Diethyl Azodicarboxylate1

[1972-28-7]  · C6H10N2O4  · Diethyl Azodicarboxylate  · (MW 174.16)

(functional group oxidations;5 dealkylation of amines;16 enophile;24 dienophile33)

Alternate Names: diethyl azidoformate; DEAD; DAD.2

Physical Data: bp 108-110 °C/15 mmHg; bp 211 °C/760 mmHg; fp 110 °C, d 1.11 g cm-3.

Solubility: sol CH2Cl2, Et2O, toluene.

Form Supplied in: orange liquid; 90% (technical grade) and 95% purity are commonly available, as is a 40% solution in toluene.

Preparative Method: although widely available, diethyl azodicarboxylate can be readily prepared from ethyl chloroformate and hydrazine, followed by oxidation of the resulting diethyl hydrazodicarboxylate.3

Purification: in most cases commercial samples are used without purification. Distillation is possible, but not recommended.

Handling, Storage, and Precautions: flammable; may produce toxic combustion byproducts. Heat and light sensitive; should be stored in dark containers under refrigerated conditions. These containers should also be vented periodically to reduce pressure. DAD has been reported to occasionally decompose violently when heated.3a,4 Use in a fume hood.

Introduction.

See Triphenylphosphine-Diethyl Azodicarboxylate for reactions involving the use of the combination of PPh3 and DAD.

Functional Group Oxidations by Dehydrogenation.

The strong electron withdrawing character of diethyl azodicarboxylate makes it suitable for certain types of oxidations. In general, diethyl hydrazocarboxylate is formed as a product of any oxidation. Primary and secondary alcohols are oxidized to aldehydes and ketones, respectively, although application of this method has been limited.5 Thiols, similarly, are oxidized to disulfides. Unsymmetrical disulfides are also available by a variation of this method.6 The oxidation of formamides to isocyanates has been accomplished at high temperatures with DAD, although the yields are frequently low and the method does not appear to be general.7

Arylhydroxylamines are readily converted into nitroso compounds with DAD at 0 °C (eq 1).8 One example of the conversion of an N,N-dimethylhydrazone to a nitrile has been reported.9 Sulfur-containing amino acids like methionine and S-ethylcysteine can be oxidized to their sulfoxides in virtually quantitative yields, although another reaction pathway occurs with most other thioethers.10 Thioethers and ethers usually react with DAD to yield a-hydrazo derivatives by hydrogen abstraction.11 The initial ether/DAD adducts can be formed thermally at 100 °C12 or photochemically at much lower temperatures.13

The oxidation of propargylic hydrazine derivatives with DAD to the corresponding propargylic diazenes (with subsequent spontaneous loss of N2) forms the basis of a powerful, yet mild, allene synthesis (eq 2).14

Dealkylation of Amines.

Treatment of a secondary or tertiary amine with diethyl azodicarboxylate in nonpolar solvents followed by acidic hydrolysis leads to the formation of monodealkylated amines.15 The mechanism of this reaction is believed to involve the formation of a triaza adduct (by Michael addition) followed by a two-step ylide rearrangement yielding an alkyl-substituted hydrazocarboxylate.12a Research on unsymmetrically substituted amines suggests that benzyl groups are more easily removed than alkyl groups; methyl groups are the hardest to remove except in cyclic amines like N-methylpiperidine (eq 3).16 The N-dealkylation of imines has also been reported.17

Purine Synthesis.

Aminopyrimidines and aminouracil derivatives can be converted into purines with diethyl azodicarboxylate in a number of closely related synthetic methods. Treatment of compound (1) with an aldehyde leads to the formation of imine (2), which is converted to purine (3) with DAD (eq 4).18 A number of researchers have applied variations of this approach.19

Treatment of 6-aminouracils20 or 6-aminopyrimidines21 (unsubstituted at the 5-position) with DAD leads to the initial formation of hydrazino Michael adducts. Treatment of these adducts with excess DAD leads to cyclization (eq 5).

This methodology has been applied to the synthesis of the antibiotic fervenulin22 and 8-dimethylaminotheophylline.23 In general, high temperatures (>100 °C) are required to complete the cyclization.

