In Situ Generated HypoIodite Activator for the C2 Sulfonylation of Heteroaromatic N-oxides

Article abstract of DOI:10.1021/acs.joc.6b00475

A mild approach for direct C2 sulfonylation of heteroaromatic N-oxides with sulfonyl hydrazides affording 2-sulfonyl quinolines/pyridines has been developed. A variety of heteroaromatic N-oxides and sulfonyl hydrazides participate effectively in this transformation which uses hypoiodites (generated in situ from NaI and TBHP) as a means of substrate activators. In this reaction, the N-oxide plays a dual role, acting as a traceless directing group as well as a source of oxygen atom.

Full text of DOI:10.1021/acs.joc.6b00475

Article
pubs.acs.org/joc
In Situ Generated HypoIodite Activator for the C2 Sulfonylation of
Heteroaromatic N‑oxides
Yuan Su, Xuejun Zhou, Chunlian He,* Wei Zhang, Xiao Ling, and Xia Xiao
Medical College, Hunan Normal University, Changsha 410081, China
*
S Supporting Information
ABSTRACT: A mild approach for direct C2 sulfonylation of heteroaromatic N-oxides with sulfonyl hydrazides affording 2-
sulfonyl quinolines/pyridines has been developed. A variety of heteroaromatic N-oxides and sulfonyl hydrazides participate
effectively in this transformation which uses hypoiodites (generated in situ from NaI and TBHP) as a means of substrate
activators. In this reaction, the N-oxide plays a dual role, acting as a traceless directing group as well as a source of oxygen atom.
INTRODUCTION
Scheme 1. Functionalization of N-Oxides via C−H
Activation
■
The development of simple and environment friendly strategy
for the formation of C−S bond is one of the fundamenta1l
challenges in synthetic organic chemistry community.
Recently, N-heteroaromatic compounds have been actively
2
3
pursued in pharmaceuticals and material sciences; and C−S
bonds attached to N-heteroaromatic compounds have been
recognized, because N-heteroaromatic compounds containing a
sulfur moiety are present in many biologically active
4
compounds. Thus, the synthesis of sulfonyl N-heteroaromatic
compounds through N-heteroaromatic compounds modifica-
tion by novel methods has attracted attention in medicinal and
5
synthetic chemistry. 2-Sulfonyl N-heteroaromatic compounds
are generally synthesized by oxidation of the corresponding
6
7
sulfides or by alkylation of sulfinate salts. Both methods suffer
drawbacks: The ultimate starting materials are often 2-
halopyridine, many of which are foul-smelling.
In 2013, Wu and Cui reported the first example of copper-
catalyzed direct sulfonylation of quinoline/pyridine N-oxides
via C−H activation. However, to realize the synthesis of the
desired 2-sulfonyl quinolines/pyridines, a harsh reagent (PCl )
3
was required to reduce the N-oxide products in this
transformation (Scheme 1A, 1). In 2015, Zhao and Chen
8
generated hypoiodite), as an environmentally benign and
inexpensive reagent that can be stored and handled in the
described a transition metal-free one pot approach to selective
synthesis of 2-sulfonyl quinolines/pyridines via H-phospho-
12
laboratory using normal laboratory methods, has not yet been
employed as the activator. We therefore considered that iodine
reagents might serve as both activating reagents and as
reductants in the regioselective sulfonylation reaction, achieving
a one-pot synthesis of 2-sulfonyl quinolines/pyridines. Herein
we report the hypoiodite-mediated C−H activation of quino-
9
nate-mediated C−H activation (Scheme 1A, 2). Despite
substantial progress, the reaction is in need for base additives as
well as strictly anhydrous reaction conditions. It is therefore
important to develop a new method that can tolerate moisture
or water.
13
line/pyridine N-oxides with sulfonyl hydrazides for the direct
Since the first example of regioselective C2 functionalization
of N-oxides with N-phenylbenzimidoyl chlorides as the
synthesis of 2-sulfonyl quinolines/pyridines without assistance
10
activators was developed by M. Henze in 1936, considerable
11
progress has been made in this area (Scheme 1B). However,
to the best of our knowledge, iodide-TBHP system (in situ
Received: March 4, 2016
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.6b00475
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
of transition-metal catalysts, base additives, or phosphorus
additives (Scheme 1C).
reaction temperature to 100 °C showed a positive result, with
the starting material consumed completely in 5 min and the
yield improved to 88% (entry 14). However, a continued
increase in temperature to 120 °C had a negative impact on the
reaction, resulting in fast decomposition of benzenesulfonohy-
drazide 1a (entry 15).
