at temperatures above 35 °C.6 By way of contrast, the
corresponding 1,3-dioxane 7 has been reported to be more
thermally stable.7 Given that both precursor alkylbromides
are commercially available, we began our investigations by
examining the efficiency of the addition of each Grignard
reagent to readily available Bn-substituted aziridine 8; our
results are outlined in Table 1.
deprotection-cyclization protocol. This process was found
to proceed efficiently with both acetal intermediates 9 and
10 to give the tetrahydropyridine 11, without loss of
enantiopurity over the two steps (Scheme 1).These studies
Scheme 1
Table 1. Optimization of Aziridine Ring Openinga
highlighted that both Grignard reagents were suitable for the
formation of tetrahydropyridines. However, the milder cy-
clization conditions employed in the 1,3-dioxolane system
prompted us to investigate the scope of the annelation
entry
Grignard
additive
yield, %
1
2
3
4
5
6, 1.5 equiv
6, 5.0 equiv
7, 5.0 equiv
7, 5.0 equiv
6, 2.0 equiv
-
-
-
33
80
22a
100
98
Table 2. Stepwise Annelation of Aziridines
20 mol % CuBr‚DMS
20 mol % CuBr‚DMS
a Reaction heated at reflux for 16 h.
Preliminary studies with the dioxolane-based reagent 6
were discouraging: a low yield of product 9 was observed
which could only be improved by the use of a large excess
of Grignard reagent (entries 1 and 2). Surprisingly, the
dioxane-based reagent 7 proved to be inferior and a low yield
of product was obtained even when a large excess of
Grignard was used. Paquette and co-workers have reported
that the dioxane reagent addition to enones can be promoted
by Cu catalysis.8 Indeed, the addition of 20 mol % of CuBr‚
DMS improved the efficiency of the Grignard addition to
the aziridine and provided the desired product in quantitative
yield (entry 4). Pleasingly, these conditions were also
applicable to the dioxolane-based reagent, and further
investigations showed that 9 could be furnished in high yield
when only 2 equiv of Grignard reagent 6 were employed
(entry 5).
We next turned our attention to the piperidine-forming
reaction and opted to perform an in situ acid-catalyzed
(3) (a) Craig, D.; McCague, R.; Potter, G. A.; Williams, M. R. V. Synlett
1998, 55. (b) Craig, D.; McCague, R.; Potter, G. A.; Williams, M. R. V.
Synlett 1998, 58. (c) Adelbrecht, J.-C.; Craig, D.; Dymock, B. W.;
Thorimbert, S. Synlett 2000, 467. (d) Adelbrecht, J.-C.; Craig, D.;
Thorimbert, S. Tetrahedron Lett. 2001, 42, 8369. (e) Adelbrecht, J.-C.; Craig,
D.; Fleming, A. J.; Martin, F. M. Synlett 2005, 2643.
(4) For a review of the chemistry of three-carbon homologating agents
see: Stowell, J. C. Chem. ReV. 1984, 84, 409.
(5) Bu¨chi Grignard reagents have been added to epoxides to prepare
pyrans: (a) Street, S. D. A.; Yeates, C.; Kocienski, P.; Campbell, S. F.
Chem. Commun. 1985, 1386. (b) Rainier, J. D.; Allwein, S. P. Tetrahedron
Lett. 1998, 39, 9601. (c) Allwein, S. P.; Cox, J. M.; Howard, B. E.; Johnson,
H. W. B.; Rainier, J. D. Tetrahedron 2002, 58, 1997.
(6) (a) Bu¨chi, G.; Wu¨est, H. J. Org. Chem. 1969, 34, 1122. (b) Sworin,
M.; Neumann, W. L. Tetrahedron Lett. 1987, 28, 3217. (c) Ponaras, A. A.
Tetrahedron Lett. 1976, 7, 3105.
a Anhydrous HCl (1 M solution in ether) used in these cases.
(7) Stowell, J. C. J. Org. Chem. 1976, 41, 560.
(8) Leone-Bay, A.; Paquette, L. A. J. Org. Chem. 1982, 47, 4173.
3090
Org. Lett., Vol. 8, No. 14, 2006