Sulfur-participated nazarov-type cyclization: A simple and efficient synthesis for 3-thio-1H-indenes

Article abstract of DOI:10.1002/adsc.200900213

An intramoluclar addition of sulfur-participated Nazarov-type cyclization affording 3-thio1H-indenes was reported. As a result of the ready availability of the starting materials and the simple and convenient operation, the type of reaction presented here

Full text of DOI:10.1002/adsc.200900213

COMMUNICATIONS
DOI: 10.1002/adsc.200900213
Sulfur-Participated Nazarov-Type Cyclization: A Simple and
Efficient Synthesis for 3-Thio-1H-indenes
Hongwei Zhou,a,* Yongfa Xie,a Lianjun Ren,a and Kai Wanga
a
Department of Chemistry, Zhejiang University (Campus Xixi), Hangzhou 310028, Peopleꢀs Republic of China
Fax : (+86)-571-88920271; e-mail: zhouhw@zju.edu.cn
Received: April 1, 2009; Revised: May 12, 2009; Published online: June 2, 2009
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200900213.
Abstract: An intramoluclar addition of sulfur-par-
ticipated Nazarov-type cyclization affording 3-thio-
1H-indenes was reported. As a result of the ready
availability of the starting materials and the simple
and convenient operation, the type of reaction pre-
sented here has potential utility in organic synthe-
sis.
Keywords: carbocations; intramolecular addition;
Nazarov cyclization; sulfur-participation; 3-thio-1H-
indenes
Scheme 1.
The indene moiety is present in a class of drug candi-
dates possessing interesting biological activities[1] and
metallocene complexes utilized in the catalysis of
olefin polymerizations.[2] Therefore, a number of clas-
sical methods for the construction of indene ring sys-
tems[3] including transition metal-catalyzed carboan-
nulations of alkynes,[4] has been developed. However,
Scheme 2. Proposed cyclic thionium species.
the synthesis of thioindenes is not well-document-
ed.[5].
The use of sulfur participation has proven to be an
effective strategy for a large number of transforma-
tions.[6] Generally, a nucleophilic sulfur atom attacks
the leaving group to form a cyclic thionium intermedi-
ate,[7,8] which could proceed further through migra-
tion, substitution or elimination.
Recently, an excellent report by Woerpel gave spec- Scheme 3. Preparation of starting materials.
troscopic evidence for the formation of an intermedi-
ate sulfonium ion in a 4-thio-substituted tetrahydro-
pyran acetal system.[9] Interestingly, the subsequent to attack the neighboring carbon-carbon double bond
nucleophilic substitution reactions are formed from to form a five-membered ring (Scheme 2).
oxocarbenium ion intermediates released by the
bridged sulfonium ion instead of the sulfonium ion bility of the cyclization of [2-(1-thiovinyl)phenyl]
itself (Scheme 1). acohol (2), which could be easily prepared by the re-
This proposal stimulated us to investigate the possi-
Enlightened by this knowledge, we proposed a action of [2-(1-thiovinyl)phenyl]lithium with aldehyde
cyclic thionium 1, which could release a carbocation (Scheme 3).
Adv. Synth. Catal. 2009, 351, 1289 – 1292
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1289

