Oxidative dual C-H thiolation of imidazopyridines with ethers or alkanes using elemental sulphur

Article abstract of DOI:10.1039/c7cc03940a

Dual C-H thiolation reactions using elemental sulphur remain a challenge. This communication discloses an oxidative radical dual sp²/sp³ C-H thiolation strategy for the coupling of imidazopyridines with ethers or alkanes using elemental sulphur.

Full text of DOI:10.1039/c7cc03940a

View Article Online
View Journal
ChemComm
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: J. Zhang, Y. Liao,
J. Deng, K. Feng, M. Zhang, Y. Ning, Z. Lin and R. Tang, Chem. Commun., 2017, DOI:
10.1039/C7CC03940A.
This is an Accepted Manuscript, which has been through the
Volume 52 Number
1 4 January 2016 Pages 1–216
Royal Society of Chemistry peer review process and has been
accepted for publication.
ChemComm
Accepted Manuscripts are published online shortly after
Chemical Communications
www.rsc.org/chemcomm
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. We will replace this Accepted Manuscript with the edited
and formatted Advance Article as soon as it is available.
You can find more information about Accepted Manuscripts in the
author guidelines.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the ethical guidelines, outlined
in our author and reviewer resource centre, still apply. In no
event shall the Royal Society of Chemistry be held responsible
for any errors or omissions in this Accepted Manuscript or any
consequences arising from the use of any information it contains.
ISSN 1359-7345
COMMUNICATION
Marilyn M. Olmstead, Alan L. Balch, Josep M. Poblet, Luis Echegoyenet al.
Reactivity differences of Sc3N@C2n (2n 68 and 80). Synthesis of the
first methanofullerene derivatives of Sc N@D5h-C80
=
3
rsc.li/chemcomm

Please do not adjust margins
Page 1 of 4
ChemComm
View Article Online
DOI: 10.1039/C7CC03940A
Journal Name
COMMUNICATION
Oxidative Dual C–H Thiolation of Imidazopyridines with Ethers or
Alkanes Using Elemental Sulphur
Received 00th January 20xx,
Accepted 00th January 20xx
Jun-Rong Zhang,a Yan-Yan Liao, a Jian-Chao Deng, a Kai-Ying Feng, a Min Zhang, a Yun-Yun Ning, a Zi-
Wei Lin, a Ri-Yuan Tang*a,b
DOI: 10.1039/x0xx00000x
www.rsc.org/
Dual C−H thiolation reactions using elemental sulphur remain the narrow substrate scope of aromatic thiols and disulphides,
challenging. This paper discloses an oxidative radical dual sp2/sp3 the development of a dual C
H thiolation reaction of
C−H thiolation strategy for the coupling of imidazopyridines with imidazopyridines with a diverse range of hydrocarbons using
ethers or alkanes using elemental sulphur. elemental sulphur is greatly desired. Herein, we report a DTBP
(Di-tert-butyl peroxide) oxidative dual sp2/sp3 C
H thiolation
−
−
The C−S bond is an important structural unit found in many
protocol for the coupling of imidazopyridines with ethers or
alkanes using elemental sulphur (Scheme 1b).
naturally occurring and bioactive molecules.1 Numerous
sulphur-containing molecules have been used as medicines
and agrochemicals.2 The construction of C
−
S bonds has
attracted considerable attention.3 Traditional methods for C
−S
bond formation commonly employ toxic and odorous thiols as
4
sulphur sources.3a, Therefore, the use of nontoxic and
odourless sulphur sources for the construction of C−S bonds is
greatly desired. To date, several stable sulphurous sources,
such as Na2S, thiourea, thiosulfate, and elemental sulphur,
have been employed for the preparation of thioethers.3a,b
Among these sulphur sources, elemental sulphur is an ideal
reagent that is an inexpensive, nontoxic, odourless, stable and
easy to handle powder.5 In recent years, significant attention
Scheme 1 Dual C-H thiolation.
During previous investigations concerning C−H thiolation,11c,d,
12
we found that oxidative radical reactions are effective
protocols for dual C−H thiolation.12b, 13 Peroxides are the most
commonly used radical initiators for such transformations.14
Thus, our studies began with the three-component thiolation
of imidazopyridine 1a with elemental sulphur and dioxane in
the presence of two equivalents of TBHP (t-
has been directed to the construction of C−S bonds using
elemental sulphur.6-8 Although some progress has been made,
the coupling of two different molecules via a dual C−H
thiolation using elemental sulphur still remains challenging.
