Di-t-butyl Azodicarboxylate1

[870-50-8]  · C10H18N2O4  · Di-t-butyl Azodicarboxylate  · (MW 230.26)

(reagent for the electrophilic amination2 of enolates; Diels-Alder dienophile)

Alternate Names: DBAD; TBAD.

Physical Data: mp 90-92 °C.

Solubility: sol most organic solvents.

Form Supplied in: yellow solid; widely available.

Preparative Method: a detailed description is given in Organic Syntheses.3

Handling, Storage, and Precautions: light sensitive; more stable than its methyl or ethyl analogs.

Reactions with Carbon Nucleophiles.

Although the electrophilic reactivity of azodicarboxylates towards C-nucleophiles was recognized long ago,4 the first reaction of di-t-butyl azodicarboxylate (1) with an organometallic reagent was reported only in 1961. The addition of t-butylmagnesium chloride to DBAD, to give the protected t-butylhydrazine (2) in 50% yield (eq 1), has been described.5 This type of reaction is not limited to aliphatic Grignard reagents; aryllithium and aryl Grignard reagents (3) add analogously to DBAD to afford arylhydrazines (5) after final deprotection (eq 2).6

Although in principle other azodicarboxylates give the same reaction, the advantage of using DBAD is the ease of removal of the protecting group. The t-butoxycarbonyl (Boc) group is readily cleaved by Trifluoroacetic Acid or Hydrogen Chloride, whereas the harsher acidic or basic conditions required for the removal of methyl or ethyl analogs can interfere with the hydrazine moiety. A comparison of anionic attack on DBAD and related azodicarboxylates with subsequent deprotection is available (eq 3).7 Deprotonation of the chiral carboximides (6) followed by reaction with azodicarboxylates produces the hydrazino acid precursors (7) in high yields. Dimethyl and diethyl azodicarboxylate give only moderate diastereoselectivity, whereas the dibenzyl and di-t-butyl derivatives afford excellent stereoselection. The phenylalanine-derived carboximide (8) adds DBAD upon deprotonation with Lithium Diisopropylamide in a similar fashion (eq 4).8

Heterocycles (7) and (9) can each be cleaved to either (S)-a-hydrazino acids (10) or, if desired, to (S)-a-amino acids (11), both of which are obtained in enantiomerically pure form within detection limits (eq 5). Since the enantiomers of (6) and (8) are readily available, (R)-a-amino acids and (R)-a-hydrazino acids can also be made. This approach has allowed generation of [14C]phenylalanine9 and 2-adamantylalanine.10 An elegant application of this methodology is seen in the synthesis of (R)- and (S)-piperazic acids (eq 6).11 Deprotonation and reaction of the carboximide (12), derived from 5-bromovaleric acid, with DBAD produces an aza anion capable of displacing bromide to give, upon final deprotection, (S)-piperazic acid (15) as a single isomer. Its enantiomer was made using the antipode of the chiral auxiliary. The asymmetric synthesis of 1,6-dihydropiperazic acid has been elaborated in a similar way; however, its TFA salt was reported to be unstable.12

Several related syntheses of either a-amino acids or a-hydrazino acids have been developed, all of them using electrophilic amination of enolates to construct the stereogenic center at the a-carbon. 10-Sulfonamidoisobornyl esters (16) are useful tools for such processes.13 These esters can be selectively deprotonated at -78 °C and converted to their corresponding O-silyl ketene acetals, which upon Lewis acid promoted addition of DBAD yield the amination products (17) in high yields (eq 7). These compounds are generally obtained with high stereoselectivity, and are diastereomerically pure after chromatography. a-Amino acids are synthesized from these precursors via a four-step procedure; the amino acids (18) are nearly enantiomerically pure (ee &egt; 95%).