Pericyclic Reactions.

In general, a-carboxyazo compounds participate in a number of pericyclic processes as noted below.

Ene Reactions.

Diethyl azodicarboxylate reacts with most simple alkenes possessing an allyl hydrogen to yield the corresponding ene products, allylic hydrazocarboxylates.24 The uncatalyzed reaction takes place at moderate temperatures (80 °C) and bis-adducts can be formed if excess DAD is used.25 The use of Tin(IV) Chloride catalyzes the reaction, allowing for rapid reaction at -60 °C.26 This reaction proceeds with a surprising degree of selectivity for (E)-alkene geometry (eq 6). A particularly useful application of the ene reaction with DAD is in the synthesis of allyl amines, which are readily available by reduction of the initial adducts with Li/NH3.27

Cycloheptatriene reacts with DAD to afford exclusively ene products,28 as do the enols of some triazene derivatives.29 Allenes with alkyl substituents react with DAD to yield ene products in most cases (eq 7).30 Ene reactions with DAD have also been found to be a useful way of cleaving allyl ethers.31

Diels-Alder [4 + 2] Cycloadditions.

Except as noted below, diethyl azodicarboxylate reacts with conjugated dienes to yield [4 + 2] cycloadducts.32 When the diene moiety is a vinyl aromatic, cycloaddition with DAD is a powerful route for the preparation of annulated tetrahydropyridazine derivatives.33 Thus the indole derivative (4) reacts with DAD at rt to afford cycloadduct (5) (eq 8).34

The reaction of vinylfurans with DAD usually affords intractable mixtures;33b,e however, furan itself undergoes cycloaddition readily, provided suitable reaction conditions35 are employed to avoid decomposition of the reactive products.36 Oxazole derivatives readily participate in [4 + 2] cycloadditions with DAD.37 An asymmetric Diels-Alder reaction between DAD and pyridazin-3-ones facilitated by Baker's Yeast has been reported with ee's in the range of 9.1-62.7%.38 The reactions of a number of acyclic heterodienes with DAD have also been reported recently, including 2-aza-1,3-dienes,39 a,b-unsaturated thioketones,40 and 1-thia-3-aza-1,3-dienes.41 The quinodimethane derivatives of a number of heterocycles have been used in cycloadditions with DAD (eq 9).42

Competition Between Ene and Diels-Alder Reactions.

One area of considerable research centers on the reactivity of diethyl azodicarboxylate with conjugated dienes, systems in which two pericyclic reaction pathways are possible: Diels-Alder and ene. Although a number of researchers have investigated this area, no clear explanation for the preference of one pathway over another has emerged.43 In most cases, one reaction course seems to be strongly predominant. At this time, only generalizations are possible.

Acyclic 1,3-dienes, for example, in which alkyl groups are present at the terminus of the diene system, tend to give ene products with DAD, while those with internal alkyl substituents yield [4 + 2] adducts. 2,3-Dimethylbutadiene therefore reacts with DAD to give the cycloadduct in 94% yield, while 2,5-dimethyl-2,4-hexadiene gives only ene products.44,55 In cases where mixed substitution is present, predictive methods fail completely.46

Reactivities among cyclic dienes are equally complicated. Cyclopentadiene gives exclusively [4 + 2] adducts.47,48 1,3-Cyclohexadiene, however, has been reported to give solely ene products,49 but careful reexamination of this reaction reveals that 5-15% yields of [4 + 2] cycloadducts can be obtained.50 The reaction can be optimized to yield exclusively cycloadducts by altering experimental conditions.43,51 In steroidal systems, dienes in internal rings tend to undergo ene reactions,52 while dienes located in the terminal ring give mixtures where cycloadditions are the predominant pathways (eq 10).53 In cholesterol derivatives, reduction of the ene adducts with Li/EtNH2 is a convenient way to isomerize the diene system (eq 11).54 It has been reported that treatment with DAD will aromatize certain cyclohexadiene systems.44,55

Other Cycloadditions.

