Ga(OTf)3-promoted sequential reactions via sulfur-assisted propargyl-allenyl isomerizations and intramolecular [4 + 2] cycloaddition for the synthesis of 1,3-dihydrobenzo[ c ]thiophenes

Article abstract of DOI:10.1021/jo902681u

A Ga(OTf)₃-promoted sequential reactions via sulfur-assisted propargyl-allenyl isomerizations and intramolecular [4 + 2] cycloaddition for the synthesis of 1,3-dihydrobenzo[c]thiophenes. As a result of the ready availability of materials and the simple and convenient operation, the type of reaction presented here has potential utility in organic synthesis.

Full text of DOI:10.1021/jo902681u

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employed to construct core skeletons of many important
compounds.5
Ga(OTf)3-Promoted Sequential Reactions via
Sulfur-Assisted Propargyl-Allenyl Isomerizations
and Intramolecular [4 þ 2] Cycloaddition for the
Synthesis of 1,3-Dihydrobenzo[c]thiophenes§
Sulfur-assisted propargyl-allenyl isomerization has been a
useful and efficient method to thio-allenes.6 The allene
moiety could be thought as an “activated olefin”, which
generally enhances the diversity of reaction possibility com-
pared with a normal olefin. Thus, it is hypothesized that the
intramolecular [4 þ 2] cycloaddition of yne-allenes should
provide a more convenient route than traditional intramo-
lecular Diels-Alder reaction for the construction of complex
ring systems. It may be reasonably envisioned that the
vinylallene serves as diene to undergo cycloaddition with
triple bonds to give cyclic compounds (Figure 1).
Hongwei Zhou,* Da Zhu, Yongfa Xie, Huafeng Huang, and
Kai Wang
Department of Chemistry, Zhejiang University (Campus
Xixi), Hangzhou 310028, People’s Republic of China
zhouhw@zju.edu.cn
Received December 20, 2009
FIGURE 1. Propargyl-allenyl isomerization and [4 þ 2] cycloaddi-
tion.
Herein we wish to report a sulfur-assisted sequential
reaction wherein vinylallenes generated in situ undergo an
intramolecular [4 þ 2] cycloaddition of yne-allenes in the
presence of Ga(OTf)3, followed by an aromatization to give
1,3-dihydrobenzo[c]thiophenes as the final products.
As a first attempt, we chose (E)-ethyl 6-(3-p-tolylprop-2-
ynylthio) hex-2-en-4-ynoate (1a)7 qtgciial and initiated our study
by testing the reaction of 1a in the presence of various bases and
examining the solvent effect. Weak inorganic bases such as
Na2CO3 or K2CO3 could not trigger the reaction, whereas strong
bases such as t-BuOK or EtONa gave an unidentified mixture.
Triethylamine, DBU (1, 8-diazabicyclo[5.4.0]undec-7-ene), and
DBN (1,5-diazabicyclo[4,3,0] non-5-ene) gave ethyl 4-p-tolyl-
1,3-dihydrobenzo[c]thiophene-5-carboxylate (2a) as the product
in a low yield (Table 1).
A Ga(OTf)3-promoted sequential reactions via sulfur-as-
sisted propargyl-allenyl isomerizations and intramolecular
[4 þ 2] cycloaddition for the synthesis of 1,3-dihydrobenzo-
[c]thiophenes. As a result of the ready availability of materi-
als and the simple and convenient operation, the type of
reaction presented here has potential utility in organic
synthesis.
The preparation of polyfunctionalized heterocyclic com-
pounds has been of interest to the organic community over
the past half century. Because of the importance of thio-
phene-based compounds in many areas including medicinal
and synthetic chemistry, benzo[c]thiophenes are also con-
