Fluorine-directed Nazarov cyclizations 2: Regioselective synthesis of 5-trifluoromethyl-2-Cyclopentenones

Article abstract of DOI:10.1055/s-1998-1817

1-Trifluoromethylvinyl vinyl ketones are treated with trimethylsilyl trifluoromethanesulfonate in CH₂Cl₂-1,1,1,3,3,3-hexafluoro-2-propanol to afford 5-trifluoromethyl-2-cyclopentenones. Both acyclic and cyclic substrates furnish the corresponding cyclized products in good to excellent yields with defined placement of the endocyclic double bond due to the strong electronic effect exerted by the trifluoromethyl group.

Full text of DOI:10.1055/s-1998-1817

August 1998
SYNLETT
927
Fluorine-Directed Nazarov Cyclizations 2: Regioselective Synthesis of 5-Trifluoromethyl-2-
cyclopentenones
Junji Ichikawa,* Masaki Fujiwara, Tatsuo Okauchi, and Toru Minami*
Department of Applied Chemistry, Kyushu Institute of Technology, Sensui-cho, Tobata, Kitakyushu 804-8550, Japan
Fax 81 93 884 3314; Bitnet ichikawa@che.kyutech.ac.jp
Dedicated to Professor E. J. Corey with deep respect on the occasion of his 70th birthday.
Received 13 May 1998
Abstract: 1-Trifluoromethylvinyl vinyl ketones are treated with
trimethylsilyl trifluoromethanesulfonate in CH Cl -1,1,1,3,3,3-
catalytic PdCl (PPh ) and CuCN8 to give the desired Nazarov
2 3 2
substrates in good yields (Scheme 2, Table 1).
2
2
hexafluoro-2-propanol to afford 5-trifluoromethyl-2-cyclopentenones.
Both acyclic and cyclic substrates furnish the corresponding cyclized
products in good to excellent yields with defined placement of the
endocyclic double bond due to the strong electronic effect exerted by the
trifluoromethyl group.
The Nazarov cyclization is versatile protocol for the construction of the
cyclopentenone framework, a structural motif found in a number of
1
natural products. While the classical reactions had limited utility due to
the lack of control of the position of the endocyclic double bond, their
improved versions, silicon- and tin-directed Nazarov cyclizations have
successfully addressed the problem of double-bond positional
selectivity.2 In the course of our studies on utilizing the properties of
Scheme 2
3
fluorine substituents in synthetic reactions, we have developed
4
fluorine-directed Nazarov cyclizations by making use of two properties
of fluorine: (i) its β-cation-destabilizing effect and (ii) its facile leaving-
group ability as fluoride ion.5 These fluorine-directed cyclizations
afford the selective synthesis of 5-alkylidene-3-fluoro-2-
cyclopentenones starting from 2,2-difluorovinyl vinyl ketones.
Regioselectivity is achieved by the electronic effect of fluorine on the
intermediary cyclopentenylic cations and the elimination of fluoride ion
to direct the position of the exo- and endocyclic double bonds.
Our interest in expanding the synthetic potential of the fluorine-directed
Nazarov cyclizations led us to investigate the introduction of fluorine at
an alternative position on the substrates, so that the β-cation-
destabilizing effect could be exerted on the cyclopentenylic cation 3
(
Scheme 1). Herein we report a new type of fluorine-directed Nazarov
We have previously found that the use of trimethylsilyl
cyclization, that provides a method for the regioselective preparation of
trifluoromethylated 2-cyclopentenones 4.6
trifluoromethanesulfonate (TMSOTf) in
a mixed solvent system,
dichloromethane (CH Cl ) and 1,1,1,3,3,3-hexafluoro-2-propanol
2
2
4,9
(
HFIP), is an optimal set of conditions for the Nazarov cyclization.
HFIP as a co-solvent dramatically accelerates cationic cyclizations due
to its high ionizing power and low nucleophilicity.10 These conditions (1
equiv of TMSOTf in CH Cl -HFIP (1:1) at room temperature) were
2
2
applied to 1a (R1 = Et, R
2
=
n
Pr), affording 5-trifluoromethyl-2-
11,12
cyclopentenone 4a in 79% yield as the sole cyclized product.
This
result indicates that the O-silylated pentadienylic cation 2 undergoes
electrocyclic ring closure to generate the cyclopentenylic cation 3, with
a subsequent positionally selective loss of a proton under the strict
1
3,14
electronic control of the trifluoromethyl group.
In contrast with 2,2-
4
difluorovinyl vinyl ketones, the elimination of fluoride ion from 3 was
not observed.15
Under similar reaction conditions several other trifluoromethylated
substrates 1b-f, including both acyclic and cyclic examples, were
examined. The cyclization of these substrates affords the corresponding
cyclopentenones 4b-f in good to excellent yields (Table 2).11 In the
cyclization of 2-butyl-4-trifluoromethyl-1,4-pentadien-3-one (1e), a
mixture of two isomers (4e/4e’ = 53/47) was obtained without formation
of isomer 4e"; here the directing effect of fluorine was exerted to place
the double bond away from the trifluoromethyl group (entry 5). The
Nazarov cyclization of the non-fluorinated counterpart of 1e yielded a
Scheme 1
We have designed the divinyl ketones 1 bearing vinylic trifluoromethyl
groups as Nazarov substrates. A series of 1-trifluoromethylvinyl vinyl
ketones 1 were prepared by Stille-type cross-coupling of tributyl(1-
7
trifluoromethylvinyl)tin (6), prepared via stannylcupration of 2-bromo-
3,3,3-trifluoropropene (5), with α,β-unsaturated acyl chlorides. The
reaction was conducted under modified conditions in the presence of

