A novel base-induced cyclization of selected benzyl alkynyl sulfides for the synthesis of 2-aryl-2,3-dihydrothiophenes

Article abstract of DOI:10.1016/S0040-4039(00)00916-3

2-Halobenzyl 1-alkynyl sulfides undergo an unprecedented dihydrothiophene formation when treated with 2 equiv. of KOtBu in CH₃CN. The reaction, believed to proceed via a 5-endo-dig cyclization, is sluggish or non-existent in the absence of the halogen. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00916-3

Tetrahedron Letters 41 (2000) 5637±5641
A novel base-induced cyclization of selected benzyl alkynyl
sul®des for the synthesis of 2-aryl-2,3-dihydrothiophenes
Laura K. McConachie and Adrian L. Schwan*
Guelph-Waterloo Centre for Graduate Work in Chemistry and Biochemistry, Department of Chemistry and Biochemistry,
University of Guelph, Guelph, ON N1G 2W1, Canada
Received 1 May 2000; accepted 2 June 2000
Abstract
2-Halobenzyl 1-alkynyl sul®des undergo an unprecedented dihydrothiophene formation when treated
with 2 equiv. of KOtBu in CH3CN. The reaction, believed to proceed via a 5-endo-dig cyclization, is sluggish
or non-existent in the absence of the halogen. # 2000 Elsevier Science Ltd. All rights reserved.
Thiophenes and their derivatives have a myriad of uses in the ®elds of medicine, physical
organic chemistry and materials chemistry.1 Syntheses of a partially saturated version, the 2,3-
dihydrothiophenes, have been the topic of a number of publications,2 7 and among the newer
approaches,3 7 methods that involve the intramolecular cyclizations are particularly related to this
work. Some recent strategies include reactions of sulfenyl iodides with intramolecularly disposed
alkynes4 and the intramolecular ole®nation of thiol esters using low valent titanium.5 Similarly,
these heterocycles are accessible through the cyclization reactions of photochemically generated
radicals6 and by a unimolecular Wittig reaction.7
Our contribution to the area of 2,3-dihydrothiophenes arises from synthetic studies directed
towards allenyl benzyl sul®des for eventual cyclization to sulfur heterocycles. Through the
exploration of established methods designed to isomerize triple bonds to allenes, it was found that
2-iodobenzyl 1-propynyl sul®de (1a) did react with 2 equiv. KOtBu/THF/aq NH4Cl (quench),
but not to a€ord an allene. Rather, the material isolated was identi®ed with the assistance of
spectroscopic data to be 2-(2-iodophenyl)-2,3-dihydrothiophene (2a), a cyclic isomer of 1a (56%
1
yield; Scheme 1). The H 1H coupling constants of 2a are consistent with those expected for
related heterocycles3d,8 and of particular note, each of the hydrogens on C-3 couples appreciably
to all of the other protons in the heterocycle.
The conditions for the cyclization were idealized by varying parameters such as solvent, reaction
temperature, amount and identity of base and substrate concentration. A selection of the results
performed on sul®de 1a is presented in Table 1 (entries 1±6). Other benzyl alkynyl sul®des were
* Corresponding author.
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00916-3

5638
Scheme 1.
prepared9 in order to probe the generality of the cyclization and the remainder of Table 1 indicates
the propensity of those sul®des for cyclization.10 On inspection of the table, it is readily noted
that an ortho halogen group appears to be vital to a synthetically useful cyclization. In those cases
where the substrate was lacking the ortho halogen, the reaction proved sluggish and the yield was
lower. Harsher reaction conditions provided a small improvement in yield for some of those
substrates.11
Table 1
Base-induced cyclizations of benzyl 1-alkynyl sul®des
Additional noteworthyꢀreactions are shown in Scheme 2. Bis-alkyne 1j was treated with 4
equiv. KOtBu/CH3CN/60 C to a€ord product 2j (47%, 1:1 dr by 13C NMR). When the alkyl chain
appended to the alkyne is longer than methyl in the starting material (1k), a mixture of dihydro-
thiophene isomers 2k and 2k0 is obtained. The mixture can be separated and if 2k0 is re-exposed
to the reaction conditions, the same ratio of double bond isomers is salvaged. It is suggested that
the cyclization conditions may induce the isomerization of the double bond in any of the
immediate cyclization products, to eventually provide the thermodynamically more stable reaction
products.

5639
Scheme 2.
Some preliminary mechanistic work has been accomplished. When 1a labelled with a 13C atom
on the methyl group underwent cyclization, the label occupied position 3 exclusively in the product,
suggesting that a direct attachment of atom 3 to the benzylic position is likely. Scrambling of the
label may be expected from some sort of elimination/addition mechanism.12 When the reaction of
1a was performed in CD3CN, the sample of 2a obtained showed full deuteration at all of the
2
heterocyclic ring positions (1H and H NMR). Subsequent control experiments indicated that
there is substantial incorporation of deuterium in 1a before cyclization.
Scheme 3 o€ers possible cyclization modes of alkyne 1 in CH3CN. Our experiments and the
literature indicate that there is probably an equilibrium comprised of the propynyl (1), allenyl (3)
and propargyl (4) species, in addition to exchange at benzylic positions. Indeed, cyclization pre-
sumably requires a benzylic anion attacking the terminal carbon of the unsaturated chain which
has assumed either the allenyl (5) or propargyl (6) tautomer. Alternatively, the benzylic anion
could rearrange via a [2,3]-thia-Wittig-like sigmatropic rearrangement, with the eventual
requirement of a thiolate to alkyne ring closure. The carbon anions formed (7, 8) will be rapidly
protonated by solvent and, as indicated above, tautomerization will furnish the thermo-
dynamically more stable product.13,14 Each of the cyclizations suggested herein are of the 5-endo-
dig variety and as such are not predicted to readily occur. However, several precedents are
available, including some that form sulfur heterocycles.4,15
Scheme 3.

