Chemoselective cyclizations of divinyl ketones to cyclohexenones mediated by Lewis acid and base

Article abstract of DOI:10.1021/ol048545b

(Chemical Equation Presented) Chemoselective cyclizations of divinyl ketones to cyclohexenones mediated by a sterically demanding Lewis acid and an amine base have been accomplished under mild reaction conditions. The extension of this methodology to the

Full text of DOI:10.1021/ol048545b

ORGANIC
LETTERS
2004
Vol. 6, No. 19
3373-3375
Chemoselective Cyclizations of Divinyl
Ketones to Cyclohexenones Mediated
by Lewis Acid and Base
Nabi A. Magomedov,* Piero L. Ruggiero, and Yuchen Tang
Department of Chemistry, UniVersity of Rochester, Rochester, New York 14627-0216
magomedoV@chem.rochester.edu
Received July 26, 2004
ABSTRACT
Chemoselective cyclizations of divinyl ketones to cyclohexenones mediated by a sterically demanding Lewis acid and an amine base have
been accomplished under mild reaction conditions. The extension of this methodology to the synthesis of eight-membered rings is also
demonstrated.
Divinyl ketones are valuable building blocks for organic
synthesis. These substrates have been utilized in Diels-Alder
reactions,1 Michael reactions,2 and conjugate addition reac-
tions to prepare various ring systems.3 The characteristic
reaction of divinyl ketones is their acid-catalyzed Nazarov
cyclization leading to cyclopentenones.4 Although it was
postulated that cyclizations of divinyl ketones could poten-
tially produce cyclohexenones,5 this viewpoint was not
demonstrated experimentally.6 In this paper, we describe
direct cyclizations of divinyl ketones that result in chemo-
selective formation of cyclohexenones under mild reaction
conditions.
Recently, we demonstrated the ring expansion reactions
of cyclobutenones to cyclohexenones that involved the facile
cyclization of intermediate 3-oxidohexatrienes bearing a
strategically positioned electron-withdrawing group.7 We
realized that the key hexatriene intermediates could alter-
natively be generated by γ-enolization of the readily available
divinyl ketones (1) (Scheme 1). Although generation of
extended enolates from R,â-unsaturated carbonyl compounds
was typically accomplished by reactions with strong bases,8
we believed that enolization of a complex of 1 with a Lewis
acid could be achieved under milder conditions using a
tertiary amine base.9 For the desired cyclization to occur,
(1) (a) Winkler, J. D.; Kim, H. S.; Kim, S.; Ando, K.; Houk, K. N. J.
Org. Chem. 1997, 62, 2957-2962. (b) Jung, M. E.; McCombs, C. A.;
Takeda, Y.; Pan, Y.-G. J. Am. Chem. Soc. 1981, 103, 6677-6685. (c)
Nazarov, I. N.; Kuvarzina, M. V. IzV. Akad. Nauk SSSR, Ser. Khim. 1948,
599-609.
(2) (a) Britten-Kelly, M.; Willis, B. J.; Barton, D. H. R. Synthesis 1980,
27-29. (b) Hamanaka, N.; Nakai, H.; Kurono, M. Bull. Chem. Soc. Jpn.
1980, 53, 2327-2329. (c) de Jongh, H. A. P.; Wynberg, H. Tetrahedron
1964, 20, 2553-2573.
(3) (a) Dunn, P. J.; Graham, A. B.; Grigg, R.; Higginson, P.; Thornton-
Pett, M. Tetrahedron 2002, 58, 7727-7733. (b) Kuehne, M. E.; Bornmann,
W. G.; Earley, W. G.; Marko, I. J. Org. Chem. 1986, 51, 2913-2927.
(c) Snider, B. B.; Harvey, T. C. Tetrahedron Lett. 1995, 36, 4587-
4590.
(4) Nazarov, I. N.; Zaretskaya, I. I.; Sorkina, T. I. Zh. Obsh. Khim. 1960,
30, 746-754. For a review, see: Habermas, K. L.; Denmark, S. E.; Jones,
T. K. Org. React. 1994, 45, 1-158.
(7) Magomedov, N. A.; Ruggiero, P. L.; Tang, Y. J. Am. Chem. Soc.
2004, 126, 1624-1625.
(8) For example: Saito, S.; Nagahara, T.; Shiozawa, M.; Nakadai, M.;
Yamamoto, H. J. Am. Chem. Soc. 2003, 125, 6200-6210.
(9) (a) Lehnert, W. Tetrahedron Lett. 1970, 4723-4724. (b) Mukaiyama,
T.; Inoue, T. Chem. Lett. 1976, 559-562. (c) Evans, D. A.; Vogel, E.;
Nelson, J. V. J. Am. Chem. Soc. 1979, 101, 6120-6123. (d) Evans, D. A.;
Nelson, J. V.; Vogel, E.; Taber, T. R. J. Am. Chem. Soc. 1981, 103, 3099-
3111. (e) Masamune, S.; Choy, W.; Kerdesky, F. A. J.; Imperiali, B. J.
Am. Chem. Soc. 1981, 103, 1566-1568. (f) Rathke, M. W.; Cowan, P. J.
J. Org. Chem. 1985, 50, 2622-2624. (g) Brown, H. C.; Dhar, R. K.; Bakshi,
R. K.; Pandiarajan, P. K.; Singaram B. J. Am. Chem. Soc. 1989, 111, 3441-
3442. (h) Crimmins, M. T.; King, B. W.; Tabet, E. A.; Chaudhary, K. J.
Org. Chem. 2001, 66, 894-902.
(5) Magnus, P. NouV. J. Chem. 1978, 2, 555-557 and references therein.
(6) Divinyl ketones were indirectly converted to cyclohexenones under
harsh reaction conditions: (a) Torok, D. S.; Scott, W. J. Tetrahedron Lett.
1993, 34, 3067-3070. (b) Fehr, C.; Galindo, J.; Guntern, O. Tetrahedron
Lett. 1990, 31, 4021-4024.
10.1021/ol048545b CCC: $27.50 © 2004 American Chemical Society
Published on Web 08/14/2004