sidered an important class.1,2
Combining two or more reactions into one sequential
reaction, which usually involves a series of inter- or intra-
molecular processes wherein the product of one reaction is
programmed to be the substrate for the next, represents an
elegant and efficient way to access novel and complex
molecules from simple, readily available starting materials.3,4
In the past decades, sequential reactions have been routinely
(5) (a) Arns, S.; Barriault, L. Chem. Commun. 2007, 2211. (b) Nicolaou,
K. C.; Edmonds, D. J.; Bulger, P. G. Angew. Chem., Int. Ed. 2006, 45, 7134.
(c) Tietze, L. F.; Modi, A. Med. Res. Rev. 2000, 20, 304.
(6) (a) Zhou, H.; Xie, Y.; Ren, L.; Su, R. Org. Lett. 2010, 12, 356.
(b) Dudnik, A. S.; Sromek, A. W.; Rubina, M.; Kim, J. T.; Kel’in, A. V;
Gevorgyan., V. J. Am. Chem. Soc. 2008, 130, 1440. (c) Sromek, A. W.;
Gevorgyan., V. Top. Curr. Chem. 2007, 274, 77. (d) Kim, J. T.; Kel’in, A. V.;
Gevorgyan, V. Angew. Chem., Int. Ed. 2003, 42, 98. (e) Zafrani, Y.; Gottlieb,
H. E.; Sprecher, M.; Braverman, S. J. Org. Chem. 2005, 70, 10166. (f) Zafrani,
Y.; Cherkinsky, M.; Gottlieb, H. E.; Braverman, S. Tetrahedron 2003, 59,
2641. (g) Braverman, S.; Cherkinsky, M.; Birsa, M. L.; Zafrani, Y. Eur. J.
Org. Chem. 2002, 18, 3198. (h) Braverman, S.; Zafrani, Y.; Gottlieb, H. E.
Tetrahedron 2001, 57, 9177. (i) Garratt, P. J.; Neoh, S. B. J. Am. Chem. Soc.
1975, 97, 3255. (j) Iwai, I.; Ide, J. Chem. Pharm. Bull. 1964, 12, 1094.
(7) The substrate 1a could be easily prepared via a Sonogashira reaction
using (E)-ethyl-3-iodoacrylate (4) and prop-2-ynyl(3-p-tolylprop-2-ynyl)-
sulfane (5) as the starting materials. To a solution of 4 (2.0 mmol) and 5
(2.4 mmol) in 10 mL of THF were added CuI (10 mg. 0.05 mmol) and
PdCl2(PPh3)2 (35 mg, 0.05mmol), and 1 mL of diisopropylamine was added
under a N2 atmosphere at room temperature for 1 h. The reaction mixture
was quenched with water, extracted with Et2O, and dried over anhydrous
Na2SO4. After evaporation of the Et2O, chromatography on silica gel
(eluent, EtOAc/petroleum ether = 1:20) of the crude product afforded 1a
in a yield of 88%. The other substrates 1b-1p could be synthesized via similar
process generally in a yield higher than 80%. For the detailed processes,
please see Supporting Information.
§ Dedicated to the memory of Prof. Xian Huang.
(1) (a) Handbook of Oligo- and Polythiophenes; Fichou, D., Ed.; Wiley-
VCH: Weinheim, 1999. (b) Polythiophenes - Electrically Conductive Polymers;
Schopf, G., Kossmehl, G., Eds.; Springer: Berlin, 1997.
(2) (a) Ortiz, R. P.; Casado, J.; Hernande, V.; Navarrete, J. T. L.; Letizia,
J. A.; Ratner, M. A.; Facchetti, A.; Marks, T. J. Chem.;Eur. J. 2009, 15,
5023. (b) Cosimelli, B.; Neri, D.; Roncucci., G. Tetrahedron 1996, 52, 11281.
(c) Hom, D. H. S.; Lamberton., J. A. Aust. J. Chem. 1963, 16, 475.
(3) (a) Tietze, L. F.; Brasche, G.; Gericke, K. M. Domino Reaction in Organic
Synthesis; Wiley-VCH: Weinheim, 2006. (b) Ho, T. L. Tandem Organic Reac-
tions; John Wiley & Sons: New York, 1992.
(4) (a) Tietze, L. F. Chem. Rev. 1996, 96, 115. (b) Parsons, P. J.; Penkett,
C. S.; Shell, A. J. Chem. Rev. 1996, 96, 195. (c) Padwa, A.; Weingarten, M. D.
Chem. Rev. 1996, 96, 223. (d) Posner, G. H. Chem. Rev. 1986, 86, 831.
2706 J. Org. Chem. 2010, 75, 2706–2709
Published on Web 03/18/2010
DOI: 10.1021/jo902681u
r
2010 American Chemical Society