(1R,2S)-N-Methylephedrine is also a suitable chiral auxiliary for the diastereoselective amination of O-silyl ketene acetals.14 The silyl ketene acetals (19), derived from corresponding esters and N-methylephedrine, react smoothly with a preformed DBAD/Titanium(IV) Chloride complex to generate the hydrazino derivatives (20) (eq 8). The major diastereomers are chromatographically separated and converted to their corresponding a-hydrazino acids (21) (from which a single isomer can also be obtained by recrystallization) or to the a-amino acids (22), respectively. Both (21) and (22) are obtained in good yields as single enantiomers.

b-Hydroxy esters (23), available in both enantiomeric forms, can be deprotonated at the a-carbon without protection of the hydroxy group. These react with DBAD to give an easily separable mixture of syn- and anti-adducts. The anti-adduct (24) is formed in up to 88% de (eq 9).15 These adducts are very useful tools since compounds with anti (allo) stereochemistry are not easily accessible by other established methods for amino acid synthesis. As in the previous cases, either amino acids or hydrazino acids are obtainable via several deprotection steps. One compound, (26; R = Me), was synthesized as a single enantiomer, but the others were initially prepared as racemic mixtures. Subsequently, as an application of this method, D-ribo-C18-phytosphingosine was stereoselectively synthesized.15b Closely related processes were published afterwards and show analogous results.16

(S)-Trifluorothreonine methyl ester (28) has been synthesized from (27) using a related approach (eq 10).17 Although an additional bulky t-butyl group is required for stereoinduction, this method gives the amination products with complete control of stereochemistry. Subsequent deprotection and hydrogenation reactions yield the desired product (28). A diastereoselective synthesis of (-)-2,3-diaminobutanoic acid from b-aminobutanoic acid has also been described (eq 11).18 The synthesis of enantiomerically pure b-aminobutanoic acid is described in the same contribution, but the amination reaction of the protected derivative (29) with DBAD was performed on the racemic mixture, giving only one diastereomer (30) as a mixture of enantiomers. Several deprotection steps produced the desired (-)-2,3-diaminobutanoic acid as its diastereomerically pure hydrochloride (32).

Methyl dithioacetate (33), upon deprotonation with n-Butyllithium, is a suitable nucleophile for reaction with DBAD (eq 12).19 The amination product (34), a precursor of a-amino thioacids, was obtained in 57% yield along with 15% of a side product resulting from attack of DBAD at the sulfur atom of the intermediate thioenolate.

The procedures described above demonstrate the potential for electrophilic amination of enolates with DBAD to yield various a-amino acids or a-hydrazino acids with high optical purity. However, other condensations with carbanions have been published recently. After deprotonation with n-BuLi, the 1,2-oxazine (35) attacks DBAD with high g-selectivity to produce (36) (eq 13).20 Carbonyl compounds and D2O also show high g-selectivity, whereas alkyl halides react primarily in the a-position. The oxazine (36) is useful as a precursor of a 1,4-diamino compound.

Reactions with Sulfur Nucleophiles.

Thiols readily react with DBAD to form sulfenohydrazides.21 For example, t-butyl thiol (37) adds to the azodicarboxylate upon treatment with catalytic amounts of sodium alcoholate to give the sulfenohydrazide (38). These compounds can transfer a thio moiety to thiols. For example, attack by a second sulfur nucleophile, such as cysteine (39) (eq 14), leads to t-butyl thiocysteine (40). The overall result is a selective (and reversible) protection of cysteine at sulfur, thus providing an alternative to the commonly used protecting groups (e.g. trityl). A useful application is the synthesis of unsymmetrical cystine peptides (44) (eq 15).21 A cysteine-containing peptide (41) is activated by DBAD, and the resulting sulfenohydrazide (42) is attacked by a different cysteine-containing peptide (43), to link two peptide chains via a disulfide. Several biologically important unsymmetrical cystine peptides and derivatives were prepared by this procedure.

Sulfides (45) react with azodicarboxylates to yield adducts (47), where the addition has not proceeded in the manner described above, but rather to the carbon adjacent to the sulfur (eq 16).22 Some of these reactions require the addition of Dibenzoyl Peroxide and/or UV irradiation to initiate the process. The reactivity order for hydrogens adjacent to sulfur atoms appears to be CH2CO2Me > benzyl > methyl, thus suggesting a carbanionic intermediate or transition state. The authors consider that association of the sulfide with the azo linkage might be accompanied by proton transfer to generate the ylide (46) in one step. Subsequent rearrangement furnishes the functionalized sulfides (47), providing a method to oxidize carbon atoms adjacent to sulfur; thus (47) can be considered a compound with a masked carbonyl group.

