Highly efficient trapping of the Nazarov intermediate with substituted arenes.

Article abstract of DOI:10.1021/ol010159w

1,4-Dien-3-ones bearing pendant arylethyl side chains were readily prepared from substituted dihydrocinnamaldehydes. When treated with TiCl(4) at low temperature, these compounds underwent domino cyclization to give benzohydrindenones in near-quantitative yield and with complete diastereoselectivity. Reaction: see text.

Full text of DOI:10.1021/ol010159w

ORGANIC
LETTERS
2001
Vol. 3, No. 19
3033-3035
Highly Efficient Trapping of the Nazarov
Intermediate with Substituted Arenes
Cindy C. Browder, Fredrik P. Marmsa1ter, and F. G. West*
Department of Chemistry, UniVersity of Utah, 315 South 1400 East, Rm 2020,
Salt Lake City, Utah 84112-0850
west@chemistry.chem.utah.edu
Received July 19, 2001
ABSTRACT
1,4-Dien-3-ones bearing pendant arylethyl side chains were readily prepared from substituted dihydrocinnamaldehydes. When treated with
TiCl4 at low temperature, these compounds underwent domino cyclization to give benzohydrindenones in near-quantitative yield and with
complete diastereoselectivity.
Benzohydrindan ring skeletons are useful intermediates in
the construction of steroidal targets1 and alkaloids2 and also
can be found in other biologically important substances.3 We
have previously reported that hydrindan skeletons can be
assembled by domino Nazarov cyclization/6-endo cation-
olefin cyclization.4 This process typically consumed the
starting trienone with high efficiency but furnished a mixture
of products via several termination pathways. In a related
study, we also described the cascade cyclization of aryl
trienones, in which 6-endo cyclization of a trisubstituted
olefin and the Nazarov oxyallyl intermediate was followed
by clean termination via addition of the resulting carbocation
to a pendant phenyl group.5 In light of these results, we
sought to learn whether the direct trapping of the Nazarov
intermediate by pendant aryl moieties was possible. Follow-
ing is a preliminary report of this work, which describes the
high-yield and stereoselective conversion of aryl dienones
to benzohydrindenones.
The necessary substrates to test the feasibility of this
process could be prepared from readily available hydrocin-
namaldehydes 1a-c (Scheme 1).6 Horner-Emmons olefi-
nation under the Roush-Masamune conditions,7 followed
by a reduction/oxidation sequence, yielded the key enals 2a-
c. Treatment with either 2-propenylmagnesium bromide,
3-lithiohexene, or 1-lithiocyclohexene gave the corresponding
dienols, which were then oxidized to dienones 3a-g using
BaMnO4.8
Initial experiments employed the simple, phenyl-substi-
tuted substrate 3a (Scheme 2). The Lewis acids BF3‚OEt2
and TiCl4 were chosen, as they have been found to be the
most generally effective mediators of other Nazarov-based
domino processes.4,5,9 Unfortunately, treatment of 3a with
TiCl4 led to complex mixtures containing no apparent domino
(6) Hydrocinnamaldehydes 1b,c were prepared from the commercially
available (Aldrich) cinnamic acids via exhaustive reduction (LiAlH4/THF)
followed by oxidation with TPAP/NMO.
(7) Blanchette, M. A.; Choy, W.; Davis, J. T.; Essenfeld, A. P.;
Masamune, S.; Roush, W. R.; Sakai, T. Tetrahedron Lett. 1984, 25, 2183.
(8) Barium manganate is a mild and effective oxidant for the conversion
of dienols to dienones: (a) Denmark, S. E.; Hite, G. A. HelV. Chim. Acta
1988, 71, 195. (b) Firouzabadi, H.; Ghaderi, E. Tetrahedron Lett. 1978,
839. (c) See also ref 9a.
(1) Nemoto, H.; Miyata, J.; Yoshida, M.; Raku, N.; Fukumoto, K. J.
Org. Chem. 1997, 62, 7850.
(2) Kopach, M. E.; Fray, A. H.; Meyers, A. I. J. Am. Chem. Soc. 1996,
118, 9876.
(3) Zeng, C.; Han, M.; Covey, D. F. J. Org. Chem. 2000, 65, 2264.
(4) Browder, C. C.; West, F. G. Synlett 1999, 1363.
(5) Bender, J. A.; Arif, A. M.; West, F. G. J. Am. Chem. Soc. 1999,
121, 7443.
(9) (a) Bender, J. A.; Blize, A. E.; Browder, C. C.; Giese, S.; West, F.
G. J. Org. Chem. 1998, 63, 2430. (b) Giese, S.; West, F. G. Tetrahedron
Lett. 1998, 39, 8393. (c) Giese, S.; Kastrup, L.; Stiens, D.; West, F. G.
Angew. Chem., Int. Ed. 2000, 39, 1970.
10.1021/ol010159w CCC: $20.00 © 2001 American Chemical Society
Published on Web 08/28/2001

