Catalyst and additive-free regioselective oxidative C-H thio/selenocyanation of arenes and heteroarenes with elemental sulfur/selenium and TMSCN

Article abstract of DOI:10.1039/c8cc07905f

A regioselective oxidative C-H thio/selenocyanation of arenes and heteroarenes with TMSCN and elemental sulfur/selenium was demonstrated under catalyst-free and additive-free conditions. Dimethyl sulfoxide (DMSO) was employed as the mild oxidant as well as the solvent. The reaction is operationally simple and scalable with a broad substrate scope.

Full text of DOI:10.1039/c8cc07905f

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Catalyst and additive-free regioselective
oxidative C–H thio/selenocyanation of arenes
and heteroarenes with elemental sulfur/selenium
and TMSCN†
Cite this: Chem. Commun., 2018,
4, 13367
5
Received 3rd October 2018,
Accepted 2nd November 2018
a
a
a
a
b
Chengtao Feng,
Ya Peng, Guangrong Ding, Xiangxiao Li, Chang Cui and
DOI: 10.1039/c8cc07905f
bc
Yizhe Yan
*
rsc.li/chemcomm
A regioselective oxidative C–H thio/selenocyanation of arenes and
heteroarenes with TMSCN and elemental sulfur/selenium was
demonstrated under catalyst-free and additive-free conditions.
Dimethyl sulfoxide (DMSO) was employed as the mild oxidant as
well as the solvent. The reaction is operationally simple and scalable
with a broad substrate scope.
Organosulfur compounds are an important class of molecules
1
due to their broad biological activities. The construction of
carbon–sulfur bonds is an important way to prepare organo-
sulfur compounds. Much effort has been made towards the
Scheme 1 Strategies for oxidative thiocyanation of arenes and heteroarenes.
formation of carbon–sulfur bonds via direct C–H functionalization, green oxidant, a catalyst or electrolyte was required and thiocyanate
2
such as trifluoromethylthiolation, thiolation and sulfonylation.
Among them, direct oxidative thiocyanation of arene C–H bonds
salts were still used as thiocyanation reagents.
Elemental sulfur is one of the most important raw materials
is a facile method for the introduction of sulfur-containing groups. of the modern chemical industry in the preparation of black
The thiocyanation product as a useful intermediate could gunpowder, the vulcanization of rubber and the synthesis of
readily be converted into other valuable sulfur-containing sulfuric acid. Over the last several years, the application of
3
compounds, such as thiophenols, sulfonyl cyanides, etc.
elemental sulfur as a readily available and green sulfur source
Conventionally, the oxidative thiocyanation of arenes and for the synthesis of sulfur-containing compounds has attracted
1
2
heteroarenes was realized using thiocyanate salts, which much attention. However, the use of elemental sulfur for C–H
mainly derived from sulfur and cyanate, as thiocyanation thiocyanation has not been reported yet. In continuation of our
1
3
reagents in the presence of various chemical oxidants, such efforts on metal-free C–H functionalization, herein we report
4
5
6
7
2 2 8 3
as hypervalent iodine reagents, K S O , oxone, Mn(OAc) , or a metal-free regioselective oxidative C–H thiocyanation of
8
other oxidants (Scheme 1a). However, the use of stoichiometric arenes and heteroarenes with elemental sulfur and TMSCN as
oxidants, the narrow substrate scope and the generation of toxic a novel combined thiocyanation source (Scheme 1e). This
wastes limited their further application. Recently, copper- reaction avoids the use of any catalyst and additive, providing
catalyzed, visible light-promoted, and electrochemical oxida- a green and operationally simple method for the synthesis of
tive thiocyanation reactions have been developed (Scheme 1b–d). thiocyanation products.