Such procedures provide economic and efficient routes to a
diverse range of thioethers (Scheme 1a). In particular, the dual
o
butylhydroperoxide) at 120 C for 24 hours. The reaction was
carried out to afford the desired product
C−H thiolation of drug skeletons is of great interest.
3 in 23% yield (table
Imidazopyridines are an important structural motif possessing
a broad range of biological activities9 and so the preparation of
imidazopyridine derivatives has gained much attention.10
Recently, thiols and disulphides have been applied to the
1, entry 1). Other peroxides, such as DTBP, BPO (benzoyl
peroxide), H2O2, and K2S2O8, were also investigated (table 1,
entries 2-5). DTBP was found to be the most effective peroxide,
giving the desired product
3 in 56% yield (table 1, entry 2),
thiolation of imidazoheterocycles.11
A three-component
while other peroxides proved to be ineffective (table 1, entries
3-5). No reaction occurred when BQ (benzoquinone) or DDQ
(2,3-Dichloro-5,6-dicyano-1,4-benzoquinone) were used as
oxidising agents (table 1, entries 6 and 7). The product yield
was increased to 82% when four equivalents of DTBP were
used (table 1, entry 8). Increasing the reaction time to 36
hours had no influence on the product yield (table 1, entry 9).
reaction consisting of imidazopyridine substrates with aryl
iodides and elemental sulphur has also been studied.6l-n Due to
Conversely, temperature had a great influence on yield, for
o
example product
3
was obtained in only 27% yield at 100 C
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
Please do not adjust margins

Please do not adjust margins
ChemComm
Page 2 of 4
COMMUNICATION
Journal Name
o
but in 70% yield at 140 C (table 1, entries 10-12). Interestingly, as 2-methyloxirane and 7-oxabicyclo[4.1.0]heptane were also
View Article Online
DOI: 10.1039/C7CC03940A
the product yield was increased to 89% yield when the loading compatible with the reaction conditions. In the presence of 4Å
of dioxane was reduced to 0.5 mL or 0.2 mL (table 1, entries 13 molecular sieve, a ring-opening reaction took place during the
and 14). In the absence of DTBP, no reaction occurred (table 1, thiolation, providing α-hydroxyl thioethers 19 and 20 in 45%
entry 15).
and 48% yields, respectively. α-Hydroxy thioethers 19 and 20
are synthetically useful intermediates.
Table 1. Screening of Optimal Conditions a
a
Table 2. Dual C−H thiolation of imidazopyridines with ethers
Entry
1b
2
3
4
5
6
7
8
Oxidant (eq) Temp (oC) Time (h) Yield (%)
TBHP (2)
DTBP (2)
BPO (2)
H2O2 (2)
K2S2O8 (2)
BQ (2)
120
120
120
120
120
120
120
120
120
100
130
140
120
120
120
24
24
24
24
24
24
24
24
36
24
24
24
24
24
24
23
56
trace
trace
trace
0
DDQ (2)
DTBP (4)
DTBP (4)
DTBP (4)
DTBP (4)
DTBP (4)
DTBP (4)
DTBP (4)
―
0
82
84
27
81
70
89
89
9
10
11
12
13c
14d
15
0
a Reaction conditions: 1a (0.4 mmol), S8 (0.8 mmol), 2a (1 mL, 24 equiv), [O]
(2 or 4 equiv). b TBHP (70% in water). c 2a (0.5 mL, 12 equiv). d (0.2 mL, 4.8
equiv).
With this oxidative dual C−H thiolation procedure in hand, the
imidazopyridine and ether scope were investigated (Table 2).
Initially, a variety of imidazopyridines were subjected to
reaction with dioxane (products
methyl group were well tolerated affording the corresponding
products in good yields (products ). A substrate bearing the
3-15). Substrates bearing a
4-6
strongly electron-donating methoxy group was also
compatible with the reaction conditions, providing the
corresponding product
methyl substituted substrate (product
Substrates with a chloro- or fluoro- group on the pyridine ring
underwent thiolation to afford products and in 54% and 70%
7
in 60% yield, lower than that of the
5
vs product ).
