Copper(II) mediated C–H methylthiolation of 2-phenyl pyridines with dimethyl sulfoxide using an amino acid ligand

Article abstract of DOI:10.1016/j.tetlet.2019.03.067

A novel protocol for the C–H methylthiolation of 2-phenyl pyridines using DMSO as the methylthio source and an amino acid ligand is described. This simple procedure requires neither an oxidant nor additional solvent. The developed protocol tolerates a wid

Full text of DOI:10.1016/j.tetlet.2019.03.067

Accepted Manuscript
Copper(II) mediated C-H methylthiolation of 2-phenyl pyridines with dimethyl
sulfoxide using an amino acid ligand
Yan Xiao, Shuo Wang, Jianyu Liu, Hui Zhang, Yongnan Xu
PII:
S0040-4039(19)30305-3
https://doi.org/10.1016/j.tetlet.2019.03.067
TETL 50708
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
26 January 2019
26 March 2019
27 March 2019
Please cite this article as: Xiao, Y., Wang, S., Liu, J., Zhang, H., Xu, Y., Copper(II) mediated C-H methylthiolation
of 2-phenyl pyridines with dimethyl sulfoxide using an amino acid ligand, Tetrahedron Letters (2019), doi: https://
doi.org/10.1016/j.tetlet.2019.03.067
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Tetrahedron Letters
Copper(II) mediated C-H methylthiolation of 2-phenyl pyridines with dimethyl
sulfoxide using an amino acid ligand
Yan Xiaoa,b, Shuo Wanga,b, Jianyu Liua,b, Hui Zhanga,b,* Yongnan Xua,b*
a Department of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Wenhua Road 106#, Shenyang, Liaoning 110016 (China)
b Key Laboratory of Structure-based Drug Design&Discovery, Ministry of Education, Shenyang Pharmaceutical University, Wenhua Road 106#, Shenyang,
Liaoning 110016 (China)
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A novel protocol for the C-H methylthiolation of 2-phenyl pyridines using DMSO as the
methylthio source and an amino acid ligand is described. This simple procedure requires neither
an oxidant nor additional solvent. The developed protocol tolerates a wide range of functional
groups including methyl, methoxy, fluoro, chloro, and in particular the formyl group. This new
strategy is highly regioselective and provides aryl methyl sulfides from 2-phenyl pyridines in
moderate to good yields.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
C-H methylthiolation
Aryl methyl sulfide
Amino acid
Dimethyl sulfoxide
Dimethyl sulfoxide (DMSO) is commonly used as an aprotic
polar solvent. It has wide applications in both laboratory and
industrial settings, as various chemicals are very soluble in
DMSO.1 Besides the use of DMSO as a solvent, it is also
frequently used as a reagent in organic synthesis. For example,
several well-known named reactions, including the Swern
oxidation2 and Pfitzner–Moffatt oxidation,3 employ DMSO as an
oxidant. Since DMSO is low molecular weight, inexpensive and
has low toxicity, developing reactions using DMSO as a reagent
is very attractive in organic synthesis. In recent years, numerous
organic transformations using DMSO as a reagent have been
developed. It has been reported as -CH3, -CHO, -CN, -SMe, -
SO2Me and oxygen sources in different organic procedures.4
drugs and biologically active molecules (Fig. 1). For example,
the anti-inflammatory prodrug Sulindac is converted to the active
sulfide metabolite 1 after absorption.5 Thioridazine (2) represents
a typical antipsychotic drug and 3 exhibits anti-angiogenic and
cytotoxic activities.6 Compound 4 was designed as a radiotracer
for quantifying the vesicular acetylcholine transporter in vivo.7
Common synthetic methods for preparing aryl methyl sulfides
include the methylthiolation of aryl halides with methyl thiol8 or
dimethyl disulfide,9 and the nucleophilic substitution reaction of
aryl thiols with methyl iodide.10 The former method often
requires activated aryl halides as substrates, or metal complexes
as catalysts, while applications of the latter method are often
limited by the availability of the aryl thiols. An alternative
method for the synthesis of aryl methyl sulfides is the reduction
of aryl methyl sulfoxides.11 In recent years, DMSO has been
explored as a powerful methylthio source for the preparation of
aryl methyl sulfides. It can be coupled with aryl halides or
arenes, providing the corresponding aryl methyl sulfides. The
Mal and Cheng group reported
a copper salt mediated
methylthiolation of aryl halides using DMSO.12 In 2010, the Qing
group reported the first example of the copper mediated C-H
methylthiolation of 2-phenyl pyridines using DMSO as the
methylthio reagent in the presence of K2S2O8 as the oxidant.13 In
2015, the Jain group reported that the C-H methylthiolation of 2-
phenyl pyridines could be achieved using air as the oxidant in the
presence of Cu(OAc)2.14 In 2012, the Gao group described a
copper mediated synthesis of heteroaryl methyl sulfides by
coupling heteroarenes with DMSO.15 The Sun group reported a
para-methylthiolation method for anilines using DMSO as a
methylthio source.16 These protocols provide easy access to
(hetero)aryl methyl sulfides from (hetero)arenes, however these
Figure 1. Representative examples of biologically active aryl methyl
sulfides
Aryl methyl sulfides are important building blocks in organic
synthesis and drug development. This scaffold is present in many
Corresponding author. Tel.: +86-24-43520208; e-mail: zh19683@163.com; ynanxu@hotmail.com