9
10
11
In these reactions, although oxygen or electrons were used as a
Initially, we began our study with the reaction of 1 equiv. of
3-phenylimidazo[1,5-a]pyridine (1a) as the model substrate,
a
2 equiv. of precipitated sulfur and trimethylsilyl cyanide as
the combined thiocyanation source, and 20 mol% of CuI as the
catalyst. When the reaction mixture was heated in 2 mL of
DMSO at 90 1C for 24 h, 3-phenyl-1-thiocyanatoimidazo[1,5-a]-
pyridine 2a was obtained in 92% yield (Table 1, entry 1). When
other copper catalysts were used as the catalysts, 2a was
obtained in slightly low yields compared with CuI (Table 1,
entries 2–9). To our surprise, the absence of copper catalyst
School of Chemical Engineering, Anhui University of Science and Technology,
Huainan, 232001, P. R. China
b
School of Food and Biological Engineering, Zhengzhou University of Light
Industry, Zhengzhou, 450000, P. R. China. E-mail: yanyizhe@mail.ustc.edu.cn
c
Henan Key Laboratory of Cold Chain Food Quality and Safety Control,
Zhengzhou, 450000, China
†
Electronic supplementary information (ESI) available: Experimental procedures
and spectral data and copies of NMR spectra for all products. See DOI: 10.1039/
c8cc07905f
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a
Table 1 Optimization of reaction conditions
b
Entry Catalyst
S source
Solvent
Yield (%)
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
CuI
CuBr
Precipitated sulfur DMSO
Precipitated sulfur DMSO
Precipitated sulfur DMSO
Precipitated sulfur DMSO
Precipitated sulfur DMSO
Precipitated sulfur DMSO
Precipitated sulfur DMSO
Precipitated sulfur DMSO
Precipitated sulfur DMSO
Precipitated sulfur DMSO
92
91
80
90
84
82
72
60
86
93
84
n.d.
n.d.
n.d.
n.d.
Cu
2
O
CuCl
CuCl
Cu(OAc)
CuSO
CuCO
CuBr
2
2
ÁH
2
O
4
3
2
0
1
2
3
4
5
6
7
8
9
0
Sublimed sulfur
Na
CH
DMSO
DMSO
DMSO
2
S
3
CSNH
2
Scheme 2 C–H thiocyanation of imidazo-fused heterocycles. Reaction
Precipitated sulfur DMF
Precipitated sulfur CH CN
conditions: 1 (0.2 mmol), S
8
(2 equiv., 0.4 mmol), TMSCN (2 equiv.,
3
0
.4 mmol), DMSO (2 mL), 90 1C, 4 h.
Precipitated sulfur 1,4-Dioxane n.d.
Precipitated sulfur EtOH
Precipitated sulfur Toluene
Precipitated sulfur DMSO
Precipitated sulfur DMSO
n.d.
n.d.
83
c
3-thiocyano product 2s was obtained in 77% yield with
-phenylimidazo[1,2-a]pyridine (1s) as the substrate. Notably,
d
85
2
a
Reaction conditions: 1a (0.2 mmol), S source (2 equiv., 0.4 mmol), TMSCN 2-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridine (Zolimidine, 1t)
(
4
2 equiv., 0.4 mmol), catalyst (20 mol%, 0.04 mmol), DMSO (2 mL), 90 1C,
h; n.d. = not detected. Isolated yield. 80 1C. 100 1C.
as a gastroprotective drug for peptic ulcer and gastroesophageal
reflux disease could afford 2t in 72% yield. In addition,
b
c
d
2
-phenylbenzo[d]imidazo[2,1-b]thiazole (1u) as the substrate
resulted in an increase of the yield (Table 1, entry 10). Among could afford 3-thiocyano product 2u in moderate yield.
the examination of various sulfur sources, such as sublimed Subsequently, we expected to realize the regioselective thio-
sulfur, Na S and thioacetamide, only sublimed sulfur afforded cyanation of indoles 3 with this synthetic protocol (Scheme 3).
a in a lower 84% yield (Table 1, entries 11–13). Notably, when The corresponding 3-thiocyano product 4a was obtained in
2
2
other solvents were used instead of DMSO, no 2a was detected, 82% yield with N-methylindole (3a) as the substrate. Moreover,
indicating that DMSO might play an important role in this the substrate scope of free indoles was also investigated. The
reaction (Table 1, entries 14–18). In addition, increasing or reaction of indoles bearing a phenyl, pyridine-2-yl or ester
reducing the reaction temperature obviously decreased the reac- group at the C2 position gave the corresponding products
tion yields (Table 1, entries 19 and 20). Therefore, the optimal 4b–4d in 97%, 94% or 97%, respectively, which suggested that
conditions were established as described in entry 10.
this protocol was not obviously affected by steric hindrance.