9
28
LETTERS
SYNLETT
mixture of the three products 7e-e" corresponding to 4e-e" in equal
quantities. These examples underscore the strong electronic bias
imposed by the trifluoromethyl group on the deprotonation of the
intermediate cation 3 .
layer chromatography on silica gel (hexane-Et O 3:1) to give 4a (31 mg,
2
1
79 %) as a colorless liquid. H NMR (500 MHz, CDCl ) δ 0.98 (3H, t, J
3
= 7.3 Hz), 0.99 (3H, t, J = 7.6 Hz), 1.61 (2H, tq, J = 7.3, 7.3 Hz), 2.22
(2H, q, J = 7.6 Hz), 2.39-2.51 (2H, m), 2.64 (1H, dd, J = 18.5, 3.1 Hz),
2
.76 (1H, dd, J = 18.5, 7.3 Hz), 3.09 (1H, qdd, J = 10.4, 7.3, 3.1 Hz).
1
3
C NMR (126 MHz, CDCl ) δ 13.0, 14.0, 16.5, 20.7, 30.5 (q, J = 3
3
CF
Hz), 32.7, 47.7 (q, J = 28 Hz), 124.9 (q, JCF = 278 Hz), 142.2, 172.1,
CF
1
99.6. 19F NMR (471 MHz, CDCl /C F ) 93.3 (3F, d, J = 9 Hz) ppm.
3 6 6 FH
IR (neat) 2840, 1680, 1610, 1430, 1415, 1325, 1225, 1125, 1080, 920
-
1
+
cm . MS (70 eV) m/z (rel intensity) 220 (M ; 41), 205 (100), 149 (24),
7
6
7 (17). Anal. Calcd for C11H15OF : C, 59.99 ; H, 6.87. Found: C,
0.02 ; H, 6.87.
3
Scheme 3
In order to further confirm the effect of fluorine on the regiochemistry in
the Nazarov cyclization we examined the substrate 1f, which is
Acknowledgments: We appreciate the financial support by a grant from
Ciba-Geigy Foundation (Japan) for the Promotion of Science and the
C.O.E. Research Fund of KIT to J. I. The analytical data given by the
Center for Instrumental Analysis KIT are greatly appreciated. We also
thank Central Glass Co., Ltd. and F-Tech, Inc. for generous gifts of
HFIP and 2-bromo-3,3,3-trifluoropropene, respectively.
dissymmetric due to the presence of
a trifluoromethyl group.
Cyclization proceeded through a defined pathway to give 4f and did not
yield the isomeric product with the double bond proximal to the
trifluoromethyl group (Table 2, entry 6). The results detailed herein
demonstrate that the trifluoromethyl substituent strongly directs the
double-bond regiochemistry of Nazarov cyclizations. Thus, we have
developed a second type of fluorine-directed Nazarov cyclization which
affords trifluoromethylcyclopentenones with excellent double-bond
References and Notes
(
1) Reviews of the Nazarov cyclization: Habermas, K. L.; Denmark,
S. E.; Jones, T. K. In Organic Reactions; Paquette, L. A. Ed.; John
Wiley & Sons: New York, 1994; Vol. 45, p 1. Denmark, S. E. In
Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I. Eds.;
Pergamon Press: Oxford, 1991; Vol. 5, p 751.
6
regioselectivity.
(
2) (a) Silicon-directed Nazarov cyclizations: Denmark, S. E.; Jones,
T. K. J. Am. Chem. Soc. 1982, 104, 2642. Denmark, S. E.;
Wallace, M. A.; Walker, Jr., C. B. J. Org. Chem. 1990, 55, 5543.
Kang, K. -T.; Kim, S. S.; Lee, J. C.; U, J. S. Tetrahedron Lett.
1
992, 33, 3495. Tin-directed Nazarov cyclizations: Peel, M. R.;
Johnson, C. R. Tetrahedron Lett. 1986, 27, 5947.
(3) Ichikawa, J.; Yokota, N.; Kobayashi, M.; Minami, T. Synlett,
1
993, 186. Ichikawa, J.; Kobayashi, M.; Yokota, N.; Noda, Y.;
Minami, T. Tetrahedron, 1994, 50, 11637. Ichikawa, J.; Yokota,
N.; Kobayashi, M.; Amano, K.; Minami, T. Synlett, 1996, 243.
Ichikawa, J.; Kobayashi, M.; Noda, Y.; Yokota, N.; Amano, K.;
Minami, T. J. Org. Chem., 1996, 61, 2763. Ichikawa, J.; Wada, Y.;
Okauchi, T.; Minami, T. Chem. Commun., 1997, 1537.
(4) Fluorine-directed Nazarov cyclizations 1: Ichikawa, J.; Miyazaki,
S.; Fujiwara, M.; Minami, T. J. Org. Chem. 1995, 60, 2320.
(
5) Smart, B. E. In Organofluorine Chemistry, Principles and
Commercial Applications, Banks, R. E.; Smart, B. E.; Tatlow, J. C.
Eds.; Plenum Press: New York, 1994; p 57.
(
6) Only a limited number of methods have been reported for the
synthesis of 5-trifluoromethyl-2-cyclopentenones despite the
potential utility of trifluoromethyl substitution in modifying the
properties and activities of biologically important small
molecules. Kawada, K.; Kitagawa, O.; Kobayashi Y. Chem.
Pharm. Bull. 1985, 33, 3670. Cruciani, G.; Margaretha, P. Helv.
Chim. Acta 1990, 73, 890. Hanzawa, Y.; Ito, H.; Kohara, N.;
Sasaki, H.; Fukuda, H.; Morikawa, T.; Taguchi, T. Tetrahedron
Lett. 1991, 32, 4143.
A typical reaction procedure is described for the synthesis of 4a. To a
solution of 1a (39 mg, 0.177 mmol) in CH Cl -HFIP (1:1, 2 ml) was
2
2
added TMSOTf (34 µl, 0.177 mmol) at room temperature under a
nitrogen atmosphere. After the reaction mixture was stirred for 8 min,
phosphate buffer (pH 7) was added to quench the reaction. Organic
(
7) Xu, Y.; Jin, F.; Huang, W. J. Org. Chem. 1994, 59, 2638.
(8) Ye, J.; Bhatt, R. K.; Falck, J. R. J. Am. Chem. Soc. 1994, 116, 1.
materials were extracted with CH Cl three times. The combined
(9) We have recently observed that fluorine-free Nazarov cyclizations
were also highly promoted under these conditions. These results
will be reported elsewhere.
2
2
extracts were washed with water and dried over Na SO . After removal
2
4
of the solvent under reduced pressure, the residue was purified by thin

