Phenyldiazomethane1

[334-88-3]  · C7H6N2  · Phenyldiazomethane  · (MW 118.15)

(alkylating agent for carboxylic acids and alcohols; synthesis of phenylaziridines and phenylcyclopropanes from imines and alkenes1)

Physical Data: liquid at room temperature, bp 37-41 °C/1.5 mmHg.

Solubility: sol most organic solvents, including ether, dichloromethane, methanol, acetonitrile.

Preparative Methods: prepared by several methods.2 The highest yielding and most commonly used method is vacuum pyrolysis of the sodium salt of the tosylhydrazone derived from benzaldehyde.3 In this preparation, the solid sodium salt is heated in the absence of solvent to a temperature of 220 °C at 0.1 mmHg. The red phenyldiazomethane that is produced is collected in a receiving flask cooled to -50 °C. It is then distilled at reduced pressure below room temperature and is typically used immediately.

Handling, Storage, and Precautions: can be stored at -80 °C for several months; however, storage at -20 °C leads to substantial decomposition after a few weeks. This material is also potentially explosive. For example, a solution which had been allowed to stand at room temperature for an hour underwent violent decomposition a few minutes after exposure to air. Explosions have also been reported when the distillation is carried out at temperatures higher than 30 °C. For these reasons, extreme care must be observed in the synthesis and use of this compound, with all operations being conducted behind a blast shield in a hood. Diazo compounds, as a class, are toxic and irritating and can be sensitizers. They must be used in a well ventilated fume hood and not come in contact with skin. For a description of the hazards associated with this class of compounds, see the handling and storage precautions listed for Diazomethane

Alkylation of Heteroatoms.

As with diazomethane, the most widely used feature of the chemistry of phenyldiazomethane is the alkylation of carboxylic acids. The reaction occurs upon addition of the diazoalkane to the carboxylic acid. The only byproduct is N2, thus reducing the workup to simple solvent removal. The reaction requires the protonation of the diazoalkane on carbon by the carboxylic acid to give the corresponding benzyl diazonium salt. This then undergoes nucleophilic attack by the carboxylate to give the benzyl ester and N2. This method has been used to protect carboxylic acids as their benzyl esters. Liberation of the acid can be accomplished by hydrogenolysis, making this a useful reagent for the protection of carboxylic acids which are base sensitive and cannot tolerate saponification to liberate the acid. This method is compatible with a variety of functional groups such as ketones, amides, alcohols (eq 1),4 imines, sulfides (eq 2),5 nitro groups (eq 3),6 and other nonacidic functional groups.

Other acidic functional groups are also alkylated with phenyldiazomethane. Thus, phosphoric acid esters (eq 4)7 and isoxazoles (eq 5)8 readily undergo esterification with phenyldiazomethane. In the case of the isoxazole, a mixture of N-alkylated and O-alkylated products is observed. As with diazomethane, less acidic functional groups require the addition of a catalyst to promote the reaction. Tetrafluoroboric Acid is an effective catalyst for the alkylation of alcohols and amines (eqs 6 and 7).9 Amines react more slowly under these conditions, thus enabling preferential reaction at the hydroxyl group of molecules containing both functional groups. Another catalyst which has been used to benzylate alcohols is Tin(II) Chloride.10 This reagent is only effective for the monoalkylation of 1,2-diols (the reaction can even be carried out in methanol as a cosolvent) and proceeds in moderate to low yield.

Cycloadditions.

As with other diazoalkanes, phenyldiazomethane undergoes cycloadditions with alkenes to provide pyrazolines.11 Upon heating, pyrazolines extrude N2 and provide the corresponding cyclopropane. In cases where the alkene is substituted with a TMS group, the product pyrazoline can undergo loss of TMS with concomitant extrusion of N2 to provide the corresponding phenyl substituted b,g-unsaturated ester (eq 8).12 This is not a general reaction of diazoalkanes but one which works well only with certain reagents, such as phenyldiazomethane. Phenyldiazomethane has also been used to synthesize cyclopropanes from alkenes. The reaction can be performed photochemically13 or by using metal complexes such as RhII or Zinc Bromide as catalysts.14 Interestingly, both reactions provide the cis-substituted cyclopropanes as the major product (eqs 9 and 10) in varying ratios. The metal-catalyzed reaction using RhII complexes works well only for very electron rich alkenes such as vinyl ethers, while the method using zinc halides typically utilizes an excess of the alkene. Finally, aziridines have been synthesized by the addition of phenyldiazomethane to imines in the presence of Zinc Iodide.15 The yields depend on the structure of the imine and range from poor (9%) to good (74%) with typical values being in the 50% range. This is not a general reaction of diazoalkanes and is not successful with diazomethane, ethyl diazoacetate, diazoacetonitrile, or dimethyl diazomalonate.

Homologation.

Phenyldiazomethane has been used in the homologation of aldehydes (eq 11). The reaction requires the addition of Lithium Bromide and gives good yields with a variety of aldehydes, with the exception of a,b-unsaturated aldehydes. Other lithium halides are not as effective as lithium bromide, and other alkali metals are ineffective.16


1. Regitz, M.; Maas, G. Diazo Compounds, Properties and Synthesis; Academic: Orlando, 1986.
2. For a discussion of other methods for the preparation of phenyldiazomethane, see: Ref. 3; Gutsch, C. D.; Jason, E. F. JACS 1956, 78, 1184; Bamford, W. R.; Stevens, T. S. JCS 1952, 4735; Closs, G. L.; Moss, R. A. JACS 1964, 86, 4042; Kaufman, G. M.; Smith, J. A.; Vander Stouw, G. G.; Shechter, H. JACS 1965, 87, 935; Yates, P.; Shapiro, B. L. JOC 1958, 23, 759.
3. Creary, X. OSC 1990, 7, 438.
4. Goulet, M. T.; Boger, J. TL 1990, 31, 4845.
5. Bose, A. K.; Manhas, M. S.; Chib, J. S.; Chawala, H. P. S.; Dayal, B. JOC 1974, 39, 2877.
6. Buchi, G.; DeShong, P. R.; Katsumura, S.; Sugimura, Y. JACS 1979, 101, 5084.
7. Engels, J. Bioorg. Chem. 1979, 8, 9.
8. Stork, G.; Hagedorn, A. A. JACS 1978, 100, 3609.
9. Liotta, L.; Ganem, B. TL 1989, 30, 4759; Liotta, L.; Ganem, B. Isr. J. Chem. 1991, 31, 215.
10. Christensen, L. F.; Broom, A. D. JOC 1972, 37, 3398.
11. Kano, K.; Scarpetti, D.; Warner, J.; Anseleme, J-P.; Springer, J. P.; Arison, B. H. CJC 1986, 64, 2211; Overberger, C. G.; Anseleme, J-P. JACS 1964, 86, 658.
12. Cunico, R. F.; Lee, H. M. JACS 1977, 99, 7613.
13. Closs, G. L.; Moss, R. A. JACS 1964, 86, 4042.
14. Doyle, M. P.; Griffin, J. H.; Bagheri, V.; Dorow, R. L. OM 1984, 3, 53; Goh, S. H.; Closs, L. E.; Closs, G. L. JOC 1969, 34, 25.
15. Bartnik, R.; Mloston, G. S 1983, 924.
16. Loeschorn, C. A.; Masayuki, N.; McCloskey, P. J.; Anselme, J-P. JOC 1983, 48, 4407.

Tarek Sammakia

University of Colorado, Boulder, CO, USA



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