Under the optimal reaction conditions, the generality of the
synthetic protocol for imidazo-fused heterocycles 1 was investi-
gated (Scheme 2). First, various 3-phenylimidazo[1,5-a]pyridines
(1a–1d) could be employed in this reaction, regioselectively afford-
ing 1-thiocyano products 2a–2d in excellent yields. Subsequently,
imidazo[1,5-a]quinolines (1e–1r) were also suitable for this protocol
due to the similarity of their chemical structure with imidazo-
[1,5-a]pyridines. 1-Phenylimidazo[1,5-a] quinolines (1e–1l)
bearing electron-donating groups (Me and OMe) or electron-
deficient ones (F, Cl, and Br) on the phenyl ring could produce
the 3-thiocyano products 2e–2l in good yields, whereas the
electron-donating groups (1f and 1g) gave higher yields than
the electron-deficient ones (1h–1l). It was noted that the steric-
hindrance effect of the group on the reaction yields was not
obvious due to the far reaction site (2j and 2l). When Br, Me, or
4
NO as an R substituent was introduced into the 7-position
2
of 1-phenylimidazo[1,5-a]quinoline, the desired 3-thiocyano
products 2m–2o were also obtained in 67–94% yields. To our
delight, 1-alkyl-imidazo[1,5-a]quinolines also generated the desired
products 2p–2r in 65–87% yields. Moreover, the corresponding
Scheme 3 C–H thiocyanation of indoles. Reaction conditions: 3 (0.2 mmol),
S
8
(2 equiv., 0.4 mmol), TMSCN (2 equiv., 0.4 mmol), DMSO (2 mL), 90 1C, 4 h.
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Scheme 5 C–H selenocyanation of arenes and heteroarenes. Reaction
conditions: substrates (0.2 mmol), Se (2 equiv., 0.4 mmol), TMSCN (2 equiv.,
Scheme 4 C–H thiocyanation of arenes. Reaction conditions: 5 (0.2 mmol),
S (2 equiv., 0.4 mmol), TMSCN (2 equiv., 0.4 mmol), DMSO (2 mL), 90 1C, 4 h.
8
0.4 mmol), DMSO (2 mL), 120 1C, 24 h.
The reaction of 3-methylindole (3e) failed, indicating an excellent
regioselectivity of the C3 position. The reactions of indoles bearing
electron-donating (5-OMe) or electron withdrawing groups
(
5-Br, 5-CN, 5-NO and 6-COOMe) on the phenyl ring proceeded
2
smoothly, affording the 3-thiocyano products 4f–4j in 42–98%
yields. Importantly, the presence of the Br, CN, NO and
2
COOMe groups provides potential for further derivatization.
Furthermore, 4-chloro-1H-pyrrolo[2,3-b]pyridine (3k) also gave
4k in 65% yield. In addition, ethyl 2-phenylpyrrolo[1,2-a]quino-
line-3-carboxylate (3l) containing a pyrrole unit could also be
tolerant in this reaction, affording the corresponding product
4
l in 64% yield. Notably, the gram-scale synthesis of 4b was
Scheme 6 Control experiments for mechanistic studies.
successfully achieved with a yield of 95%.