Zhou et al.
JOCNote
TABLE 1. Base and Solvent Effects on the Sequential Reactiona
SCHEME 1
entry
base
Na2CO3 THF
Na2CO3 toluene 24 h
solvent
time temp (°C)
yield of 2a (%)
NR
NR
NR
NR
SCHEME 2
1
2
3
4
5
6
7
8
24 h
reflux
reflux
reflux
reflux
rt
K2CO3
K2CO3
t-BuOK THF
THF
24 h
toluene 24 h
3 min
5 min
unidentified mixture
EtONa
Et3N
Et3N
Et3N
DBN
DBN
DBU
DBU
DBU
DBU
THF
rt
unidentified mixture
toluene 48 h
THF 72 h
reflux
reflux
reflux
90
reflux
90
reflux
90
50
12b
8c
9
benzene 72 h
toluene 24 h
15d
27
30
18
20
0
10
11
12
13
14
15
THF
toluene 24 h
THF 24 h
24 h
DMSO 1 h
CH3CN 1 h
7
aSubstrate 1a (0.5 mmol) and base (2 mmol) in solvent (5 mL) under a
N2 atmosphere. b60% of 1a was recovered. c70% of 1a was recovered.
d65% of 1a was recovered.
SCHEME 3
TABLE 2. Lewis Acid Effects in the Presence of Lewis Basea
entry base M(OTf)n solvent time (h) temp (°C) yield of 2a (%)
1
2
3
4
5
6
7
8
9
Et3N Cu(OTf)2 toluene
Et3N Cu(OTf)2 toluene
Et3N Sc(OTf)3 toluene
Et3N Sc(OTf)3 toluene
Et3N Ga(OTf)3 toluene
Et3N Ga(OTf)3 toluene
Et3N Ga(OTf)3 benzene
Et3N Zn(OTf)2 toluene
Et3N Zn(OTf)2 toluene
24
24
24
24
16
24
48
24
24
24
24
24
24
24
reflux
90
reflux
90
reflux
90
reflux
reflux
90
reflux
90
reflux
90
90
16
20
46
42
56
63
45
18
16
28
32
22
19
68b
10 DBN Ga(OTf)3 toluene
11 DBN Ga(OTf)3 toluene
12 DBU Ga(OTf)3 toluene
13 DBU Ga(OTf)3 toluene
14 Et3N Ga(OTf)3 toluene
aAll reactions were run under the following conditions, unless other-
wise specified: substrate 1a (0.5 mmol), base (2 mmol), and M(OTf)n
(0.025 mmol) in solvent (5 mL) under a N2 atmosphere. bA mixture of
1 mL of Et3N and 4 mL of toluene was used as the solvent.
For further optimization, we expected use of Lewis acid to
promote the [4 þ 2] cycloaddition. Although it is well-known
that Lewis acids can accelerate pericyclic reactions, finding
the right Lewis acid and reaction conditions remains a
challenging task for organic chemists because the Lewis acid
may react with the Lewis base before activating the pericyclic
reactions.8 We chose metal triflates to examine this reaction
because of their stability to Lewis bases (Table 2).
(8) For reviews of bifunctional catalysis of cooperative Lewis acid/base
systems, please see: (a) Paull, D. H.; Abraham, C. J.; Scerba, M. T.; Alden-
Danforth, E.; Lectka, T. Acc. Chem. Res. 2008, 41, 655. (b) Murahashi, S. C.;
Takaya, H. Acc. Chem. Res. 2000, 33, 225.
J. Org. Chem. Vol. 75, No. 8, 2010 2707

Zhou et al.
JOCNote
TABLE 3. Synthesis of 1,3-Dihydrobenzo[c]thiophenesa
aAll reactions were run under the following conditions, unless otherwise specified: substrate 1a (0.5 mmol) and Ga(OTf)3 (0.025 mmol) in solvent
(5 mL) under a N2 atmosphere. bA mixture of 1 mL of Et3N and 4 mL of toluene was used as the solvent.
With this result in hand, we examined the scope of the
reaction and obtained 1,3-dihydrobenzo[c]thiophenes in
moderate to good yields under mild conditions (Table 3).
We examined the reaction of (3-cyclohexenylprop-2-ynyl)-
(3-phenylprop-2-ynyl)sulfane (3)9 under the same conditions
(compared with entry 3) but recovered only the starting
material in 92% yield, demonstrating that the electron-with-
drawing group, such as an ester group or carbonyl group, is
essential to trigger the propargyl-allenyl isomerization in the
presence of a mild base (Scheme 1).
We propose a plausible pathway as shown in Scheme 2. At
first 1, via a propargyl-allenyl isomerization in the presence of
Et3N, gives intermediate A,6b which undergoes an intramole-
cular [4 þ 2] cycloaddition of yne-allenes in the presence
(9) Braverman, S.; Zafrani, Y.; Gottlieb, H. E. J. Org. Chem. 2002, 67, 3277.
2708 J. Org. Chem. Vol. 75, No. 8, 2010

