Radical cyclizations of 2-(ω-haloalkylthio)enones to thiapolycycloalkanones

Article abstract of DOI:10.1016/S0040-4039(00)00161-1

Radical cyclization of 2-(ω-haloalkylthio)enones gives predominantly fused-thiapolycycloalkanones. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00161-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 2279–2282
Radical cyclizations of 2-(ω-haloalkylthio)enones to
thiapolycycloalkanones
∗
Anthony A. Ponaras and Ömer Zaim
Department of Chemistry, The Catholic University of America, Washington, DC 20064, USA
Received 3 December 1999; accepted 14 January 2000
Abstract
Radical cyclization of 2-(ω-haloalkylthio)enones gives predominantly fused-thiapolycycloalkanones. © 2000
Elsevier Science Ltd. All rights reserved.
Keywords: heterocyclic compounds; polyheterocyclic compounds; sulfur heterocycles; radicals and radical reactions;
cyclization; enones; α-sulfenyl ketones.
We have previously prepared oxapolycycloalkanones via cyclization of radicals (e.g., 1, Z=O) generat-
1
ed from diosphenol ω-haloalkyl ethers. We decided to examine radical cyclization of analogous sulfur-
tethered systems for several reasons. First, due to the high nucleophilicity of thiols and thiolates, the cycli-
2
3
zation substrates can be prepared efficiently from a variety of precursors. Second, thiacycloalkanones,
4
the expected products, are of interest in mechanistic and conformational analysis studies, and should
be useful in the preparation of heterocyclic analogues of physiologically-active substances.
5–7
Third,
mechanistic considerations suggested that, since sulfur stabilizes adjacent radical centers more than
8
oxygen, replacement of oxygen by sulfur would result in a greater preference for fused products.
9
9
Polarized transition state 2 is strongly influenced by Z; polarized transition state 4 is less strongly
influenced by Z, since Z is one atom further removed from the developing radical center (Scheme 1).
Scheme 1.
∗
Corresponding author.
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040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00161-1
tetl 16441

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The experiments described below suggest that this hypothesis is correct. For example, when 6s2,10 was
subjected to the same cyclization conditions as 6o, the exclusive product was the trans-fused 7s (Scheme
1
1
2).
Scheme 2.
Results with three other systems are presented in Scheme 3 (yields by isolation or gas
chromatography).12
Scheme 3.
It is notable that for each thia-substrate there is more fused product than in the oxa-series and, with
the exception of 14, less uncyclized (reduced) product.13 The increased amount of 5-endo cyclization in
1
4
1
4 (compared to its oxa analogue) can also be attributed to the longer C–S bond length. As previously
1
noted, aryl radicals (cf. 6s) cyclize well, whereas benzyl radicals (cf. 18) cyclize poorly.
Application of transformations typical of α-sulfenylketones15 leads to further possibilities. For
example, Raney nickel desulfurization of 11 and 12 gives 3-propylcyclohexanone 22 and 2-
propylcyclohexanone 23, respectively, thereby providing a method to distinguish fused- from
spiro-cyclization (Scheme 4).