Then the regioselective thiocyanation of electron-rich arenes
was realized using this synthetic protocol (Scheme 4). First, the (BHT) as the radical inhibitor (Scheme 6a). This implied that the
thiocyanation of 1,3,5-trimethoxybenzene (5a) could produce reaction might not proceed via a radical pathway. Moreover, the
1,3,5-trimethoxy-2-thiocyanatobenzene (6a) in 83% yield under absence of TMSCN resulted in the generation of a stable product (8)
standard conditions. Moreover, using N,N-dimethylaniline (5b) in 42% yield and a trace amount of an unstable product (11), which
as the substrate, 4-thiocyano product 6b was obtained in 80% could be detected by LC-MS (Scheme 6b). To prove the reaction
yield. Expectedly, the reaction of free anilines bearing Me and intermediate, the reaction between 8 and TMSCN was performed
Br at the ortho position (5c–5e) also gave the 4-thiocyano with or without 2 equiv. of S8 under standard conditions
products 6c–6e in 71–96 yields. Similarly, when quinolin-8- (Scheme 6c). Notably, only the reaction in the presence of S
amine (5f) was used as the substrate, 5-thiocyano product 6f give 2a in 96% yield. This result revealed that 8 is an important
was obtained in low yield. Interestingly, the reaction of intermediate, which could react with S and TMSCN to produce the
-bromoaniline (5g) did not generate the 2-thiocyano product final product through an unclear pathway.
8
could
8
4
but gave 6-bromobenzo[d]thiazol-2-amine (6g) in 36% yield
through a further intramolecular cyclization.
On the basis of the results above and previous reports, a
plausible mechanism was proposed (Scheme 7). Initially, a C–S
Organic selenocyanates are also an important class of com- bond is formed by a nucleophilic attack of an arene or heteroarene
pounds because of their broad range of bioactivities such as (1, 3 or 5) on the S ring, generating an intermediate (9), which can
8
1
4
15
antioxidative, antitumor activities, etc. Encouraged by the be changed into thiophenol 10. Then the oxidative homo-
results above, we expected to realize regioselective selenocyana- coupling of thiophenol by DMSO readily generates a disulphide,
tion using elemental selenium and TMSCN as a novel seleno- 11, which can be attacked by various nucleophiles. Because both
cyanation source. To our delight, when various heterocycles the (hetero)arene and TMSCN have good nucleophilicity, there are
(1a, 1n, 1s and 3c) and arenes (5a, 5b and 5d) were employed as the two possible pathways (paths a and b) for thiocyanation. In the
substrates, the desired selenocyanation products 7a–7g were absence of TMSCN, the attack of the (hetero)arene on disulphide
16
obtained with the same regioselectivity to the thiocyanation can generate a symmetrical thioether, 8. Although the details
process in moderate to excellent yields at 120 1C (Scheme 5). remain unclear at present, 8 could be converted to the thiocyana-
To gain insight into the mechanism, several control experiments tion product (2, 4 or 6) in the coexistence of S and TMSCN
8
were carried out (Scheme 6). First, it was observed that the reaction (Scheme 7, path a). Moreover, disulphide could be also directly
was hardly inhibited in the presence of 2 equiv. of 2,2,6,6-tetra- attacked by TMSCN, giving the thiocyanation product and 10
17
methyl-1-piperidinyloxy (TEMPO) or 2,6-di-tert-butyl-4-methylphenol (Scheme 7, path b).
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Chem., Int. Ed., 2015, 54, 4070; (i) W. Xu, J. Ma, X.-A. Yuan, J. Dai,
J. Xie and C. Zhu, Angew. Chem., Int. Ed., 2018, 57, 10357; C–H
thiolation: ( j) F.-L. Yang and S.-K. Tian, Angew. Chem., Int. Ed., 2013,
52, 4929; (k) J. Yuan, X. Ma, H. Yi, C. Liu and A. Lei, Chem. Commun.,
2014, 50, 14386; (l) Y. Yang, S. Zhang, L. Tang, Y. Hu, Z. Zha and
Z. Wang, Green Chem., 2016, 18, 2609 C–H sulfonylation: (m) F. Xiao,
H. Chen, H. Xie, S. Chen, L. Yang and G.-J. Deng, Org. Lett., 2014,
16, 50; (n) S. Tang, Y. Wu, W. Liao, R. Bai, C. Liu and A. Lei, Chem.
