Polarizing the Nazarov Cyclization: Efficient Catalysis under Mild Conditions

Article abstract of DOI:10.1021/ja037910b

Substituted divinyl ketones were studied in the Nazarov cyclization. α-Carbomethoxy divinyl ketones underwent efficient Nazarov cyclization with catalytic copper triflate (2 mol %) to give a single cyclopentenone regio- and stereoisomer. The efficiency of

Full text of DOI:10.1021/ja037910b

Published on Web 10/30/2003
Polarizing the Nazarov Cyclization: Efficient Catalysis under Mild Conditions
Wei He, Xiufeng Sun, and Alison J. Frontier*
Department of Chemistry, UniVersity of Rochester, Rochester, New York 14627
Received August 13, 2003; E-mail: frontier@chem.rochester.edu
Table 1. Effect of Vinyl Electrophile â-Substitution on Reactivity
The Nazarov cyclization is a 4π-electrocyclization that converts
divinyl ketones to cyclopentenones by activation with a Lewis acid.1
The potential synthetic utility of the reaction is considerable,2,3 given
the stereospecific nature of the cyclization4 and the ability of
existing stereocenters to effect diastereoselective ring closure
(torquoselectivity).1a,5 However, these advantages have been over-
shadowed by the following shortcomings: in general, either protic
acid or strong Lewis acid (e.g., BF3, SnCl4, TiCl4, AlCl3) is required
to promote the reaction, one or more molar equivalents of Lewis
acid is necessary for best results,6 and the regioselectivity of the
elimination step can be poor, giving a mixture of cyclopentenone
isomers.7
entry
ketone
R
time
yield
1
2
3
4
5
6
7a
3a
3b
3c
3d
3e
3f
2,4,6-trimethoxyphenyl
4-methoxyphenyl
3-methoxyphenyl
phenyl
2-furyl
cyclohexyl
5 min
3.5 h
>99%
99%
96%
99%
99%
<50%
>99%
48 h
108 h
12 h
240 h
2 h
3f
cyclohexyl
In contrast, Diels-Alder, aldol, Michael, and ene-like reactions
can be effected using mild Lewis acids as catalysts.8 These reaction
types involve addition of an electron-rich π-system to an electron-
poor π-system, a bond-forming process similar to the 4π Nazarov
cyclization. With this in mind, we designed divinyl ketones with a
“vinyl nucleophile” and a “vinyl electrophile”(see 1, Scheme 1).
We reasoned that activation of 1 might occur with a mild Lewis
acid to give 2, and that polarized pentadienyl cation 2 should cyclize
more readily than a symmetric, unpolarized π-system.9-12
a Optimized conditions: Cu(OTf)2 (2 mol %), Cl(CH2)2Cl (0.5 M), 55 °C.
Table 2. Effect of Vinyl Nucleophile R-Substitution on Reactivitya
Scheme 1. A Polarized Nazarov Reaction
Initial experiments were conducted on divinyl ketones 313 bearing
an oxygen at the R-position of the vinyl nucleophile and an ester
at the R-position of the vinyl electrophile. The potential for
coordination of both carbonyl groups to a chiral promoter to induce
asymmetry during the cyclization was an important motivation for
the study of these substrates. Copper triflate (2 mol %) catalyzed
the Nazarov cyclization of â-aryl-substituted enoates 3a-e in
chlorinated solvent at room temperature in air to give excellent
yields of cyclopentenones 4 (Table 1).14 Electron-rich aromatic
substituents increased reaction rates, especially when the electron-
donating group was a resonance contributor to the enone system
(compare entries 1-5). Even the nonaromatic cyclohexyl substrate
3f (entries 6 and 7) could be induced to cyclize efficiently if the
reaction was run at higher concentration and elevated temperature.
Each â-keto ester 4 was isolated as a single regio- and
stereoisomer with a trans relationship of the R and â substituents
on the former vinyl electrophile. Stereochemical assignments were
made based on the assumption that thermodynamic cyclopentenone
products 4 are formed under the reaction conditions.15
a R ) 2,4,6-trimethoxyphenyl. Reaction conditions: 2 mol % Cu(OTf)2,
CH2Cl2, or Cl(CH2)2Cl (0.06 M). b 1.2/1 ratio of cyclohexene regioisomers.
c Isolated yield of the major component of a regioisomeric mixture.
smoothly, but more slowly than the dihydropyran vinyl nucleophile
(Table 1, entry 1). Quaternary center formation was also possible;
cyclization of divinyl ketone 11a gave cyclopentenone 12a as a
single regio- and stereoisomer (entry 4).16 However, cyclization of
R-unsubstituted 13a (entry 5) was slower and low-yielding, and
elimination was less regioselective.
Substrates with R-unsubstituted vinyl electrophiles were also
submitted to the optimized cyclization conditions. In every case,
substrates with carbomethoxy substitution cyclized more efficiently
(compare entry 1 to 2, 3 to 4, etc; Table 3). In general, the more
polarizing groups on the divinyl ketone, the more efficient the
reaction. Some substrates missing key substituents still cyclized
well (entries 2, 4, 5, and 7), but as polar substitution on the divinyl
ketone was reduced to a minimum, reaction behavior became
complex and decomposition began to compete with cyclization
(entries 4, 6, and 8).17
Substrates equipped with a range of vinyl nucleophiles were
examined under optimized cyclization conditions (Table 2). Cyclic,
acylic, and aromatic vinyl nucleophiles (entries 1, 2, and 3) cyclized
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J. AM. CHEM. SOC. 2003, 125, 14278-14279
10.1021/ja037910b CCC: $25.00 © 2003 American Chemical Society