Scheme 1
Scheme 2
Finally, use of a furan terminator14 was examined to further
probe the scope of this process. Furan-containing dienone
3h was prepared from (E)-3-furanacrylic acid in analogy to
the route employed above (Scheme 3). Notably, enal
cyclization products, while BF3‚OEt2 effected clean conver-
sion to cyclopentenone 4a resulting from Nazarov cyclization
followed by the standard eliminative termination pathway.
Failure to observe the desired domino process in this case
was likely due to inadequate nucleophilicity of the phenyl
trap, in analogy to earlier related photochemical studies.10
We therefore directed our attention to the more electron-
rich substrates 3b-g.
Scheme 3
Again, BF3‚OEt2 proved unsuitable as the Lewis acid
initiator, giving mixtures of simple Nazarov cyclization and
domino cyclization products. In contrast, TiCl4 rapidly and
cleanly effected the desired transformation of 3b-g to 5b-g
in 90-99% yield.11 As expected, the arene substitution
reaction occurred at the sterically less demanding position
in all cases (para to the methoxy substituent for 5b-d and
meta/para to the methylenedioxy group for 5e-g). This was
readily apparent from the coupling pattern of the aromatic
protons. In analogy to other Nazarov-based domino pro-
cesses, the ring-fusion stereochemistry was assigned as cis,
while the neighboring R2 group at C-3 (e.g., 5c,d,f,g) must
be cis to the bridgehead proton after conrotatory closure per
the demands of orbital symmetry.12 The configuration at C-2
was assigned as shown on the basis of prior observation of
selective enolate protonation from the convex face of the
cis-hydrindan system.13 This stereochemical assignment was
confirmed by X-ray crystallography in the case of 5f, and
those of the other products were assigned by analogy.
intermediate 2d (perillenal) is a naturally occurring phero-
mone of the pine saw fly.15 The route described here offers
a convenient method for preparing this substance in quan-
(10) West, F. G.; Willoughby, D. W. J. Org. Chem. 1993, 58, 3796.
3034
Org. Lett., Vol. 3, No. 19, 2001

