A novel consecutive reaction of lithium acetylides with 2-aryl-1-chlorovinyl p-tolyl sulfoxides leading to the formation of (Z)-enediynes

Article abstract of DOI:10.1016/j.tetlet.2012.11.152

The reaction of (E)-2-aryl-1-chlorovinyl p-tolyl sulfoxides with lithium acetylides gave a variety of (Z)-3-arylhex-3-ene-1,5-diynes in yields of up to 80% with high stereoselectivity. The structure of the (Z)-enediyne was confirmed by X-ray molecular structure analysis. The result of the reaction with deuterium- and ¹³C-labeled sulfoxide suggested that the reaction proceeds through cleavage of the C-H bond at the β-position of the 2-aryl-1-chlorovinyl unit in sulfoxide.

Full text of DOI:10.1016/j.tetlet.2012.11.152

Tetrahedron Letters 54 (2013) 1049–1051
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Tetrahedron Letters
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A novel consecutive reaction of lithium acetylides with 2-aryl-1-chlorovinyl
p-tolyl sulfoxides leading to the formation of (Z)-enediynes
Tsutomu Kimura a, Yuka Nishimura b, Naoyuki Ishida b, Hitoshi Momochi b, Hironori Yamashita b,
Tsuyoshi Satoh a,b,
⇑
a Department of Chemistry, Faculty of Science, Tokyo University of Science, 12 Ichigaya-funagawara-machi, Shinjuku-ku, Tokyo 162-0826, Japan
b Graduate School of Chemical Sciences and Technology, Tokyo University of Science, 12 Ichigaya-funagawara-machi, Shinjuku-ku, Tokyo 162-0826, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The reaction of (E)-2-aryl-1-chlorovinyl p-tolyl sulfoxides with lithium acetylides gave a variety of
(Z)-3-arylhex-3-ene-1,5-diynes in yields of up to 80% with high stereoselectivity. The structure of the
(Z)-enediyne was confirmed by X-ray molecular structure analysis. The result of the reaction with
deuterium- and 13C-labeled sulfoxide suggested that the reaction proceeds through cleavage of the
C–H bond at the b-position of the 2-aryl-1-chlorovinyl unit in sulfoxide.
Received 24 October 2012
Revised 19 November 2012
Accepted 26 November 2012
Available online 21 December 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
1-Chlorovinyl p-tolyl sulfoxides
Lithium acetylides
(Z)-Enediynes
Consecutive reaction
(Z)-Hex-3-ene-1,5-diynes, also referred to as (Z)-enediynes, are
a class of highly unsaturated conjugated compounds that are capa-
ble of undergoing Bergman cycloaromatizations.1 Since the discov-
ery of the antitumor activity of (Z)-enediynes,2 considerable effort
has been devoted to developing efficient methods for the synthesis
of these compounds.3–6 A representative method for construction
of the (Z)-enediyne structure is the Pd-catalyzed coupling reaction
of 1,2-dihalogenated olefins with terminal acetylenes.4 Geometri-
cally pure cis-dihaloalkenes are substantially required for the cou-
pling reaction.4d,7 An alternative route for the preparation of
enediynes is the formation of a central double bond by the elimina-
tion reaction of 1,5-diynes that contain a leaving group.5 However,
the elimination process suffers from low geometric selectivity.
Recently, we have reported various synthetic transformations of
1-chlorovinyl p-tolyl sulfoxides.8 Among these transformations,
2,2-dialkyl-substituted sulfoxides 1 reacted with lithium acety-
lides 2 to give 1-chlorobut-3-ynyl sulfoxides 3, and treatment of
these sulfoxides 3 with a Grignard reagent afforded conjugated
enynes 4 via the [1,2]-acetylide migration of the resultant magne-
sium carbenoids (Scheme 1, Eq. 1).9 By contrast, 2-monoalkyl-
substituted sulfoxides 5 were directly converted into conjugated
enynes 7 bearing a sulfinyl group by reaction with lithium acety-
lides 2 through the [1,2]-hydride shift of the intermediates 6
(Scheme 1, Eq. 2).9 In a continuation of our effort to investigate
the reaction of 1-chlorovinyl p-tolyl sulfoxides, we found that
Scheme 1. Reaction of 2,2-dialkyl- and 2-monoalkyl-substituted 1-chlorovinyl
p-tolyl sulfoxides 1 and 5 (R = alkyl) with lithium acetylides 2.