Diethyl azodicarboxylate has seen little application to other types of pericyclic reactions. DAD has been reported to undergo [2 + 2]56 cycloadditions with tetramethoxyallene.57 Two reports of [8 + 2] cycloadditions involving DAD have emerged recently, one involving 7-alkylidene-1,3,5-cyclooctatrienes58 and the other 3-methoxy-3a-methyl-3aH-indene.59 Indolizine, which is known to undergo [8 + 2] reactions with electron deficient alkenes,60 reacts with DAD exclusively in Michael fashion.61 A photochemically induced 1,3-dipolar cycloaddition involving DAD has been reported.62

Similar Reagents.

In most of the reactions involving diethyl azodicarboxylate, two closely related compounds can be employed instead. In many cases, 4-methyl-1,2,4-triazoline-3,5-dione (MTAD) (6) and 4-Phenyl-1,2,4-triazoline-3,5-dione (PTAD) (7) exhibit greater reactivity than DAD.15,30a,37b,63


1. Fahr, E.; Lind, H. AG(E) 1966, 5, 372.
2. The abbreviations DAD and DEAD have been frequently used to represent diethyl acetylenedicarboxylate as well. To avoid confusion, the abbreviation DAD will be used throughout to represent diethyl azodicarboxylate.
3. (a) Kauer; J. C. OSC 1963, 4, 411. (b) Moriarty, R. M.; Prakash, I.; Penmasta, R. SC 1987, 17, 409. (c) Rabjohn, N. OSC 1955, 3, 375. (d) Kenner, G. W.; Stedman, R. J. JCS 1952, 2089. (e) Curtius, T.; Heidenreich, K. B 1894, 27, 773. (f) Stollé, R.; Mampel, J.; Holzapfel, J.; Leverkus, K. C. B 1912, 45, 273. (g) Picard, J. P., Boivin, J. L. CJC 1951, 29, 223.
4. Fieser, L. F.; Fieser, M. F. FF 1967, 1, 245.
5. (a) Yoneda, F.; Suzuki, K.; Nitta, Y. JACS 1966, 88, 2328. (b) Yoneda, F.; Suzuki, K.; Nitta, Y. JOC 1967, 32, 727.
6. Mukaiyama, T.; Takahashi, K. TL 1968, 5907.
7. Fu, P. P.; Boyer, J. H. JCS(P1) 1974, 2246.
8. (a) Taylor, E. C.; Yoneda, F. CC 1967, 199. (b) Brill, E. E 1969, 25, 680.
9. Borras-Almenar, C.; Sepulveda-Arques, J.; Medio-Simon, M.; Pindur, U. H 1990, 31, 1927.
10. Axen, R.; Chaykovsky, M.; Witkop, B. JOC 1967, 32, 4117.
11. Woodward, R. B.; Huesler, J.; Gosteli, J.; Naegeli, P.; Oppolzer, W.; Ramage, R.; Ranganathan, S.; Vorbrügen, U. JACS 1966, 88, 852.
12. (a) Huisgen, R.; Jakob, F. LA 1954, 37, 590. (b) Diels, O.; Paquin, M. B 1913, 46, 2000.
13. Cookson, R. C.; Stevens, I. D. R.; Watts, C. T. CC 1965, 259.
14. Myers, A. G.; Finney, N. S.; Kuo, E. Y. TL 1989, 30, 5747.
15. Kenner, G. W.; Stedman, R. J. JCS 1952, 2089.
16. Smissman, E. E.; Makriyannis, A. JOC 1973, 38, 1652.
17. Doleschall, G.; Tóth, G. T 1980, 36, 1649.
18. Nagamatsu, T.; Yamasaki, H. H 1992, 33, 775.