Hongwei Zhou et al.
Table 1. Synthesis of 3-thio-1H-indenes.[a]
COMMUNICATIONS
Using
1-{2-[1-(ethylthio)vinyl]phenyl}butan-1-ol
(2a) as the starting material, we examined the cycliza-
tion reaction of 2a in the presence of trifluorometh-
ACHTUNGTRENNUNGanesulfonic anhydride and pyridine in dichlorome-
thane at À208C. Luckily, we isolated 3-ethylthio-1-
propyl-1H-indene (3a) from a mixture containing at
least 10 compounds in a yield of 28%. Considering
the reactivity of the carbocation, we reduced the reac-
tion temperature to À788C and obtained 3a as the
major product in 75% yield (Scheme 4).
Entry
R1
R2
R3
Yield [%]
1
2
3
4
5
6
7
8
H
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Ph
Me
Me
Me
Et
Ph
Et
Et
n-Pr
n-Pr
Et
Et
t-Bu
n-Pr
Et
i-Pr
Bn
t-Bu
i-Pr
Et
n-Pr
t-Bu
2-prop-1-enyl
2-prop-1-enyl
n-Pr
75 (3a)
68 (3b)
72 (3c)
78 (3d)
76 (3e)
63 (3f)
70 (3g)
77 (3h)
58 (3i)
79 (3j)
80 (3k)
72 (3l)
75 (3m)
77 (3n)
69 (3o)
61 (3p)
60 (3q)
46 (3r)[c]
50 (3s)[d]
Me
Me
H
n-Pr
n-Pr
n-Pr
H
H
H
Me
H
Ph
Ph
Ph
Me
H
9
Scheme 4. The first attempt for the proposal.
10
11
12
13
14
15
16
17
Encouraged by this result, a series of [2-(1-thio-
ACHTUNGTRENNUNGvinyl)phenyl]acohols was synthesized as substrates,
and 3-thio-1H-indenes (3) were obtained in moderate
to good yields (Table 1).
We proposed a plausible pathway as shown in 18
Scheme 5. At first the sulfur atom attacks the
Me
Me
vinyl
Ph
19
trifluoroACHTUNGTRENNUNGmethanesulfonate to afford cyclic thionium
[a]
All reactions were run under the following conditions,
unless otherwise specified: 0.5 mmol of 2, 0.75 mmol of
Tf2O and 2 mmol of pyridine in 3 mL of CH2Cl2 at
À788C followed by warming to À408C under an N2 at-
mosphere for 2 h.
Isolated yields.
22% of E-1-ethylidene-3-ethylthio-2-methyl-1H-indene
was observed.
1[10] via an SN2 process. Intermediate 1 releases
carbon cation A,[9] which gives intermediate B via a
Nazarov-type cyclization. The intermediate B affords
the product in the presence of pyridine (Scheme 5).
The point of the pathway is whether the intermedi-
ate A originates from the cyclic thionium 1 (pathway
2, SN2 process) or from the solvolysis of benzyl triflate
(pathway 1, SN1 process). Thus, we firstly prepared 1-
[2-(1-ethoxyvinyl)phenyl]propan-1-ol (4a) and 1-[2-(1-
methoxyvinyl)phenyl]-propan-1-ol (4b) for replacing
the sulfur by oxygen and conducted the reaction
under the same conditions. Only an unidentified mix-
ture was observed, illustrating that the sulfur atom
might play a role in this reaction (Scheme 6).
[b]
[c]
[d]
10% of 1-ethylthio-2-methyl-3-phenyl-1H-indene was ob-
served.
Then we synthesized 1-phenyl-1-{2-[1-(phenylthio)-
vinyl]phenyl}ethanol (2t) as the substrate to examine
the reaction, in which the secondary alcohols (2a–2s)
were changed to a tertiary alcohol for blocking the
SN2-type attack of the sulfur atom. If the reaction pro-
ceeded through the SN1-type pathway 1, the tertiary
alcohol 2t should not prevent the generation of a ter-
tiary carbocation. Interestingly, we obtained an unex-
pected product 5 (Scheme 7). This totally different
result demonstrates that the SN2-type pathway is
more reasonable.
The product 5 might originate from the cyclization
of
phenyl{1-[2-(1-phenylvinyl)phenyl]vinyl}sulfane,
which could be produced via the elimination of the Scheme 5. The proposed mechanism.
1290
asc.wiley-vch.de
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2009, 351, 1289 – 1292