tity.16 Upon treatment with TiCl4, 3h was converted to
furohydrindenone 5h in 55% yield. In contrast to the other
examples, warming to room temperature was required for
complete consumption of the starting dienone. Although it
was not possible to characterize the remaining material, it is
likely that the lower yield in this case may be due to
competing oligomerization or other decomposition processes
that can occur at higher temperatures.
The efficiency with which 3b-h underwent electrophilic
aromatic substitution in competition with other termination
pathways is striking. Acyclic oxyallyl cations can react with
simple arenes in intermolecular processes to give a mixture
of simple substitution products and [4 + 3] adducts.17 The
geometric constraints of the intramolecular substrates militate
against the formation of similar bridged structures in the
present study. However, it is possible that formation of
products 5b-h may occur through an abortive cycloaddition
pathway.18
In summary, 1,4-dien-3-ones with pendant electron-rich
aryl groups undergo domino cyclization to give arene-fused
hydrindenones stereoselectively and in high yield. Further
mechanistic studies and application of this facile process to
other structural classes will be reported elsewhere in due
course.
Acknowledgment. We thank NIH (GM 44720) for
support of this work and Dr. Atta Arif for assistance in
obtaining the X-ray crystal structure of 5f.
Supporting Information Available: Representative pro-
cedures for the synthesis of substrates 3a-h; characterization
1
data for 3a-h, 4a and 5b-h; H NMR spectra of 2a-d,
3a,c-e,g, 4a, and 5b-h, and X-ray data for 5f. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL010159W
(13) For other examples of selective protonation from the convex face
of the enolate intermediate, see refs 4, 5, and 9a.
(14) (a) Tanis, S. P.; Deaton, M. V.; Dixon, L. A.; McMills, M. C.;
Raggon, J. W.; Collins, M. A. J. Org. Chem. 1998, 63, 6914. (b) Tanis, S.
P.; Robinson, E. D.; McMills, M. C.; Watt, W. J. Am. Chem. Soc. 1992,
114, 8349. (c) Tanis, S. P.; McMills, M. C.; Scahill, T. A.; Kloosterman,
D. A. Tetrahedron Lett. 1990, 31, 1977.
(15) (a) Ahlgren, G.; Bergstroem, G.; Loefqvist, J.; Jansson, A.; Norin,
T. J. Chem. Ecol. 1979, 5, 309. (b) Wassgren, A. B.; Anderbrant, O.;
Loefqvist, J.; Hansson, B. S.; Bergstroem, G.; Hedenstroem, E.; Hoegberg,
H. E. J. Insect Physiol. 1992, 38, 885.
(16) Previous syntheses of 2d: (a) Baeckstroem, P.; Okecha, S.; De Silva,
N.; Wijekoon, D.; Norin, T. Acta Chem. Scand., Ser. B 1982, B36, 31. (b)
Baker, R.; Ekanayake, N.; Johnson, S. A. J. Chem. Res., Synop. 1983, 74.
(c) Bernasconi, S.; Colombo, M.; Jommi, G.; Sisti, M. Gazz. Chim. Ital.
1986, 116, 69. (d) Bock, I.; Bornowski, H.; Ranft, A.; Theis, H. Tetrahedron
1990, 46, 1199. (e) Nishizawa, M.; Takenaka, H.; Kohno, T.; Takao, H.;
Yamada, H. Chem. Pharm. Bull. 1993, 41, 791.
(11) Representative procedure for domino Nazarov cyclization/arene
trapping. Dienone 3f (51 mg, 0.18 mmol) was dissolved in CH2Cl2 (18
mL) and cooled to -78 °C. A solution of TiCl4 in CH2Cl2 (0.050 mL of a
3.51 M solution, 0.18 mmol) was added dropwise, and after 5 min TLC
showed complete consumption of starting material. The reaction was
quenched with water (5 mL) and allowed to warm to room temperature,
the layers were then separated, and the aqueous layer was extracted with
CH2Cl2 (3 × 5 mL). The combined organic layers were dried (MgSO4)
and concentrated to give 51 mg (99%) of 5f as colorless crystals, deemed
pure by TLC and NMR analysis: mp 71-72 °C; Rf 0.48 (1:4 EtOAc/
1
hexanes); IR (thin film) 2959, 2923, 2867, 1731 cm-1; H NMR (CDCl3,
500 MHz) δ 6.97 (s, 1H), 6.49 (s, 1H), 5.86 (s, 2H), 2.76 (ddd, J ) 17.2,
13.0, 6.0 Hz, 1H), 2.63 (ddd, J ) 17.1, 6.2, 1.6 Hz, 1H), 2.02 (dddd, J )
13.9, 5.2, 3.3, 1.8 Hz, 1H), 1.87 (dddd, J ) 13.5, 13.5, 6.1, 3.7 Hz, 1H),
1.82-1.75 (m, 2H), 1.71-1.66 (m, 1H), 1.54-1.45 (m, 2H), 1.34 (s, 3H),
1.12 (d, J ) 6.1 Hz, 3H), 0.65 (t, J ) 7.5 Hz, 3H); 13C NMR (CDCl3, 125
MHz) δ 221.6, 146.3, 146.3, 129.1, 128.4, 108.8, 108.4, 100.9, 56.6, 51.9,
48.8, 33.3, 27.2, 25.1, 21.9, 18.4, 17.7, 11.2.
(12) For recent reviews, see: (a) Habermas, K. L.; Denmark, S. E.; Jones,
T. K. Org. React. 1994, 45, 1. (b) Denmark, S. E. In ComprehensiVe Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol.
5, pp 751-784.
(17) (a) Hill, A. E.; Hoffmann, H. M. R. J. Am. Chem. Soc. 1974, 96,
4597. (b) Shimizu, H.; Tanaka, M.; Tsuno, Y. J. Am. Chem. Soc. 1982,
104, 1330.
(18) We thank an anonymous reviewer for the suggestion of this
intriguing possibility.
Org. Lett., Vol. 3, No. 19, 2001
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