Having established conditions for this cyclization reaction,
we investigated the scope of the process (Table 1). Substrates
Scheme 1. Proposed Cyclization of Divinyl Ketones to
Cyclohexenones
Table 1. Cyclizations of Divinyl Ketones to Cyclohexenonesa
enolization of complex 2 had to produce the E-enolate 3-E.
Hence, a study aimed at identification of a competent Lewis
acid/base combination was a logical point of departure.
The initial experiments demonstrated that activation of
dienone 8 with a range of oxophilic Lewis acids, such as
Mg(ClO4)2, LiClO4, TiCl2(O-i-Pr)2, Zn(OTf)2, Sc(OTf)3, or
AlCl3, followed by addition of triethylamine returned the
starting material unchanged. Use of trimethylaluminum,
however, produced the desired cyclohexenone 9, albeit in
poor yield.10 During their studies of vinylogous aldol
reactions, Yamamoto and co-workers utilized an ATPH/LDA
system for the stereoselective generation of E-dienolates from
R,â-unsaturated carbonyl compounds.8,11 We reasoned that
a sterically demanding aluminum Lewis acid might increase
the population of the productive E-enolate and result in a
faster and more efficient cyclization reaction. We were
pleased to find that treatment of 8 with MAD (2.0 equiv)
and NEt3 (1.1 equiv) in toluene at room temperature
furnished 9 in 86% isolated yield (Scheme 2).12 Toluene was
a See the Supporting Information for detailed experimental procedures.
b Isolated yields. c The substrate was isomerized to the corresponding allylic
sulfone. d N-Methylpyrrolidine was utilized as a base. e Stereochemistry was
established by X-ray crystallographic analysis.
Scheme 2. Cyclization of 8 Mediated by MAD/NEt3
bearing a substituent at the R-position to the carbonyl were
well tolerated and cyclized to the corresponding cyclo-
hexenones at 60 °C (entries 1 and 7). The reaction in entry
2 produced a cyclohexenone bearing a quaternary carbon
center. In addition to aromatic groups, the â′-carbon of 1
could bear a tertiary alkyl group (entry 3). However, the
isomeric substrate possessing a primary alkyl did not form
cyclohexenone (13) (entry 4), but rather underwent re-
arrangement to the corresponding allylic sulfone.
The stereochemistry of the process (entries 5-7) was of
particular interest because it could provide insights into the
mechanism of the cyclization step, which could be viewed
(10) Friedel-Crafts acylation of alkenes with â,γ-unsaturated acid
chlorides produces, among other products, cyclohexenones. The formation
of cyclohexenones was rationalized by electrocyclization of intermediate
aluminum trienolates: Faure, R.; Pommier, A.; Pons, J. M.; Rajzmann, M.;
Santelli, M. Tetrahedron 1992, 48, 8419-8430.
found to be the optimal solvent for this cyclization, as
reactions in stronger coordinating solvents (THF, MeCN)
resulted in poor reaction conversion. In addition to triethyl-
amine, N-methylpyrrolidine was a competent base, whereas
Hunig’s base gave lower reaction conversion. Notably, no
cyclization occurred in the absence of a base or in the
presence of stronger bases, such as DBU and N,N,N′,N′-
tetramethylguanidine.
(11) ATPH is aluminum tris(2,6-diphenylphenoxide).
(12) (a) Starowieyski, K. B.; Pasynkiewicz, S.; Skowronska-Ptasinska,
M. J. Organomet. Chem. 1975, 90, C43-C44. (b) Maruoka, K.; Itoh, T.;
Sakurai, M.; Nonoshita, K.; Yamamoto, H. J. Am. Chem. Soc. 1988, 110,
3588-3597. For a review, see: Saito, S.; Yamamoto, H. J. Chem. Soc.,
Chem. Commun. 1997, 1585-1592.
3374
Org. Lett., Vol. 6, No. 19, 2004

