Efficient 2-sulfolmethyl quinoline formation from 2-methylquinolines and sodium sulfinates under transition-metal free conditions

Article abstract of DOI:10.1039/c4cc07546c

An efficient procedure for 2-sulfolmethyl quinoline preparation from 2-methylquinolines and sodium sulfinates under transition-metal free conditions is described. Halogen functional groups were well tolerated to give the corresponding products in good to

Full text of DOI:10.1039/c4cc07546c

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Efficient 2-sulfolmethyl quinoline formation from
2-methylquinolines and sodium sulfinates under
transition-metal free conditions†
Cite this:DOI: 10.1039/c4cc07546c
Received 24th September 2014,
Accepted 16th November 2014
Fuhong Xiao,* Shuqing Chen, Ya Chen, Huawen Huang and Guo-Jun Deng*
DOI: 10.1039/c4cc07546c
www.rsc.org/chemcomm
An efficient procedure for 2-sulfolmethyl quinoline preparation from substitution of halides with sulfinic acid sodium salts.7 However, the
2-methylquinolines and sodium sulfinates under transition-metal free methods for the synthesis of 2-sulfolmethyl quinolines are rare. In
conditions is described. Halogen functional groups were well tolerated 2004, Masson and co-workers developed an approach for 2-sulfol-
to give the corresponding products in good to high yields.
methyl quinoline preparation from 2-halidemethyl quinolines and
sodium arenesulfinates.8 Obviously, this method requires advance
Organosulfones are important intermediates in organic synthesis preparation of the benzylic halides. It is highly desirable to develop
and have a wide application in the fields of agrochemicals, pharma- general methods for the synthesis of 2-sulfolmethyl quinolines via
ceuticals and materials chemistry.1 Among numerous organosulfone direct sulfonylation of 2-methylquinolines.
derivatives, 2-sulfolmethyl quinolines are an important class of
In recent years, the direct sulfonylation via C–H functionaliza-
compounds due to their broad spectrum of biological activity and tion has attracted great interest since this method can potentially
pharmacological value.2 For example, compound Q1 can be used lead to more efficient synthesis with a reduced number of synthetic
as potent drugs for anti-hepatitis B virus (HBV) activities (Fig. 1).3 operations.9 Among the various sulfonylation reagents employed,
Compound Q2 can be used as antiproliferative activity against sodium sulfinates are stable and easy to handle, and they have
cancer cell lines in vitro.4 Compound Q3 is a leukotriene antagonist been widely used as sulfonylating agents.7,10 Recently, we and
and inhibitor of leukotriene biosynthesis.5 Due to their great value in others have developed various approaches for C–H arylation
pharmaceuticals, the preparation of 2-sulfolmethyl quinolines has (via extrusion SO2),11 sulfenylation12 and sulfonylation13 using
gained much attention. Traditionally, benzylic sulfones are generally sodium sulfinates as starting materials. To the best of our
knowledge, there is no report on the 2-sulfolmethyl quinoline
synthesis directly from 2-methylquinolines. As our continuing
efforts using sodium sulfinates as the sulfonylating agents for
the C–S bond formation, herein, we describe a KI-mediated direct
sulfonylation of 2-methylquinolines with sodium sulfinates under
mild conditions, affording 2-sulfolmethyl quinolines in good to
high yields (Scheme 1).
To identify the best reaction conditions, 2-methylquinoline
(1a) and sodium benzenesulfinate (2a) were initially used as the
standard substrates under different conditions (Table S1 in ESI†).
Several iodide-containing additives were investigated, and among
them KI (100 mol%) showed the best efficiency to give the corre-
sponding product 3a in 92% yield at 80 1C when TBHP was used as
the oxidant (entry 7). Other oxidants were also investigated and
showed less efficiency (entries 8–12). The product was observed in
62% yield when oxygen was used as the sole oxidant (entry 12).
Fig. 1 Selected drugs containing 2-sulfolmethyl quinolines.
prepared by oxidation of the corresponding sulfides6 or nucleophilic
Key Laboratory of Environmentally Friendly Chemistry and Application of Ministry
of Education, College of Chemistry, Xiangtan University, Xiangtan 411105, China.
E-mail: 494707822@163.com, gjdeng@xtu.edu.cn; Fax: +86-0731-5829-2251;
Tel: +86-0731-5829-8601
Scheme 1 New strategy for the synthesis of 2-sulfolmethyl quinolines.
† Electronic supplementary information (ESI) available. See DOI: 10.1039/c4cc07546c
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Table 2 Sulfonylation of various 2-methylquinolines with 2aa
Other organic solvents such as DMSO, AcOH, PhCl, anisole and
toluene were less effective for this kind of reaction (entries 13–17).
Decreasing the reaction temperature or the amounts of KI or TBHP
all did not enhance the reaction yields (entries 20–22).
Under the optimized conditions, various sodium sulfinates