Sulfur-Participated Nazarov-Type Cyclization
COMMUNICATIONS
Experimental Section
General Procedure for Synthesis of 3-Thio-1H-
indenes (3)
To
a
solution of [2-(1-thiovinyl)phenyl]acohol (2)
(0.5 mmol) and 2 mmol of pyridine in 3 mL of anhydrous
CH2Cl2 was added 0.75 mmol of Tf2O under an N2 atmos-
phere at À788C, followed by a warming to À408C for 2 h.
The reaction mixture was quenched with water, extracted
with CH2Cl2, and dried over anhydrous Na2SO4. After evap-
oration, chromatography on silica gel (eluent: petroleum
ether) of the crude product afforded the desired product 3
in yields 58–80%.
Scheme 6. The O-analogue.
Compound 3a: Yield: 82 mg (75%); oil; 1H NMR
(400 MHz, CDCl3): d=7.44–7.38 (m, 2H), 7.34–7.30 (m,
1H), 7.28–7.24 (m, 1H), 6.23 (d, J=1.8 Hz, 1H), 3.57–3.54
(t, J=5.4 Hz, 1H), 3.03–2.98 (q, J=7.2 Hz, 2H), 1.93–1.88
(m, 1H), 1.54–1.46 (m, 3H), 1.44–1.41 (t, J=7.4 Hz, 3H),
1.00–0.96 (t, J=7.2 Hz, 3H); 13C NMR (CDCl3, 100 MHz):
d=147.7, 143.3, 136.6, 131.0, 126.4, 125.4, 122.7, 119.2, 49.8,
34.2, 25.8, 20.9, 14.4, 14.1; MS: m/z=218 (M, 18), 217
Scheme 7. Reaction of a tertiary alcohol.
(MÀ1, 90); IR (neat): n=1713.3, 1604.9, 1462.4, 748.1 cmÀ1
HR-MS: m/z=218.1122, calcd. for C14H18S: 218.1129.
;
triflate of 2t in the presence of pyridine. We tried to
prepare phenyl{1-[2-(1-phenylvinyl)phenyl]vinyl}sul-
fane via a Wittig reaction using phenyl{2-[1-(phenyl-
thio)vinyl]phenyl}methanone as the material. How-
Acknowledgements
ACHTUNGTRENNUNG
Financial support was received from the Natural Science
Foundation of China (No. 20702046), the Natural Science
Foundation of Zhejiang Province (R405066).
ACHTUNGTRENNUNG
tions, which gave indirectly further proof for the path-
way proposed in Scheme 5 (Scheme 8).
References
[1] a) S. Tu, L. H. Xu, L. Y. Ye, X. Wang, Y. Sha, Z. Y.
Xiao, J. Agric. Food Chem. 2008, 56, 5247; b) Y. Ito, T.
Matsuura, M. Wada, T. Kato, J. Med. Chem. 1996,
39,3636; c) N. J. Clegg, S. Paruthiyil, D. C. Leitman,
T. S. Scanlan, J. Med. Chem. 2005, 48, 5989; d) J. Palm,
K. P. Boegesoe, T. Liljefors, J. Med. Chem. 1993,
36,2878; e) D. T. Witiak, S. V. Kakodkar, G. E. Brunst,
J. R. Baldwin, R. G. Rahwan, J. Med. Chem. 1978, 21,
1313; f) C. Senanayake, F. E. Roberts, L. DiMichele, K.
Ryan, J. Liu, L. Fredenburgh, B. Foster, Tetrahedron
Lett. 1995, 36, 3993.
[2] H. G. Alt, A. Koeppl, Chem. Rev. 2000, 100, 1205.
[3] a) Z. A. Khan, T. Wirth, Org. Lett. 2009, 11, 229;
b) Z. B. Zhu, M. Shi, Chem. Eur. J. 2008, 14, 10219;
c) X. Zhou, H. Zhang, X. Xie, Y. Li, J. Org. Chem.
2008, 73, 3958; d) S. Ikeda, N. Chatani, Y. Kajikawa, K.
Ohe, S. Murai, J. Org. Chem. 1992, 57, 2; e) R. A.
Moss, S. Xue, R. R. Sauers, J. Am. Chem. Soc. 1996,
118, 10307; f) S. Saito, M. Homma, V. Gevorgyan, Y.
Yamamoto, Chem. Lett. 2000, 722.
[4] a) L. N. Guo, X. H. Duan, J. Hu, H. P. Bi, X. Y. Liu,
Y. M. Liang, Eur. J. Org. Chem. 2008, 1418; b) H. P. Bi,
L. N. Guo, F. R. Gou, X. H. Duan, X. Y. Liu, Y. M.
Liang, J. Org. Chem. 2008, 73, 4713; c) D. Zhang, Z.
Liu, E. K. Yum, R. C. Larock, J. Org. Chem. 2007, 72,
251; d) R. Deng, L. Sun, Z. Li, Org. Lett. 2007, 9, 5207;
Scheme 8.
In summary, we have developed a facile and effi-
cient method for the synthesis of 3-thio-1H-indenes.
As a result of the ready availability of the starting
materials and the simple and convenient operation,
the type of reaction presented here has potential utili-
ty in organic synthesis. Studies on the application and
expansion of the sulfur-activated carbocations are cur-
rently in progress.
Adv. Synth. Catal. 2009, 351, 1289 – 1292
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1291