RESULTS AND DISCUSSION
■
We initially chose benzenesulfonohydrazide (1a) as a model
substrate to react with 6-methylquinoline N-oxide (2a) in the
presence of iodine and tert-butyl hydroperoxide (TBHP, 70% in
water) in acetonitrile at 80 °C under an air atmosphere. Much
to our delight, the reaction proceeded to give access to the
desired sulfonylation product 3a, albeit with a low yield (40%,
Table 1, entry 1). Encouraged by this result, we planned to
Having identified the optimized reaction conditions, we
subsequently explored the substrate scope (Table 2). A set of
sulfonyl hydrazides including aromatic and aliphatic could
efficiently sulfonylation of quinoline N-oxides to deliver the
desired 2-sulfonyl quinolines 3 in moderate to high yields.
Reactions of m-, o, and p-toluenesulfonyl hydrazides proceeded
well, and almost equal yields were achieved, suggesting that the
steric effect of substituents on aromatic rings is negligible (3b−
a
Table 1. Optimization of the Reaction Conditions
3
d). Arylsulfonyl hydrazides possessing either electron-
donating (3d−3f) or electron-withdrawing substituents (3g−
j) were well tolerated in this sulfonylation, affording the
3
desired products in moderate to excellent yields. The electron-
donating substituted benzenesulfonylhydrazines showed supe-
rior reaction efficiency to that of the electron-withdrawing ones.
This protocol was tolerant of synthetically valuable functional
groups on the phenyl moiety (for example, alkoxy, fluoro,
chloro, bromo and acetyl groups), which could allow an
opportunity for further transformations. The sulfonylation
process also occurred well with polycyclic and heteroaromatic
sulfonyl hydrazides, affording the targeted compounds 3k−3m
in 52−85% yields. Besides the aromatic sulfonyl hydrazides,
aliphatic sulfonyl hydrazides were also found to be suitable
sulfonylation reagents for the standard conditions (3n−3o).
We next turned our attention to the scope of heteroaromatic
N-oxides. To our delight, the current catalytic system was
suitable for a wide range of substituted quinoline N-oxides
additive
(equiv)
oxidant
(equiv)
temp.
yield
b
entry
solvent
(°C)
(%)
1
2
I2 (1.0)
n-Bu NI
TBHP (2.5) CH CN
80
80
40
13
3
TBHP (2.5) CH CN
4
3
(2.0)
3
4
5
6
7
8
9
NaI (2.0)
KI (2.0)
TBHP (2.5) CH CN
80
80
80
80
80
80
80
80
80
52
52
24
−
3
TBHP (2.5) CH CN
3
NIS (2.0)
PIFA (2.0)
NaBr (2.0)
NaI (2.0)
NaI (2.0)
NaI (2.0)
NaI (2.0)
TBHP (2.5) CH CN
3
TBHP (2.5) CH CN
3
TBHP (2.5) CH CN
−
3
H O (6)
CH CN
48
28
19
trace
2
2
3
BPO (1.75)
CH CN
3
1
1
0
1
TBPB (1.75) CH CN
3
NaS O
CH CN
3
2
8
(
1.75)
(
3p−3ab). No matter whether the N-heteroaromatic ring is
12
13
14
NaI (2.0)
NaI (2.0)
NaI (2.0)
oxone (1.75) CH CN
80
80
trace
26
3
substituted with either sterically hindered group, electron-
donating (Me and OMe), or electron-withdrawing (Cl, Br, I
O2
CH CN
3
TBHP (3)
DMF/H O
100
88
2
and NO ), all of them delivered the desired products in good to
(
1:1)
2
a
excellent yields (3p−3z). Notably, isoquinoline N-oxide and
pyridine N-oxide could proceed efficiently and afford the
corresponding products (3aa and 3ab) in 71% and 72% yields,
respectively. However, substituted pyridine N-oxides (3ac and
3ad) failed to produce the desired products under the optimal
reaction conditions
Reaction conditions: a mixture of 1a (0.2 mmol), 2a (0.4 mmol),
iodine regent, oxidant, solvent (2 mL) was stirred for 10 min at 80 °C.