19. (a) Kaplita, P. V.; Abreu, M. E.; Connor, J. R.; Erickson, R. H.; Ferkany, J. W.; Hicks, R. P.; Schenden, J. A.; Noronha-Blob, L.; Hanson, R. C. Drug. Dev. Res. 1990, 20, 429. (b) Yoneda, F.; Higuchi, M. H 1976, 4, 1759.
20. Yoneda, F.; Matsumoto, S.; Higuchi, M. CC 1975, 146.
21. Taylor, E. C.; Sowinski, F. JOC 1974, 39, 907.
22. Taylor, E. C.; Sowinski, F. JACS 1968, 90, 1374.
23. Walsh, E. B.; Nai-Jue, Z.; Fang, G.; Wamhoff, H. TL 1988, 29, 4401.
24. For reviews of the ene reaction, see: (a) Hoffmann, H. M. R. AG(E) 1969, 8, 556. (b) Boyd, G. V. In The Chemistry of Double-Bonded Functional Groups; Patai, S., Ed; Wiley: New York, 1989; Vol 2, Part 1, pp 477-526. (c) Oppolzer, W.; Snieckus, V. AG(E) 1978, 17, 476. (d) Mikami, K.; Shimizu, M. CR 1992, 92, 1021.
25. Thaler, W. A.; Franzus, B. JOC 1964, 29, 2226.
26. Brimble, M. A.; Heathcock, C. H. JOC 1993, 58, 5261.
27. Denmark, S. E.; Nicaise, O.; Edwards, J. P. JOC 1990, 55, 6219.
28. Cinnamon, J. M.; Weiss, K. JOC 1961, 26, 2644.
29. Bessiére-Chrétien, Y.; Serne, H. JHC 1974, 11, 317.
30. (a) Lee, C. B.; Taylor, D. R. JCS(P1) 1977, 1463. (b) Lee, C. B.; Newman, J. J.; Taylor, D. R. JCS(P1) 1978, 1161.
31. Ho, T.-L.; Wong, C. M. SC 1974, 4, 109.
32. For pertinent reviews of the Diels-Alder reaction see: (a) Gillis, B. T. In 1,4-Cycloaddition Reactions; Hamer, J., Ed.; Academic: New York, 1967; pp 143-177. (b) Needleman, S. B.; Changkuo, M. C. CR 1962, 62, 405. (c) Weinreb, S. M.; Staib, R. R. T 1982, 36, 3087.
33. Cycloadducts with (a) 1-phenyl-5-vinylpyrazole: Medio-Simón, M.; Alvarez de Laviada, M. J.; Seqúlveda-Arques, J. JCS(P1) 1990, 2749. (b) 2-(1-Trimethylsilyloxyvinyl)thiophene: Sasaki, T.; Ishibashi, Y.; Ohno, M. H 1983, 20, 1933. (c) 3-Vinylcoumarins and chromenes: Minami, T.; Matsumoto, Y.; Nakamura, S.; Koyanagi, S.; Yamaguchi, M. JOC 1992, 57, 167. (d) Cyanovinylthiophene: Abarca, B.; Ballesteros, R.; Soriano, C. T 1987, 43, 991. (e) Vinylpyridines: Jones, G.; Rafferty, P. T 1979, 35, 2027. (f) Jones, G.; Rafferty, P. TL 1978, 2731.
34. Pindur, U.; Kim, M.-H.; Rogge, M.; Massa, W.; Molinier, M. JOC 1992, 57, 910.
35. Yur'ev, Y. K.; Zefirov, N. S. JGU 1959, 29, 2916.
36. Barenger, P.; Levisalles, J. BSF(2) 1957, 704.
37. (a) Ibata, T.; Nakano, S.; Nakawa, H.; Toyoda, J.; Isogami, Y. BCJ 1986, 59, 433. (b) Shi, X.; Ibata, T.; Suga, H.; Matsumoto, K. BCJ 1992, 65, 3315. (c) Ibata, T.; Suga, H.; Isogami, Y.; Tamura, H.; Shi, X. BCJ 1992, 65, 2998.
38. Kakulapati, R. R.; Nanduri, B.; Yadavalli, V. D. N.; Trichinapally, N. S. CL 1992, 2059.
39. Barluenga, J.; González, F. J.; Fustero, S. TL 1990, 31, 397.
40. Motoki, S.; Matsuo, Y.; Terauchi, Y. BCJ 1990, 63, 284.
41. Barluenga, J.; Tomás, M.; Ballesteros, A.; López, L. A. TL 1989, 30, 6923.