Hongwei Zhou et al.
COMMUNICATIONS
e) H. P. Bi, X. Y. Liu, F. R. Gou, L. N. Guo, X. H.
Duan, Y. M. Liang, Org. Lett. 2007, 9, 3527; f) D.
Zhang, E. K. Yum, Z. Liu, R. C. Larock, Org. Lett.
2005, 7, 4963.
[8] a) V. Gevorgyan, A. V. Kel’in, J. T. Kim, Angew. Chem.
2003, 115, 102; Angew. Chem. Int. Ed. 2003, 42, 98;
b) A. Converso, P. L. Saaidi, K. B. Sharpless, M. G.
Finn J. Org. Chem.2004, 69, 7336; c) H. Kwart, D.
Drayer, J. Org. Chem. 1974, 39, 2157; d) D. E. Sunko,
B. Jursic, M. Ladika J. Org. Chem. 1987, 52, 2299;
e) E. L. Eliel, D. E. Knox, J. Am. Chem. Soc. 1985, 107,
2946; f) E. I. Eliel, W. H. Pearson, L. H. Jewell, A. G.
Abatjoglou, Tetrahedron Lett. 1980, 21, 331; g) H.
Zhou, J. Yao, G. Liu, Tetrahedron Lett. 2008, 49, 226;
h) J. Skarzewski, M. Zielinska-Blajet, S. Roszak, I. Tur-
owska-Tyrk, Tetrahedron 2003, 59, 3621.
[5] a) T. E.; Ready, J. C. W. Chien, M. D. Rausch, J. Orga-
nomet. Chem. 1996, 519, 21; b) H. Klaus, S. P. Anne-
gret, Liebigs Ann. Chem. 1984, 3, 552.
[6] a) K. Bobrowski, G. L. Hug, D. Pogocki, B. Marciniak,
C. Schoneich, J. Am. Chem. Soc. 2007, 129, 9236;
b) J. T. Smoot, P. Pornsuriyasak, A. V. Demchenko,
Angew. Chem. 2005, 117, 7285; Angew. Chem. Int. Ed.
2005, 44, 7123; c) A. Rajender, H. J. Gais, Org. Lett.
2007, 9, 579.
[7] For reviews on sulfur participation, please see: a) A. W.
Sromek, V. Gevorgyan. Top. Curr. Chem. 2007, 274,
77; b) D. J. Fox, D. House, S. Warren, Angew. Chem.
2002, 114, 2572; Angew. Chem. Int. Ed. 2002, 41, 2462;
c) D. House, S. Warren, Phosphorus Sulfur Silicon
Relat. Elem. 1999, 153, 59.
[9] M. G. Beaver, S. B. Billings, K. A. Woerpel, J. Am.
Chem. Soc. 2008, 130, 2082.
[10] a) J. C. Martin, R. J. Basalay. J. Am. Chem. Soc. 1973,
95, 2572; b) M. G. Beaver, S. B. Billings, K. A. Woerpel,
Eur. J. Org. Chem. 2008, 771.
1292
asc.wiley-vch.de
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2009, 351, 1289 – 1292