Commun., 2014, 50, 4496; (o) F. Xiao, S. Chen, Y. Chen, H. Huang
and G.-J. Deng, Chem. Commun., 2015, 51, 652.
(a) R. Riemschneider, J. Am. Chem. Soc., 1956, 78, 844; (b) T. Nguyen,
M. Rubinstein and C. Wakselman, J. Org. Chem., 1981, 46, 1938;
3
4
Scheme 7 A plausible mechanism for C–H thiocyanation.
(
(
c) Z. Zhang and L. S. Liebeskind, Org. Lett., 2006, 8, 4331;
d) Y. T. Lee, S. Y. Choi and Y. K. Chung, Tetrahedron Lett., 2007,
48, 5673; (e) B. Exner, B. Bayarmagnai, F. Jia and L. J. Goossen,
In summary, we have developed a regioselective oxidative
C–H thiocyanation of (hetero)arenes with elemental sulfur and
TMSCN. Moreover, the selenocyanation process was also rea-
lized by replacing sulfur with selenium. Compared to previous
reports, this protocol is distinguished by (1) avoiding the use of
any catalyst or additive, (2) the novel SCN/SeCN source, (3) the
different reaction mechanism, and (4) gram-scale synthesis.
The current research paves a way for the application of elemental
sulfur/selenium and TMSCN as a unique thio/selenocyanation
source in organic chemistry.
Chem. – Eur. J., 2015, 21, 17220; ( f ) B. Bayarmagnai, C. Matheis,
K. Jouvin and L. J. Goossen, Angew. Chem., Int. Ed., 2015, 54, 5753.
(a) A. De Mico, R. Margarita, A. Mariani and G. Piancatelli, Chem.
Commun., 1997, 1237; (b) F. Wang, X. Yu, Z. Qi and X. Li, Chem. –
Eur. J., 2016, 22, 511.
5 D. Yang, K. Yan, W. Wei, G. Li, S. Lu, C. Zhao, L. Tian and H. Wang,
J. Org. Chem., 2015, 80, 11073.
6
G. Wu, Q. Liu, Y. Shen, W. Wu and L. Wu, Tetrahedron Lett., 2005,
6, 5831.
7 X.-Q. Pan, M.-Y. Lei, J.-P. Zou and W. Zhang, Tetrahedron Lett., 2009,
0, 347.
4
5
8
(a) V. K. Jadhav, R. R. Pal, P. P. Wadgaonkar and M. M. Salunkhe,
Synth. Commun., 2001, 31, 3041; (b) J. S. Yadav, B. V. S. Reddy,
S. Shubashree and K. Sadashiv, Tetrahedron Lett., 2004, 45, 2951;
We are grateful to the National Natural Science Foundation
of China (21502177), the Education Bureau of Anhui Province
(
c) M. A. Karimi Zarchi and R. Banihashemi, J. Sulfur Chem., 2014,
35, 458; (d) M. A. Karimi Zarchi and R. Banihashemi, J. Sulfur Chem.,
(KJ2017A080, gxyqZD2018037), the Scientific and Technological
2016, 37, 282.
Breakthrough Plan of Henan Province (182102310903), and the
Doctoral Research Foundation of Zhengzhou University of
Light Industry (2014BSJJ032).
9 (a) H. Jiang, W. Yu, X. Tang, J. Li and W. Wu, J. Org. Chem., 2017,
2, 9312; (b) J. Chen, T. Wang, T. Wang, A. Lin, H. Yao and J. Xu, Org.
8
Chem. Front., 2017, 4, 130.
1
0 (a) W. Fan, Q. Yang, F. Xu and P. Li, J. Org. Chem., 2014, 79, 10588;
(
8
b) S. Mitra, M. Ghosh, S. Mishra and A. Hajra, J. Org. Chem., 2015,
0, 8275.
Conflicts of interest
1
1 V. A. Kokorekin, V. L. Sigacheva and V. A. Petrosyan, Tetrahedron
Lett., 2014, 55, 4306.
There are no conflicts to declare.