7
8
9
yields, respectively. Substrates bearing methyl, methoxy,
fluoro, or chloro groups on the benzene ring of the
imidazopyridines were investigated. All of these substrates
underwent the thiolation smoothly to afford the desired
products in moderate yields (products 10-15). Next, several
other
tetrahydrothiophene,
ethers,
including
tetrahydro-2H-pyran,
2-methyloxirane,
THF,
7-
a Reaction conditions: 1 (0.4 mmol), 2 (0.5 mL, 12 equiv), S8 (2 equiv), DTBP (4
oxabicyclo[4.1.0]heptane, and 1,2-dimethoxyethane, were
examined. Reaction of tetrahydro-2H-pyran provided its
corresponding product 16 in 56% yield. Although the low
boiling point of THF may influence the reactivity, thiolation
with THF still occurred to give product 17 in 40% yield in the
presence of 4Å molecular sieve. Tetrahydrothiophene (which
has a higher boiling point compared to THF) performed well to
afford product 18 in 67% yield. To our delight, epoxides such
equiv) at 120 oC for 24 h. b dioxane (0.2 mL, 4.8 equiv). c dioxane (1 mL), reaction
d
for 36 h. 4Å molecular sieve powder (50 mg, dried at 130 oC for 6 hours) was
added. e S8 (3 equiv), reaction for 30 h.
1,2-Dimethoxyethane also underwent reaction to give isomers
21a and 21b in a ratio of 3:2 and in 40% total yield. However,
the present thiolation protocol is not compatible with 2-
ethylimidazo[1,2-a]pyridine, suggesting that the reaction
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 3 of 4
ChemComm
Please do not adjust margins
Journal Name
COMMUNICATION
activity is dependent on the aromatic conjugation effect. Other amount of byproduct, methylthiolated imidazopyridine, was
View Article Online
DOI: 10.1039/C7CC03940A
heterocycles, such as indole and pyrazole, were also examined, observed by GC-MS analysis. It is noteworthy that the addition
but these substrates yielded no thiolation products.
of 4Å molecular sieve powder could improve the reaction
efficiency (products 16 17 19 20 30 32).
,
,
,
,
-
a
Table 2. Dual C-H thiolation of imidazopyridines with alkanes
To elucidate the reaction mechanism, the control experiments
shown in scheme 2 were conducted. It was shown that, in the
presence of DTBP, cyclohexane reacted with S8 to yield
dicyclohexylsulfane 36 and 1,2-dicyclohexyldisulfane 37 in 3%
and 61% yields, respectively (Scheme 2, Eqn 1). This
observation suggested that 1,2-dicyclohexyldisulfane 37 may
be a reaction intermediate; however, reaction between
imidazopyridine 1a and 1,2-dicyclohexyldisulfane 37 was
unsuccessful (Scheme 2, Eqn 2). Although another possible
intermediate, 2-phenylimidazo[1,2-a]pyridine-3-thiol 38, was
not discovered in the reaction, it was prepared and reacted
with cyclohexane.15 The target product 22 was obtained in
only 13% yield (Scheme 2, Eqn 3) suggesting that compound 38
may not be a reaction intermediate. To confirm that the
reaction proceeds through an oxidative radical mechanism, the
reaction was conducted with four equivalents of TEMPO
(2,2,6,6-tetramethylpiperidinooxy). The reaction was greatly
suppressed, signifying that this reaction may proceed through
a radical process.
a Reaction conditions: 1 (0.4 mmol), alkane (0.5-1 mL), S8 (2 equiv) at 120 oC for
b
c
30 h. S8 (2 equiv). (toluene, 1 mL). d 4Å molecular sieve powder (50 mg, dried
at 130 oC for 6 hours) was added.
Scheme 2 Control experiments
Subsequently, several inert alkanes were also examined (table
2). Cyclohexane successfully underwent thiolation with a
variety of imidazopyridines and elemental sulphur.
Substituents, such as methyl, methoxy, chloro and fluoro
groups, were well tolerated giving the corresponding products
Based on our results and our previous reports concerning the
oxidative radical transformation of disulphides12b and
imidazoheterocycles,16
a
possible mechanism has been
proposed (Scheme 3). In the presence of DTBP, cyclohexane is
first oxidized to give radical intermediate (Scheme 3, Eqn
1),17 which is then trapped by S8 to afford intermediate
A
in moderate to good yields (products 22
and cyclooctane also underwent reaction but their respective
products were obtained in low yields (products 31 and 32
−30). Cycloheptane
B
.
Intermediate
intermediate
sulphur radical subsequently reacts with radical
B
C
reacts with radical
and a sulphur radical (Scheme 3, Eqn 2). The
to afford
(Scheme 3, Eqs 2 and 3). Finally, the newly formed
can react with 1a to give intermediate , which
A to produce the radical
,
respectively). The thiolation also proceeded with n-hexane;
however, the product was obtained as a mixture of isomers
which was difficult to isolate. Interestingly, the thiolation also
proceeded with toluene, p-xylene, and mesitylene, with the
reaction selectively occurring at the methyl group (products
A
radical
radical
C
C
F
undergoes oxidation to give the target product 22
.
