Facile synthesis of 3,4-diiododihydrothiophenes via electrophilic iodocyclization

Article abstract of DOI:10.1016/j.tetlet.2010.12.075

A facile, efficient, and general synthetic method for the construction of 3,4-diiododihydrothiophenes has been developed via the electrophilic iodocyclization of various S-hydroxy-2-butynyl ethanethioates. Application of the resulting iodine-containing pr

Full text of DOI:10.1016/j.tetlet.2010.12.075

Tetrahedron Letters 52 (2011) 936–938
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Facile synthesis of 3,4-diiododihydrothiophenes via electrophilic
iodocyclization
Fan Yang a, Tienan Jin a,b, , Ming Bao c, Yoshinori Yamamoto a,b,
⇑
⇑
a Department of Chemistry, Graduate School of Science, Tohoku University, Sendai 980-8578, Japan
b WPI-AIMR (WPI-Advanced Institute for Materials Research), Tohoku University, Sendai 980-8577, Japan
c State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian 116012, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A facile, efficient, and general synthetic method for the construction of 3,4-diiododihydrothiophenes has
been developed via the electrophilic iodocyclization of various S-hydroxy-2-butynyl ethanethioates.
Application of the resulting iodine-containing products in organic transformations has been investigated.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 21 October 2010
Accepted 19 December 2010
Available online 23 December 2010
Keywords:
3,4-Diiododihydrothiophenes
Iodocyclization
Iodine
S-4-Hydroxy-2-butynyl ethanethioates
Dihydrothiophenes are one of the most important classes of
heterocycles which are used as versatile intermediates in the syn-
thesis of natural and unnatural molecules with diverse biological
activities and optoelectronic properties.1–3 While the synthesis of
functionalized dihydrothiophenes have attracted much less atten-
tion comparing to thiophenes and tetrahydrothiophenes, some
efficient methodologies have been developed. The earliest ap-
proaches such as McIntosh cycloaddition of mercapto ketons or
aldehydes with vinyl Wittig reagents,4 modified McMurry cycliza-
tion of diketo sulfides,5 and Birch reduction of thiophenes6 still re-
mains the most common approaches. Recently, new preparative
methods have been reported, for example, copper-catalyzed ring
expansion of vinyl thiiranes,2a gold-catalyzed hydrothiolation of
allenes,7 and olefin metathesis.8 However, these approaches repre-
sent important general methods for the synthesis of dihydrothi-
ophene derivatives, each of them suffers from either harsh
conditions or limited scope of applications. Thus, the development
of a facile and efficient methodology for the synthesis of the multi-
functionalized dihydrothiophenes would be highly desirable.
The electrophilic iodocyclization is one of the most powerful
methods for the efficient synthesis of a variety of functionalized
carbocycles and heterocycles under mild conditions.9–14 Further-
more, the corresponding iodine-containing products can be readily
derived to the interesting structurally elaborated compounds by
using transition metal-catalyzed transformations. While iodocycli-
zations for the preparation of O- and N-containing heterocycles
have been well studied, iodocyclizations for the construction of
S-containing heterocycles such as dihydrothiophenes or thio-
phenes have not been well explored.12 In 1937, Kruglov reported
an interesting iodocyclization of acetylene glycols, producing 3,4-
diiododihydrofuran derivatives efficiently.13 In the continuation
of our interest in the development of efficient synthetic methods
of heterocycles15 and in iodocyclization chemistry,14 we envi-
sioned that if one of hydroxyl groups in acetylene glycols is re-
placed with a suitable sulfide group, 3,4-diiododihydrothiophene
derivatives might be produced via an intramolecular iodocycliza-
tion. Herein, we report for the first time a facile and efficient syn-
thesis of 3,4-diiododihydrothiophenes by the electrophilic
iodocyclization of various substituted S-4-hydroxy-2-butynyl eth-
anethioates [Eq. 1]. This communication provides not only a new
protocol for the construction of dihydrothiophenes but also an
alternative avenue for the synthesis of the highly functionalized
thiophene derivatives.