b
c
Yield of 3a was determined by HPLC on crude products. 1.75 equiv
d
e
of 1a was used. 2.25 equiv of 1a was used. 1 mL DMF aqueous was
used as the solvent. 3 mL DMF aqueous was used as the solvent.
f
employ different iodine regents, oxidants, and solvents to
search for the optimal reaction conditions. Iodine regents, such
In order to prove the practicality of this approach, a gram-
scale synthesis of the 3a (1.703g, 86% yield) and 3t (1862g,
89% yield) was performed, respectively, which suggested that
such methodology could also be efficiently scaled up (Scheme
2).
as n-Bu NI, NaI, KI, and NIS could provide 13−52% yields
4
(entries 2−5). NaI was superior to the others and proved to be
the best catalyst (entry 3). No desired product was observed
when phenyliodine bis(trifluoroacetate) (PIFA) or NaBr was
used as a catalyst (entries 6−7). The optimization of various
oxidants indicated that TBHP was the best choice, whereas the
others like hydrogen peroxide (H O , 30% in water), benzoyl
To clarify the mechanism of the regioselective sulfonylation
process, the following control experiments were performed.
First, a radical trapping reagent (for example, TEMPO and
BHT) had little effect on the reaction efficiency, suggesting that
free radical intermediate is not involved in this reaction
2
2
peroxide (BPO), tert-butyl peroxybenzoate (TBPB), Na S O ,
2
2
8
5a,c,e,f,14
oxone, and O were less effective (entries 8−13). Various
(Scheme 3a).
Second, intermolecular kinetic isotope
2
solvents were then probed to promote the reaction, and the
effects (KIE) were investigated with regard to the C(sp )−H/D
2
solvent mixture DMF/H O (1:1) was found to be particularly
bonds for the quinoline substrates. A clear KIE value of 1.0 was
2
effective for this sulfonylation (see SI). In an attempt to
improve the reaction efficiency, other reaction parameters were
tested, including loading of NaI and TBHP, substrate ratio and
concentration (see SI). After careful optimization, we found
that adjusting the dosage of NaI to 2.0 equiv and substrate ratio
to 1:2 (1a:2a) in the presence of 2.0 equiv of NaI in 1 mL
observed in a 1:1 mixture of quinoline N-oxide 2a and
quinoline-D N-oxide ([D ]-2a) (Scheme 3b), indicating that
1
the quinoline N-oxide C(sp )−H bond breaking might not be
2
the rate-limiting step. Third, considering that this type of
coupling reaction may involve the 2-iodoquinoline intermedi-
ate, generated from the regioselective C2-iodination, we
attempted to treat 1a with 2-iodo-6-methylquinoline N-oxides
(4a) and 2-iodo-6-methylquinoline (4a′). However, no
DMF/H O (1:1) at 80 °C further facilitated the reaction
2
process and afforded 81% yield of 3a (see SI). Elevating the
B
DOI: 10.1021/acs.joc.6b00475
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
a
Table 2. Reaction Scope
a
Compound 1 (0.2 mmol) and 2 (0.4 mmol), NaI (0.4 mmol), TBHP (0.6 mmol, 70% in water). No reaction is denoted by “--”.
Scheme 2. Gram-Scale Synthesis of 3a
−
formation of product 3a was observed under the standard
conditions (Scheme 3c). The decomposition of the sulfonyl
hydrazide 1a in the absence of 2a gave the sulfonothioate 5a
and disulfide 6a in 11 and 35% yields, respectively (Scheme
to form the potential actual oxidant species hypoiodite ([IO] ).
Subsequently, nucleophilic addition reaction of [IO]− by
quinoline N-oxide afforded the intermediate A. The sulfonyl
nucleophile generated from base-accelerated decomposition of
benzenesulfonohydrazide attacks α-carbon of intermediate A.
The resulting intermediate B underwent deprotonation/
aromatization to give the targeted product 3 and release of
3d). However, the desired product 3a was not obtained when
5a or 6a was treated under the standard conditions (Scheme
3e), suggesting that 5a and 6a might not be an intermediate in
the unstable HIO , which undergo disproportionation to
this reaction. Moreover, the effect of iodine was also
2
−
produce I and IO .
investigated (Scheme 3f). When 2 equiv of PhI(OAc) or
2
3
2
IBX was employed instead of our catalytic system, no 3a was
obtained. In contrast, when NaIO generated in situ from I and
CONCLUSIONS
2
■
NaOH was used, the reaction gave target product 3a in a 21%
yield. This result clearly shows that the N-oxide of the substrate
not only directs the remote C−H activation but also delivers an
oxygen atom.
