Facile one-pot synthesis of naphthoquinone 1,3-dithioles via 2,3-dichloro-1,4-naphthoquinone and amines involving CS2

Article abstract of DOI:10.1246/cl.130330

An efficient, simple, and facile one-pot approach of synthesizing naphthoquinone1,3-dithioles via 2,3-dichloro-1,4-naphthoquinone and amines involving CS₂ was investigated. Both amino acid esters and aliphatic primary amines were applicable to

Full text of DOI:10.1246/cl.130330

doi:10.1246/cl.130330
Published on the web May 31, 2013
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Facile One-pot Synthesis of Naphthoquinone­1,3-Dithioles via 2,3-Dichloro-1,4-naphthoquinone
and Amines Involving CS2
1
2
1
1
1
1
1
Huanming Huang, Jing Han, Fang Xu, Yujin Li,* Huaqing Dong, Wubin Yu, and Jianrong Gao*
1
State Key Laboratory Breeding Base of Green Chemistry-Synthesis Technology,
Zhejiang University of Technology, Hangzhou 310032, P. R. China
Xiao Shan Entry-Exit Inspection and Quadrant Bureau, Zhejiang, P. R. China
2
(
Received April 11, 2013; CL-130330; E-mail: lyjzjut@zjut.edu.cn)
An efficient, simple, and facile one-pot approach of
synthesizing naphthoquinone­1,3-dithioles via 2,3-dichloro-
O
O
S
S
S
S
S
S
S
S
S
1,4-naphthoquinone and amines involving CS2 was investigated.
S
O
Both amino acid esters and aliphatic primary amines were
applicable to this reaction and gave the corresponding hetero-
cycles in good yields through the two-step sulfur-attack process.
O
O
O
O
S
S
S
S
S
S
S
S
O
In recent years, maximizing synthetic efficiency while at the
same time minimizing unnecessary synthetic steps is a very
important and extremely powerful tool offering a straightfor-
ward route to generate complexity and diversity in a single
Figure 1. Several TTFs molecules.
Table 1. Optimization between 2,3-dichloro-1,4-naphthoqui-
none (1), phenylalanine ethyl ester hydrochloride (2a), and
CS2 (3)
1
operation to construct numerous biologically active molecules.
Compounds containing the sulfur heterocycles have shown a
wide range of pharmacological activities, found in common
O
O
O
Cl
S
S
H N
2
N
O
O
O
CS2
2
HCl
structural scaffolds in natural products and bioactive molecules.
Cl
O
O
Additionally, derivatives of sulfur heterocycles such as 1,3-
dithioles have been widely explored as new materials because of
their superconducting, optical, and electronic switching proper-
1
2a
3
4a
Temperature
Base
Yield
/%
Entrya 1:2a:3
Solvent
1
3
b
ties. In particular, tetrathiafulvalenes (TTFs) (Figure 1) are the
/°C
(equiv)
most successful class of heterocycles in terms of creating highly
conducting and superconducting organic crystalline materials,
1
2
3
4
5
6
1:1.2:3
1:2:3
1:1.2:3
1:1.2:3
1:1.2:3
1:1.2:3
0
0
R.T.
40
0
CH2Cl2 Et3N (1.2) 56.5 40.5
CH2Cl2 Et3N (2.0) 60.1 35.2
CH Cl Et N (1.2) 40.5 51.2
4
and TTF­quinones systems constitute a promising field of
applications due to the interesting optoelectronic properties they
2
2
3
CH2Cl2 Et3N (1.2) 35.6 53.5
CH Cl Et N (2.0) 70.5 18.1
5
exhibiting.
2
2
3
At the same time, the quinone structure is common in
numerous natural products6 and important pharmacophores.
Furthermore, a number of quinone structures, particularly,
0
CH2Cl2 Et3N (3.2) 82.3
®
7
aReaction conditions: the mixture of 1a (1.0 mmol), 2a (1.2­
2.0 mmol), 3 (3 mmol), Et3N (1.2­3.2 mmol), and solvent
(5.0 mL) was stirred for 2.5 h under corresponding temper-
8
heterocyclic quinones are associated with anticancer, antibac-
9
10
11
terial, antimalarial, and fungicide activities, and antiparasitic
b
1
2
ature. Yield of the isolated product.
agents.
There are few protocols for the corresponding synthesis of
heterocyclic quinone derivatives involving C­S bond formation,
Compared to the new C­N and C­O bond-forming technologies,
despite the importance of sulfur-containing compounds. During
the past decades, several examples of synthesis of naphtho-
quinone­1,3-dithioles(naphtho[2,3-d][1,3]dithiole-4,9-quinones)
had been reported via 2,3-dichloro-1,4-naphthoquinone and 1,1-
dithiolate, which was prepared by amine and CS2.13 Herein, we
investigated an efficient, simple, and facile one-pot approach of
synthesizing the naphthoquinone­1,3-dithioles via 2,3-dichloro-
obtained in 56.5% yield, and 40.5% of 1 was recycled (Table 1,
Entry 1). Encouraged by these results, we then started to
optimize the reaction conditions to make sure that the 2,3-
dichloro-1,4-naphthoquinone (1) consumed up and improve the
chemical yield. As the quantity of 2a was up to 2 equiv, the yield
of 4a increased only slightly (Table 1, Entry 2). Several means
had been tried to make sure that 1 consumed up, but the results
were all unsatisfactory due to the volatility of CS2 as the
temperature increased (Table 1, Entries 3 and 4). Excitingly, the
1,4-naphthoquinone and amines involving CS2.
yield of 4a had significantly increased with Et N increased
3
In order to synthesize the sulfur-containing heterocyclic
(Table 1, Entries 1, 5, and 6). With the optimized conditions
(Table 1, Entry 6), the corresponding product 4a was obtained
in 82.3% yield.
With the optimized reaction conditions in hand, we
investigated the substrate scope for this reaction (Tables 2
and 3). As highlighted in Table 2, a variety of amino acid ester
hydrochlorides 2a­2h could react efficiently with 2,3-dichloro-
compounds, our initial investigations were focused on examin-
ing the feasibility of the reaction of 2,3-dichloro-1,4-naphtho-
quinone (1) and phenylalanine ethyl ester hydrochloride (2a)
with CS2 (3) and optimizing the reaction conditions for
application to synthesize a variety of naphthoquinone­1,3-
dithiole derivatives. To our delight, the desired product 4a was
Chem. Lett. 2013, 42, 921­923
© 2013 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