5640
The cyclization reaction is a useful protocol for preparing 2-(2-haloaryl) thiophene derivatives.
Though apparently limiting, the ortho halogen does provide a handle for further elaboration of
compounds 2 with applications in the growing areas of sulfur-containing organic materials16,17
and in solid supported synthesis.17 We are currently pursuing the synthetic scope and mechanism
of this reaction, with particular attention being paid to the rate enhancing role played by the
ortho halogen substituent.
Acknowledgements
The authors are grateful to the NSERC of Canada for funding this project through a Research
Grant to ALS and a PGS A Scholarship to LKM.
References
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L. E. E. In Comprehensive Heterocyclic Chemistry II, Vol. 2.; Bird, C. W., Ed. Katritzky, A. R.; Rees, C. W.;
Scriven, E. F., Series Eds. Pergamon: Oxford, 1986; Chapter 2.12.
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Compounds, 2nd Ed. Springer-Verlag: New York, 1989; p. H100.
9. Alkynes 1 are prepared via the reaction of an acetylide anion with compounds ArCH2SX (XˆCN and/or SO2Tol;
yields 55, 72, 79±95%). Similar displacement reactions are known; XˆSO2Tol: Takeda, H.; Shimada, S.; Ohnishi,
S.; Nakanushi, F.; Matsuda, H. Tetrahedron Lett. 1998, 39, 3701±3704.; XˆCN: Klein, T. R.; Bergemann, M.;
Yehia, N. A. M.; Fanghanel, E. J. Org. Chem. 1998, 63, 4626±4631. The thiotosylates and thiocyanates are made
through substitution reactions of KSSO2Tol and KSCN, respectively, with benzylic halides or mesylates.
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NMR, IR and elemental analysis or MS.
C
10. The cyclization of 1b is presented as an example of the general experimental procedure: To KOtBu (1.73 mmol) in
dry CH3CN (10 mL) at 0ꢀC, was added 2-bromobenzyl 1-propynyl sul®de (1b) (0.867 mmol) in dry CH3CN (10
mL). The mixture was stirred at 0ꢀC for 24 h and was quenched with H2O. The layers were separated, and the aq.
layer was extracted with EtOAc (3Â10 mL). The combined organic layers were washed with brine, dried over
MgSO4, and concentrated. Flash chromatography on silica gel (100% hexanes) a€orded pure 2-(2-bromophenyl)-
1
2,3-dihydrothiophene (2b, 74%) as a yellow liquid. H NMR (400 MHz, CDCl3) ꢀ 7.62 (dd, J=7.7, 1.6 Hz, 1H),
7.55 (dd, J=7.7, 1.2 Hz, 1H), 7.29 (dt, J=7.7, 1.2 Hz, 1H), 7.11 (dt, J=7.7, 1.6 Hz, 1H), 6.24 (ddd, J=6.0, 2.6, 1.7
Hz, 1H), 5.61 (dt, J=6.0, 2.9 Hz, 1H), 5.27 (dd, J=9.7, 4.9 Hz, 1H), 3.27 (ddt, J=16.8, 9.7, 2.6 Hz, 1H), 2.86
(dddd, J=16.8, 4.9, 2.9, 1.7 Hz, 1H). 13C NMR ꢀ 142.5, 132.7, 128.7, 128.1, 127.9, 125.4, 123.3, 120.4, 50.8, 42.3.
IR (cm^1) 3062, 2938, 2896, 2842, 1588, 1567, 1467, 1440, 1265, 1025. EIMS, m/z (%): 242 (20, M+ for 81Br), 128
(100); Analysis calcd for C10H9BrS: C, 49.81; H, 3.76. Found: C, 49.79; H, 3.88.

5641
11. Compounds 2e±h could not be successfully separated from the starting sul®de. Their structure was assigned by
observation of the heterocycle's unique 1H NMR splitting pattern, already established for isolated products 2a±c,
i±k. In one instance, the crude mixture containing 1e and 2e was oxidized (MCPBA) and the resulting S,S-dioxide
of 2e was isolated and fully characterized.
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J. Org. Chem. 1992, 57, 4507±4512.
13. The proposed mechanism(s) suggests that allenyl sul®des 3 and propargyl sul®des 4 should also be starting
materials for the cyclization. Indeed upon exposure of 3a and 4a to the standard conditions, 2a was obtained in
43 and 38% yields, respectively.
14. Quenching the mixtures with D2O or MeI rather than aq. NH4Cl gave the same product, indicating that anions
such as 7 and 8 gain their H+ from the reaction environs.
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