as either a 6π-electrocyclic ring closure or an intramolecular
Michael reaction.13 Cyclization of the camphor-derived enone
furnished a single diastereomer of the product (entry 5),
whose stereochemistry was consistent with a disrotatory 6π-
electrocyclization involving the exo face of the intermediate
enolate.7 The reaction in entry 6 appeared to be more
complicated and produced a mixture of two diastereomers
in a 78:22 ratio. Apparently, the observed product ratio
reflects the thermodynamic stability of the two diastereomers,
as a sample of pure trans-15 gives rise to the same ratio of
isomers upon standing in chloroform for 3 days at room
temperature (Scheme 3).14 A reasonable mechanism for
sulfone 20 mediated by MAD (1.1 equiv) and NEt3 (1.0
equiv) in toluene at room temperature afforded the cyclo-
octatriene 21 in 99% yield within 5 min (Scheme 4).
Scheme 4. Synthesis of Cyclooctane Derivatives
Scheme 3. Possible Mechanism for Epimerization of 15
epimerization at C-4 of 15 involves the 6π-electrocyclic ring
opening of enol 17, which is in equilibrium with trans-15,
followed by the ring closure of intermediate hexatriene 18.
However, transformation 18 f 19 cannot be explained by a
thermal 6π-electrocyclization, which is a stereospecific
disrotatory process.15 The formation of cis-15 presumably
involves the addition of an extended enol to the electron-
deficient double bond.
It should be noted that triethylamine significantly acceler-
ates the interconversion of cis- and trans-15, which reach
equilibrium distribution within 15 min at room temperature.
In this particular case, the reaction probably proceeds via
the ammonium enolate of 17, as the 6π-electrocyclic ring
opening of hexatrienes is known to be charge-accelerated.16
We imagined that the cyclization strategy outlined in
Scheme 1 could be applied to the synthesis of other ring
systems. We were delighted to discover that the reaction of
Moreover, the type of substitution at the δ-position was not
limited to aromatic groups as demonstrated by the successful
reaction of 22. The formation of the eight-membered rings
instead of the six-membered carbocycles provides indirect
evidence for the importance of an electrocyclization pathway
in the ring-forming step. Pericyclic reactions often choose
to proceed through the symmetry-allowed transition states
involving the longest conjugated chain.17
In summary, we demonstrated a new cyclization reaction
of divinyl ketones that produces cyclohexenones. The insights
gained in this study may be used for the synthesis of other
ring systems, as we illustrated by the preparation of cyclo-
octane derivatives.
Acknowledgment. We thank the University of Rochester,
the Research Corporation, and Amgen for financial support.
We are grateful to Dr. Christine Flaschenriem for the X-ray
analyses.
(13) Aside from the stereochemical probe, it is hard to distinguish
between the two mechanistic pathways because orbital interactions that favor
Michael-type addition also enhance electrocyclization: Davies, I. W.;
Marcoux, J.-F.; Kuethe, J. T.; Lankshear, M. D.; Taylor, J. D. O.; Tsou,
N.; Dormer, P. G.; Hughes, D. L.; Houk, K. N.; Guner, V. J. Org. Chem.
2004, 69, 1298-1308.
Supporting Information Available: Experimental pro-
cedures, characterization data for new compounds, and X-ray
data for trans-15, 16, and 21. This material is available free
of charge via the Internet at http://pubs.acs.org.
(14) The same ratio of isomers was obtained when a sample of pure
trans-15 was submitted to the cyclization conditions.
(15) (a) Woodward, R. B.; Hoffmann, R. The ConserVation of Orbital
Symmetry; Academic Press: New York, 1970. (b) Okamura, W. H.; De
Lera, A. R. In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming,
I., Paquette, L. A., Eds.; Pergamon Press: New York, 1991; Vol. 5, pp
699-750.
(16) Evans, D. A.; Hart, D. J.; Koelsch, P. M. J. Am. Chem. Soc. 1978,
100, 4593-4594. See also: Evans, D. A.; Golob, A. M. J. Am. Chem. Soc.
1975, 97, 4765-4766.
OL048545B
(17) See, for example: (a) Paquette, L. A.; Barrett, J. H. J. Am. Chem.
Soc. 1966, 88, 2590-2591. (b) Goldstein, M. J.; Dai, S.-H. J. Am. Chem.
Soc. 1973, 95, 933-935.
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