Sulfur-assisted Propargyl-Allenyl isomerizations and electrocyclizations for the convenient and efficient synthesis of polyfunctionalized benzenes and naphthalenes

Article abstract of DOI:10.1021/ol101479d

A facile and efficient electrocyclization for the synthesis of polyfunctionalized benzene and naphthalene derivatives was reported. As a result of the ready availability of starting materials and simple operation, this type of reaction has potential utility in organic synthesis.

Full text of DOI:10.1021/ol101479d

ORGANIC
LETTERS
2010
Vol. 12, No. 16
3674-3677
Sulfur-Assisted Propargyl-Allenyl
Isomerizations and Electrocyclizations
for the Convenient and Efficient
Synthesis of Polyfunctionalized
Benzenes and Naphthalenes
Hongwei Zhou,* Yanpeng Xing, Jinzhong Yao, and Junhui Chen
Department of Chemistry, Zhejiang UniVersity (Campus Xixi),
Hangzhou 310028, PR China
zhouhw@zju.edu.cn
Received June 28, 2010
ABSTRACT
A facile and efficient electrocyclization for the synthesis of polyfunctionalized benzene and naphthalene derivatives was reported. As a result
of the ready availability of starting materials and simple operation, this type of reaction has potential utility in organic synthesis.
The benzenoid aromatic compounds might be the most ubiq-
uitous in nature and the laboratory among all cyclic compounds.
Thus, the preparation of polyfunctionalized benzenes has been
of interest for the organic community over the past century.
Besides direct functionalization to benzene, construction of a
new benzene ring using building blocks represents an efficient
way to access polysubstituted benzenes from simple, readily
available starting materials.
Diels-Alder cycloaddition.2c On the basis of the understanding
of sulfur-assisted propargyl-allenyl isomerization,3 it may be
reasonably envisioned that the sulfur-assisted propargyl diene
could undergo cycloaddition via a diene-allene intermediate
to give cyclic compounds (Scheme 1).
Scheme 1
Allene-mediated cyclization reactions have attracted much
attention by organic chemists, and the electrocyclization of
diene-allenes were used as a key step to construct a benzene
ring because of the unstable properties of the cyclization product
isotoluene.1 Recently, our group reported the sulfur-assisted
Nazarov cyclization,2a thio-Claisen rearrangement,2b and
(1) (a) Nakamura, I.; Zhang, D.; Terada, M. J. Am. Chem. Soc. 2010,
132, 7884. (b) Cabaleiro-Lago, E. M.; Rodriguez-Otero, J.; Garcia-Lopez,
R. M.; Pena-Gallego, A.; Hermida-Ramon, J. M. Chem.sEur. J. 2005, 11,
5966. (c) Lopez, C. S.; Faza, O. N.; Cossio, F. P.; York, D. M.; de Lera,
A. R. Chem.sEur. J. 2005, 11, 1734. (d) Wang, F.; Tong, X.; Cheng, J.;
Zhang, Z. Chem.sEur. J. 2004, 10, 5338. (e) Rodriguez-Otero, J.; Cabaleiro-
Lago, E. M. Angew. Chem., Int. Ed. 2002, 41, 1147. (f) Myers, A. G.;
Dragovicb, P. S.; Kuo, E. Y. J. Am. Chem. Soc. 1992, 114, 9369. (g) Porter,
N. A.; Hogenkamp, D. J.; Khouri, F. F. J. Am. Chem. Soc. 1990, 112, 2403.
As a first attempt, we chose (2E,4Z)-ethyl 5-phenyl-8-
(phenylthio)octa-2,4-dien-6-ynoate (1a)4 as the starting ma-
terial, which could be easily prepared via a Sonogashira
reaction with (2E,4Z)-ethyl 5-iodo-5-phenylpenta-2,4-di-
enoate and phenyl(prop-2-ynyl)sulfane (Scheme 2).
10.1021/ol101479d  2010 American Chemical Society
Published on Web 07/16/2010