2
Tetrahedron
methods often suffer from the requirement to use an excess
the yield dropped to 39% when the reaction was carried out
under air (Table 1, entry 16).
amount of metal salts, an oxidant, and/or low yields; therefore the
development of reaction systems is still needed. Herein, we
report for the first time an amino acid assisted CuSO4 mediated
C-H ortho-methylthiolation of 2-phenylpyridines using DMSO as
the methylthio source.
We further studied the effect of different amino acids on the
reaction performance. All selected amino acids facilitated the
methylthiolation of 2-phenyl pyridine (Table 2). With the
exception of L-proline and L-alanine, the amino acids showed
comparable efficacy in this transformation; however, among
these amino acids, glycine gave the highest yield.
Table 1. Reaction condition screening for the C-H
methylthiolation of 2-phenyl pyridine with DMSO.a
Table 2. Effect of the amino acid on the C-H methylthiolation
of 2-phenyl pyridine.a
Entry
[Cu]
Ligand
Temp (oC)
Yield 6a
(%)b
1
2
Cu(OAc)2
CuCl2
-
-
140
140
140
140
140
140
140
140
140
140
140
140
130
120
140
140
10
41
Entry Ligand
Yield
6a
Entry Ligand
Yield 6a
(%)b
(%)b
3
CuSO4
CuSO4
CuSO4
CuSO4
CuSO4
CuSO4
CuI
-
48
1
2
3
4
Glycine
81
78
76
43
6
7
8
9
L-Lysine
79
67
73
77
4
Ethylene glycol
1,10-Phen
2-Aminoethanol
Oxalic acid
Glycine
Glycine
Glycine
Glycine
Glycine
Glycine
Glycine
Glycine
Glycine
18
L-Cysteine
L-Tryptophan
L-Proline
L-Alanine
L-Tyrosine
5
19
6
41
L-
7
8
Phenylalanin
e
8
81, 80c
Trace
Trace
48
5
L-Serine
71
10
L-Valine
75
9
a
Reagents and conditions: 2-phenyl pyridine (0.5 mmol), DMSO (0.1 mL),
10
11
12
13
14
15
16
CuF2
b
CuSO4 (1.0 equiv.), amino acid (0.05 mmol), 24 h. Isolated yield after
column purification.
CuCl2
Cu(OAc)2
CuSO4
CuSO4
CuSO4
CuSO4
9
To evaluate the scope of this protocol, we evaluated 2-phenyl
pyridines using our procedure. Several 2-phenyl pyridines were
subjected to the optimized condition, and generally, moderate to
good yields of the corresponding methylthiolated products were
obtained (Table 3). Alkyl and methoxy groups were well
tolerated. ortho-Methyl substituted 2-phenyl pyridine (5b) gave a
lower yield than meta- and para-substituted 2-phenyl pyridine
(5c and 5d) due to steric effects. It is notable that our protocol is
highly regioselective since ortho-methylthiolation occurred
predominately. No by-product formation was observed for meta-
and para-methyl substituted 2-phenyl pyridines. A small amount
of the dimethylthiolated product was observed by GC-MS when
2-phenyl pyridine was substituted by a meta-F on the phenyl
ring, and 6i was obtained in only 49% yield. It is noteworthy that
