Aziridine-2-carboxylic Acid1

[54080-06-7]  · C3H5NO2  · Aziridine-2-carboxylic Acid  · (MW 87.08)

(building block for chiral amino acids;2 can be used for synthesis of heterocycles3)

Physical Data: Li salt: mp 260-268 °C; methyl ester: bp 68 °C/11 mmHg; n20D 1.440; nitrile: bp 38 °C/0.1 mmHg; n20D 1.475; amide: mp 132-133 °C.

Solubility: esters and nitrile miscible with H2O, and virtually all organic solvents. Amide and metal salts are soluble in H2O, lower alcohols, DMF, DMSO.

Form Supplied in: (S)-form of Li salt as white solid.

Handling, Storage, and Precautions: free acid is not available, because of its low stability. The only stable aziridinecarboxylic acid is crystalline 3,3-dimethylaziridine-2-carboxylic acid.4 Salts, esters, and amides are stable.

Synthesis of Derivatives of Aziridine-2-Carboxylic Acids.

Racemic salts, esters, nitriles, and amides are prepared by modified Gabriel synthesis from the reaction of ammonia with vicinal dihalocarboxylic acids.5 Better yields were obtained by cyclization of b-hydrazinium propionates with base (eq 1).6

Various substituted aziridine-2-carboxylic acids have been prepared from the corresponding azirines with nucleophiles.7 This method is limited because optically pure aziridines and aziridinecarboxylic acids are not easily obtained. Amination of electron deficient alkenes with 3,3-pentamethyleneoxaziridine,8 diphenyl sulfimide,9 and O-(Mesitylsulfonyl)hydroxylamine10 yields aziridinemono- and dicarboxylic acids. Aziridinecarboxylic acids can be prepared from serine esters,11a but not from threonine esters,11b using diethoxytriphenylphosphorane. All these methods give racemic aziridines. However, recent investigations have led to chiral aziridines via chiral oxirane-2-carboxylic esters (eq 2),12a,b chiral cyclic sulfamidates (eq 3),11b D-ribose and D-lyxose,12c or functional group transformations of chiral aziridines.13 High cis stereoselectivity is observed when N-trimethylsilylimines react with Li enolates of a-halo esters (eq 4).14a Complete control of enantioselectivity can be achieved by proper choice of the metal enolate (eq 5).14b

Ring Cleavage of Aziridines.

Aziridinecarboxylic acids are important building blocks in peptide chemistry.15 They are easily incorporated using serine or threonine derivatives. Convenient syntheses of actinomycin D,15b dehydroamino acid containing peptides,15c and phosphopeptides have been achieved.15d Thiobenzoic acid has been utilized for the cleavage of the aziridine ring to prepare commercially expensive D-cysteine derivatives (eq 6).16

The reaction of aziridinecarboxylic acids with HCl2,5a,d or HF17 usually gives mixtures of isomers, depending on the conditions used. Unsubstituted aziridinecarboxylic acid derivatives form regioisomeric mixtures with indole18 and thiols,19 with the predominant product arising from attack at C-2. Zinc Trifluoromethanesulfonate is the only Lewis acid of a large number examined that promotes the reaction of (2R)- or (2S)-aziridine-2-carboxylates with indoles to obtain optically pure tryptophans (eq 7),20 albeit in only moderate yield. Only introduction of N-activating groups (acyl, alkoxycarbonyl, sulfonyl) make possible the SN2-type ring-opening reactions with various nucleophiles.2 Indole and Thiophenol lead to attack at C-3, but Azidotrimethylsilane leads to attack at C-2.

Ring opening of N-substituted aziridinecarboxylates with Wittig reagents2c (which provide stabilized phosphorus ylides) and organocuprate reagents2 may be useful for the preparation of amino acids.

Other Reactions.