R3
S
AcS
R1
OH
R3
R2
R1
I2 (3 equiv)
R2
ð1Þ
CH2Cl2, rt, 1 h
I
I
1
2
In the preliminary studies, we investigated the effect of solvents
on the iodine-mediated electrophilic cyclization of 1a for the for-
mation of the 3,4-diiododihydrothiophene 2a. The use of CH3CN
and CH3NO2 led to good yields of 2a (ꢀ80%), while the use of a
protic solvent MeOH resulted in decomposition of 1a. CH2Cl2 was
⇑
Corresponding authors. Tel.: +81 22 795 3585; fax: +81 22 795 6784 (T.J.); tel.:
+81 22 795 6581; fax: +81 22 795 6784 (Y.Y.).
E-mail addresses: tjin@m.tohoku.ac.jp (T. Jin), yoshi@m.tohoku.ac.jp (Y. Yama-
moto).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.12.075

F. Yang et al. / Tetrahedron Letters 52 (2011) 936–938
937
Table 1
S
R1
Br
R2
IBr (2 equiv)
AcS
R1
OH
R2
Synthesis of 3,4-diiododihydrothiophenes by iodocyclizationa
CH2Cl2, rt, 1 h
Entry
Substrate 1
Product 2
Yieldb (%)
I
ð2Þ
1a R1 = H, R2 = Ph
2a' 76%
AcS
OH
R2
S
R2
2s' 55%
1s R1 = Ph, R2 = p-tolyl
(d.r.= 1.6:1)
I
I
Based on these observations, the present iodocyclization mech-
anism is proposed as shown in Scheme 1. Presumably, initial acti-
vation of the propargyl hydroxyl group of 1a with a Lewis acidic
iodine16 leads to the propargyl carbocation intermediate A or al-
lene cation B17 along with an unstable hypoiodous acid (HOI)
1
2
3
4
5
6
7
8
9
10
1a R2 = Ph
2a
2b
2c
2d
2e
2f
2g
2h
2i
89
93
93
85
71
91
39
96
78
98
1b R2 = 4-Me–C6H4
1c R2 = 2-Me–C6H4
1d R2 = 4-Cl–C6H4
1e R2 = 4-CO2Me–C6H4
1f R2 = (E)–CH@CHC6H5
1g R2 = n-C5H11
and an iodine anion. Attack of the iodine anion onto c-position of
1h R2 = 2-thienyl
A or the cation in B affords iodoallene C which will react with
hypoiodous acid to form an iodonium intermediate D.18 Subse-
quent intramolecular nucleophilic addition of sulfide atom to the
activated allene followed by deprotection of acetyl group produces
2a and acetic acid.
1i R2 = 2-furanyl
1j R2 = 2-(1-tosyl)pyrrolyl
2j
AcS
OH
S
S
R1
n
R1
As shown in Schemes 2 and 3, dihydrothiophenes 2q and 2s0
were readily converted to the corresponding thiophenes 3q and
3s0 by DDQ aromatization. Aiming at examining the potential
application in synthesis of highly functionalized thiophenes posse-
sing interesting photophysical and electrochemical properties,
transformations of 3q and 3s to the synthesis of 2,3,4,5-tetrasubsti-
tuted thiophenes have been investigated. For example, in the case
of 3q, double Pd-catalyzed Still couplings, n-BuLi-mediated deio-
dination, and double Sonogashira couplings have afforded the cor-
responding symmetric thiophenes 4q, 5q, and 6q in 97%, 95%, and
81% yields, respectively (Scheme 2). Similarly, in the case of 3s, se-
quence Still couplings and Suzuki–Miyaura couplings have fur-
nished the corresponding unsymmetric thiophenes 4s and 5s19 in
88% and 66% yields, respectively (Scheme 3).
