10
J . Org. Chem. 1996, 61, 10-11
Sch em e 1
Syn th esis of F u n ction a lized N-Alk yl
Heter ocycles fr om Keton es by a Sequ en tia l
Rin g Exp a n sion /Nu cleop h ilic Ad d ition
P r ocess
Vijaya Gracias, Gregory L. Milligan, and
J effrey Aube´*
Department of Medicinal Chemistry, University of Kansas,
Lawrence, Kansas 66045-2506
Received November 3, 1995
The utility of the Schmidt reaction1 in heterocyclic
chemistry has been expanded by the discovery of variants
that use alkyl azides as nucleophiles.2 The intermolecu-
lar reaction of alkyl azides with ketones was initially
limited by the types of ketones and azides that would
react in high yield.2b This ceiling was largely lifted by
the realization that 1,2- or 1,3-hydroxy azides were
superior to simple alkyl azides as Schmidt reaction
partners.2i In these reactions, initial hemiketal forma-
tion rendered the azide addition step intramolecular
(Scheme 1). The primary reaction products were imi-
nium ethers 2a or 2b that could be transformed into
N-hydroxyalkyl lactams by the addition of hydroxide
ion.
This report details how the scope of this sequence can
be extended by exploiting the ambident electrophilicity3
of iminium ethers like 2a and 2b. N-Alkyloxazolinium
salts, usually prepared by alkylation of lactams, imides,
or oxazolines, can be reacted with heteroatom or carbon
nucleophiles4 via the two pathways indicated in Scheme
1; a related pathway operates in the cationic polymeri-
zation5 of oxazolines. Kinetic attack occurs at the
formally positive carbon giving a neutral intermediate
(path a) that can render product but that may also revert
to the relatively stable 2. Thus, the reversible addition
of nucleophiles at this center may ultimately result in
attack at the distal end of the N-O tether, as shown in
path b.
Of course, one of these pathways was already demon-
strated in the aqueous base workup leading to lactam
products 3, with HO- as the nucleophile.2i Iminium
ethers 2a and 2b were prepared from cyclohexanone as
previously reported and treated with a variety of nucleo-
philic reagents. Most heteroatom-based nucleophiles
gave functionalized N-alkyl lactams by reacting through
path b (Table 1). In this way, azides, alcohols, ethers,
sulfides, and halides could be directly obtained from the
activated lactams formed in the Schmidt reaction. In
addition, carbon-carbon bonds were formed in good
yields by the addition of nitrile or the anion of bis-
(phenylsulfonyl)methane.
* To whom correspondence should be addressed: Tel: (913) 864-
4496. Fax: (913) 864-5326. E-mail: jaube@rx.pharm.ukans.edu.
(1) Reviews of the Schmidt reaction: (a) Wolff, H. Org. React. N. Y.
1946, 3, 307-336. (b) Smith, P. A. S. In Molecular Rearrangements;
de Mayo, P., Ed.; J ohn Wiley and Sons: New York, 1963; Vol. 1; pp
457-591. (c) Banthorpe, D. V. In The Chemistry of the Azido Group;
Patai, S., Ed.; J ohn Wiley and Sons: London, 1971; pp 397-330. (d)
Abramovich, R. A.; Kyba, E. P. In The Chemistry of the Azido Group;
Patai, S., Ed.; J ohn Wiley and Sons: London, 1971; pp 221-329. (e)
Kyba, E. P. In Azides and Nitrenes: Reactivity and Utility; Scriven,
E. F. V., Ed.; Academic: Orlando, 1984; pp 2-34.
(2) (a) Aube´, J .; Milligan, G. L. J . Am. Chem. Soc. 1991, 113, 8965-
8966. (b) Aube´, J .; Milligan, G. L.; Mossman, C. J . J . Org. Chem. 1992,
57, 1635-1637. (c) Pearson, W. H.; Bergmeier, S. C.; Williams, J . P.
