Iodine-Mediated Synthesis of Aromatic Thioethers with Aromatic Amines and Sulfonyl Hydrazides in High Regioselectivity via C(sp2)-H Bond Functionalization

Article abstract of DOI:10.1002/adsc.201500943

An iodine-mediated synthesis of aromatic thioethers from aromatic amines and sulfonyl hydrazides via C(sp²)-H bond functionalization and C-S bond formation has been developed. In this procedure, various substituents on the sulfonyl hydrazides, such as alkyl, methoxyl, chloro, bromo and fluoro groups, and aromatic amines are tolerated in the thiolation which generates the desired products in moderate to good yields.

Full text of DOI:10.1002/adsc.201500943

UPDATES
DOI: 10.1002/adsc.201500943
Iodine-Mediated Synthesis of Aromatic Thioethers with Aromatic
Amines and Sulfonyl Hydrazides in High Regioselectivity via
2
À
C(sp ) H Bond Functionalization
Xiaobo Pang,a Likui Xiang,a Xiaodong Yang,a and Rulong Yana,*
a
State Key Laboratory of Applied Organic Chemistry, Key Laboratory of Nonferrous Metal Chemistry and Resources
Utilization of Gansu Province, Department of Chemistry, Lanzhou University, Lanzhou, Gansu 730000, Peopleꢀs Republic
of China
Fax: (+86)-931-891-2596; e-mail: yanrl@lzu.edu.cn
Received: October 6, 2015; Revised: October 29, 2015; Published online: January 12, 2016
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201500943.
Abstract: An iodine-mediated synthesis of aromatic
thioethers from aromatic amines and sulfonyl hy-
methods. In those procedures, various thiolating/
À
sulfenylating reagents had been applied for C S bond
2
drazides via C(sp ) H bond functionalization and
formation.[14] In 2013, Kumarꢀs group reported a tran-
sition metal-free synthetic method for unsymmetrical
diaryl chalcogenides from arenes and diaryl dichalco-
genides.[15] More recently, Wangꢀs group reported an
À
À
C S bond formation has been developed. In this
procedure, various substituents on the sulfonyl hy-
drazides, such as alkyl, methoxyl, chloro, bromo
and fluoro groups, and aromatic amines are tolerat-
ed in the thiolation which generates the desired
products in moderate to good yields.
iodine-catalyzed arylthiation of substituted anilines
[16]
À
with thiols to form the C S bond. Nevertheless, it
is still a great challenge to synthesize diaryl sulfides
from readily accessible substrates through metal-free
oxidative reactions.
À
Keywords: aromatic thioethers; C S bond forma-
Sulfonyl hydrazide, as an ideal thiolating agent, has
emerged as a candidate due to its ready accessibility
and stability. To the best of our knowledge, there are
as yet no examples concerning a method for the con-
tion; hydrazines; iodine; regioselectivity; sulfur
À
struction the C S bond to a benzene ring directly
À
Organic compounds containing C S bond are widely uzsing sulfonyl hydrazides as sulfenylating agents
present in many functional materials.[1] Furthermore, under metal-free conditions. Inspired by previous
organosulfur compounds are important building works[17]and our experience in development of new
blocks for the synthesis many bioactive[2] and pharma- and efficient methods for the construction of the C S
À
ceutical compounds.[3] Particularly, the structural unit bond,[18] herein we have developed a direct C S bond
À
of diaryl sulfides exists extensively in potential drug formation method between aromatic amines and sul-
candidates with antifungal and anticancer activities as fonyl hydrazides under I2-mediated conditions with
well as for HIV, Alzheimerꢀs or Parkinsonꢀs diseas- high regioselectivity (Scheme 1).
es.[4] A number of transition metal-catalyzed ap-
N,N-Dimethylaniline 1a and p-toluenesulfonyl hy-
proaches to synthesize diaryl sulfides has been devel- drazide 2a were firstly chosen as model substrates in
oped.[5] Most of the transition metal-catalyzed strat- the presence of I2 (0.5 equiv.) in THF at 1008C, no re-
egies, such as Pd,[6] Cu,[7] Co,[8] Rh,[9] etc.[10] have simi- action occurred under these conditions. It was gratify-
lar drawbacks for extensive applications due to the ing that with the use of 0.5 equiv. 2,2,2-trifluoroacetic
expensive and toxic transition metal catalysts. With acid (TFA) as the additive, N,N-dimethyl-4-(p-tolyl-
the increased concern about environmental issues, thio)aniline 3aa was isolated in 52% (Table 1,
metal-free cross-coupling reactions for the construc- entry 2). Extensive evaluating of other acids as addi-
À
tion of the C S bond have been demonstrated as tives, such as boron fluoride·diethyl etherate
highly efficient protocols and have received much at- (Et2O·BF3), trifluoromethanesulfonic acid (TfOH),
tentions. In the past several years, excellent and sig- Sc(OTf)3, pivalic acid (PivOH) and InBr3, lower or no
À
nificant works on the construction of the C S bond yields of 3aa were obtained (Table 1, entries 3–7).
have been reported by the groups of Tian,[11] Jiang,[12] Then different amounts of TFA were used in the reac-