C O M M U N I C A T I O N S
Table 3. Effect of Vinyl Electrophile R-Substitution on Reactivityd
and 12a (CIF). This material is available free of charge via the Internet
at http://pubs.acs.org.
References
(1) For reviews, see: (a) Habermas, K. L.; Denmark S. E.; Jones, T. K. Org.
React. 1994, 45, 1. (b) Santelli-Rouvier, C.; Santelli, M. Synthesis 1983,
429.
(2) Sequences involving Nazarov cyclization followed by trapping or reduction
of the intermediate cation have been developed by West: (a) Zuev, D.;
Paquette, L. A. Chemtracts 1999, 12, 1019. (b) Giese, S.; Kastrup, L.;
Stiens, D.; West, F. G. Angew. Chem., Int. Ed. 2000, 39, 1970. (c)
Browder, C. C.; Marmsater, F. P.; West, F. G. Org. Lett. 2001, 3, 3033.
(d) Giese, S.; West, F. G. Tetrahedron 2000, 56, 10221. (e) Wang, Y.;
Schill, B. D.; Arif, A. M.; West, F. G. Org. Lett. 2003, 5, 2747.
(3) For studies of the Nazarov cyclization of allenyl vinyl ketones, see: (a)
Tius, M. A. Acc. Chem. Res. 2003, 36, 284, and references therein. (b)
Leclerc, E.; Tius, M. A. Org. Lett. 2003, 5, 1171. (c) Bee, C.; Tius, M.
A. Org. Lett. 2003, 5, 1681.
(4) Woodward, R. B.; Hoffmann, R. The ConserVation of Orbital Symmetry;
a
Verlag Chemie: Weinheim, Germany, 1970; pp 38-64.
Reaction was stopped when all divinyl ketone was consumed.
b Mixture of cyclohexene regioisomers. c Multicomponent product mixture;
see Supporting Information. d TMP ) 2,4,6-trimethoxyphenyl; Chx )
cyclohexyl. Reaction conditions: Cu(OTf)2 (2 mol %), Cl(CH2)2Cl (0.2
M).
(5) Houk, K. N. In Strain and Its Implications in Organic Chemistry;
deMeijere, A., Blechert, S., Eds.; Kluwer Academic Publishers: Dodrecht,
The Netherlands,1989; pp 25-37.
(6) Isolated examples of Nazarov cyclization with catalytic Lewis acid have
been reported: (a) Jones, T. K.; Denmark, S. E. HelV. Chim. Acta 1983,
66, 2377 (40 mol % FeCl3 for â-silyl divinyl ketones). (b) Reference 2d
(10 mol % SnCl4, 200 mol % Et3SiH). (c) Reference 2e (10 mol % BF3‚
OEt2).
Scheme 2. Effect of Polarization on the Electrocyclic Process
(7) Denmark’s â-silyl alkenes, which suffer elimination with excellent
regioselectivity, are an exception. Denmark, S. E.; Jones, T. K. J. Am.
Chem. Soc. 1982, 104, 2642. Also see ref 1a and references therein.
(8) For leading references for all four reaction types, see: (a) Catalytic
Asymmetric Synthesis, 2nd ed.; Ojima, I., Ed.; Wiley-VCH: Weinheim,
Germany, 2000; Chapter 8. (b) Johnson, J. S.; Evans, D. A. Acc. Chem.
Res. 2000, 33, 325.
(9) This strategy has been used successfully for the development of highly
reactive dienes for the Diels-Alder reaction: (a) Danishefsky, S. J. Acc.
Chem. Res. 1981, 14, 400. (b) Kozmin, S. A.; Janey, J. M.; Rawal, V. H.
J. Org. Chem. 1999, 64, 3039.
(10) R-Carboalkoxy divinyl ketones have been reported as highly reactive
substrates that undergo regioselective elimination in Nazarov cyclizations
with stoichiometric promoter: (a) Marino, J. P.; Lindermann, R. J. J. Org.
Chem. 1981, 46, 3696. (b) Andrews, J. F. P.; Regan, A. C. Tetrahedron
Lett. 1991, 32, 7731. (c) Kerr, D. J.; Metje, C.; Flynn, B. L. Chem.
Commun. 2003, 1380. Until Flynn’s recent report, yields were consistently
low.
(11) R-Heteroatom-substituted divinyl ketones have been found to be particu-
larly reactive substrates in Nazarov cyclizations: Tius, M. A.; Kwok, C.-
K.; Gu, X.-q.; Zhao, C. Synth. Commun. 1994, 24, 871.
