in the synthesis of complex organic molecules5 and their
preparation typically involves oxidative and/or acidic condi-
tions,6 we decided to investigate further the mild generation
of these intermediates from â-sulfenyl enol triflate precursors.
The results of these studies are presented herein.
The cyclic â-sulfenyl enol triflates used in our studies were
prepared from the corresponding R-sulfenyl ketones7,8 by
enolization with KHMDS in THF at -78 °C and subsequent
trapping of the potassium enolate with PhNTf2 or 2-[N,N-
bis(trifluoromethylsulfonyl)amino]-5-chloro-pyridine (Comins’
reagent) (Scheme 3).1,9 With the exception of cyclopen-
tanone-derived enol triflate 18, these intermediates were
moderately stable oils, isolated in yields ranging from 68 to
98%.10
Conditions for the thermal fragmentation step were
optimized using cyclohexenyl triflate 8 (Scheme 3). Initial
experiments showed that the conversion of 8 to R-sulfenyl
ketone 10 was the cleanest in the presence of an added base;
2,6-lutidine was found to be suitable for this purpose. A
variety of solvents were examined for this reaction: heptane,
PhH, PhMe, EtOAc, 1,4-dioxane, DME, 2-butanone, 1,2-
dichloroethane, MeCN, N,N-dimethylacetamide, DMF, DMSO,
and EtOH.11 With the exception of EtOH, the reaction
proceeded cleanly in all solvents examined.12 The conversion
of 8 to 10 was fastest in polar aprotic solvents, with the rate
of conversion being highest in DMSO and MeCN. Utilization
of DMSO as the solvent gave complete conversion of 8 to
10 within 10 h at temperatures between 70 and 80 °C.
The scope of this synthesis of cyclic R-sulfenyl enones
was explored using thermolysis conditions found to be
optimal for the conversion of 8 to 10: 80 °C in DMSO
containing 1.5 equiv of 2,6-lutidine. As summarized in
Scheme 3, cyclohexenyl and cycloheptenyl R-methylthio
enones (9, 10, 13, and 16) were formed in good yields. Alkyl
substitution was tolerated both adjacent to the triflate and at
the allylic position of the enone product. The conversion of
2-(methylthio)cyclopentanone (17) to R-sulfenyl enone 19
was low yielding, undoubtedly reflecting the instability of
triflate 18. When the sulfur substituent was phenyl, the
thermal fragmentation step was slower. For example, 48 h
was required for the conversion of â-phenylthio enol triflate
21 to enone 22.13 This conversion was not as clean as the
analogous transformation in the methylthio series (8 f 10).
However, the attenuated reactivity of â-phenylthio enol
triflate intermediates proved to be advantageous in the
cyclopentenyl series. Whereas methylthio triflate 18 could
not be isolated, phenylthio congener 24 was isolated without
incident. Subsequent thermolysis of 24 in DMSO at 80 °C
for 24 h resulted in the production of 2-(phenylthio)-
cyclopenten-2-one (25) in 80% yield.
Scheme 3a
Acetonitrile is also a convenient solvent for the thermal
fragmentation step. For example, cyclohexenyl triflate 26 was
converted to R-methylthio cyclohexenone 27 within 12 h at
(5) Selected examples: (a) Aratani, M.; Dunkerton, L. V.; Fukuyama,
T.; Kishi, Y.; Kakoi, H.; Sugiura, S.; Inoue, S. J. Org. Chem. 1975, 40,
2009-2011. (b) Yechezkel, T.; Ghera, E.; Ostercamp, D.; Hassner, A. J.
Org. Chem. 1995, 60, 5135-5142. (c) Lebsack, A. D.; Overman, L. E.;
Valentekovich, R. J. J. Am. Chem. Soc. 2001, 123, 4851-4852.
(6) Acidic: (a) Monteiro, H. J. J. Org. Chem. 1977, 42, 2324-2326.
Vankar, Y. D.; Kumaravel, G.; Bhattacharya, I.; Vankar, P.; Kaur, K.
Tetrahedron 1995, 51, 4829-4840. (b) Guaciaro, M. A.; Wovkulich, P.
M.; Smith, A. B., III. Tetrahedron Lett. 1978, 47, 4661-4664. Oxidative:
(c) Tomoeda, M.; Inuzuka, M.; Furuta, T.; Shinozuka, M. Tetrahedron 1968,
24, 959-974. Tobias, M. A.; Strong, J. G.; Napier, R. P. J. Org. Chem.
1970, 35, 1709-1711. (d) Sugihara, Y.; Wakabayashi, S.; Saito, N.; Murata,
I. J. Am. Chem. Soc. 1986, 108, 2773-2775. Oxidative and acidic: (e)
Monteiro, H. J.; Gemal, A. L. Synthesis 1975, 437-438.
(7) (a) 2-(Methylthio)cycloalkanones were obtained from commercial
sources or were prepared according to the procedure of Scholz, D. Synthesis
1983, 944-945.7 (b) 2-(Phenylthio)cycloalkanones were prepared according
to the procedure of Trost, B. M.; Massiot, G. S. J. Am. Chem. Soc. 1977,
99, 4005-4412.
(8) A serious explosion occurred when preparing MeSSO2Me according
to the procedure described in ref 6a. Alternative methods for the preparation
of this reagent should be utilized; see: Chemla, F.; Karoyan, P. Org. Synth.
2000, 78, 99-103 and references cited therein.
(9) (a) Comins, D. L.; Dehghani, A. Tetrahedron Lett. 1992, 33, 6299-
6302. (b) Compounds 21 and 24 proved to be difficult to purify when
prepared using PhNTf2.
(10) These delicate intermediates could be stored for several weeks as
solutions in pentane at -20 °C.
(11) These experiments were run at 80 °C in the presences of ca. 5 equiv
of 2,6-lutidine for 4 h; conversion was assessed by 1H NMR analysis of
crude reaction products.
(12) A complex mixture of products that included 10 was formed in
EtOH; no attempt was made to identify the other components.
(13) The greater thermal stability of R-phenylthio than R-methylthio enol
triflates explains why Heck cyclization of 2a suceeded, whereas the related
cyclization of 2b was low yielding.1
a Conditions: (a) KHMDS, PhNTf2; (b) 2,6-lutidine, DMSO, 80
°C; (c) KHMDS, Comins’ reagent.
930
Org. Lett., Vol. 4, No. 6, 2002