2-monoaryl-substituted 1-chlorovinyl p-tolyl sulfoxides showed a
different type of reactivity toward lithium acetylides than that
shown by alkyl-substituted sulfoxides. Herein, we report the
⇑
Corresponding author.
E-mail address: tsatoh@rs.kagu.tus.ac.jp (T. Satoh).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.11.152

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T. Kimura et al. / Tetrahedron Letters 54 (2013) 1049–1051
Table 2
Synthesis of the (Z)-enediynes 10h–m from sulfoxides (E)-8 and lithium phenylacet-
ylide
Ar
Ph
H/BuLi
Ar
O
S
9a
Ph
Tol
THF
Cl
r.t., 30 min
Ph
10h-m
(E)-8
Entry
Sulfoxide (E)-8
10
Yield (%)
Ar
(E)-8
1
2
4-MeSC6H4
(E)-8b
10h
75
65
(E)-8c
10i
3
4
5
6
4-CF3C6H4
4-ClC6H4
1-Naphthyl
2-Thienyl
(E)-8d
(E)-8e
(E)-8f
(E)-8g
10j
10k
10l
56
44
37
48
Scheme 2. Reaction of 1-chloro-2-phenylvinyl p-tolyl sulfoxides (E)- and (Z)-8a
with lithium phenylacetylide.
10m
reaction of 2-aryl-1-chlorovinyl p-tolyl sulfoxides with lithium
acetylides leading to the formation of (Z)-enediynes.
A variety of 2-aryl-substituted sulfoxides (E)-8 were subjected
to the reaction with lithium phenylacetylide (Table 2). The sulfox-
ides (E)-8b–e, having either an electron-donating or electron-
withdrawing group on the aromatic ring, underwent a consecutive
reaction with lithium acetylide to give the corresponding
(Z)-enediynes 10h–k in moderate yields (entries 1–4). The struc-
ture of the (Z)-enediyne 10k was unequivocally confirmed by
X-ray molecular structure analysis (see Supplementary data).12
Treatment of the sulfoxide (E)-8f, bearing a 1-naphthyl group, with
lithium acetylide afforded the enediyne 10l in 37% yield (entry 5).
The sulfoxide (E)-8g derived from thiophene-2-carbaldehyde could
Initially, the reaction of the (E)-1-chloro-2-phenylvinyl p-tolyl
sulfoxide (E)-8a with lithium phenylacetylide was carried out
(Scheme 2).10 A solution of the sulfoxide (E)-8a in THF was added
to a solution of lithium phenylacetylide (5 equiv) in THF at room
temperature, and the mixture was stirred at that temperature for
30 min. As a result, the (Z)-enediyne (Z)-10a, in which two acety-
lenic components were introduced to both the a- and b-positions
of styrene, was obtained in 80% yield.6d,11 Unexpectedly, a similar
reaction with the other geometric isomer (Z)-8a gave not an
(E)-enediyne but the (Z)-enediyne (Z)-10a in 36% yield. When the
reaction was carried out with an unseparated mixture of the geo-
metric isomers (E)-8a and (Z)-8a, the (Z)-enediyne (Z)-10a was ob-
tained as a single isomer in 49% yield.
