Diphenyldiazomethane1

[883-40-9]  · C13H10N2  · Diphenyldiazomethane  · (MW 194.25)

(alkylating agent for carboxylic acids; reagent for the synthesis of diphenylcyclopropanes from alkenes1)

Physical Data: red solid, mp 29-32 °C.

Solubility: sol most organic solvents including ether, dichloromethane, petroleum ether, ethanol.

Preparative Methods: most commonly prepared by the oxidation of benzophenone hydrazone. The oxidants that are most frequently used are Mercury(II) Oxide2 and Nickel(II) Peroxide,3 though the use of Manganese Dioxide,4 Silver(II) Oxide,5 and Peracetic Acid6 have been reported. Typical reaction conditions involve addition of the oxidant to a solution of the hydrazone in a suitable solvent at rt. The oxidation requires 1-6 h to complete, depending on the conditions employed. Solvents that have been used are petroleum ether, diethyl ether and other ethereal solvents, and dichloromethane. When mercury(II) oxide is used, the addition of a basic ethanol solution speeds up the reaction and allows the oxidation to occur at a lower temperature. The reagent is typically not stored and is synthesized immediately prior to use. If the reagent is to be used for the esterification of a carboxylic acid, then an in situ oxidation can be employed using phenyliodine(III) diacetate ((Diacetoxyiodo)benzene)7 or peracetic acid with a trace of iodine.8 Interestingly, phenyliodine(III) diacetate provides a low yield of diphenyldiazomethane when used in the absence of a carboxylic acid, this has led the authors to suggest that the active alkylating agent is a species other than diphenyldiazomethane.

Handling, Storage, and Precautions: diphenyldiazomethane is potentially explosive. For this reason, extreme care must be observed in the synthesis and use of this compound with all operations being conducted behind a blast shield in a fume hood. There are also health related hazards that must be considered. Diazo compounds, as a class, are toxic and irritating and can be sensitizers. For a description of the hazards associated with this class of compounds, see the handling and storage precautions listed for Diazomethane.

Alkylation of Carboxylic Acids.

Diphenyldiazomethane is an effective reagent for the alkylation of carboxylic acids. As with other diazoalkanes, the reaction occurs upon addition to a carboxylic acid. The only byproduct is N2, thus reducing the workup to simple removal of the solvent. The reaction requires the protonation of the diazoalkane on carbon by the carboxylic acid to give the corresponding diphenylmethyl diazonium salt. This then undergoes nucleophilic attack by the carboxylate to give the diphenylmethyl ester and N2. This method has been used to protect carboxylic acids as their diphenylmethyl esters. Liberation of the acid can be accomplished by acid-catalyzed hydrolysis, or hydrogenolysis, making this a useful method for the protection of carboxylic acids which are base sensitive and cannot tolerate saponification. This reagent has been used for the esterification of free amino acids. Treatment of amino acids with diphenyldiazomethane does not lead to a reaction, due to the low acidity of the zwitterionic amino acid. However, the addition of a strong acid protonates the amino acid and thereby provides a reagent which will undergo alkylation with diphenyldiazomethane (eq 1).9 Both serine and cysteine provide high yields of the desired ester in this reaction, indicating that hydroxyl and thiol groups do not interfere with this reagent. If the free amino group is converted to an amide or a urethane, then the reaction will proceed without the addition of an equivalent of acid. Thus N-protected amino acids have been esterified by the in situ conversion of benzophenone hydrazone to diphenyldiazomethane using phenyliodine(III) diacetate.7 Common nitrogen protecting groups such as Boc, Cbz, Fmoc, and Troc are all effective in this reaction (eq 2). A wide range of substrates have been esterified with diphenyldiazomethane, including carbohydrates (eq 3)10 and b-lactam derivatives (eq 4).8 In the case of the b-lactam esterification, the diphenyldiazomethane was produced in situ by oxidation with peracetic acid. Interestingly, the acetic acid that is present as a contaminant in peracetic acid does not compete effectively for the diazo compound and a near stoichiometric amount of oxidant can be employed.