42. (a) N-Benzoylindole-2,3-quinodimethane: Haber, M.; Pindur, U. T 1991, 47, 1925. (b) 4,5-Dihydro-4,5-dimethylene-1-phenyl-1,2,3-triazole: Mertzanos, G. E.; Stephanidou-Stephanatou, J.; Tsoleridis, C. A.; Alexandrou, N. E. TL 1992, 33, 4499. (c) 4,5-Dihydro-4,5-dimethylene-3-phenylisoxazole: Mitkidou, S.; Stephanidou-Stephanatou, J. TL 1991, 32, 4603. (d) Benzotheite: Jacob, D.; Peter-Neidermann, H.; Meier, H. TL 1986, 27, 5703.
43. Jenner, G.; Salem, R. B. JCS(P2) 1990, 1961.
44. Gillis, B. T.; Beck, P. E. JOC 1962, 27, 1947.
45. Measurement of the rate of reaction with 2,3-dimethylbutadiene in many solvents: Desimoni, G.; Faita, G.; Righetti, P. P.; Toma, L. T 1990, 46, 7951.
46. (a) Gillis, B. T.; Beck, P. E. JOC 1963, 28, 3177. (b) Jacobson, B. M.; Feldstein, A. C.; Smallwood, J. I. JOC 1977, 42, 2849.
47. This reaction is one of the oldest examples of the Diels-Alder reaction: Diels, O.; Blom, J. H.; Koll, W. LA 1925, 443, 242.
48. For representative applications of the [4 + 2] reaction of DAD and cyclopentadiene: (a) Kam, S.-T.; Portoghese, P. S.; Gerrard, J. M.; Dunham, E. W. JMC 1979, 22, 1402. (b) Lyons, B. A.; Pfeifer, J.; Peterson, T. H.; Carpenter, B. K. JACS 1993, 115, 2427. (c) Adam, W.; Finzel, R. JACS 1992, 114, 4563. (d) Wyvratt, M. J.; Paquette, L. A. TL 1974, 2433.
49. Pirsh, J.; Jörgl, J. B 1935, 68, 1324.
50. (a) Franzus, B.; Surridge, J. H. JOC 1962, 27, 1951. (b) Franzus, B. JOC 1963, 28, 2954.
51. Askani, R. B 1965, 98, 2551.
52. van der Gen, A.; Lakeman, J.; Gras, M. A. M. P.; Huisman, H. O. T 1964, 20, 2521.
53. Tomoeda, M.; Kikuchi, R.; Urata, M.; Futamura, T. CPB 1970, 18, 542.
54. Anastasia, M.; Fiecchi, A.; Galli, G. JOC 1981, 46, 3421.
55. (a) Mehta, G.; Kapoor, S. K. OPP 1972, 4, 257. (b) Medion-Simon, M.; Pindur, U. HCA 1991, 74, 430.
56. Review: Muller, L. L.; Hamer, J. 1,2-Cycloadditions: The Formation of Three- and Four-Membered Heterocycles; Wiley: New York, 1967.
57. Hoffmann, R. W. AG(E) 1972, 11, 324.
58. Ferber, P. H.; Gream, G. E.; Kirkbride, P. K. TL 1980, 21, 2447.
59. Gilchrist, T. L.; Rees, C. W.; Tuddenham, D. JSC(P1) 1981, 3214.
60. Galbraith, A.; Small, T.; Barnes, R. A.; Bockelheide, V. JACS 1961, 83, 453.
61. Masamura, M.; Yamashita, Y. H 1979, 12, 787.
62. Gilgren, P.; Heimgartner, H.; Schmid, H. HCA 1974, 57, 1382.
63. (a) Stickler, J. C.; Pirkle, W. H. JOC 1966, 31, 3444. (b) Cookson, R. C.; Galani, S. S. H.; Stevens, I. D. R. TL 1962, 615. (c) McLellan, J. F.; Mortier, R. M.; Orszulik, S. T.; Paton, R. M. CI(L) 1963, 94.

Eric J. Stoner

Abbott Laboratories, North Chicago, IL, USA



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