and 2-methylquinoline were explored as the substrates, and the
results are summarized in Table 1. A series of para-substituted
sodium sulfinates could smoothly react with 1a to give 2-sulfol-
methyl quinolines in good to high yields (Table 1, entries 2–5).
Functional groups such as halogens, trifluoromethyl, and tri-
fluoromethoxy could survive well under the optimized reaction
conditions (entries 6–10). It should be noted that no cleavage of
the C–halogen bond was observed as determined by GC-MS
analysis. More bulky substrates such as 2-naphthylsulfinic acid
sodium salt (2k) also reacted with 1a and gave the product in
51% yield (entry 11). To our delight, apart from aromatic sodium
sulfinates, less reactive aliphatic sodium sulfinates such as sodium
methanesulfinate (2l) and sodium cyclopropanesulfinate (2m) could
also couple with 2-methylquinoline to give the desired products 3l
and 3m in 50% and 56% yields, respectively (entries 12 and 13).
The influence of the substituents on the 2-methylquinoline moiety
was also evaluated and the results are presented in Table 2. A series of
functional groups including methyl, methoxy, chloro and fluoro were
tolerated under the optimal reaction conditions, and the desired
products were obtained in high yields (entries 1–6). The pattern of
substituents did not significantly affect the reaction yields. Notably,
the active hydroxy group was also compatible, and the desired product
3t was obtained in 76% yield (entry 7). Besides 2-methylquinolines,
this reaction system could also be applied to the direct sulfonylation
Product
Entry
Quinoline
Yieldb [%]
1
2
3
4
5
6
7
R = 6-Me
R = 6-F
R = 6-Br
R = 7-F
R = 7-Cl
R = 8-OCH3
R = 8-OH
1b
1c
1d
1e
1f
1g
1h
3n
86
75
84
94
90
92
76
3o
3p
3q
3r
3s
3t
8
9
1i
1j
3u (R0 = Me)
3v (R0 = Ph)
50
69
10
1k
37
a
Reaction conditions: 1 (0.5 mmol), 2a (1.25 mmol), KI (100 mol%),
TBHP (1 equiv.), DMSO : AcOH (v/v = 1 : 1, 1.6 mL), 80 1C, air, 16 h.
b
Isolated yield.
of 2,3-dimethylquinoxaline (1i) and 2-methyl-3-phenylquinoline (1j)
with sodium benzenesulfinate (entries 8–9). Unexpectedly, the
disulfonylation product (3w) was obtained when using 4-chloro-
6-fluoro-2-methylquinoline (1k) as the substrate (entry 10).
To gather more information about the reaction mechanism,
some control experiments were set up under various reaction
conditions. No desired product 3a was observed when stoichio-
metric amount of TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy)
was added (Scheme 2a). This result indicates that the reaction
may proceed through a radical pathway. No 2-(iodomethyl)-
quinoline was observed when treating 1a with KI and TBHP
(Scheme 2b). This observation implies that the reaction does
not proceed through a nucleophilic substitution reaction of
2-(iodomethyl)quinoline with sodium benzenesulfinate. When
a competitive reaction between 2e and 2i with 1a was carried
out within 3 h, C–H sulfonylation products 3e and 3i were
determined by GC in 1 : 2.5 ratio (Scheme 2c). This means the
reaction may not be realized by nucleophilic attack.
Based on these observations, a plausible mechanism to
rationalize this transformation is illustrated in Scheme 3. An oxygen-
centered radical A is generated by oxidation of sulfinate with an
iodide radical. The oxygen-centered radical can be resonated to a
sulphonyl radical B.13a The addition of the sulphonyl radical
with intermediate C, which is generated from 1a by the Brønsted
acid-promoted isomerization, affords an intermediate D, which
can be further oxidized by an iodide radical to generate the
desired product 3a and release HI.
Table 1 Sulfonylation of 1a with various sodium sulfinatesa
Entry
Sodium sulfinate
Yieldb [%]
Product
1
2
3
4
5
6
7
8
9
R1 = H
2a
2b
2c
2d
2e
2f
2g
2h
2i
3a
3b
3c
3d
3e
3f
3g
3h
3i
92
90
76
68
90
62
71
72
65
71
R1 = CH3
R1 = iso-propyl
R1 = tert-butyl
R1 = OCH3
R1 = F
R1 = Cl
R1 = Br
R1 = CF3
10
R1 = OCF3
2j
3j
11
2k
3k
51
12
13
CH3SO2Na
2l
3l
50
56
2m
3m
a
Reaction conditions: 1a (0.5 mmol), 2 (1.25 mmol), KI (0.5 mmol),
TBHP (0.5 mmol), DMSO : AcOH (v/v = 1 : 1, 1.6 mL), 80 1C, air, 16 h.
b
Isolated yield.
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Scheme 3 Proposed mechanism.
In summary, we have developed a convenient and highly
efficient method for the direct sulfonylation reaction of 2-methyl-
quinolines mediated by KI using sodium sulfinates as the sulfonyla-
tion reagent. Functional groups such as alkyl, halogen, and hydroxy
were well tolerated under the optimized conditions. This
method afforded a novel and alternative approach for the
synthesis of biologically important hetero benzylic sulfones
via C–H functionalization.
We are grateful for the financial support from the National
Natural Science Foundation of China (21172185, 21372187), the
New Century Excellent Talents in University from Ministry of
Education of China (NCET-11-0974) and Scientific Research Fund
of Xiangtan University (KZ08055).
Notes and references
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Chem. Commun.