also be used as
a substrate, and the heteroaryl-substituted
enediyne 10m was obtained in 48% yield (entry 6). In all cases,
the sulfoxides (E)-8 were completely consumed within 30 min
(Tables 1 and 2). However, the (Z)-enediynes 10 were obtained in
low to moderate yields in several cases. By-products originating
from the 2-aryl-1-chloro-vinyl component of the sulfoxides (E)-8
appeared to be volatile materials and were lost during the workup
process.13
The scope of this reaction was investigated with a range of aro-
matic and aliphatic acetylenes 9 (Table 1). The sulfoxide (E)-8a re-
acted with lithium arylacetylides, which were generated from BuLi
and the aromatic acetylenes 9b–e bearing a methyl, methoxy, flu-
oro, or chloro group at the p-position of the benzene ring, to give
the corresponding (Z)-enediynes 10b–e in 44–63% yield (entries
1–4). The bis(trimethylsilyl)-protected (Z)-enediyne 10f was
obtained from the sulfoxide (E)-8a and trimethylsilylacetylene
(9f) in 65% yield (entry 5). In the case of the reaction with the
alkyl-substituted acetylene 9g, the desired (Z)-enediyne 10g was
produced in low yield.
To gain insight into the mechanism of this unprecedented reac-
13
tion, deuterium- and C-labeled sulfoxide (E)-8a0 was prepared
from benzaldehyde-a- a
13C, -d1 (Ph13CDO) and chloromethyl
p-tolyl sulfoxide, and the sulfoxide (E)-8a0 was subjected to reac-
tion with lithium phenylacetylide (Scheme 3). Consequently, the
(Z)-enediyne (Z)-10a0 having carbon-13 and deuterium atoms at
the 3- and 4-positions was obtained with a low deuterium content.
This result indicated that not the 13C–Ph bond but the 13C–D bond
in the sulfoxide (E)-8a0 was cleaved during the reaction.
Table 1
In summary, we investigated the reaction of 2-aryl-1-chlorovinyl
p-tolyl sulfoxides and lithium acetylides that lead to the formation
of (Z)-enediynes. In this reaction, two acetylenic components were
consecutively introduced to the alkene unit, and various enediynes
were obtained in a highly (Z)-stereoselective manner. The reaction
utilizing deuterium- and 13C-labeled sulfoxide demonstrated that
Synthesis of the (Z)-enediynes 10b–g from sulfoxide (E)-8a and lithium acetylides
Entry
Acetylene
10
Yield (%)
R
9
1
2
3
4
5
6
4-MeC6H4
4-MeOC6H4
4-FC6H4
4-ClC6H4
Me3Si
9b
9c
9d
9e
9f
10b
10c
10d
10e
10f
63
62
52
44
65
19
Scheme 3. Reaction of 13C-labeled (E)-1-chloro-2-deuterio-2-phenylvinyl p-tolyl
sulfoxide (E)-8a0 with lithium phenylacetylide.
PhCH2CH2
9g
10g

T. Kimura et al. / Tetrahedron Letters 54 (2013) 1049–1051
1051
Yonemitsu, O.; Tsuji, J. J. Org. Chem. 1996, 61, 5716; (d) Trost, B. M.; Hachiya, I.;
McIntosh, M. C. Tetrahedron Lett. 1998, 39, 6445; (e) de Araujo, M. A.; Raminelli,
C.; Comasseto, J. V. J. Braz. Chem. Soc. 2004, 15, 358.
the reaction proceeds via a C–H bond cleavage. Further investigation
of the reaction of lithium acetylides with various types of 1-chloro-
vinyl sulfoxides is ongoing and will be reported in due course.
7. (a) Hénaff, N.; Stewart, S. K.; Whiting, A. Tetrahedron Lett. 1997, 38, 4525; (b)
Yao, M.-L.; Reddy, M. S.; Yong, L.; Walfish, I.; Blevins, D. W.; Kabalka, G. W. Org.
Lett. 2010, 12, 700.
8. (a) Satoh, T. Chem. Rec. 2004, 3, 329; (b) Satoh, T. Chem. Soc. Rev. 2007, 36, 1561;
(c) Satoh, T. Heterocycles 2012, 85, 1; (d) Satoh, T. In The Chemistry of
Organomagnesium Compounds; Rappoport, Z., Marek, I., Eds.; John Wiley &
Sons: Chichester, 2008; pp 717–769.