12 T. B. Nguyen, Adv. Synth. Catal., 2017, 359, 1066 and references therein.
13 (a) Y. Yan, Z. Li, H. Li, C. Cui, M. Shi and Y. Liu, Org. Lett., 2017,
9, 6228; (b) S.-S. Wu, C.-T. Feng, D. Hu, Y.-K. Huang, Z. Li, Z.-G. Luo
1
Notes and references
and S.-T. Ma, Org. Biomol. Chem., 2017, 15, 1680; (c) Y. Yan, B. Niu,
K. Xu, J. Yu, H. Zhi and Y. Liu, Adv. Synth. Catal., 2016, 358, 212;
1
(a) A. Houmam, E. M. Hamed and A. W. J. Still, J. Am. Chem. Soc.,
003, 125, 7258; (b) A. Casini, J.-Y. Winum, J.-L. Montero,
A. Scozzafava and C. T. Supuran, Bioorg. Med. Chem. Lett., 2003,
(
d) Y. Yan, Y. Xu, B. Niu, H. Xie and Y. Liu, J. Org. Chem., 2015, 80, 5581.
4 (a) R. K. Das, S. K. U. Hossain and S. Bhattacharya, Cancer Lett.,
005, 230, 90; (b) J. Thomas, W. Maes, K. Robeyns, M. Ovaere, L. V.
2
1
2
1
1
3, 837; (c) M. Mellah, A. Voituriez and E. Schulz, Chem. Rev., 2007,
07, 5133; (d) J. T. Jarrett, J. Biol. Chem., 2015, 290, 3972; (e) M. Feng,
Meervelt, M. Smet and W. Dehaen, Org. Lett., 2009, 11, 3040; (c) N. B.
Rashid Baig, R. N. Chandrakala, V. Sai Sudhir and S. Chandrasekaran,
J. Org. Chem., 2010, 75, 2910; (d) J. C. Guillemin, Curr. Org. Chem., 2011,
15, 1670.
B. Tang, S. Liang and X. Jiang, Curr. Top. Med. Chem., 2016, 16, 1200.
For reviews, see: (a) C. Shen, P. Zhang, Q. Sun, S. Bai, T. S. Andy Hor
and X. Liu, Chem. Soc. Rev., 2015, 44, 291; (b) X.-H. Xu, K. Matsuzaki
2
and N. Shibata, Chem. Rev., 2015, 115, 731; (c) Z. Qiao and X. Jiang, 15 (a) T. B. Nguyen, L. Ermolenko, P. Retailleau and A. Al-Mourabit,
Org. Biomol. Chem., 2017, 15, 1942; C–H trifluoromethylthiolation:
Angew. Chem., Int. Ed., 2014, 53, 13808; (b) H. Xie, J. Cai, Z. Wang,
H. Huang and G.-J. Deng, Org. Lett., 2016, 18, 2196.
e) Y.-D. Yang, A. Azuma, E. Tokunaga, M. Yamasaki, M. Shiro and 16 (a) F. Shibahara, T. Kanai, E. Yamaguchi, A. Kamei, T. Yamauchi
(
(
d) C. Chen, L. Chu and F. Qing, J. Am. Chem. Soc., 2012, 134, 12454;
N. Shibata, J. Am. Chem. Soc., 2013, 135, 8782; ( f ) C. Xu, B. Ma and
Q. Shen, Angew. Chem., Int. Ed., 2014, 53, 9316; (g) S. Guo, X. Zhang
and T. Murai, Chem. – Asian J., 2014, 9, 237; (b) Y. Yang, W. Li,
B. Ying, H. Liao, C. Shen and P. Zhang, ChemCatChem, 2016, 8, 2916.
and P. Tang, Angew. Chem., Int. Ed., 2015, 54, 4065; (h) H. Wu, 17 K. Yamaguchi, K. Sakagami, Y. Miyamoto, X. Jin and N. Mizuno,
Z. Xiao, J. Wu, Y. Guo, J.-C. Xiao, C. Liu and Q.-Y. Chen, Angew. Org. Biomol. Chem., 2014, 12, 9200.
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