In summary, for the first time, a NaI/TBHP-mediated direct
C -sulfonylation of heteroaromatic N-oxides has been devel-
2
oped for the synthesis of 2-sulfonylquinolines/pyridines. This
transition metal and base additive-free synthetic process works
well with a wide range of heteroaromatic N-oxides and can be
safely conducted on a gram scale. The features such as
generality, high efficiency, short reaction time, and air- and
moisture-insensitive reaction conditions make the present
Based on these observations and previous literature
1
1c,d,15
reports,
Scheme 4). First, the oxidation of iodide with TBHP might
produce I , which could be further oxidized in the same fashion
a mechanism can tentatively be proposed
(
2
C
DOI: 10.1021/acs.joc.6b00475
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Scheme 3. Control Experiments
Scheme 4. Proposed Reaction Mechanisms
method an attractive alternative for the preparation of 2-
sulfonylquinolines/pyridines.
General Procedure for the Synthesis of 3. A solution of
heteroaromatic N-oxide (0.2 mmol), sulfonyl hydrazide (0.4 mmol),
NaI (60 mg, 0.4 mmol), and TBHP (70%, 77 mg, 0.6 mmol) in DMF/
water (1:1) (4 mL) was stirred under an air atmosphere at 100 °C for
a desired time (monitored by TLC). After the reaction was finished,
the mixture was added to 5 mL water and extracted with ethyl acetate
EXPERIMENTAL SECTION
■
General Information. Unless otherwise noted, all commercial
materials and solvents were used without further purification. Column
chromatography was performed using silica gel (100−200 mesh) as
the stationary phase. All reactions were monitored by thin-layer
chromatography (TLC). NMR spectra were recorded with 400 MHz
(
3 × 5 mL), and the organic phase was dried over Na SO , filtered,
2 4
and concentrated under reduced pressure. The residue was separated
on a silica gel column with petroleum ether/ethyl acetate (1/5) as the
eluent to get product 3.
1
13
Kinetic Isotope Effect. A 1:1 mixture of 2a and the deuterated
spectrometers for H NMR and 100 MHz for C NMR. Chemical
substrate [D ]-2a was subjected to the standard reaction condition for
1
shifts δ are given in ppm relative to the residual signals of
3
min. The GC-MS analysis of 6-methylquinoline N-oxide 2a and 6-
1
tetramethylsilane in CDCl or deuterated solvent CDCl for H and
3
3
methylquinoline-D N-oxide ([D ]-2a) quinoline N-oxide in residual
1
3
1
C NMR. Multiplicities are given as s (singlet), d (doublet), t
triplet), dd (doublet of doublets), dq (doublet of quartets), q
quartet), or m (multiplet). IR spectra were recorded on a FT-IR
spectrometer, and only major peaks are reported in cm . High-
resolution mass spectra were taken with GCT-TOF instrument with
EI or ESI source.
material reveals a nearly equal mixture of isotopes, corresponding to an
(
(
intermolecular KIE of K /K = 1.1.
H
D
6
-Methyl-2-(phenylsulfonyl)quinolone (3a). White solid, mp 150−
−1
1
152 °C, yield: 86% (48.6 mg). H NMR (500 MHz, CDCl ) δ: 8.24
3
(d, J = 5.0 Hz, 1H), 8.15 (d, J = 10.0 Hz, 1H), 8.12 (d, J = 10.0 Hz,
2H), 8.04 (d, J = 10.0 Hz, 1H), 7.59 (d, J = 10.0 Hz, 2H), 7.57 (d, J =
D
DOI: 10.1021/acs.joc.6b00475
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The Journal of Organic Chemistry
Article
0.0 Hz, 1H), 7.51 (t, J = 5.0 Hz, 2H), 2.53 (s, 3H); 13C{ H} NMR
1
2-((4-Bromophenyl)sulfonyl)-6-methylquinoline (3i). Yellow solid,
1
(
1
1
1
125 MHz, CDCl ) δ: 21.8, 117.8, 126.4, 128.9, 129.0, 130.0, 133.4,
33.6, 137.8, 139.4, 139.7, 146.1, 157.1; IR (KBr) ν 2960, 1302,
260, 1132, 803, 604 cm ; HRMS (ESI): M + H found 284.0750;
mp 123−124 °C, yield: 73%, 52.6 mg. H NMR (400 MHz, CDCl ) δ:
3
3
8.20 (d, J = 8.0 Hz, 1H), 8.07 (m, J = 8.0 Hz, 1H), 7.95 (d, J = 12.0
Hz, 1H), 7.91 (d, J = 12.0 Hz, 2H), 7.59 (d, J = 8.0 Hz, 2H), 7.54 (d, J
max
−1
+
= 8.0 Hz, 2H), 2.47 (s, 3H); 13C{ H} NMR (100 MHz, CDCl ) δ:
1
C H NO S requires 284.0754.