n
I
I
11
12
13
14
15
1k n = 1, R1 = H
1l n = 1, R1 = Me
2k
2l
2m
2n
2o
86
71
63
89
54
1m n = 1, R1 = Ph
1n n = 2, R1 = H
1o n = 3, R1 = H
AcS
OH
R1
R2
R1
R2
I
I
16c
17
18
1p R1 = Me, R2 = Ph
1q R1 = Ph, R2 = Ph
1r R1 = 2-thienyl,
R2 = 2-thienyl
2p
2q
2r
67d
76e
48f
Ac = acetyl, Ph = phenyl, Me = methyl, tosyl = toluenesulfonyl.
a
Reaction conditions: 1 (0.2 mmol), I2 (0.6 mmol), anhydrous CH2Cl2 (0.1 M),
room temperature, 1 h.
b
Isolated yields.
Diastereomeric ratio (d.r.) of 1p is 20:1.
d.r. is 1.5:1.
d.r. is 1.4:1.
c
SAc
SAc
I2
I-
AcS
d
1a
e
-HOI
-I-
Ph
f
d.r. is 1.3:1.
I
Ph
Ph
A
B
C
Ac
S
Ac
S+
observed as a best choice of solvents, giving 2a in 89% yield (Table
1, entry 1). This iodocyclization was extended to the various
substituted S-4-hydroxy-2-butynyl ethanethioates 1 to examine
the methodology for general utility for the synthesis of functional-
ized 3,4-diiododihydrothiophenes. The reactions of substrates 1b–
e bearing an electron-donating and an electron-withdrawing aro-
matic group (R2) at the propargyl alcoholic carbon produced the
corresponding tri-substituted dihydrothiophenes 2b–e in good to
high yields (entries 2–5). Remarkably, the presence of a double
bond in substrate 1f was also tolerated; the desired dihydrothioph-
ene 2f was obtained in 91% yield (entry 6). In the case of 1g having
an alkyl substituent at R2, the product 2g was formed in moderate
yield (entry 7). Substrates 1h–j having heteroaromatic rings such
as thienyl, furanyl, and pyrrolyl, showed a high compatibility with
the present reaction conditions, producing 2h–j in high yields (en-
tries 8–10). Interestingly, cyclic tertiary alcohols (1k–o) with a
cyclohexyl, cycloheptyl, or cyclooctyl ring were transformed into
the expected [4.n]thiaspirocycles 2k–o in good yields (entries
11–15). The reaction also worked well with the substrates 1p–r
having two substituents at the both propargylic carbons, furnish-
ing the expected tetrasubstituted dihydrothiophenes 2p–r as a
mixture of two diastereomers, respectively (entries 16–18).
We further tested this iodocyclization with IBr electrophile in-
stead of iodine. Fortunately, in the presence of 2 equiv of IBr, sub-
strates 1a and 1s underwent the electrophilic iodocyclization
smoothly to afford the corresponding 3-bromo-4-iodo-dihydrothi-
ophenes 2a0 and 2s0 in good yields as a single regioisomer, in which
2s0 was obtained as a 1.6:1 diastereomeric mixture [Eq. 2].
Ph
OH-
HOI
-OH-
Ph
2a
I+
-AcOH
I
I
I
D
E
Scheme 1. Proposed reaction mechanism for the formation of 3,4-
diiododihydrothiophenes.
2q
(a)
S
Ph
Ph
S
(b)
Ph
Ph
Ph
Ph
(c)
S
Ph
Ph
I
I
4q
3q
5q
(d)
S
6q
Scheme 2. Reagents and conditions: (a) DDQ (3 equiv), toluene, reflux, 93%; (b)
Pd(PPh3)4 (20 mol %), LiCl, DMF, allyltributylstannane, 100 °C, 97%; (c) nBuLi
(2 equiv), THF, ꢁ78 °C then H2O, 95%; (d) (i) Pd(PPh3)2Cl2 (5 mol %), CuI
(10 mol %), DIPA, THF, 60 °C, ethynyltrimethylsilane; (ii) K2CO3, MeOH/THF, rt,
81% for two-steps. DDQ = 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, DIPA = diiso-
propylamine, nBu = n-butyl.