August 1998
SYNLETT
929
(
10) Schadt, F. L.; Schleyer, P. v. R.; Bentley, T. W. Tetrahedron Lett.
974, 2335. Allard, B.; Casadevall, A.; Casadevall, E.; Largeau,
(14) For reports on cationic cyclizations where fluorine acts as an α-
cation-stabilizing substituent, see: Johnson, W. S.; Daub, G. W.;
Lyle, T. A.; Niwa, M. J. Am. Chem. Soc. 1980, 102, 7800.
Johnson, W. S.; Lyle, T. A.; Daub, G. W. J. Org. Chem. 1982, 47,
161. Fish, P. V.; Johnson, W. S.; Jones, G. S.; Tham, F. S.; Kullnig,
R. K. J. Org. Chem. 1994, 59, 6150 and references cited therein.
Morikawa, T.; Kumadaki, I.; Shiro, M. Chem. Pharm. Bull. 1985,
1
C. Nouv. J. Chim. 1979, 3, 335. For recent reports on the cationic
reactions conducted in HFIP, see: Ref. 4. Leonard, N. J.; Neelima
Tetrahedron Lett. 1995, 36, 7833. Ohwada, A.; Li, H.; Sakamoto,
T.; Kikugawa, Y. Heterocycles 1997, 46, 225.
11) All new compounds were fully characterized by 1H, 19F, 13
(
C
3
3, 5144.
NMR, IR, MS and combustion analysis (±0.3%) and/or HRMS.
(
15) The differing propensities of these substrates for defluorination
are not yet fully understood. Crowley, P. J.; Percy, J. M.;
Stansfield, K. Tetrahedron Lett. 1996, 37, 8233.
(
12) Acids such as TMSOTf, FeCl3, EtAlCl2, SnCl4, and
trifluoromethanesulfonic acid (TfOH) in CH Cl also promoted
2
2
these cyclizations at room temperature in moderate yields.
(
13) Allen, A. D.; Fujio, M.; Mohammed, N.; Tidwell, T. T.; Tsuji, Y.
J. Org. Chem. 1997, 26, 246 and references cited therein.