Acknowledgments
We gratefully acknowledge support for this work from Grant-
in-Aid for Scientific Research No. 22590021 from the Ministry of
Education, Culture, Sports, Science and Technology, Japan, and
from a TUS Grant for Research Promotion from the Tokyo Univer-
sity of Science.
9. Ishida, N.; Saitoh, H.; Sugiyama, S.; Satoh, T. Tetrahedron 2011, 67, 3081.
10. Typical procedure: A 1.65 M solution of BuLi in hexane (0.30 mL, 0.50 mmol)
was added to a solution of phenylacetylene (51 mg, 0.50 mmol) in THF (1.2 mL)
at room temperature, and the mixture was stirred at that temperature for
2 min. A solution of (E)-8a (28 mg, 0.10 mmol) in THF (0.8 mL) was added to
the resultant solution at room temperature, and the reaction mixture was
stirred at that temperature for 30 min. The reaction was quenched with sat. aq.
NH4Cl (1 mL), and the mixture was extracted with CHCl3 (3 ꢀ 5 mL). The
organic layer was dried over MgSO4 and concentrated under reduced pressure.
The residue was purified by column chromatography on silica gel [Rf = 0.13
(hexane–AcOEt, 200:1)] to give (Z)-10a (24.4 mg, 0.080 mmol, 80%) as a yellow
solid. Mp: 66.5–67.0 °C; IR (KBr): 3351, 2180, 1595, 1486, 1441, 1068, 1026,
Supplementary data
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.
11.152.
913, 753, 687 cmꢁ1 1H NMR (500 MHz, CDCl3): d = 6.56 (s, 1H), 7.30–7.39 (m,
;
9H), 7.52–7.53 (m, 2H), 7.59–7.60 (m, 2H), 7.73 (d, J = 7.9 Hz, 2H); 13C NMR
(126 MHz, CDCl3): d = 87.6 (C), 89.0 (C), 98.4 (C), 98.5 (C), 113.7 (CH), 123.1 (C),
123.4 (C), 126.1 (CH), 126.4 (CH), 128.4 (CH), 128.5 (CH), 128.6 (CH), 128.7
(CH), 128.8 (CH), 131.6 (CH), 131.8 (CH), 133.4 (C), 136.7 (C); MS (EI): m/z (%)
304 (M+); HRMS (EI) calcd. for C24H16: 304.1252, found: 304.1247.
References and notes
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11. The geometry of (Z)-10a was confirmed by spectroscopic comparison with the
authentic samples of (E)-10a and (Z)-10a, which were prepared by
a
Sonogashira coupling reaction. For details, see the Supplementary data.
12. Crystal data for 10k:
0.14 ꢀ 0.14 ꢀ 0.11 mm,
A
C
pale yellow block crystal, crystal dimensions
24H15Cl, M = 338.81, monoclinic, space group
P2(1)/n, a = 6.076(5) Å, b = 11.949(9) Å, c = 25.110(19) Å, b = 95.463(15)°, V =
1815(2) Å3, Z = 4, F(000) = 704.0, Dcalcd = 1.240 g cmꢁ3
T = 173 K, radiation = 0.71073 Å, 4447 reflections, 226 parameters, R1 = 0.084,
Rw = 0.226 [I >2 (I)], GOF = 0.871. Crystallographic data (excluding structure
,l(Mo Ka ,
) = 0.212 mmꢁ1
r
factors) for 10k have been deposited with the Cambridge Crystallographic Data
Centre under the supplementary publication no. CCDC 901661. Copies of the
data can be obtained, free of charge, on application to CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK [fax: +44 (0)1223 336033 or e-mail: deposit@ccdc.
cam.ac.uk].
13. In the case of the reaction of sulfoxide (E)-8c with lithium phenylacetylide
(Table 2, entry 2), 5-ethynyl-benzo[1,3]dioxole was obtained as a by-product.