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Scheme 4.
Reductive alkylation or sulfur-directed regioselective enolate formation followed by alkylation are
1
6
other attractive sequences. We are continuing to explore the synthetic possibilities of these cyclizations.
Acknowledgements
We thank the National Science Foundation and the Petroleum Research Fund (administered by the
American Chemical Society) for their financial support.
References
1
2
. Ponaras, A. A.; Zaim, Ö. Tetrahedron Lett. 1993, 34, 2879.
. Preparation of 6s: rxn of 2-bromo-2-cyclohexen-1-one with potassium 2-iodobenzyl thiolate in THF (cf., Fujisawa, T.;
Sakai, K.; Shirokata, H.; Fukushima, A. (Sagami Chemical Research Center) Jpn. Kokai Tokkyo Koho JP 54,088,210
(
1977) Chem. Abstr. 1979, 92, 76093c. Preparation of 10: heating 1,2-cyclohexanedione and 3-chloro-1-propanethiol in
benzene (cat. TsOH) under a Dean–Stark trap, followed by treatment with sodium iodide in acetone. Preparation of 13, 14,
7 and 21: rxn of 2,3-epoxycyclohexanone with the appropriate sodium thiolate in ethanol (cf., Tobias, M. A.; Strong,
1
J. G.; Napier R. P. J. Org. Chem. 1970, 35, 1709. Preparation of 18: rxn of 2,3-epoxycyclohexanone with sodium 2-
hydroxymethyl benzenethiolate in ethanol, followed by treatment with chlorotrimethylsilane/HMDS, followed by treatment
with iodotrimethylsilane.
3
4
. For a review of thiadecalins, see: Klimenko, S. K.; Stolbova, T. V. Usp. Khim. 1985, 54, 803.
. (a) Claus, P. K.; Rieder, W.; Vierhapper, F. W. Mh. Chem. 1978, 109, 609. (b) Vierhapper, F. W.; Willer, R. L. J. Org. Chem.
1
977, 42, 4024. (c) Claus, P. K.; Vierhapper, F. W.; Willer, R. L. J. Org. Chem. 1977, 42, 4016.
5
6
. Heterocyclic steroids: (a) Suginome, H.; Yamada, S.; Wang, J. B. J. Org. Chem. 1990, 55, 2170. (b) Ramadas, S. R.;
Chenchaiah, P. C.; Kumar, N. S. C.; Krishna, M. V.; Srinivasan, P. S.; Sastry, V. V. S. K.; Rao, J. A. Heterocycles 1982,
1
9, 861. (c) Huisman, H. O.; Speckamp, W. N. Int. Rev. Sci., Org. Chem., Ser. Two 1976, 8, 207.
. Heterocyclic inhibitors of terpenoid biosynthesis: (a) Bull, H. G.; Harris, G.; Myers, R. W. (Merck and Co., Inc.), US Patent
,756,480, (1996); Chem. Abstr. 1998, 129, 16283n. (b) Bakshi, R. K.; Patel, G. F.; Rasmusson, G. H.; Tolman, R. L. (Merck
5
and Co., Inc.), PCT Int. Appl. WO 97 15,564 (1997); Chem. Abstr. 1997, 127, 50846s.
. Heterocyclic prostaglandins: Orth, D.; Radunz, H. E. Top. Curr. Chem. 1977, 72, 51.
. Inter alia: (a) Giese, B. Angew. Chem., Int. Ed. Engl. 1983, 22, 753. (b) Viehe, H. G.; Merenyi, R.; Janousek, Z. Pure Appl.
Chem. 1988, 60, 1635.
7
8
9
. (a) Struble, D. A.; Beckwith, A. L.; Gream, G. A. Tetrahedron Lett. 1968, 3701. (b) Beckwith, A. L.; Schiesser, C. H.
Tetrahedron 1985, 41, 3925. (c) Spellmeyer, D. C.; Houk, K. N. J. Org. Chem. 1987, 52, 959.
1
1
0. All new compounds were fully characterized: 60 MHz H NMR (CDCl
6
3
) and IR (film) data are presented below. Compound
−1
s: NMR δ 1.7–2.7 (m, 6H), 3.98 (s, 2H), 6.79 (t, J=4.5 Hz, 1H), 6.9–8.0 (m, 4H); IR 1678, 1589, 1245, 1160 cm
Compound 7s: NMR δ 1.4–3.1 (m, 7H), 3.46 (d, J=12 Hz, 1H), 3.68 (s, 2H), 6.9–7.5 (m, 4H); IR 1715, 1654, 1541, 1489,
.
−
−
−
1
1
1
1
1
1
1
456 cm . Compound 10: NMR δ 1.7–3.0 (m, 10H), 3.27 (t, J=6.5 Hz, 2H), 6.80 (t, J=4.5 Hz, 1H); IR 1677, 1589, 1210,
1
125 cm . Compound 11: NMR δ 1.1–2.1 (m, 9H), 2.1–2.6 (m, 4H), 3.19 (d, J=9 Hz, 1H); IR (KBr) 1699, 1454, 1318,
1
122 cm . Compound 14: NMR δ 1.8–2.8, (m, 6H), 6.63 (t, J=4.5 Hz, 1H), 6.9–7.9 (m, 4H); IR 1680, 1590, 1421, 1330,
−
1
125, 1007 cm . Compound 15: NMR δ 1.6–2.7 (m, 6H), 3.4–4.0 (m, 1H), 4.27 (d, J=7, 1H), 6.7–7.4 (m, 4H); IR 1708,
−1
665, 1446, 1233 cm . Compound 17: NMR δ 1.6–2.7 (m, 6H), 6.53 (t, J=4.5 Hz, 1H), 7.1–7.6 (m, 4H); IR 1676, 1592,
−
1
440, 1346, 1262, 750 cm . Compound 18: NMR δ 1.7–2.8 (m, 6H), 4.63 (s, 2H), 6.28 (t, J=4.5 Hz, 1H) 6.9–7.5 (m, 4H);

2
282
IR 1674, 1593, 1234, 1159 cm 1. Compound 19: NMR (90 MHz) δ 1.4–3.0 (m, 9H), 3.96, (d, J=12 Hz, 1H), 6.9–7.3 (m,
−
−
1
4
6
H); IR 1704, 1567, 1474, 1436, 1417 cm . Compound 21: NMR δ 1.6–2.7, (m, 6H), 2.36 (s, 3H), 6.12 (t, J=4.5, 1H),
1
−
.9–7.5 (m, 4H); IR 1676, 1590, 1470, 1329 cm
.
1
1
1. Only the trans-fused 7s could be detected. In analogy with 7o, it is presumed that both cis and trans are initially formed and
that cis isomerizes to trans under the reaction and/or workup conditions.
2. Typical experimental procedure: a 0.407 g (1.4 mmol) portion of tributyltin hydride was added all at once under nitrogen
to a magnetically stirred solution of 0.330 g (1 mmol) of 14 and 0.01 g azobisisobutyronitrile in 5 mL dry benzene. The
mixture was heated at reflux for 1 h, then solvent was removed under vacuum. The residue was dissolved in 10 mL of ether
and stirred with 10 mL of 10% aq. potassium fluoride solution for 30 min. The white precipitate (presumably tributyltin
fluoride) was separated by filtration and the aqueous phase extracted with 10 mL of ether. The combined ether extracts
were washed with brine, dried over anhyd. magnesium sulfate, and evaporated, giving 0.325 g residue. This residue was
dissolved in a minimum amount of chloroform and chromatographed on 40 g silica gel (Davisil grade 643, 200–425 mesh)
1
0
2,10
packed in benzene:ethyl acetate (19:1) giving 0.125 g (61%) of 15 followed by 0.067 g (33%) of 17.
In a parallel
experiment, the crude reaction mixture was desulfurized with Raney nickel in ethanol, giving 3-phenylcyclohexanone but
no 2-phenylcyclohexanone, thus establishing the absence of 16.
13. Reactions were typically conducted with substrate concentrations of 0.2 M. It is likely that greater dilution would diminish
the amount of uncyclized (reduced) product.
1
1
1
4. Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 734.
5. (a) Trost, B. M. Chem. Rev. 1978, 78, 363. (b) Trost, B. M. Accounts Chem. Res. 1978, 11, 453.
6. Coates, R. M.; Pigott, H. D.; Ollinger, J. Tetrahedron Lett. 1974, 3955.