33−35). Generally, in these thiolation reactions, a small
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
Please do not adjust margins

Please do not adjust margins
ChemComm
Page 4 of 4
COMMUNICATION
Journal Name
(a) K.-D. Asmus, Acc. Chem. Res., 1979, 12, 436. (b) C.-F. Lee,
4
Conclusion
Y.-C. Liu and S. S. Badsara, Chem-AsianDJO.,I:21001.140,3V99i/eCw7ACrtCic0le3O9n4l0inAe
, 706.
5
6
Beat Meyer, Chem. Rev., 1976, 76, 367.
In summary, an oxidative radical dual C−H thiolation using
Metal-catalyzed method: (a) F.-J. Chen, G. Liao, X. Li, J. Wu,
and B.-F. Shi, Org. Lett., 2014, 16, 5644. (b) R. Han and G. L.
Hillhouse, J. Am. Chem. Soc., 1998, 120, 7657. (c) C. Chen, L.
Chu and F.-L. Qing, J. Am. Chem. Soc., 2012, 134, 12454. (d) Z.
elemental sulphur has been developed for the first time. In the
presence of DTBP, the coupling of imidazopyridines with
ethers or inert alkanes providing compounds bridged by a
single sulphur atom, has been achieved. A variety of thiolated
imidazopyridines can be prepared using this dual
thiolation protocol. It is worth noting that the elemental
sulphur used for the dual C H thiolation is a stable, nontoxic,
inexpensive and commercially available reagent. The dual C
thiolation strategy is an efficient and straightforward synthetic
route for the construction of C S bonds. The dual C
Zhou, Y. Liu, J. Chen, E. Yao and J. Cheng, Org. Lett., 2016, 18
5268. (e) A. S. Reddy and K. C. K. Swamy, Org. Lett., 2015, 17
,
,
C−H
2996. (f) M. Arisawa, T. Ichikawa and M. Yamaguchi, Org.
Lett., 2012, 14, 5318. (g) C. Chen, Y. Xie, L. Chu, R.-W. Wang,
−
X. Zhang and F.-L. Qing, Angew. Chem., Int. Ed., 2012, 51
,
−
H
2492. (h) Y. Huang, X. He, X. Lin, M. Rong and Z. Weng, Org.
Lett., 2014, 16, 3284. (i) F. Shibahara, T. Kanai, E. Yamaguchi,
A. Kamei, T. Yamauchi and T. Murai, Chem. Asian. J., 2014,
9,
−
−H
237. (j) Z.Weng, W. He, C. Chen, R. Lee, D. Tan, Z. Lai, D. Kong,
thiolation of other useful heterocycles (indoles, pyrazoles,
pyrroles, etc.) with functionalized alkanes using elemental
sulphur remains to be addressed.
Y. Yuan and K.-W. Huang, Angew. Chem., Int. Ed., 2013, 52
1548. (k) R. Paul and T. Punniyamurthy, RSC Adv., 2012,
,
,
2
7057 and references cited therein. (l) J. Li, C. Li, S. Yang, Y. An,
W. Wu and H. Jiang, J. Org. Chem., 2016, 81, 7771. (m) C.
Ravi, N. N. K. Reddy, V. Pappula, S. Samanta, S. Adimurthy, J.
Org. Chem., 2016, 81, 9964. (n) F. Xiao, S. Chen, C. Li, H.
Huang, G.-J. Deng, Adv. Synth. Catal., 2016, 358, 3881.
Metal-free method: (a) G. Zhang, H. Yi, H. Chen, C. Bian, C.
Liu, and A. Lei, Org. Lett., 2014, 16, 6156. (b) Z. Wang, Y.
Wang, W.-X. Zhang, Z. Hou and Z. Xi, J. Am. Chem. Soc., 2009,
131, 15108. (c) T. B. Nguyen, L. Ermolenko and A. Al-
Mourabit, Org. Lett., 2013, 15, 4218. (d) M. Wang, Q. Fan
and X. Jiang, Org. Lett., 2016‚ 18‚ 5756.
7
8
9
For the synthesis of thioamide, see: (a) T. B. Nguyen, M. Q.
Tran, L. Ermolenko and A. Al-Mourabit, Org. Lett., 2014, 16
,
310. (b) T. Guntreddi, R. Vanjari and K. N. Singh, Org. Lett.,
2014, 16, 3624.
(a) C. Enguehard-Gueiffier and A. Gueiffier, Mini-Rev. Med.
Chem., 2007,
7, 888. (b) F. Couty and G. Evano,
Comprehensive Heterocyclic Chemistry; Elsevier: Oxford,
2008.
