Carbocyclic ring construction via intramolecular ionic Diels-Alder reactions of in situ -generated, heteroatom-stabilized allyl cations in highly polar media

Full text of DOI:10.1021/ja9531992

J. Am. Chem. Soc. 1996, 118, 2095-2096
2095
transition state between the axial C(5) hydrogen atom and the
olefinic hydrogen atom of the diene (cf. 4). Similar observations
Carbocyclic Ring Construction Wia Intramolecular
Ionic Diels-Alder Reactions of in Situ-Generated,
Heteroatom-Stabilized Allyl Cations in Highly
Polar Media
Paul A. Grieco,* Michael D. Kaufman, John F. Daeuble, and
Naoki Saito
Ernest E. Campaigne and MarVin Carmack Laboratory of
Organic Chemistry, Department of Chemistry
were made with substrate 5 (eq 2). When 5 was subjected to
identical conditions, the reaction was facile, giving rise to a
91% yield of 6 and 78a in a ratio of 4:1, with the major product
being derived from an exo transition state. Both 6 and 7 are
stable under the reaction conditions.
Indiana UniVersity, Bloomington, Indiana 47405
ReceiVed September 18, 1995
The intramolecular Diels-Alder reaction, which has received
enormous attention during the past 25 years, is a powerful meth-
od for the formation of two rings in a one-step process.1 In
many of the cases cited in the literature, particularly those in-
volving conformationally restricted substrates, temperatures in
excess of 180 °C or ultrahigh pressures are required. We detail
below a general strategy for the construction of carbocyclic ring
systems Via intramolecular ionic Diels-Alder reactions2 in
highly polar media3 which obviates the necessity for high temp-
eratures and pressures. The method features in situ generation
of heteroatom-stabilized allyl cations which undergo subsequent
[4 + 2] cycloaddition at ambient temperature (cf. eq 1).
Evidence that the above reactions are, indeed, ionic Diels-
Alder reactions which proceed Via heteroatom stabilized allyl
cations rather than the corresponding cyclohexenone follows
from a number of control experiments. Note that when lithium
perchlorate is excluded from the reaction (eq 2), only cyclo-
hexenone 8 is isolated (>90% yield). Exposure of cyclohex-
enone 86 to 5.0 M lithium perchlorate in diethyl ether containing
10 mol % trifluoroacetic acid requires 24 h to go to completion
and gives rise not to tricyclic ketones 6 and 7 but, instead, to
tricyclic ketone 9, in which the diene migrates prior to [4 + 2]
cycloaddition.9 We were surprised to find that the intramolecular
The strategy outlined in eq 1 was based, in part, on our
observation that â,â-disubstituted allylic alcohols give rise to
allyl cations upon exposure to concentrated solutions of lithium
perchlorate in diethyl ether containing catalytic acid.4 It was
reasoned that (1) the highly polar medium would further stabilize
the heteroatom-stabilized allyl cation 2 and (2) anhydrous
lithium perchlorate would effectively sequester any water
produced, thus preventing conversion of 2 to the corresponding
cyclohexenone. In a preliminary experiment, a 0.02 M solution
of 15 in diethyl ether was slowly added Via a syringe pump (1
h) to a 5.0 M solution of lithium perchlorate in diethyl ether
containing 10 mol % trifluoroacetic acid. After 30 min at
ambient temperature, tricyclic ketone 37 was isolated in 87%
yield. The exclusive formation of the exo cycloadduct 3 is
undoubtedly due to an unfavorable interaction in the endo
Diels-Alder reactions of 4-substituted cyclohexenones such as
8 do not proceed in 5.0 M lithium perchlorate-diethyl ether in
the absence of protic acids. Conventional thermal cycloaddition
of 8 required 40 h at 180 °C in order to realize a 53% yield of
6 and 7 in a ratio of 2:1. None of the endo product 10 could
(7) Satisfactory combustion analyses and/or high-resolution mass spectra
1
were obtained for all new compounds. In all cases, H NMR, 13C NMR,
and IR spectra were consistent with the assigned structures. The stereo-
chemical assignment for 3 was based on the 13C NMR and 1H NMR spectra
of 9, whose structure was confirmed by single-crystal X-ray analysis of
the derived p-phenylbenzoate i.
(1) For reviews on the intramolecular Diels-Alder reaction, see:
Ciganek, E. Org. React. 1984, 32, 1. Roush, W. R. In ComprehensiVe
Organic Synthesis; Trost, B. M., Fleming, I., Eds; Pergamon: Oxford, 1991;
Vol. 5, Chapter 4.4, pp 513-550.
(2) For examples of intramolecular ionic Diels-Alder reactions, see: (a)
Roush, W. R.; Gillis, H. R.; Essenfeld, A. P. J. Org. Chem. 1984, 49, 4674.
(b) Gassman, P. G.; Singleton, D. A. J. Org. Chem. 1986, 51, 3075.
Gassman, P. G.; Gorman, D. B. J. Am. Chem. Soc. 1990, 112, 8623.
Gassman, P. G.; Gorman, D. B. J. Am. Chem. Soc. 1990, 112, 8624.
Gorman, D. B.; Gassman, P. G. J. Org. Chem. 1995, 60, 977.
(3) For the use of highly polar media to promote Diels-Alder reactions,
see: Grieco, P. A.; Nunes, J. J.; Gaul, M. D. J. Am. Chem. Soc. 1990, 112,
4595. Grieco, P. A.; Handy, S. T.; Beck, J. P. Tetrahedron Lett. 1994, 35,
2663. Grieco, P. A. Aldrichim. Acta 1991, 24, 59. Also see: Grieco, P.
A. Organic Chemistry in Lithium Perchlorate/Diethyl Ether. In Organic
Chemistry: Its Language and Its State of the Art; Kisaku¨rek, V., Ed.;
VCH: Basel, 1993; p 133.
(8) (a) The structures for 6 and 7 were determined by single-crystal X-ray
analysis of the derived bromo ether ii and alcohol iii, respectively.
(b) The structure of 14 was determined by single-crystal X-ray analysis.
(c) The structure of 15 was assigned on the basis of extensive 1H NMR
decoupling experiments and NOE measurements (cf. iv).
(4) Grieco, P. A.; Collins, J. L.; Henry, K. J., Jr. Tetrahedron Lett. 1992,
33, 4735.
(5) (a) Prepared from the corresponding vinylogous ester6 by reduc-
tion with lithium aluminum hydride in diethyl ether at 0 °C, followed
by a nonaqueous workup. (b) Me or Et can be substituted for i-Bu.
(6) The starting vinylogous esters and the 4-substituted cyclohexenones
were prepared by the method of Stork: Stork, G.; Danheiser, R. L. J. Org.
Chem. 1973, 38, 1775.
(9) Cf.: Grieco, P. A.; Beck, J. P.; Handy, S. T.; Saito, N.; Daeuble, J.
F. Tetrahedron Lett. 1994, 35, 6783.
0002-7863/96/1518-2095$12.00/0 © 1996 American Chemical Society