938
F. Yang et al. / Tetrahedron Letters 52 (2011) 936–938
2. (a) Rogers, E.; Araki, H.; Batory; McInnis, C. E.; Njardarson, J. T. J. Am. Chem. Soc.
2s'
(a)
2007, 129, 2768–2769; (b) Brandau, S.; Maerten, E.; Jorgensen, K. J. Am. Chem.
Soc. 2006, 128, 14986–14991; (c) De Clercq, P. J. Chem. Rev. 1997, 97, 1755–
1792.
S
Ph
p-tolyl
S
Ph
p-tolyl
3. (a) Dang, Y.; Chen, Y. Eur. J. Org. Chem. 2007, 5661–5664; (b) Dang, Y.; Chen, Y. J.
Org. Chem. 2007, 72, 6901–6904; (c) Rosy, P. A.; Hoffmann, W.; Muller, N. J. Org.
Chem. 1980, 45, 617–620.
S
Ph
p-tolyl
(c)
(b)
4. (a) McIntosh, J. M.; Goodbrand, H. B. Tetrahedron Lett. 1973, 34, 3157–3160; (b)
McIntosh, J. M.; Goodbrand, H. B.; Masse, G. M. J. Org. Chem. 1974, 39, 202–206;
(c) McIntosh, J. M.; Masse, G. M. J. Org. Chem. 1975, 40, 1294–1298.
5. (a) Nakayama, J.; Machida, H.; Hoshino, M. Tetrahedron Lett. 1985, 26, 1981–
1982; (b) McMurry, J. E.; Kees, K. L. J. Org. Chem. 1977, 42, 2655–2656.
6. (a) Birch, S. F.; McAllan, D. T. Nature 1950, 165, 899; (b) Blenderman, W. G.;
Joullie, M. M. Tetrahedron Lett. 1979, 20, 4985–4988.
7. Morita, N.; Krause, N. Angew. Chem., Int. Ed. 2006, 45, 1897–1899.
8. (a) Spagnol, G.; Heck, M.-P.; Nolan, S. P.; Mioskowski, C. Org. Lett. 2002, 4,
1767–1770; (b) Conrad, J. C.; Pamas, H. H.; Snelgrove, J. L.; Fogg, D. E. J. Am.
Chem. Soc. 2005, 127, 11882–11883.
Br
I
MeO
CF3
5s
4s
3s'
Scheme 3. Reagents and conditions: (a) DDQ (3 equiv), toluene, reflux, 98%; (b) (i)
Pd(PPh3)4 (10 mol %), LiCl, DMF, allyltributylstannane, 100 °C, 24 h; (ii) Pd(PPh3)4
(10 mol %), LiCl, DMF, tributylvinylstannane, 100 °C, 24 h, 88% for two-steps; (c) (i)
Pd(PPh3)4 (3 mol %), PPh3, K2CO3, THF, 4-(trifluoromethyl)phenylboronic acid, 80 °C,
12 h; (ii) Pd(PPh3)4 (6 mol %), K3PO4, toluene/dioxane, 4-methoxyphenylboronic
acid, 100 °C, 12 h, 66% for two-steps. DMF = dimethylforamide, THF =
tetrahydrofuran.
9. For a review, see: Larock, R. C. In Acetylene Chemistry. Chemistry, Biology, and
Material Science; Diederich, F., Stang, P. J., Tykwinski, R. R., Eds.; Wiley-VCH:
New York, 2005; pp 51–99. Chapter 2.