Scheme 2
Table 2. Synthesis of Polyfunctionalized Benzenesa
On the basis of the previous investigation, we initiated
our study by testing the reaction of 1a in the presence of
various bases and examining the solvent effect because
the base and the reaction solvent may significantly
influence the propargyl-allenyl isomerization.2c Triethyl-
amine, DBU (1,8-diazabicyclo[5.4.0]undec-7-ene), and
DBN (1,5-diazabicyclo[4.3.0]non-5-ene) could trigger the
expected reaction and give ethyl 3-(phenylthiomethyl)bi-
phenyl-4-carboxylate (2a) as the product. Further exami-
nation showed that triethylamine and DBU could offer
acceptable yields at 60 °C and room temperature, respec-
tively, and acetonitrile was the suitable reaction medium
for this reaction (entries 6 and 12, Table 1).
Table 1. Base and Solvent Effecta
entry base solvent time (h) temp (°C) yield of 2a (%)
1
2
3
4
5
6
7
8
Et3N toluene
Et3N THF
Et3N MeCN
Et3N toluene
Et3N THF
Et3N MeCN
DBN toluene
DBN THF
DBN MeCN
DBU toluene
DBU THF
24
24
24
12
12
12
6
4
4
6
4
rt
rt
rt
90
60
60
rt
rt
rt
rt
rt
rt
NR
NR
NR
mixture
55
80
mixture
38
48
mixture
45
9
10
11
12
DBU MeCN
4
75
a Substrate 1a (0.5 mmol) and base (1.0 mmol) in solvent (3 mL) under
a N2 atmosphere.
Inspired by this result, we examined the scope of the
reaction and obtained polyfunctionalized benzenes in moder-
ate to good yields under mild conditions (Table 2).
(E)-Ethyl 3-(2-(3-(phenylthio)prop-1-ynyl)phenyl)acryl-
ate (3a), in which the Z-double bond of 1a was replaced
by a benzene ring, could be thought of as a promising
expansion of 1a and might be the starting material for
the synthesis of ethyl 3-(phenylthiomethyl)-2-naphthoate
a Method A: 1 (0.5 mmol) and triethylamine (1.0 mmol) in acetonitrile
(3 mL) under a N2 atmosphere at 60 °C for 12 h. Method B: 1 (0.5 mmol)
and DBU (1.0 mmol) in acetonitrile (3 mL) under a N2 atmosphere at room
temperature for 3 h.
Org. Lett., Vol. 12, No. 16, 2010
3675

(4a). However, we failed to obtain any product using
triethylamine as the base. Luckily, DBU in acetonitrile at
60 °C gave the desired product 4a in a yield of 72%, and
a series of polysubstituted naphthalenes were prepared in
satisfactory yields (Table 3).
Scheme 3
Table 3. Synthesis of Polysubstituted Naphthalenesa
deuterium on the new benzene ring was observed, probably
because the propargyl-allene isomerization is so fast that
the protonated triethylamine does not have enough time to
leave (Scheme 4).
Scheme 4
Notably, the electron-withdrawing groups (ester or amide
group) of 1 or 3, which could increase the acidity of the
methylene group adjacent to the sulfur atom, are essential
to the propargyl-allenyl isomerization promoted by the mild
bases and may improve the consequential 6 π-electrocy-
clization process.2c Importantly, the ester or amide group,
which would be playing a role as a reactivity controlling
element during the process, could also be used as a
convenient chemical handle for preparing other useful
compounds. We treated 2a and 4b with LiAlH4 and NaBH4/
BF3·Et2O to access alcohol (5) and amine (6), respectively,
in good yields (Figure 1).
a Substrate 3 (0.5 mmol) and DBU (1.0 mmol) in acetonitrile (3 mL) at
60 °C under a N2 atmosphere.
Although we did not detect the allene intermediate, we
conducted control experiments which might be helpful for
supporting the pathway proposed in Scheme 1. We treated
(E)-ethyl 3-(2-(3-(butylthio)prop-1-ynyl)cyclohex-1-enyl)-
acrylate (1f) with 20 equiv of methanol-d4 in acetonitrile
and obtained deuterated 2f. We observed 60% deuterium
on one of the protons of the methylene group adjacent to
the sulfur atom, which might come from the base-assisted
isomerization of the intermediate isotoluene (Scheme 3).
We had expected more deuterium on the new benzene ring
before conducting this control experiment, but only 25%
On the other hand, the sulfane group, which triggered the
propargyl-allenyl isomerization, might be used as a “key” for
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Tetrahedron 2009, 65, 10660. (b) Yusubov, M. S.; Yusubova, R. Y.; Funk,
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3676
Org. Lett., Vol. 12, No. 16, 2010

availability of starting materials and the simple operation,
this type of reaction presented here has potential utility in
organic synthesis.
Acknowledgment. Dedicated to the memory of Prof. Xian
Huang. Financial support was received from the Natural
Science Foundation of China (Nos. 20702046 and
20972134).
Supporting Information Available: Experimental pro-
cedures and NMR spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
Figure 1. Reduction of 2a and 4b.
OL101479D
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further generation of chemical diversity, such as oxidation to
sulfoxide5 and sulfone,6 reduction,7 alkylation,8 and acylation.9
In summary, we developed a facile and efficient electro-
cyclization for the synthesis of polyfunctionalized benzene
and naphthalene derivatives. As a result of the ready
(9) (a) Arroyo, Y.; Rodri g´uez, J. F.; Santos, M.; Tejedor; Ruano, J. L. G.
J. Org. Chem. 2007, 72, 1035. (b) Harada, T.; Morimoto, M.; Nagasawa,
M.; Takamura, N.; Inoue, H.; Ohishi, T.; Takeda, M. Chem. Pharm. Bull.
1992, 40, 1986.
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