Diels-Alder23 and Related Cycloadditions.

Azodicarboxylates have been long known to react with dienes in a [4 + 2] cycloaddition.24 DBAD undergoes a variety of cycloadditions, e.g. Diels-Alder reactions, but is somewhat less reactive in these processes than its methyl or ethyl counterparts due to the bulky Boc groups. However, since the two Boc groups are more easily cleaved in the later steps of a reaction sequence than methoxycarbonyl groups, DBAD is still an attractive dienophile. In addition, DBAD has a higher thermal stability than its methyl or ethyl analog (e.g. dimethyl azodicarboxylate has to be distilled behind a safety shield). The condensation of cyclopentadiene with diethyl azodicarboxylate has been known since 1925, but the reaction can be done with DBAD in a similar manner (eq 17).5,25 Several substituents and an additional keto function do not affect cycloadditions with azodicarboxylates, but interestingly, the intermediate Diels-Alder adducts rearrange and give oxadiazines (52) (eq 18).26

o-Quinoidal bismethylene arenes like (54) are very reactive dienes, which are prepared in situ via iodide-induced 1,4-elimination, and can be trapped with various dienophiles. The use of DBAD in this case leads to pyridazines (55) (eq 19).27 A related reaction affords tetrahydroindeno[1,2-d]pyridazine (58). The process involves a similar 1,4 elimination of the precursor (56) followed by subsequent cycloaddition (eq 20).28

The thermal valence isomerization between the benzenoid structure (59) and the o-quinoidal structure (60) allows a range of [8 + 2] cycloadditions; condensation with DBAD leads to 2H-3,4-dihydro-1,2,3-benzothiadiazine (61) (eq 21).29 2-Vinyl-1,4-benzodioxin (62) undergoes facile Diels-Alder reaction with DBAD to produce the hydrazino aminal derivative (63) (eq 22).30 3-Vinylpyridines, 4-vinylpyridines, and 2-vinylthiophene undergo similar cycloadditions with DBAD.31

Mitsunobu-Type Reactions.

One of the most common reactions for dimethyl and diethyl azodicarboxylate is the Mitsunobu reaction.1b Surprisingly, very little is known about Mitsunobu reactions using DBAD. Only one publication, studying the mechanism of the Mitsunobu reaction, describes a comparative study of several azodicarboxylates, concluding that such reactions can be performed using DBAD.32 A Mitsunobu-type reaction has been published recently, starting from alcohol (64). Treatment with triphenylphosphine and DBAD gives the hydrazine derivative (65) in one step (eq 23), presumably by a displacement reaction of the intermediate hydrazide anion and the triphenylphosphine/alcohol adduct.33

Related Reagents.

Diethyl Azodicarboxylate.