In conclusion, we have developed a facile, efficient, and general
method for the synthesis of dihydrothiophenes through the elec-
trophilic iodocyclization. This methodology accommodates a wide
range of functional groups and affords various highly substituted
3,4-diiododihydrothiophenes efficiently under mild reaction con-
ditions. The resulting iodine-containing products can be readily
transferred to the more complex thiophenes by using known or-
ganic transformations. Investigation into the extension of the pres-
ent methodology to the construction of other heterocycles and
application to the synthesis of useful optoelectronic materials are
in progress.
General procedure: I2 (0.6 mmol, 152 mg) was added to a solu-
tion of S-hydroxy-4-phenylbut-2-ynyl ethanethioate 1a (0.2 mmol,
44 mg) in dichloromethane (2 mL), and the resulting mixture was
stirred at room temperature for 1 h. The reaction mixture was di-
luted with 10 mL dichloromethane, washed with saturated sodium
thiosulfate. The organic layer was dried with anhydrous MgSO4.
After concentration of the filtrate, the residue was purified by chro-
matography on silica gel to afford 3,4-diiodo-2-phenyldihydrothi-
ophenes 2a (73.6 mg, 89%) as a slight yellow solid.
10. For selected recent examples of the synthesis of O-heterocycles, see: (a)
Mancuso, R.; Mehta, S.; Gabriele, B.; Salerno, G.; Jenks, W. S.; Larock, R. C. J. Org.
Chem. 2010, 75, 897–901; (b) Verma, A. K.; Aggarwal, T.; Rustagi, V.; Larock, R.
C. Chem. Commun. 2010, 46, 4064–4066; (c) Mehta, S.; Waldo, J. P.; Larock, R. C.
J. Org. Chem. 2009, 74, 1141–1147; (d) Worlikar, S. A.; Kesharwani, T.; Yao, T.;
Larock, R. C. J. Org. Chem. 2007, 72, 1347–1353; (e) Bew, S. P.; EL-Taeb, G. M. M.;
Knight, D. V.; Tan, W.-F. Eur. J. Org. Chem. 2007, 5759–5770; (f) Barluenga, J.;
Vázquez-Villa, H.; Ballesteros, A.; Gánzalez, J. M. J. Am. Chem. Soc. 2003, 125,
9028–9029.
11. For selected recent examples of the synthesis of N-heterocycles, see: (a)
Barluenga, J.; Trincado, M.; Rubio, E.; González, J. M. Angew. Chem., Int. Ed.
2003, 42, 2406–2409; (b) Yue, D.; Larock, R. C. Org. Lett. 2004, 6, 1037–1040; (c)
Amjad, M.; Knight, D. W. Tetrahedron Lett. 2004, 45, 539–541; (d) Zhang, X.;
Campo, M. A.; Yao, T.; Larock, R. C. Org. Lett. 2005, 7, 763–766; (e) Huang, Q.;
Hunter, J. A.; Larock, R. C. J. Org. Chem. 2002, 67, 3437–3444.
12. (a) Ren, X. F.; Konaklieva, M. I.; Shi, H.; Dickey, S.; Lim, D. V.; Gonzalez, J.; Turos,
E. J. Org. Chem. 1998, 63, 8898–8917; (b) Flynn, B. L.; Flynn, G. P.; Hamel, E.;
Jung, M. K. Bioorg. Med. Chem. Lett. 2001, 11, 2341–2343; (c) Ren, X. F.; Turos,
E.; Lake, C. H.; Churchill, M. R. J. Org. Chem. 1995, 60, 6468–6483; (d) Ren, X. F.;
Konaklieva, M. I. L.; Krajkowski, M.; Janik, T. S.; Turos, E.; Lake, C. H.; Churchill,
M. R. J. Org. Chem. 1995, 60, 6484–6495; (e) Hessian, K. O.; Flynn, B. L. Org. Lett.
2003, 5, 4377–4380.