Activated aziridines react with acetonitrile in the presence of Boron Trifluoride Etherate leading to imidazolines (eq 8),2 which yield a,b-diaminocarboxylic acids on standing. Various azabicyclic systems, 1,3-diazabicyclo-[3.1.0]hexan-4-ones, 1,3,4-triazabicyclo[4.1.0]heptan-5-ones (eqs 9 and 10),3 and 1-azabicyclo[3.3.0]oct-3-enes (eq 11),21 can be obtained from derivatives of aziridine-2-carboxylic acids.

The Michael addition of acetylenecarboxylates is stereospecific, leading to mostly (E) isomers.22 C-Lithioaziridines, accessible by tin-lithium exchange, are converted to aziridinecarboxylic acid derivatives (eq 12).23

Derivatives of aziridinemono-24 and dicarboxylic acids25 are halogenated with strong Cl+ donors like t-Butyl Hypochlorite. The latter gives optically active cis and trans isomers. 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) was used for the dehydrohalogenation step to yield azirine-2-carboxylic acids in low to moderate yields. Other bases (pyridine, triethylamine, KO-t-Bu, NaOMe, etc) and halogens (bromo derivatives) did not alter these results.

Related Reagents.


1. (a) Dermer, O. C.; Ham, G. E. Ethylenimine and Other Aziridines; Academic Press: New York, 1969. (b) Deyrup, J. A. Chem. Heterocycl. Compd., 1983, 42, 1. (c) Okawa, K.; Nakajima, K.; Tanaka, T. Yuki Gosei Kagaku Kyokaishi 1984, 42, 390.
2. (a) Legters, J.; Willems, J. G. H.; Thijs, L.; Zwanenburg, B. RTC 1992, 111, 59. (b) Legters, J.; Thijs, L.; Zwanenburg, B. RTC 1992, 111, 16. (c) Tanner, D. AG(E) 1994, 33, 599.
3. (a) Trapentsier, P. T.; Kalvinsh, I. Ya.; Liepinsh, E. E.; Lukevich, E. Ya.; Bremanis, G. A.; Eremeev, A. V. KGS (Engl. Transl.) 1985, 21, 646. (b) Trapentsier, P. T.; Kalvinsh, I. Ya.; Liepinsh, E. E.; Lukevits, E. Ya. KGS (Engl. Transl.) 1983, 19, 283.
4. Sammes, M. P.; Rahman, A. JCS(P1) 1972, 344.
5. (a) Kyburz, E.; Els, H.; Majnoni, St.; Englert, G.; von Planta, C.; Fuerst, A.; Plattner, P. A. HCA 1966, 49, 359. (b) Kawashima, N.; Higuchi, C.; Kato, T.; Mita, R.; Yamaguchi, A.; Nagai, S.; Takano, T. Eur. Patent 30 870, 1980 (CA 1981, 95, 187 053w). (c) Berlin, K. D.; Williams, L. G.; Dermer, O. C. TL 1968, 873. (d) Jaehnisch, K.; Weight, E.; Bosies, E. S 1992, 1211.
6. (a) Harvey, G. R. JOC 1968, 33, 887. (b) Giller, S. A.; Eremeev, A. V.; Kalvinsh, I. Ya.; Liepinsh, E. E.; Semenikhina, V. G. KGS (Engl. Transl.), 1975, 11, 1378. (c) Trapentsier, P. T.; Kalvinsh, I. Ya.; Liepinsh, E. E.; Lukevits, E. KGS (Engl. Transl.) 1983, 19, 982.
