glass, R.; Stempel, A.; Toome, V.; Williams, T. JMC 1973, 16, 397.
24. Nishiyama, H.; Nagase, H.; Ohno, K. TL 1979, 20, 4671.
25. Muller, v. H.; Huber-Emden, H.; Rundel, W. LA 1959, 623, 34.
26. Seagusa, T.; Ito, Y.; Kobayashi, S.; Hirota, K.; Shimizu, T. TL 1966, 7, 6131.
27. In addition to acid chlorides, a-diazo ketones can be synthesized from carboxylic acid anhydrides; however, in this case one equivalent of the carboxylic acid is converted to the corresponding methyl ester. Furthermore, the anhydride can be formed in situ using DCC. See Hodson, D.; Holt, G.; Wall, D. K. JCS(C) 1970, 971.
28. For a review of the Wolff rearrangement, see: Meier, H.; Zeller, K.-P. AG(E) 1975, 14, 32.
29. Bergmann, E. D.; Hoffmann, E. JOC 1961, 26, 3555.
30. Clark, R. D. SC 1979, 9, 325.
31. Smith, A. B.; Dorsey, M.; Visnick, M.; Maeda, T.; Malamas, M. S. JACS 1986, 108, 3110.
32. Smith, A. B.; Toder, B. H.; Branca, S. J.; Dieter, R. K. JACS 1981, 103, 1996.
33. Rosenquist, N. R.; Chapman, O. L. JOC 1976, 41, 3326.
34. Hudliky, T.; Sheth, J. P. TL 1979, 20, 2667.
35. For a review of intramolecular reactions of a-diazo ketones, see: Burke, S. D.; Grieco, P. A. OR 1979, 26, 361.
36. Murai, A.; Kato, K.; Masamune, T. TL 1982, 23, 2887.
37. Iwata, C.; Fusaka, T.; Fujiwara, T.; Tomita, K.; Yamada, M. CC 1981, 463.
38. For a review on the reactions of a-diazo ketones with acid, see: Smith, A. B.; Dieter, R. K. T 1981, 37, 2407.
39. Ackeral, J.; Franco, F.; Greenhouse, R.; Guzman, A.; Muchowski, J. M. JHC 1980, 17, 1081.
40. Ghatak, U. R.; Sanyal, B.; Satyanarayana, G.; Ghosh, S. JCS(P1) 1981, 1203.
41. Blair, I. A.; Mander, L. N. AJC 1979, 32, 1055.
42. Smith, A. B.; Toder, B. H.; Branca, S. J.; Dieter, R. K. JACS 1981, 103, 1996. Smith, A. B.; Dieter, K. JACS 1981, 103, 2009. Smith, A. B.; Dieter, K. JACS 1981, 103, 2017.
43. Smith, A. B.; Toder, B. H.; Branca, S. J. JACS 1984, 106, 3995.
44. Smith, A. B.; Toder, B. H.; Richmond, R. E.; Branca, S. J. JACS 1984, 106, 4001.
45. Holmquist, C. R.; Roskamp, E. J. JOC 1989, 54, 3258. Padwa, A.; Hornbuckle, S. F.; Zhang, Z. Z.; Zhi L. JOC 1990, 55, 5297.
46. Holmquist, C. R.; Roskamp, E. J. TL 1992, 33, 1131.
47. For a review of this reaction, see: Gutsche, C. D. OR 1954, 8, 364.
48. For a review, see: Smith, P. A. S.; Baer, D. R. OR 1960, 11, 157.
49. House, H. O.; Grubbs, E. J.; Gannon, W. F. JACS 1960, 82, 4099.
50. Majerski, Z.; Djigas, S.; Vinkovic, V. JOC 1979, 44, 4064.
51. Greene, A. E.; Depres, J-P. JACS 1979, 101, 4003.
52. For a review, see: Regitz, M.; Heydt, H. In 1,3-Dipolar Cycloadditions Chemistry; Padwa, A.; Ed.; Wiley: New York, 1984; p 393.
53. For a discussion of the orbital interactions that control dipolar additions of diazomethane, see: Fleming, I. Frontier Molecular Orbitals and Organic Chemical Reactions; Wiley: New York, 1976; pp 148-161.
54. Van Auken, T. V.; Rienhart, K. L. JACS 1962, 84, 3736.
55. This is a very reactive reagent combination which will cyclopropanate benzene and other aromatic compounds. See: Vogel, E.; Wiedeman, W.; Kiefe, H.; Harrison, W. F. TL 1963, 4, 673. Muller, E.; Kessler, H.; Kricke, H.; Suhr, H. TL 1963, 4, 1047.
56. Kuehne, M. E.; King, J. C. JOC 1973, 38, 304.
57. Pincock, R. E.; Wells, J. I. JOC 1964, 29, 965.
58. Suda, M. S 1981, 714.
59. Raduchel, B.; Mende, U.; Cleve, G.; Hoyer, G. A.; Vorbruggen, H. TL 1975, 16, 633.
60. Doering, W. von E.; LaFlamme, P. JACS 1956, 78, 5447.
61. Duncan, F. J.; Cvetanovic, R. J. JACS 1962, 84, 3593.
62. Fischer, N.; Opitz, G. OSC 1973, 5, 877.
63. Hata, Y.; Watanabe, M. JACS 1973, 95, 8450.
64. Cunico, R. F.; Lee, H. M.; Herbach, J. JOM 1973, 52, C7.
65. Helmkamp, G. K.; Pettit, D. J. OSC 1973, 5, 1099.

Tarek Sammakia

University of Colorado, Boulder, CO, USA

Copyright 1995-2000 by John Wiley & Sons, Ltd. All rights reserved.