Zhou et al.
JOCNote
SCHEME 4
Interestingly, we just observed 22% deuterium on the new
benzene ring, probably because the propargyl-allene isomer-
ization is so fast that the protonated triethylamine does not
have enough time to leave (Scheme 4).
In summary, we developed a Ga(OTf)3-promoted sequential
reactions via sulfur-assisted propargyl-allenyl isomerizations
and intramolecular [4 þ 2] cycloaddition for the synthesis of
1,3-dihydrobenzo[c]thiophenes. As a result of the ready avail-
ability of materials and the simple and convenient operation,
this type of reaction presented here has potential utility in
organic synthesis.
Experimental Section
Typical Procedure for Synthesis of 1,3-Dihydrobenzo-
[c]thiophenes (2). To a solution of (E)-ethyl-6-(3-p-tolylprop-
2-ynylthio) hex-2-en-4-ynoate (1a, 0.5 mmol) in 5 mL of
solvent (toluene/Et3N = 4:1) was added 0.025 mmol of
Ga(OTf)3 under a nitrogen atmosphere at 90 °C for 24 h.
The reaction mixture was quenched with 20 mL of water,
extracted with ethyl ether, and dried over anhydrous Na2SO4.
After evaporation of the ethyl ether, chromatography on
silica gel (eluent, petroleum ether/EtOAc = 25:1) of the crude
product afforded the desired product 2a: yield 68%, 101 mg;
1
oil; H NMR (400 MHz, CDCl3) δ 7.79-7.77 (m, 1H),
7.29-7.26 (m, 1H), 7.21-7.19 (m, 2H), 7.09-7.07 (m, 2H),
4.35 (s, 2H), 4.07-4.01 (q, J = 7.1 Hz, 2H), 3.97 (s, 2H),
2.40 (s, 3H), 1.00-0.97 (t, J = 7.0 Hz, 3H); 13 C NMR (CDCl3,
100 MHz) δ 167.7, 144.0, 140.7, 139.6, 136.8, 136.8, 130.0,
128.9, 128.8, 127.8, 123.3, 60.7, 38.3, 37.8, 21.2, 13.6; MS
(m/z) 298 (M, 60), 297 (M - 1, 30); IR (neat, cm-1) 1709.2,
1285.1, 1124.2. HRMS calcd for C18H18O2S: 298.1208.
Found: 298.1206§Dedicated to the memory of Prof. Xian Huang.
of Ga(OTf)3, followed by an aromatization to give 1,3-
dihydrobenzo[c]thiophenes as the final products 2 (Scheme 2).
Garrant reported a bisallene-diradical mechanism,6i and
Braverman demonstrated the presence of a diradical inter-
mediate,6e-h in contrast with the [4 þ 2] cycloaddition
mechanism suggested by Iwai.6j To examine the possible
pathway for our reaction, we treated 1d with 20 equiv of
methanol-d4 in 5 mL of Et3N-toluene (1:4) in the presence of
0.05 equiv of Ga(OTf)3 at 90 °C and obtained deuterated 2d.
However, only one proton of the two methylene groups
adjacent to the sulfur atom was deuterated, showing that
the monoallene intermediate and [4 þ 2] cycloaddition
mechanism are more plausible in the case of our reaction
because the bisallene-diradical pathway should influence
both methylene groups (Scheme 3).
Acknowledgment. Financial support was received from
the Natural Science Foundation of China (Nos. 20702046,
20972134), the Natural Science Foundation of Zhejiang
Province (R405066).
Supporting Information Available: Experimental proce-
dures and NMR spectra. This material is available free of charge
via the Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 75, No. 8, 2010 2709