7. (a) Nishiwaki, T.; Fujiyama, F. S 1972, 569. (b) Szeimies, G.; Mannhardt, K.; Mickler, W. CB 1977, 110, 2922. (c) Nishiwaki, T.; Fujiyama, F. JCS(P1) 1972, 1456. (d) Sato, Y.; Yonezawa, Y.; Shiu, C. H 1982, 19, 1463.
8. Schmitz, E.; Janisch, K. KGS (Engl. Transl.) 1974, 10, 1432.
9. (a) Furukawa, N.; Oae, S. S 1976, 30. (b) Furukawa, N.; Yoshimura, T.; Ohtsu, M.; Akasaka, T.; Oae, S. T 1980, 36, 73.
10. Metra, P.; Hamelin, J. CC 1980, 1038.
11. (a) Kuyl-Yeheskiely, E.; Dreef-Tromp, C. M.; van der Marel, G. A.; van Boom, J. H. RTC 1989, 108, 314. (b) Kuyl-Yeheskiely, E.; Lodder, M.; van der Marel, G. A.; van Boom, J. H. TL 1992, 33, 3013.
12. (a) Legters, J.; Thijs, L.; Zwanenburg, B. RTC 1992, 111, 1. (b) Legters, J.; Thijs, L.; Zwanenburg, B. TL 1989, 30, 4881. (c) Dubois, L.; Dodd, R. H. T 1993, 49, 901.
13. Nakajima, K.; Takai, F.; Tanaka, T.; Okawa, K. BCJ 1978, 51, 1577.
14. (a) Cainelli, G.; Panunzio, M.; Giacomini, D. TL 1991, 32, 121. (b) Fujisawa, T.; Hayakawa, R.; Shimizu, M. TL 1992, 33, 7903.
15. (a) Tanaka, T.; Nakajima, K.; Maeda, T.; Nakamura, A.; Hayashi, N.; Okawa, K. BCJ 1979, 52, 3579. (b) Nakajima, K.; Tanaka, T.; Neya, M.; Okawa, K. BCJ 1982, 55, 3237. (c) Okawa, K.; Nakajima, K.; Tanaka, T.; Neya, M. BCJ 1982, 55, 174. (d) Okawa, K.; Yuki, M.; Tanaka, T. CL 1979, 1085. (e) Okawa, K.; Nakajima, K. Biopolymers, 1981, 20, 1811. (f) Tanaka, T.; Nakajima, K.; Okawa, K. BCJ 1980, 53, 1352.
16. Wakamiya, T.; Shimbo, K.; Shiba, T., Nakajima, K., Neya, M.; Okawa, K. BCJ 1982, 55, 3878.
17. (a) Ayi, A. I.; Guedj, R. JCS(P1) 1983, 2045. (b) Ayi, A. I.; Remli, M.; Guedj, F. JFC 1981, 18, 93. (c) Wade, T. N. JOC 1980, 45, 5328.
18. Styngach, E. P.; Kuchkova, K. I.; Efremova, T. M.; Semenov, A. A. KGS (Engl. Transl.) 1973, 9, 1378.
19. (a) Hata, Y.; Watanabe, M. T 1987, 43, 3881. (b) Ploux, O.; Caruso, M.; Chassaing, G.; Marquet, A. JOC 1988, 53, 3154.
20. Sato, K.; Kozikowski, A. P. TL 1989, 30, 4073.
21. Hudlicky, T.; Frazier, J. O.; Seoane, G.; Tiedje, M.; Seoane, A.; Kwart, L. D.; Beal, C. JACS 1986, 108, 3755.
22. Trapentsier, P. T.; Kalvinsh, I. Ya., Liepinsh, E. E.; Lukevits, E. Ya. KGS (Engl. Transl.) 1983, 19, 391.
23. Vedejs, E.; Moss, W. O. JACS 1993, 115, 1607.
24. Legters, J.; Thijs, L.; Zwanenburg, B. RTC 1992, 111, 75.
25. (a) Antolini, L.; Bucciarelli, M.; Forni, A.; Moretti, I.; Prati, F.; Torre, G. JCS(P2) 1992, 959. (b) Antolini, L.; Forni, A.; Moretti, I.; Schenetti, L.; Prati, F. JCS(P2) 1992, 1541.

Peteris Trapencieris

Latvian Institute of Organic Synthesis, Riga, Latvia

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