1. For reviews on azodicarboxylates, see: (a) Fahr, E.; Lind, H. AG(E) 1966, 5, 372. (b) Mitsunobu, O. S 1981, 1.
2. For reviews on aminating reagents, see: (a) Tamura, Y.; Minamikawa, J.; Ikeda, M. S 1977, 1. (b) Erdik, E.; Ay, M. CRV 1989, 89, 1947.
3. Carpino, L. A.; Crowley, P. J. OS 1964, 44, 18.
4. (a) Diels, O.; Behncke, H. CB 1924, 57, 653. (b) Diels, O. LA 1922, 429, 1.
5. Carpino, L. A.; Terry, P. H.; Crowley, P. J. JOC 1961, 26, 4336.
6. Demers, J. P.; Klaubert, D. H. TL 1987, 28, 4933.
7. Trimble, L. A.; Vederas, J. C. JACS 1986, 108, 6397.
8. (a) Evans, D. A.; Britton, T. C.; Dorow, R. L.; Dellaria, J. F. JACS 1986, 108, 6395. (b) Evans, D. A.; Britton, T. C.; Dorow, R. L.; Dellaria, J. F., Jr. T 1988, 44, 5525.
9. Lee, H. T.; Hicks, J. L.; Johnson, D. R. J. Labelled Compd. Radiopharm. 1991, 29, 1065.
10. Tilley, J. W.; Danho, W.; Shiuey, S. J.; Kulesha, I.; Sarabu, R.; Swistok, J.; Makofske, R.; Olson, G. L.; Chiang, E.; Rusiecki, V. K.; Wagner, R.; Michalewsky, J.; Triscari, J.; Nelson, D.; Chiruzzo, F. Y.; Weatherford, S. Int. J. Pept. Protein Res. 1992, 39, 322.
11. Hale, K. J.; Delisser, V. M.; Manaviazar, S. TL 1992, 33, 7613.
12. Schmidt, U.; Riedl, B. CC 1992, 1186.
13. (a) Oppolzer, W.; Moretti, R. HCA 1986, 69, 1923. (b) Oppolzer, W.; Moretti, R. T 1988, 44, 5541.
14. Gennari, C.; Colombo, L.; Bertolini, G. JACS 1986, 108, 6394.
15. (a) Guanti, G.; Banfi, L.; Narisano, E. T 1988, 44, 5553. (b) Guanti, G.; Banfi, L.; Narisano, E. TL 1989, 30, 5507.
16. (a) Genêt, J. P.; Juge, S.; Mallart, S. TL 1988, 29, 6765. (b) Greck, C.; Bischoff, L.; Ferreira, F.; Pinel, C.; Piveteau, E.; Genêt, J. P. SL 1993, 475.
17. Gautschi, M.; Seebach, D. AG(E) 1992, 31, 1083.
18. Estermann, H.; Seebach, D. HCA 1988, 71, 1824.
19. Hartke, K.; Brutsche, A.; Gerber, H. D. LA 1992, 927.
20. Unger, C.; Zimmer, R.; Reissig, H.-U.; Würthwein, E.-U. CB 1991, 124, 2279.
21. (a) Romani, S.; Moroder, L.; Goehring, W.; Scharf, R.; Wuensch, E.; Barde, Y. A.; Thoenen, H. Int. J. Pept. Protein. Res. 1987, 29, 107. (b) Romani, S.; Moroder, L.; Wuensch, E. Int. J. Pept. Protein Res. 1987, 29, 99. (c) Wuensch, E.; Moroder, L.; Romani, S. Hoppe-Seyler's Z. Physiol. Chem. 1982, 363, 1461. (d) Wuensch, E.; Romani, S. Hoppe-Seyler's Z. Physiol. Chem. 1982, 363, 449.
22. Wilson, G. E., Jr.; Martin, J. H. E. JOC 1972, 37, 2510.
23. For selected reviews on Diels-Alder reactions, see: (a) Oppolzer, W. AG(E) 1977, 16, 10. (b) Brieger, G.; Bennett, J. N. CRV 1980, 80, 63. (c) Fallis, A. G. CJC 1984, 62, 183.
24. Diels, O.; Blom, J. H.; Koll, W. LA 1925, 443, 242.
25. Stout, D. M.; Takaya, T.; Meyers, A. I. JOC 1975, 40, 563.
26. (a) Mackay, D.; Pilger, C. W.; Wong, L. L. JOC 1973, 38, 2043. (b) Dao, L. H.; Mackay, D. CJC 1978, 56, 1724.
27. Dyker, G.; Kreher, R. P. CB 1988, 121, 1203.
28. Lahousse, H.; Martens, H. J.; Toppet, S.; Hoornaert, G. J. JOC 1982, 47, 2001.
29. Jacob, D.; Peter-Niedermann, H.; Meier, H. TL 1986, 27, 5703.
30. Lee, T. V.; Leigh, A. J.; Chapleo, C. B. SL 1989, 30.
31. (a) Jones, G.; Rafferty, P. T 1979, 35, 2027. (b) Jones, G.; Rafferty, P. TL 1978, 30, 2731.
32. von Itzstein, M.; Jenkins, I. D. AJC 1983, 36, 557.
33. Stanek, J.; Frei, J.; Mett, H.; Schneider, P.; Regenass, U. JMC 1992, 35, 1339.

Michael Klinge & John C. Vederas

University of Alberta, Edmonton, AB, Canada

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