10 J. Koubachi, S. El Kazzouli, M. Bousmina and G Guillaumet,
Eur. J. Org. Chem., 2014, 2014, 5119, and references cited
therein.
Scheme 3 A possible reaction mechanism
11 Selected references, see: (a) Y. Siddaraju and K. R. Prabhu, J.
Org. Chem., 2016, 81, 7838. (b) J. Rafique, S. Saba, A. R.
Acknowledgment
Rosario and A. L. Braga, Chem.
―Eur. J., 2016, 22, 11854. (c)
We gratefully thank the NSFC (No. 21202121), Science
Technology Program Project of Guangdong Province (No.
2016B020204005) and Guangzhou Science Technology
Program Project (No. 201607010142) for their financial
support.
J. Jiao, L. Wei, X.-M. Ji, M.-L. Hu and R.-Y. Tang, Adv. Synth.
Catal., 2016, 358, 268. (d) X.-M. Ji, S.-J. Zhou, F. Chen, X.-G.
Zhang and R.-Y. Tang, Synthesis., 2015, 47, 659. (e) M.-A.
Hiebel and S. Berteina-Raboin, Green Chem., 2015, 17, 937. (f)
C. Ravi, D. Chandra Mohan and S. Adimurthy, Org. Lett., 2014,
16, 2978. (g) S. Mitra, M. Ghosh, S. Mishra and A. Hajra, J.
Org. Chem., 2015, 80, 8275. (h) D. Yang, K. Yan, W. Wei, G. Li,
S. Lu, C. Zhao, L. Tian and H. Wang, J. Org. Chem., 2015, 80
,
Notes and references
11073. (i) Q. Wang, Z. Qi, F. Xie and X. Li, Adv. Synth. Catal.,
2015, 357, 355.
1
(a) J. T. Jarrett, J. Biolog. Chem., 2015, 290, 3972. (b) M. I.
Konaklieva and B. J. Plotkin, Recent Pat. Anti-Infect. Drug
12 (a) L. Wei, L. Xu and R.-Y. Tang, RSC Adv., 2015, 5, 107927. (b)
Discovery, 2006, 1, 177. (c) M. Feng, B. Tang, S. H. Liang and
R.-Y. Tang, Y.-X. Xie, Y.-L. Xie, J.-N. Xiang and J.-H. Li, Chem.
Commun., 2011, 47, 12867.
X. Jiang, Curr. Top. Med. Chem., 2016, 16, 1200.
2
(a) C. Hansch, P. G. Sammes and J. B. Taylor, Comprehensive
medicinal chemistry; the rational design, mechanistic study
& therapeutic application of chemical compounds, Pergamon
Press, Oxford, New York, 1990, ch. 7.1, p. 2. (b) A. Casini, J.-Y.
Winum, J.-L. Montero, A. Scozzafava and C. T. Supuran,
Bioorg. Med. Chem. Lett., 2003, 13, 837; (c) M. Mellah, A.
Voituriez and E. Schulz, Chem. Rev., 2007, 107, 5133.
13 (a) Q. Liu, R. Jackstell and M. Beller, Angew. Chem., Int. Ed.,
2013, 52, 13871. (b) C. Liu, D. Liu and A. Lei, Acc. Chem. Res.,
2014, 47, 3459.
14 (a) S. A. Girard, T. Knauber and C. -J. Li, Angew. Chem., Int.
Ed., 2014, 53, 74. (b) C.-J. Li, Acc. Chem. Res., 2009, 42, 335.
15 The procedure for the preparation of compound 38, see ESI†.
16 (a) X.-M. Ji, L. Wei, F. Chen and R.-Y. Tang, RSC Adv., 2015, 5,
3
Reviews for the construction of C−S bond, see: (a) A. Ghaderi,
29766. (b) X.-M. Ji, L. Xu, Y. Yan, F. Chen and R.-Y. Tang,
Synthesis, 2016, 48, 687.
Tetrahedron., 2016, 72, 4758, and references cited therein.
(b) Z. Qiao and X. Jiang Org. Biomol. Chem., 2017‚ 15, 1942.
(c) C. Shen, P. Zhang, Q. Sun, S. Bai, T. S. Andy Hor and X. Liu,
Chem. Soc. Rev., 2015, 44, 291.
17 (a) J. Zhao, H. Fang, J. Han, Y. Pan and G. Li, Adv. Synth. Catal.,
2014, 356, 2719. (b) B. Du, B. Jin and P. Sun, Org. Lett., 2014,
16, 3032.
4 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins