9
hydroxy methoxyallenyl pyranes. The azacycloheptane unit
can be prepared by nitrogen insertion using a Beckmann or
Scheme 1. MARDi Cascade
10
5b,11
Schmidt reaction, by ring enlargement of fused aziridines,
and from the reaction of piperidones with diazoacetates,
1
2
and to a lesser extent, some free-radical transpositions are
1
3
documented, which can also be used in the sulfur series.
The two-carbon ring enlargement approach is much more
limited and essentially rests upon the reactivity of four-
membered rings5b or involves very specific intermediates.14
Oxepines and azepines can be prepared by palladium-
catalyzed cyclization of bromoallenes bearing a nucleophilic
heteroatom,15 and [5 + 2] rhodium-catalyzed cycloaddition
of cyclopropyl imines with electron-poor alkynes provides
16
an entry to dihydroazepines. Ring-closing methathesis has
also proven popular for the synthesis of these unsaturated
heterocycles in recent years.17
thiafuranone 1c22 depicted in Figure 1 using acrolein (2a)
In this paper, we wish to report on a new approach for
the selective preparation of aza, oxa-, and thiacycloheptanes
using the MARDi cascade, a domino reaction discovered in
our group.18 The overall process is an indirect two-carbon
ring expansion of the easily accessible heterocyclic five-
membered â-ketoesters 1 which, in the presence of base and
methanol, combine with an R,â-unsaturated aldehyde 2 to
give stereoselectively either the cycloheptanols 3 or the
cycloheptenic acids 4 as a function of the substitution pattern
of the aldehyde (Scheme 1). This cascade reaction involving
MeOH as a third component proceeds in substantial yields
under thermodynamic control via an heterocyclic bicyclo-
Figure 1. Substrates and aldehydes used for the study.
19
[3.2.1]-bridged intermediate.
The MARDi cascade in the different heterocyclic series
was first tested with furanone 1a, pyrrolidone 1b, and
20
21
as the aldehyde partner (Table 1). The reactions were
conducted in dry MeOH at various concentrations, and a
(
(
8) Lakshmipathi, P.; Gr e´ e, D.; Gr e´ e, R. Org. Lett. 2002, 4, 451-454.
9) Nagao, Y.; Tanaka, S.; Hayashi, K.; Sano, S.; Shiro, M. Synlett 2004,
2 3
substoichiometric amount of K CO proved to be the most
efficient base for the transformation. The best yields of the
expected seven-membered rings were obtained in relatively
diluted medium. Actually, these cycloheptanols are relatively
unstable in the reaction mixture, particularly in concentrated
basic media. For example, at concentrations higher than 0.2
M, the furanone 1a gave the corresponding hydroxyoxepane
4
81-484.
(
10) (a) Craig, D. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 7, p 689. (b) Aub e´ ,
J. Chem. Soc. ReV. 1997, 26, 269-277. (c) Furness, K.; Aub e´ , J. Org. Lett.
1
999, 1, 495-497.
(
11) Pfister, J. R. Heterocycles 1986, 24, 2099-2103.
(12) (a) Krogsgaard-Larsen, P.; Hjeds, H. Acta Chem. Scand. B 1976,
B30, 884-888. (b) Adams, C. P.; Fairway, S. M.; Hardy, C. J.; Hibbs, D.
E.; Hursthouse, M. B.; Morley, A. D.; Sharp, B. W.; Vicker, N.; Warner,
I. J. Chem. Soc., Perkin Trans. 1 1995, 2355-2362.
3
a (R ) H) in very low yield as a 1.5:1 mixture of epimers
(entry 1). Lowering the concentration to 0.1 and 0.04 M
entries 2 and 3) had no effect on diastereoselectivity but
(
13) Dowd, P.; Choi, S.-C. Tetrahedron 1991, 47, 4847-4860.
(
(14) Pitsch, W.; Russel, A.; Zabel, M.; K o¨ nig, B. Tetrahedron 2001,
5
7, 2345-2347.
15) Ohno, H.; Hamaguchi, H.; Ohata, M.; Kosaka, S.; Tanaka, T. J.
Am. Chem. Soc. 2004, 126, 8744-8754.
16) Wender, P. A.; Pedersen, T. M.; Scanio, M. J. C. J. Am. Chem.
Soc. 2002, 124, 15154-15155.
17) (a) Sutton, A. E.; Seigal, B. A.; Finnegan, D. F.; Snapper, M. L. J.
allowed the formation of 3a in 24% and 46% yield,
respectively. Unfortunately, this compound suffered degrada-
tion upon silica gel chromatography and only a small quantity
of 3a could be isolated. Thus, the crude product 3a (R ) H)
was silylated prior purification, allowing the isolation of the
corresponding silyl ether 3a (R ) TMS) in 42% yield from
(
(
(
Am. Chem. Soc. 2002, 124, 13390-13391. (b) Wu, C.-J.; Madhushaw, R.
J.; Liu, R.-S. J. Org. Chem. 2003, 68, 7889-7892. (c) Basu, S.; Waldmann,
H. J. Org. Chem. 2006, 71, 3977-3979. (d) Hanessian, S.; Sailes, H.;
Munro, A.; Therrien, E. J. Org. Chem. 2003, 68, 7219-7233. (e) Pearson,
W. H.; Aponick, A.; Dietz, A. L. J. Org. Chem. 2006, 71, 3533-3539.
1
a (entry 4). The reaction between the pyrrolidone 1b and
acrolein under the optimized conditions for 1a provided a
(18) MARDi is an acronym for the domino three-component sequence
1
1
:1 mixture of the expected hydroxyazepane 3b (dr ) 3.5:
) and the corresponding azepine 3c (R ) Me) in 36% yield
Michael Aldol Retro-Dieckmann. (a) Filippini, M.-H.; Rodriguez, J.; Santelli,
M. J. Chem. Soc., Chem. Commun. 1993, 1647-1648. (b) Filippini, M.-
H.; Rodriguez, J. J. Org. Chem. 1997, 62, 3034-3035. The structure of
2 3
(entry 5). Increasing the quantity of K CO to 1 and 1.5 equiv
2
the carbocyclic cycloheptenic acid 4 (X ) Y ) CH2; R ) CH3) has been
revisited and confirmed to be as depicted in Scheme 1 by X-ray diffraction
analysis of a derivative (see the Supporting Information). (c) Rodriguez, J.
Synlett 1999, 505-518. The full detailed study of the MARDi cascade will
be reported in due time.
(20) Moyer, M. P.; Feldman, P. L.; Rapoport, H. J. Org. Chem. 1985,
50, 5223-5230.
(21) McHugh, M.; Proctor, G. R. J. Chem. Res., Miniprint 1984, 8,
(
19) (a) Filippini, M.-H.; Rodriguez, J. Chem. ReV. 1999, 99, 27-76.
b) Lavoisier-Gallo, T.; Charonnet, E.; Pons, J.-M.; Rajzman, M.; Faure,
R.; Rodriguez, J. Chem.sEur. J. 2001, 7, 1056-1068.
2230-2254.
(
(22) Honek, J. F.; Mancini, M. L.; Belleau, B. Synth. Commun. 1984,
14, 483-491.
4820
Org. Lett., Vol. 8, No. 21, 2006