Cycloadditions.11

Diphenyldiazomethane undergoes cycloadditions with electron deficient alkenes to provide the corresponding diphenylpyrazolines. In the presence of a trace of acid the pyrazolines so obtained spontaneously undergo loss of N2 to provide the corresponding cyclopropane.12 This reaction is so sensitive to acid that base-washed glassware must be used in order to isolate the pyrazoline with certain substrates such as methyl acrylate (eq 5). If no acid is present, or if a mild base such as Triethylamine is added, then the pyrazolines must be heated in order to extrude N2. Thus treatment of the azlactone derivative shown in eq 6 with diphenyldiazomethane and triethylamine at 80 °C provides the diphenylcyclopropane derivative in good yield. Interestingly, in this case, reaction in the absence of base provides none of the cycloadduct. The reaction can also be promoted by photolysis (eq 7).13 The evidence suggests that this reaction proceeds by the extrusion of N2 to provide diphenylcarbene, which then undergoes addition to the alkene.

Formation of cyclopropanes with diphenyldiazomethane and transition metal catalysts has also been studied. Various transition metals can be used, including Cu, Pd, and Rh. The chemoselectivity of the reaction depends on the metal complex used. Thus cyclopropanation of the norbornene derivative shown in eq 8 with diphenyldiazomethane under Palladium(II) Chloride catalysis provides the cyclopropane derived from the internal alkene, whereas the same reaction with Rh2(OAc)2 provides the cyclopropane derived from the exocyclic alkene.14 Cyclopropanation of enamines with Copper(II) Acetylacetonate has also been reported (eq 9).15 This catalyst is less active and will not cyclopropanate ethyl vinyl ether or cyclohexene.

Acetal Formation.

Treatment of diphenyldiazomethane with 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone and an alcohol (or thiol) produces the corresponding benzophenone acetal (or thioacetal) (eq 10).16 If the starting alcohol component is a diol, the reaction produces a cyclic acetal. Macrocyclic crown ether acetals have been synthesized by this method in moderate to high yields (eq 11).17


1. (a) Regitz, M.; Maas, G. Diazo Compounds, Properties and Synthesis; Academic: Orlando, 1986. (b) Regitz, M.; Heydt, H. In 1,3-Dipolar Cycloaddition Chemistry; Padwa A., Ed.; Wiley: New York, 1984; Vol. 1, Chapter 4.
2. (a) Smith, L. I.; Howard, K. L. OSC 1955, 3, 351. (b) Miller, J. B.; JOC 1959, 24, 560.
3. Nakagawa, K.; Onoue, H.; Minami, K. CC 1966, 730.
4. Barakat, M. Z.; Abdel-Wahab, M. F.; El-Sadr, M. M. JCS 1956, 4685.
5. Schroeder, W.; Katz, L.; JOC 1954, 19, 718.
6. Adamson, J. R.; Bywood, R.; Eastlick, D. T.; Gallagher, G.; Walker, D.; Wilson, E. M. JCS(P1) 1975, 2030. This paper examines several other oxidants, as well as the effects of additives on these reactions.
7. Lapatsanis, L.; Milias, G.; Paraskewas, S. S 1985, 513.
8. Bywood, R.; Gallagher, G.; Sharma, G. K.; Walker, D. JCS(P1) 1975, 2019.
9. (a) Hisky, R. G.; Adams, J. B.; JACS 1965, 87, 3969. (b) Aboderin, A. A.; Delpierre, G. R.; Fruton, J. S. JACS 1965, 87, 5470. For the application of this method to more complex substrates, see (c) Stelakatos, G. C.; Zervas, L. JCS(C) 1966, 1191. (d) Taylor-Papadimitriou, J.; Yovanidis, C.; Paganou, A.; Zervas, L. JCS(C) 1967, 1830.
10. Hagedorn, H.-W.; Merton, H.; Brossmer, R. Carbohydr. Res. 1992, 236, 89.
11. For a review on cycloadditions of diazoalkanes, see Regitz, M.; Heydt, H. In 1,3-Dipolar Cycloaddition Chemistry, Padwa A., Ed.; Wiley: New York, 1984; Vol. 1, Chapter 4.
12. Jones, W. M.; Glenn, T. H.; Baarda, D. G. JOC 1963, 28, 2887.
13. Oku, A.; Yokoyama, T.; Harada, T. JOC 1983, 48, 5333.
14. Doyle, M. P.; Wang, L. C.; Loh, K-L. TL 1984, 37, 4087.
15. Nozaki, H.; Taklaya, H.; Noyori, R. T 1968, 24, 3655.
16. Oshima, T.; Nishioka, R.; Nagai, T. TL 1980, 21, 3919
17. (a) Oshima, T.; Nishioka, R.; Ueno, S.; Nagai, T. JOC 1982, 47, 2114. (b) Ueno, S.; Oshima, T.; Nagai, T. JOC 1984, 49, 4060.

Tarek Sammakia

University of Colorado, Boulder, CO, USA



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