13. (a) Kruglov, A. A. Zh. Obshch. Biol. 1937, 7, 2605–2608; (b) Ji, K.-G.; Zhu, H.-T.;
Yang, F.; Shu, X.-Z.; Zhao, S.-C.; Liu, X.-Y.; Shaukat, A.; Liang, Y.-M. Chem. Eur. J.
2010, 16, 6151–6154.
14. (a) Fischer, D.; Tomeba, H.; Pahadi, N. K.; Patil, N. T.; Yamamoto, Y. Angew.
Chem., Int. Ed. 2007, 46, 4764–4766; (b) Fischer, D.; Tomeba, H.; Pahadi, N. K.;
Patil, N. T.; Huo, Z.; Yamamoto, Y. J. Am. Chem. Soc. 2008, 130, 15720–15725; (c)
Huo, Z.; Tomeba, H.; Yamamoto, Y. Tetrahedron Lett. 2008, 49, 5531–5533; (d)
Huo, Z.; Gridnev, I. D.; Yamamoto, Y. J. Org. Chem. 2010, 75, 1266–1270.
15. For reviews, see: (a) Nakamura, I.; Yamamoto, Y. Chem. Rev. 2004, 104, 2127–
2298; (b) Yamamoto, Y. J. Org. Chem. 2007, 72, 7817–7831; (c) Patil, N. T.;
Yamamoto, Y. Chem. Rev. 2008, 108, 3395–3442.
Acknowledgment
This work was financially supported by a Scientific Research (B)
from Japan Society for Promotion of Science (JSPS). F.Y. acknowl-
edges the support of China Scholarship Council (CSC).
16. Rossen, K.; Reamer, R. A.; Volante, R. P.; Reider, P. J. Tetrahedron Lett. 1996, 37,
6843–6846.
Supplementary data
17. For the Lewis acidic iodine-catalyzed C- and O-nucleophilic substitution
reactions of propargyl alcohols, see: (a) Srihari, P.; Bhunia, D. C.; Sreedhar, P.;
Mandal, S. S.; Reddy, J. S. S.; Yadav, J. S. Tetrahedron Lett. 2007, 48, 8120–8124;
(b) Yadav, J. S.; Reddy, B. V. S.; Thrimurtulu, N.; Reddy, N. M.; Prasad, A. R.
Tetrahedron Lett. 2008, 49, 2031–2033.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.12.075.
18. (a) Ishikawa, T.; Manabe, S.; Aikawa, T.; Kudo, T.; Saito, S. Org. Lett. 2004, 6,
2361–2364; (b) Yao, L.-F.; Shi, M. Org. Lett. 2007, 9, 5187–5190; (c) Yao, L.-F.;
Shi, M. Chem. Eur. J. 2009, 15, 3875–3881; (d) Komeyama, K.; Saigo, N.; Miyagi,
M.; Takaki, K. Angew. Chem., Int. Ed. 2009, 48, 9875–9878.
References and notes
19. The 1H and 13C NMR spectra of 5s are identical to the reported literature, see:
Yanagisawa, S.; Ueda, K.; Sekizawa, H.; Itami, K. J. Am. Chem. Soc. 2009, 131,
14622–14623.
1. (a) Mishra, A.; Ma, C.-Q.; Bäuerle, P. Chem. Rev. 2009, 109, 1141–1276; (b) Liu,
H. H.; Chen, Y. J. Mater. Chem. 2009, 19, 706–709; (c) Wu, C.; Decker, E. R.; Blok,
N.; Bui, H.; You, T. J.; Wang, J.; Bourgoyne, A. R.; Knowles, V.; Berens, K. L.;
Holland, G. W.; Brock, T. A.; Dixon, R. A. F. J. J. Med. Chem. 2004, 47, 1969–1989;
(d) Bagli, J. F.; Mackay, W. D.; Ferdinandi, E. J. Med. Chem. 1976, 19, 876–882; (e)
Schatz, J. Sci. Synth. 2001, 9, 287–422.