(12) For a study of the influence of divinyl ketone substituents on the silicon-
directed Nazarov cyclization, see Denmark, S. E.; Habermas, K. L.; Hite,
G. A. HelV. Chim. Acta 1988, 71, 168.
(13) Synthesis of all R-carboalkoxy divinyl ketones was achieved by Knoev-
enagel condensation of a â-keto ester and an aldehyde, catalyzed by a
secondary amine. Desimoni, G.; Faita, G.; Ricci, M.; Righetti, P.
Tetrahedron 1998, 54, 9581. Most divinyl ketones were isolated as a single
trisubstituted olefin and are drawn as the Z-isomer, but we have been
unable to confidently assign the olefin geometry at this time.
(14) When the catalyst was stirred with 2.5 mol % potassium carbonate before
addition of substrate, the rate of cyclization was unchanged, ruling out
adventitious catalysis by triflic acid. Reactions run under argon gave
comparable results.
(15) Support for the stereochemical assignments: The stereochemistry of
representative â-ketoester 4b is stable under equilibrating conditions
(NaOH/MeOH/THF/55 °C, 2h), trans stereochemistry was found to be
thermodynamically favored for similar compounds reported in the literature
(refs 7 and 10c), and trans stereochemistry of 3a was confirmed by an
X-ray diffraction study.
We have found that Nazarov cyclization is facilitated by the
presence of polar substituents on the divinyl ketone. One possible
factor is the greater Lewis basicity of 3: formation of carbocation
A from 3 is expected to be more favorable than formation of
carbocation A′ from 3′ (Scheme 2).18 The electron-donating and
withdrawing groups should polarize the π-system of cation A, which
would be expected to cyclize more readily than the symmetric
π-system of cation A′. Finally, regioselectivity of the elimination
of B is likely controlled by the position of the positive charge,
localized adjacent to the stabilizing oxygen atom. In oxyallyl cation
B′, the positive charge is fully delocalized and elimination is not
expected to be regioselective.
In summary, we report a mild, Lewis acid-catalyzed procedure
for Nazarov cyclization of polarized divinyl ketones. Further
research will focus upon improving our understanding of polariza-
tion in the cyclization, utilizing Lewis acids with chiral ligands to
promote enantioselective cyclization, and synthetic applications of
the methodology.
Acknowledgment. We thank the Research Corporation, the
Petroleum Research Fund (administered by the ACS), and the
University of Rochester for support of this research. We are also
grateful to Professor P. Holland for assistance with X-ray crystal-
lography. A.J.F. thanks Professor A. Kende for helpful discussions.
(16) The structure of 12a was determined by an X-ray diffraction study.
(17) After submission, it was found that cyclization of 17f improved
significantly when conducted in an inert atmosphere. This anomalous result
will be examined carefully in due course.
(18) Copper triflate probably coordinates to both carbonyl groups: (a) Evans,
D. A.; Rovis, T.; Kozlowski, M. C.; Tedrow, J. S. J. Am. Chem. Soc.
1999, 121, 1994. (b) Evans, D. A.; Scheidt, K. A.; Johnson, J. N.; Willis,
M. C. J. Am. Chem. Soc. 2001, 123, 4480.
Supporting Information Available: Representative experimental
procedure, spectral data for 3-18 (PDF), X-ray structure data for 3a
JA037910B
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