J . Org. Chem. 1992, 57, 3977-3987. (d) Pearson, W. H.; Scheryantz,
J . M. J . Org. Chem. 1992, 57, 6783-6789. (e) Pearson, W. H.;
Schkeryantz, J . M. Tetrahedron Lett. 1992, 33, 5291-5294. (f) Aube´,
J .; Rafferty, P. S.; Milligan, G. L. Heterocycles 1993, 28, 1141-1147.
(g) Pearson, W., H; Walavalkar, R.; Schkeryantz, J . M.; Fang, W.-k.;
Blickensdorf, J . D. J . Am. Chem. Soc. 1993, 115, 10183-10194. (h)
Pearson, W. H.; Fang, W.-k.; Kampf, J . W. J . Org. Chem. 1994, 59,
2682-2684. (i) Gracias, V.; Milligan, G. L.; Aube´, J . J . Am. Chem. Soc.
1995, 117, 8047-8048. (j) Pearson, W. H.; Fang, W.-k. J . Org. Chem.
1995, 60, 4960-4961. (k) Molina, P.; Alca´ntara, J .; Lo´pez-Leonardio,
C. Synlett 1995, 363-364.
The regiochemistry of carbon nucleophilic addition
depended on the nature of the anion-stabilizing groups.6
Thus, in contrast to the result in entry 5 (Table 1), NaCH-
(CN)2 reacted only via path a followed by elimination,
yielding 5 (Scheme 2). As previously reported,6c the anion
of dimethyl malonate gave reaction by path b but afforded
O-alkylation material. Reductions also utilized path a
to lead directly to the fully reduced tertiary amines.
Besides the sodium borohydride reaction shown, catalytic
hydrogenation conditions also afforded 6 in 87% yield.
These mild conditions stand in contrast to the usual
reductions of lactams with lithium aluminum hydride or
borane reagents. In these reactions, the iminium ethers
were reacted without isolation; see, for example, the
direct formation of 7 from 2-methoxycyclohexanone in
64% overall yield. In general, the reactions given in
Table 1 could also be carried out on iminium ethers
(3) Hu¨nig, S. Angew. Chem., Int. Ed. Engl. 1964, 3, 548-560.
(4) (a) Wiley, R. H.; Bennett, L. L., J r. Chem. Rev. 1949, 44, 447-
476. (b) Meyers, A. I.; Collington, E. W. J . Am. Chem. Soc. 1970, 92,
6676-6678. (c) Frump, J . A. Chem. Rev. 1971, 71, 483-505. (d)
Forestie`re, A.; Sillion, B. J . Heterocycl. Chem. 1980, 17, 1381-1383.
(e) Brunel, S.; Fixari, B.; Le Perchec, P.; Scillion, B. Tetrahedron Lett.
1985, 26, 1013-1014. (f) Brunel, S.; Chevalier, Y.; Le Perchec, P.
Tetrahedron 1989, 45, 3363-3370.
(5) (a) Kagiya, T.; Matsuda, T. J . Macromol. Sci., Chem. 1971, A5(8),
1265-1285. (b) Kagiya, T.; Matsuda, T.; Nakato, M.; Hirata, R. J .
Macromol. Sci., Chem. 1972, A6(8), 1631-1652. (c) Saegusa, T.; Ikeda,
H.; Fujii, H. Polym. J . 1972, 3, 176-180.
(6) (a) Dreme, M.; Le Perchec, P.; Garapon, J .; Sillion, B. Tetrahe-
dron Lett. 1982, 23, 73-74. (b) Dreme, M.; Brunel, S.; Llauro, M. F.;
Le Perchec, P. Tetrahedron 1984, 40, 349-354. (c) Dreme, M.; Brunel,
S.; Le Perchec, P. Tetrahedron 1984, 40, 4947-4953.
0022-3263/96/1961-0010$12.00/0 © 1996 American Chemical Society