the formyl group is also compatible with our procedure (see 6k
and 6l). It should be noted that tri-substituted phenyl rings were
also compatible with our conditions, providing the corresponding
ortho-methylthiolated products in moderate yields (6m-o). In
addition, we expanded the directing group to the 2-quinolyl
group. 2-Phenylquinoline 7 was successfully converted to the
methylthiolated product 8 in 53% yield under the optimized
conditions (Fig. 2).
43, 74c
18, 33c
34d
39e
a Reagents and conditions: 2-phenyl pyridine (0.5 mmol), DMSO (0.1 mL),
b
copper salt (1.0 equiv.), ligand (0.05 mmol), 24 h. Isolated yield after
column purification. c 48 h. d CuSO4 (0.5 equiv.). e in air.
2-Phenyl pyridine (5a) was chosen as a model substrate and
treated with DMSO at 140 °C under an argon atmosphere.
Initially, the reaction was carried out without any additives and
several copper salts were screened. CuSO4, which has never been
reported in the C-H methylthiolation with DMSO, gave a higher
yield than other copper salts (Table 1, entries 1-3). A bidentate
ligand is often helpful for copper mediated coupling reactions by
stabilizing the substrate-copper complex intermediate.17
Unfortunately, ethylene glycol, 1,10-phenanthroline, 2-
aminoethanol and oxalic acid provided no improvement (Table 1,
entries 4-7). However, the addition of glycine significantly
increased the reaction yield to 81% (Table 1, entry 8). Using
glycine as the ligand, various copper salts were screened. Trace
amounts of product were obtained when CuI and CuF2 were used
(Table 1, entries 9-10). The reaction with CuCl2 gave 2-(2-
chlorophenyl)pyridine as a by-product (Table 1, entry 11).
Lowering the reaction temperature decreased the yields even
when the reaction time was increased to 48 h (Table 1, entries
13-14). The use of a smaller amount of CuSO4 (0.5 equiv.)
provided 6a in a lower 34% yield (Table 1, entry 15). Although
the Jain group reported the C-H methylthiolation of 2-phenyl
pyridine using air as the oxidant,14 it is interesting that in our case
A plausible reaction pathway was proposed for this C-H
methylthiolation reaction (Fig. 3). The bidentate ligand (glycine)
facilitated the coordination of Cu(II) and the nitrogen atom of the
directing group. Two different pathways may be involved in the
transformation from the copper complex to 6a. In pathway A, the
C-S bond could be formed via intramolecular electrophilic
aromatic substitution and subsequent cleavage of the S-O bond to
give a sulfonium, which can be further converted to 6a in the
presence of the sulfate anion.18 In pathway B, activation of the C-
H bond by Cu(II) provides a five-membered metalacycle, which

