bromosuccinimide and acetonitrile in the presence of a Lewis
acid catalyst. They have also reported conversion of cyclo-
hexene to the corresponding chloroacetamide using N-chloro-
succinimide (NCS) acetonitrile in the presence of a Lewis
acid; however, it requires longer reaction time (20 h). For
fluoroamination reactions, selectfluor has been used11 ex-
tensively as a source of fluorine. 2-Deoxy or 2-substituted
1-amino sugar derivatives are precursors for the synthesis
of pharmaceutically and biologically important 2-deoxy-N-
glycopeptides.12 It has also been reported that sugar modified
nucleosides are promising candidates for treatment of cancer
and AIDS.13 Although 2-iodo or 2-bromo glycosyl amino
derivatives are readily obtained from glycals,9 there is not
much biological significance associated with these products.
On the other hand, 2-fluoro and 2-chloro glycosyl amino
derivatives are biologically more important.14 For example,
2-deoxy-2-chloro-ribonucleotide was one of the first inhibi-
tors of enzyme ribonucleotide reductase,15 an important target
for treating viral diseases, AIDS, and cancer.
As part of an ongoing research program12c,16 in function-
alizing glycals toward the synthesis of biologically important
molecules, we proposed to introduce a new method to
procure 2-nitro-1-amino sugars with the hope that the 2-nitro
group could be converted into a variety of other function-
alities.17 Further, the nitro group could be reductively
removed under radical conditions to form 2-deoxy sugar
derivatives. A few years ago, we introduced18 a new reagent
system, namely ClSiMe3-AgNO3-CrO3 for one-pot conver-
sion of olefins into R-nitro ketones. This reagent system is
believed to be a source of nitronium ion. We therefore
anticipated that a new and somewhat similar reagent system,
oxalyl chloride-AgNO3-CH3CN, could introduce a nitro
group and acetamido group onto olefins as shown in Scheme
1 (path A). However, what we observed was formation of
Scheme 1. Tentative Mechanism for Chloroamidation of
Olefins
the corresponding 2-deoxy-2-chloro-1-acetamido sugars from
glycals (path B) indicating that path A, involving a nitronium
ion, was not operational. In view of the importance of sugar-
derived chlorinated molecules (vide supra) we explored this
chemistry in synthesizing a variety of sugar-derived vicinal
chloro amines and chloro N-peptides and studied the cyto-
toxicity of some of them.
In initial experiments, the cyclohexene 6 was treated with
the reagent system oxalyl chloride-silver nitrate in acetoni-
trile, and after optimization it was found that 1.5 equiv of
oxalyl chloride and 1.5 equiv of silver nitrate in acetonitrile
when mixed at -20 °C followed by the addition of
cyclohexene gave 1-chloro-2-acetamido cyclohexane in 80%
yield. The stereochemistry of the product was found to be
(9) (a) Castro, M. D.; Marzabadi, C. H. Tetrahedron Lett. 2004, 45, 6501.
(b) Boschi, A.; Chiappe, C.; De Rubertis, A.; Russe, M. F. J. Org Chem.
2000, 65, 8470. (c) Kumar, V.; Ramesh, N. G. Tetrahedron 2006, 62, 1877.
(d) Owens, J. M.; Yung, B. K. S.; Hill, D. C.; Petillo, P. A. J. Org. Chem.
2001, 66, 1484. (e) Kim, H. M.; Kim, J. J.; Danishefsky, S. J. J. Am. Chem.
Soc. 2001, 123, 35. (f) Spassova, M. K.; Bornmann, W. G.; Ragupathi, G.;
Sukenick, G.; Livingston, P. O.; Danishefsky, S. J. J. Org. Chem. 2005,
70, 3383. (g) Garcia, J. I.; Mateo, F. H.; Flores, F. G. C.; Gonzalez, F. S.
J. Org. Chem. 2004, 69, 202. (h) Raghvan, S.; Reddy, S. R.; Tony, K. A.;
Kumar, C. N.; Nanda, S. Synlett, 2001, 851. (i) Griffith, D. A.; Danishefsky,
S. J. J. Am. Chem. Soc. 1996, 118, 9526.
Table 1. Chloroamidation of Olefins
(10) Yeung, Y. Y.; Gau, X.; Corey, E. J. J. Am. Chem. Soc. 2006, 128,
9644.
(11) Nyffeler, P. T.; Duron, S. G.; Burkart, M. D.; Vincet, S. P.; Wong,
C. H. Angew. Chem., Int. Ed. 2005, 44, 192.
(12) (a) Kaneshiro, C. M.; Michael, K. Angew. Chem., Int. Ed. 2006,
45, 1077. (b) He, Y.; Hinklin, R. J.; Chang, J.; Kiessling, L. L. Org. Lett.
2004, 6, 4479. (c) Reddy, B. G.; Madhusudanan, K. P.; Vankar, Y. D. J.
Org. Chem. 2004, 69, 2630. (d) Wagner, M.; Dziadek, S.; Kunz, H. Chem.
Eur. J. 2003, 9, 6018. (e) Peluso, S.; Imperiali, B. Tetrahedron Lett. 2001,
42, 2085. (f) Arsequell, G.; Valencia, G. Tetrahedron: Asymmetry 1999,
10, 3045.
(13) Cerqueira, N. M. F. S. A.; Fernandes, P. A.; Ramos, M. J. J. Phys.
Chem. B 2006, 110, 21272.
(14) Cerqueira, N. M. F. S. A.; Pereira, S.; Fernandes, P. A.; Ramos,
M. J. Curr. Med. Chem. 2005, 12, 1283.
(15) Robins, M. J.; Wnuk, S. F.; Thirrig, A. E. H.; Samano, M. C. J.
Am. Chem. Soc. 1996, 118, 11341.
(16) (a) Rawal, G. K.; Rani, S.; Madhusudanan, K. P.; Vankar Y. D.
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2006, 47, 8667. (c) Jayakanthan, K.; Vankar, Y. D. Org. Lett. 2005, 7,
5441. (d) Reddy, B. G.; Vankar, Y. D. Angew. Chem., Int. Ed. 2005, 44,
2001 and references cited therein.
trans19 which indicated that this reagent system is a source
of chloronium ion (Cl+). The scope of this chloroamidation
process was explored by using different olefins like dihydro-
pyran, trans-stilbene, styrene, and methyl acrylate (Table 1)
(17) Feuer, H.; Nielsen, A. T. In Nitro Compounds; VCH Publishers
Inc.: New York, 1990.
(18) Shahi, S. P.; Gupta, A.; Pitre, S. V.; Reddy, M. V. R.; Kumare-
swaran, R.; Vankar, Y. D. J. Org. Chem. 1999, 64, 4509.
(19) Trans stereochemistry of the cyclohexene derivative 6 was confirmed
by comparison of its spectral data as well as its M.P.
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