Synthesis of N-Protected Cyano Aziridines

Abstract

A concise and inexpensive route to 2-cyano aziridine-2-carboxylates and 2,2-dicyano aziridines is reported by reaction of the easily obtainable corresponding α,β-unsaturated nitriles with sulfonyloxycarbamates in the presence of calcium oxide.

aminations - Michael additions - nitriles - carbamates - ring closure

References

1a Bicker UW. In Immune Modulation Agents and their Mechanisms   Fenical RG. Chirigos MA. Marcel Dekker; New York and Basel: 1984.  p.447 

1b Iyengar BS. Dorr RT. Alberts DS. Hersh EM. Salmon SE. Remers WA. J. Med. Chem.  1999,  42:  510 

2 Iyengar BS. Dorr RT. Remers WA. J. Med. Chem.  2004,  47:  218 

3a Remers W, and Iyengar B. inventors; US  6476236.  ; Chem. Abstr. 2002, 137, 337772

3b Lopez-Berestein G, Remers WA, and Hersh EM. inventors; PCT Int. Appl.  2002041871.  ; Chem. Abstr. 2002, 137, 10970

3c Kitagawa S, Minafuji M, and Yokoi T. inventors; Jpn. Kokai Tokkyo Koho JP  61140561.  ; Chem. Abstr. 1987, 106, 50009

3d Bosies E, Berger H, Kampe W, Bicker U, and Grafe A. inventors; US  4410532.  ; Chem. Abstr. 1984, 100, 68151

3e Berger H, Gall R, Kampe W, Bicker U, and Kuhn R. inventors; Ger. Offen DE  2948832.  ; Chem. Abstr. 1981, 95, 115257

4 Boukhris S. Souizi A. Tetrahedron Lett.  2003,  44:  3259 

5a Tanner D. Angew. Chem., Int. Ed. Engl.  1994,  33:  599 

5b Li A.-H. Dai L.-X. Aggarwal VK. Chem. Rev.  1997,  97:  2341 

5c Stamm H. J. Prakt. Chem.  1999,  4:  319 

5d Atkinson RS. Tetrahedron  1999,  55:  1519 

5e McCoull W. Davis FA. Synthesis  2000,  1347 

5f Sweeney JB. Chem. Soc. Rev.  2002,  31:  247 

6a Goodridge TH. Huntress WT. Bratzell RP. Cancer Chemother. Rep.  1963,  26:  341 

6b Dermer OC. Ham GE. Ethyleneimine and other Aziridines   Academic Press; New York and London: 1969.  p.425 

7a Dauban P. Dodd RH. Tetrahedron Lett.  1998,  39:  5739 

7b Schirmeister T. Peric M. Bioorg. Med. Chem.  2000,  8:  1281 

8a Fioravanti S. Morreale A. Pellacani L. Tardella PA. Synthesis  2001,  1975 

8b Fioravanti S. Morreale A. Pellacani L. Tardella PA. J. Org. Chem.  2002,  67:  4972 

8c Colantoni D. Fioravanti S. Pellacani L. Tardella PA. Org. Lett.  2004,  6:  197 

9 Texier-Boullet F. Foucaud A. Tetrahedron Lett.  1982,  23:  4927 

10 Lwowski W. Maricich TJ. J. Am. Chem. Soc.  1965,  87:  3630 

11

Typical Experimental Procedure: All compounds were synthesized with a Carousel Reaction Station from Radleys Discovery Technologies (UK). The synthesis involved the following sequential steps. To the stirred solutions of 2.0 mmol of ethyl cyanoacetate or malononitrile in CH₂Cl₂, 2.4 mmol of aldehyde and 1.0 g of basic Al₂O₃ were added. Upon completion, reaction mixtures were filtered. To the so obtained unsaturated nitriles in CH₂Cl₂, CaO and nosyloxycarbamates were added in the amounts reported in Table [1] and Table [2] . After completion (TLC), the crude aziridines were filtered through plugs filled with silica gel using a 9:1 hexane/EtOAc mixture and obtained as pale yellow oils after solvent removal. Selected spectral data of new compounds. Compound 2a: IR (CCl₄): 2253, 1761, 1731 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 1.13 (t, J = 7.2 Hz, 3 H), 1.24 (t, J = 7.2 Hz, 3 H), 1.34 (t, J = 7.2 Hz, 3 H), 1.68-1.82 (m, 2 H), 3.08 (t, J = 6.6 Hz, 1 H), 4.09-4.23 (m, 2 H), 4.23-4.45 (m, 2 H). ¹³C NMR (75 MHz, CDCl₃): δ = 10.4, 14.0, 14.2, 23.3, 38.6, 51.3, 63.4, 64.1, 113.3, 157.2, 162.6. GC/MS: m/z (%) = 240 (9) [M⁺], 114 (24), 95 (46), 94 (12), 68 (100), 67 (10). HRMS (ES Q-TOF) calcd for C₁₁H₁₇N₂O₄ (M + H)⁺: 241.1188; found: 241.1200. Compound 2k: IR (CCl₄): 2253, 1756 cm^-1. ¹H NMR (200 MHz, CDCl₃): δ = 1.18 (t, J = 7.3 Hz, 3 H), 1.35 (t, J = 7.3 Hz, 3 H), 1.66-1.89 (m, 2 H), 3.19 (t, J = 6.6 Hz, 1 H), 4.22-4.48 (m, 2 H). ¹³C NMR (50 MHz, CDCl₃): δ = 9.9, 14.0, 23.1, 25.0, 52.4, 64.9, 110.3, 110.8, 156.2. GC/MS: m/z (%) = 193 (3) [M⁺], 121 (21), 94 (100), 93 (53), 83 (10), 68 (15), 67 (75), 66 (38), 65 (10), 56 (23), 54 (11). HRMS (ES Q-TOF) calcd for C₉H₁₂N₃O₂ (M + H)⁺: 194.0930; found: 194.0927.

12 Lwowski W. In Nitrenes   Lwowski W. John Wiley and Sons; New York: 1970.  Chap. 6.

13 Fioravanti S. Morreale A. Pellacani L. Tardella PA. Eur. J. Org. Chem.  2003,  4549 

14a Banks MR. Cadogan JIG. Gosney I. Hodgson PKG. Langridge-Smith PRR. Millar JRA. Taylor AT. J. Chem. Soc., Chem. Commun.  1995,  885 

14b N-Boc-protected O-sulfonyl hydroxylamine showed no predictable reactivity, see ref.¹³ and: Fioravanti S. Marchetti F. Morreale A. Pellacani L. Tardella PA. Org. Lett.  2003,  5:  1019 

15

9-Fluorenylmethyl nosyloxycarbamate (NsONHFmoc) was synthesized in 80% yield, starting from commercial 9-fluorenylmethyl N-hydroxycarbamate (HONHFmoc) and nosyl chloride following the standard procedure, see ref.¹⁰

16a De Kimpe N. Sulmon P. Verhé R. De Buyck L. Schamp N. J. Org. Chem.  1983,  48:  4320 

16b Charrier J. Foucaud A. Person H. Loukakou E. J. Org. Chem.  1983,  48:  481