could also be converted to the sulfonium via electrophilic
Figure 3. Plausible reaction pathway for C-H methylthiolation.
aromatic substitution and subsequent rearrangement.13
In conclusion, we have developed a facile protocol for the
synthesis of aryl methyl sulfides via CuSO4 mediated direct
coupling reaction of 2-phenyl pyridines and DMSO in the
presence of an amino acid.
Table 3. C-H methylthiolation of 2-phenyl pyridines with
DMSO.a
Acknowledgements
This work was supported by Natural Science Foundation of
Liaoning Province, China (No. 20170540148).
References
[1]
[2]
K. M. Roy, "Sulfones and Sulfoxides" in Ullmann's Encyclopedia of
Industrial Chemistry, 2002, Wiley-VCH, Weinheim.
6a, 81%
6d, 76%
6g, 84%
6j, 70%
6b, 53%
6e, 68%
6h, 77%
6k, 62%
6c, 69%
6f, 76%
6i, 49%
6l, 51%
(a) K. Omura, D. Swern, Tetrahedron 1978, 34, 1651-1660; (b) A. J.
Mancuso, D. S. Brownfain, D. Swern, J. Org. Chem. 1979, 44, 4148-4150.
K. E. Pfitzner, J. G. Moffatt, J. Am. Chem. Soc. 1963, 85, 3027-3028.
X. F. Wu, K. Natte, Adv. Synth. Catal. 2016, 358, 336-352; (2) E. Jones-
Mensah, M. Karki, J. Magolan, Synthesis 2016, 48, 1421-1436.
D. E. Duggan, Drug Metab Rev. 1981, 12, 325-37.
[3]
[4]
[5]
[6]
R. K. V. Devambatla, S. Choudhary, M. Ihnat, E. Hamel, S. L. Mooberry, A.
Gangjee, Bioorg. Med. Chem. Lett. 2018, 28, 3085-3093.
[7]
Z. Luo, H. Liu, H. Jin, J. Gu, Y. Yu, K. Kaneshige, J. S. Perlmutter, S. M.
Parsons, Z. Tu, ChemMedChem 2018, 13, 1978-1987.
[8]
[9]
H. Hata, A. Onoe, JP 10072431 A, 1998, Mar 17.
(a) O. Baldovino-Pantaleon, S. Hernandez-Ortega, D. Morales-Morales, Adv.
Synth.Catal. 2006, 348, 236-242; (b) N. Taniguchi, J. Org. Chem. 2004, 69,
6904-6906; (c) V. Gomez-Benitez, O. Baldovino-Pantaleon, C. Herrera-
Alvarez, R. A. Toscano, D. Morales-Morales, Tetrahedron Lett. 2006, 47,
5059-5062.
[10] T. I. Reddy, R. S. Varma, Chem. Commun. 1997, 6, 621-622.
[11] T. Uematsu, Y. Ogasawara, K. Suzuki, K. Yamaguchi, N. Mizuno, Catal.
Sci. Technol. 2017, 7, 1912-1920.
[12] (a) T. Jia, A. Bellomo, K. E. L. Baina, S. D. Dreher, P. J. Walsh, J. Am.
Chem. Soc. 2013, 135, 3740−3743; (b) Ketaki Ghosh, Sadananda Ranjit,
Dipakranjan Mal, Tetrahedron Lett. 2015, 56, 5199-5202; (c) F. Luo, C. Pan,
L. Li, F. Chen, J. Cheng, Chem. Commun. 2011, 47, 5304–5306.
[13] L. Chu, X. Yue, F.-L. Qing, Org. Lett. 2010, 12, 1644-1647.
[14] P. Sharma, S. Rohilla, N. Jain, J. Org. Chem. 2015, 80, 4116-4122.
[15] C. Dai, Z. Xu, F. Huang, Z. Yu, Y. F. Gao, J. Org. Chem. 2012, 77, 4414-
4419.
6m, 58%
6n, 63%
6o, 67%
[16] Y. Xu, T. Cong, P. Liu, P. Sun, Org. Biomol. Chem. 2015, 13, 9742-9745.
[17] I. P. Beletskaya, A. V. Cheprakov, Coordin. Chem. Rev. 2004, 248, 2337-
2364.
a
Reagents and conditions: 2-phenyl pyridines (0.5 mmol), DMSO (0.1 mL),
CuSO4 (1.0 equiv.), amino acid (0.05 mmol), 24 h; isolated yield.
[18] G. Brasche, S. L. Buchwald, Angew. Chem. Int. Ed. 2008, 47, 1932-1934.
Supplementary Material
Experimental details and NMR spectra for all reported
compounds can be found in supplementary material.
Figure 2. C-H methylthiolation of 2-phenylquinoline 7.

4
Tetrahedron
Graphical Abstract
Copper(II) mediated C-H methylthiolation of
2-phenyl pyridines with dimethyl sulfoxide
using amino acid as ligand
Leave this area blank for abstract info.
Yan Xiao, Shuo Wang, Jianyu Liu, Hui Zhang*, Yongnan Xu*

Highlight
·Amino acid functions as a ligand in the C-H
methylthiolation of 2-phenyl pyridines with
DMSO.
·Aryl methyl sulfides are readily prepared from the
corresponding 2-phenyl pyridines in moderate to
good yields.
·Neither an oxidant nor other additives are required
in this transformation.