Dibenzyl Azodicarboxylate1

[2449-05-0]  · C16H14N2O4  · Dibenzyl Azodicarboxylate  · (MW 298.30)

(efficient diene in the hetero Diels-Alder reaction with furanoid and pyranoid glycals;2 source of positive nitrogen, used in the preparation of a-hydrazino and a-amino acids from chiral lithium enolates3)

Alternate Name: DBAD.

Physical Data: mp 44-46 °C.

Solubility: sol CH2Cl2; insol cyclohexane.

Form Supplied in: orange solid.

Hetero Diels-Alder Reaction.

Dibenzyl azodicarboxylate adds to furanoid and pyranoid glycals,2 under irradiation at 350 nm in cyclohexane/CH2Cl2 solution, to provide [4 + 2] cycloadducts in high yields (eq 1). The photoisomerization4 of trans-DBAD to the cis isomer is essential to allow the cycloaddition reaction to take place (eq 2). This cycloaddition reaction is highly stereoselective; the adduct is usually obtained as a single isomer. The approach of DBAD to the glycal double bond is directed by the orientation of the C-3 substituent to give the cycloadduct with the 2-amino function trans to the C-3 substituent. The cycloaddition reaction of DBAD and glycals allows, in a single operation, the introduction of an amino moiety at C-2 of a carbohydrate and a latent nucleofugal group at the C-1 position. The dibenzyl adducts, namely dihydrooxadiazines, can be efficiently opened by various nucleophiles such as alcohols, hydrides, and acids, in the presence of an activator (eq 1). The resulting hydrazides can then be converted to their corresponding free amines under hydrogenolysis conditions. This methodology has been applied to the synthesis of simple and complex 2-amino saccharides.5 The cycloaddition reaction of DBAD with galactal and glucal was used for the synthesis of subunits of tunicamycin.6

It has been observed that the rate of cycloaddition is related to the electronic nature of the C-3 substituent.2a,b The cycloaddition reaction does not take place with substrates having electron-withdrawing groups at the C-3 position.

Under thermal conditions, DBAD undergoes a [4 + 2] cycloaddition reaction with derivatized 2-oxazolones. The reaction shows moderate diastereofacial selectivity (eq 3).7

Synthesis of a-Hydrazino and a-Amino Acids.

DBAD is an efficient source of electrophilic nitrogen and has been used in the preparation of a-hydrazino and a-amino acids.3 Aminated carboximides were obtained from the condensation of (Z)-lithium enolates of chiral carboximides with DBAD (eq 4). The selectivity observed in this amination reaction was generally greater than 85% de, depending on the bulk of the side chain (Me < CH2Ph < i-Pr). Similar results were obtained in studies with other azodicarboxylates such as Di-t-butyl Azodicarboxylate.8 The aminated products were then converted to their corresponding a-hydrazino acids under hydrogenolysis conditions (Palladium on Carbon, H2) and then to their free amines with Raney Nickel/H2.

1. Böshagen, H.; Ullrich, J. CB 1959, 92, 1478.
2. (a) Leblanc, Y.; Labelle, M. In Cycloaddition Reactions in Carbohydrate Chemistry; Guiliano, R. M., Ed.; ACS Symp. Ser., 1992, 494, 81. (b) Leblanc, Y.; Fitzsimmons, B. J. TL 1989, 30, 2889. (c) Leblanc, Y.; Fitzsimmons, B. J.; Springer, J. P.; Rokach, J. JACS 1989, 111, 2995. (d) Fitzsimmons, B. J.; Leblanc, Y.; Rokach, J. JACS 1987, 109, 285. (e) Fieser, M. FF 1990, 15, 111.
3. Trimble, L. A.; Vederas, J. C. JACS 1986, 108, 6397.
4. (a) Firl, J.; Sommer, S. TL 1972, 4713. (b) Firl, J.; Sommer, S. TL 1971, 4193. (c) Firl, J.; Sommer, S. TL 1970, 1929. (d) Koerner von Gustorf, E.; White, D. V.; Kim, B.; Hess, D.; Leitich, J. JOC 1970, 35, 1155.
5. Fitzsimmons, B. J.; Leblanc, Y.; Chan, N.; Rokach, J. JACS 1988, 110, 5229.
6. Danishefsky, S.; DeNinno, S. L.; Chen, S. H.; Boisvert, L.; Barbachyn, M. JACS 1989, 111, 5810.
7. Matsunaga, H.; Ishizuka, T.; Marubayashi, N.; Kunieda, T. CPB 1992, 40, 1077.
8. (a) Gennari, C.; Columbo, L.; Bertolini, G. JACS 1986, 108, 6394. (b) Evans, D. A.; Britton, T. C.; Dorow, R. L.; Dellaria, J. F. JACS 1986, 108, 6395. (c) Evans, D. A.; Britton, T. C.; Dorow, R. L.; Dellaria, J. F. Jr. T 1988, 44, 5525.

Yves Leblanc

Merck Frosst Centre for Therapeutic Research, Kirkland, Québec, Canada

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