9
22
Table 2. Extending scopes using different amino acid ester
hydrochlorides
O
O
Cl
O
R2
S
S
H2N
O
HCl
CS2
N
O
Cl
R1
R1
O
O
O
R2
1
2
3
4
Yield
Entry
2
R1
R2
4
/%
1a
2
3
4
5
2a
2b
2c
2d
2e
2f
PhCH2­
(CH3)2CH­
H­
CH3CH2­
CH3­
CH3CH2­
CH3­
4a
4b
4c
4d
4e
4f
82.3
72.8
52.3
46.2
70.0
73.2
H­
(CH ) CH­
CH CH ­
3
2
3
2
6
CH3­
CH3CH2­
Figure 2. ORTEP drawing of 4a.
7
8
2g
CH3CH2­
4g
66.9
O
O
O
Cl
Cl
S
S
R1
N
HO
H2N
R1
HCl
CS2
2
3
O
2h
CH3CH2­
4h
75.0
1
4
Et
HCl
3
N
-
N
H
O
O
O
O
S
Cl
S
Cl
S
SH
S
S
aSee ref 14 for details of experimental procedure.
R1
R1
Et3N
-HCl
R
R
R
N
N
N
N
SH
N
H
H
H2
N
R1
H
urea
5
H
6
7
Table 3. Extending scopes using different primary amine
hydrochlorides
Scheme 1. Proposed reaction pathway.
O
O
R1
N
Cl
S
S
H2N
R1
HCl
CS2
as the reactant under the same condition as above and urea was
used as the by-product with the side reaction of CS2 and amine.
Excitingly, the yield of 4k improved to 89.3% when propyl-
amine hydrochloride and Et3N were employed (Table 3,
Entry 3). The different primary amine hydrochlorides 2i­2r
bearing the various linear and branched chain alkyl groups,
benzyl group all yielded the corresponding products in 48.9­
Cl
O
O
1
2
3
4
Yield
Entry
2
R1
4
/%
1
2
3
4
5
6
7
8
9
2i
2j
2k
2l
2m
2n
2o
2p
2q
CH3­
CH3CH2­
4i
78.2
83.6
89.3
58.8
73.3
73.1
78.6
60.2
60.1
4j
4k
4l
8
9.3% yields (Table 3, Entries 1­10). Cyclohexylamine was
CH3CH2CH2­
(CH ) CH­
obtained in 48.9% yield because of the low reactivity due to the
steric hindrance of cyclohexylamine.
3
2
CH3CH2CH2CH2­
C H ­
4m
4n
4o
4p
4q
According to these results, a possible mechanism for this
reaction was proposed in Scheme 1. First, the intermediate 5
6
13
1
7
C10H21­
C12H25­
PhCH2­
was afforded by the addition of amine to CS2. Subsequently,
the initial addition product 6 was obtained as the sulfur of
intermediate 5 attacked 1 and further to its tautomer 7, and then,
the product 4 was obtained through the same sulfur-attack
procedure. At the same time, the intermediate 5 added to the
1
0
2r
4r
48.9
1
8
amine and turned into the by-product urea.
In summary, we have developed an efficient and facile one-
pot approach of synthesizing naphthoquinone­1,3-dithioles via
2,3-dichloro-1,4-naphthoquinone and amines involving CS2.
Fatty amines and amino acid ester all gave the corresponding
product in good yield. This reaction will stimulate the synthetic
applications of sulfur-containing heterocycles by employing
these inexpensive reagents of CS2. Therefore, the potential
applications of these compounds will be interesting in pharma-
ceutical and material research. Further related investigation on
the synthesis and applications will be ongoing in our laboratory.
1
,4-naphthoquinone in the presence of CS2, and the correspond-
ing products could be obtained in good to excellent yields
Table 2, Entries 1­8). Unfortunately, lower yields of 4c and 4d
(
were obtained: 52.3 and 46.2%, respectively; the reason may be
that the side reaction of urea was increased due to the small
steric effect of glycine ester (Table 2, Entries 3 and 4). The
structure of 4a was determined by X-ray crystal analysis
1
6
(Figure 2).
In order to further extend the applicability of this reaction,
we also investigated the aliphatic primary amines in this
reaction; the results are summarized in Table 3. Propylamine
was used in order to establish the full scope of this interesting
reaction at first. Unfortunately, the corresponding product 4k
was only obtained in 68.5% yield when propylamine was used
We gratefully acknowledge the financial support from the
Natural Science Foundation of China (No. 21176223) and the
Key Innovation Team of Science and Technology in Zhejiang
Province (No. 2010R50018).
Chem. Lett. 2013, 42, 921­923
© 2013 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

9
23
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Chem. Lett. 2013, 42, 921­923
© 2013 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/