2096 J. Am. Chem. Soc., Vol. 118, No. 8, 1996
Communications to the Editor
Table 1. Intramolecular Ionic Diels-Alder Reactions of in
Situ-Generated, Heteroatom-Stabilized Silyl Cationsa
lithium perchlorate in diethyl ether containing 10 mol %
trifluoroacetic acid gave rise after a total of 3 h at ambient
temperature to a 72% yield of 148b and 158c in a ratio of 4:1,
along with 15% of the corresponding enone. No products,
including the thermodynamically more stable tricyclic ketone
16,11 resulting from a stepwise process could be detected!
Results from other substrates are shown in Table 1. In gen-
eral, reactions are complete within 1 h after addition of the sub-
strate is complete. It is of interest to note that, in the case lead-
ing to the formation of a 6-7-6 carbocyclic ring system, only
the product derived from an endo transition state was observed.
It would thus appear that the observed cycloadducts are
derived from a concerted process. However, in one isolated
case (cf. substrate 17), cycloadducts have been isolated (cf. 20
and 21) which are the result of a stepwise process. When
substrate 17 was exposed to 5.0 M LiClO4-Et2O containing
10% TFA for 1 h, a 56% yield of cycloadducts 18 and 19 was
isolated in a ratio of 2:1. In addition, the partially cyclized
decalones 20 and 21 were isolated in 24% yield in a ratio of
1.5:1, respectively. Note that the formation of 18 and 19 is
consistent with a concerted mechanism, whereas 20 and 21 are
the direct result of a competing stepwise reaction mechanism.
a To a 0.01 M solution of substrate in 5.0 M LiClO4-Et2O was added
10 mol % trifluoroacetic acid. After addition was complete, stirring
was continued for 1 h. b Isolated yields. c A 31% yield of the corre-
sponding cyclohexenone was isolated.
be detected, presumably because 10 equilibrates completely to
7 under the thermal conditions. Use of Lewis acids (e.g., Et2-
AlCl) only served to decompose the starting enone.
The origin of trans-fused product 7 obtained upon exposure
of 5 to 5.0 M LiClO4-Et2O containing 10 mol % trifluoroacetic
acid warrants comment. Formation of 7 appears to be the result
of the endo-derived [4 + 2] cycloadduct 10 undergoing complete
equilibration adjacent to the carbonyl in the highly polar
medium. Calculations indicate that 7 is more stable than 10
by 7.2 kcal! Alternatively, 7 could arise Via a concerted
reaction, followed by enolization of the intermediate oxonium
ion 11 to isobutyl enol ether 12. Such a mechanism would also
In summary, an efficient, synthetically useful protocol has
been developed for the construction of functionalized carbocy-
clic systems, which complements the work of Gassman.2b
Further studies are underway to examine the scope of this ionic
cycloaddition process for carbocyclic ring synthesis.
account for the absence of 10. Enol ether 12 has been isolated
after very short reaction times. For example, when a 0.01 M
solution of 5 in 5.0 M lithium perchlorate-diethyl ether was
treated with 10 mol % trifluoroacetic acid for 1 min and
quenched with an ice-cold saturated aqueous sodium bicarbonate
solution, a 71% yield of 6 and 7 was isolated in a 4:1 ratio,
along with a 7% yield of enol ether 12. Alternatively, trans-
fused 7 might arise from a stepwise cyclization2b,10 that
establishes the trans stereochemistry directly, thus bypassing
both 10 and 11. To test this possibility, we have examined a
case in which the initial Diels-Alder adduct cannot undergo
equilibration to a more stable cycloadduct. Slow addition of a
0.02 M solution of 13 in diethyl ether to a 5.0 M solution of
Acknowledgment. This investigation was supported by a Public
Health Service Research Grant from the National Institute of General
Medical Sciences (GM 33605) and Zeneca Pharmaceuticals.
Supporting Information Available: Spectral and other analytical
data for all compounds reported, along with ORTEP views of five
structures determined by single-crystal X-ray analysis and a representa-
tive experimental procedure (11 pages). This material is contained in
many libraries on microfiche, immediately follows this article in the
microfilm version of the journal, can be ordered from the ACS, and
can be downloaded from the Internet; see any current masthead page
for ordering information and Internet access instructions.
(10) Haynes, R. K.; King, G. R.; Vonwiller, S. C. J. Org. Chem. 1994,
59, 4743.
(11) Calculations indicate that 16 is more stable than 15 by 2.5 kcal.
JA9531992