and others[13] through eco-friendly and economical tion (Table 1, entries 8–11) and 1.2 equiv. of TFA
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Xiaobo Pang et al.
est yield was achieved when 0.5 equiv. I2 was used.
Moreover, we found that I2 was crucial for this reac-
tion and no desired product was isolated in the ab-
sence of I2 (Table 1, entries 12–14). After the reaction
conditions had been screened, it could be concluded
that the optimal reaction should be performed in the
presence of I2 (0.5 equiv.) and TFA (1.2 equiv.) in
THF at 1008C (Table 1, entry 11).
Under these optimal reaction conditions, a series of
arylsulfonyl hydrazides was investigated for this reac-
tion (Table 2). To our delight, various substituted sul-
fonyl hydrazides could react with N,N-dimethylaniline
and generate the desired products in moderate to
high yields. In this process, the electronic effect of the
substituted sulfonyl hydrazides had mo major influ-
ence on the reaction and the sulfonyl hydrazides with
electron-donating and electron-withdrawing groups
gave the desired products in similar yields. Neverthe-
less, when 1a reacted with 4-nitrobenzenesulfonohy-
drazide 2o under the optimal reaction conditions, just
only a trace of 3ao was detected by TLC. Moreover,
the thiophene-2-sulfonohydrazide 2n was also tolerat-
ed in this process, furnishing the target compounds
3an in excellent yield.
À
Scheme 1. C S bond formation reactions.
À
The success of C S bond formations between sub-
stituted sulfonyl hydrazides and N,N-dimethylaniline
inspired us to investigate a variety of substituted aro-
matic amines. Then, various aromatic amines were
also investigated in the process (Table 3) and most of
the aromatic amines could couple with 2a in moderate
yields. It was clearly observed that moderate yields
were afforded when the aromatic amines with nitro-
gen heterocycles, such as 1-(o-tolyl)piperazine 1f, 4-
phenylmorphline 1g, 1-phenylpyrrolidine 1h were
used. However, when 1-phenyl-1H-pyrrole 1i, N-
methylaniline 1j and aniline 1k were employed under
the optimal reaction conditions, only trace amounts of
3ia, 3ja and 3ka were obtained.
To gain further insights into this transformation,
firstly, we performed experiments of coupling 1a and
2a at 1008C with 0.5 equiv. I2 in THF for 10 h, the by-
products 4, 5 and product 3aa were detected in the re-
action mixture. Next, the compounds 4 and 5 can
both react with 1a to give the desired product 3aa in
70% and 74% yields, respectively (Scheme 2).
On the basis of previous relevant studies and exper-
imental results, a proposed mechanism for this pro-
cess is depicted in Scheme 3. First, sulfonyl hydrazide
2 was converted to intermediated 4 under the cataly-
sis of iodine. At the same time, N2, HOI and HI were
generated in this process.[17a] Subsequently, intermedi-
ate 5 which was produced by reduction of 4 reacted
with HI to form sulfenyl iodide 6. Finally, the target
compound 3 was accessed by electrophilic substitution
between 6 and 1.
Table 1. Optimization of reaction condition.[a]
Entry Catalyst (equiv.) Additive (equiv.) Yield [%][b]
1
I2 (0.5)
I2 (0.5)
I2 (0.5)
I2 (0.5)
I2 (0.5)
I2 (0.5)
I2 (0.5)
I2 (0.5)
I2 (0.5)
I2 (0.5)
I2 (0.5)
–
–
–
2
3
4
5
6
7
8
9
10
11
12
13
14
15[c]
TFA (0.5)
Et2O·BF3 (0.5)
TfOH (0.5)
Sc(OTf)3 (0.5)
PivOH (0.5)
InBr3 (0.5)
TFA (0.2)
TFA (0.8)
TFA (1.0)
TFA (1.2)
TFA (1.2)
TFA (1.2)
TFA (1.2)
TFA (1.2)
52
42
–
–
–
–
–
60
72
88
–
43
80
63
I2 (0.2)
I2 (1.0)
I2 (0.5)
[a]
Reaction conditions: 1a (0.3 mmol), 2a (0.6 mmol), addi-
tive, THF (2 mL), 1008C, 12 h.
Isolated yield.
[b]
[c]
0.36 mmol of 2a was used in this process.
gave an excellent yield for this reaction. After screen-
In summary, we have developed a straightforward
ing the amount of I2 for the transformation, the high- method for the synthesis of aromatic thioethers in
322
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Iodine-Mediated Synthesis of Aromatic Thioethers
Table 2. Thiolation of substituted sulfonyl hydrazides and
N,N-dimethylaniline.
Table 3. Thiolation of substituted aromatic amines and p-tol-
uenesulfonyl hydrazides.
2
À
high regioselectivity through C(sp ) H bond function-
alization of aromatic amines. A series of aromatic
amines and sulfonyl hydrazides were tolerated in this Scheme 2. Control experiments.
Adv. Synth. Catal. 2016, 358, 321 – 325
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UPDATES
Xiaobo Pang et al.
Scheme 3. Proposed mechanism.
transformation and generated synthetically valuable
aromatic thioethers in moderate to good yields when
utilizing iodine and TFA.
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General Procedure for the Synthesis of the Desired
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An oven-dried pressure tube was charged with aromatic
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