1
6
14
2
3
6
-Methyl-2-(o-tolylsulfonyl)quinoline (3b). White solid, mp 144−
21.8, 117.6, 126.4, 128.8, 129.0, 129.1, 129.9, 130.5, 132.3, 133.5,
1
1
(
45 °C, yield: 78% (46.3 mg). H NMR (500 MHz, CDCl ) δ: 8.30
d, J = 10.0 Hz, 1H), 8.27 (d, J = 10.0 Hz, 1H), 8.12 (d, J = 10.0 Hz,
H), 7.99 (d, J = 10.0 Hz, 1H), 7.63 (s, 1H), 7.59 (d, J = 10.0 Hz, 1H),
137.9, 138.3, 139.9, 146.1, 156.7; IR (KBr) ν 2984, 1567, 1300,
3
max
−1
+
1179, 825, 512 cm ; HRMS (ESI): M + H found 361.9857;
C H BrNO S requires 361.9859.
1
7
1
1
1
7
16
13
2
.48 (t, J = 5.0 Hz, 1H), 7.41 (t, J = 5.0 Hz, 1H), 7.23 (d, J = 5.0 Hz,
2-((4-Acetylphenyl)sulfonyl)-6-methylquinoline (3j),. White solid,
H), 2.54 (s, 6H); 13C{ H} NMR (125 MHz, CDCl ) δ: 20.7, 21.8,
1
mp 174−176 °C, yield: 50%, (32.5 mg). H NMR (400 MHz, CDCl )
1
3
3
17.8, 126.40, 126.46, 129.0, 130.0, 130.5, 132.4, 133.3, 133.8, 137.3,
37.7, 139.0, 139.7, 145.8, 157.2; IR (KBr) ν 2926, 1302, 1168, 816,
07, 605, 574 cm ; HRMS (ESI): M + H found 298.0908;
δ: 8.29 (d, J = 8.0 Hz, 1H), 8.23 (d, J = 8.0 Hz, 2H), 8.18 (d, J = 8.0
Hz, 1H), 8.08 (d, J = 8.0 Hz, 2H), 8.03 (d, J = 8.0 Hz, 1H), 7.64 (t, J =
8.0 Hz, 2H), 2.62 (s, 3H), 2.56 (s, 3H); C{ H} NMR (100 MHz,
max
−1
+
13
1
C H NO S requires 298.0910.
CDCl ) δ: 20.8, 25.9, 116.7, 125.4, 125.5, 127.7, 128.3, 128.9, 131.2,
1
7
16
2
3
6
-Methyl-2-(m-tolylsulfonyl)quinoline (3c). White solid, mp 143−
132.6, 136.9, 139.0, 139.6, 142.1, 155.5, 196.8; IR (KBr) ν 2925,
max
1
−1
+
1
(
44 °C, yield: 80% (47.5 mg). H NMR (400 MHz, CDCl ) δ: 8.18
d, J = 8.0 Hz, 1H), 8.07 (d, J = 8.0 Hz, 1H), 7.99 (d, J = 8.0 Hz, 1H),
1688, 1320, 1260, 1159, 820, 675 cm ; HRMS (ESI): M + H found
326.0843; C H NO S requires 326.0845.
3
18
16
3
7
2
2
1
6
.85 (d, J = 4.0 Hz, 2H), 7.53 (d, J = 8.0 Hz, 2H), 7.32 (d, J = 8.0 Hz,
8-Methyl-2-(naphthalen-2-ylsulfonyl)quinoline (3k). White solid,
H), 2.46 (s, 3H), 2.32 (s, 3H); 13C{ H} NMR (100 MHz, CDCl ) δ:
1
1
mp 137−139 °C, yield: 52% (34.6 mg). HNMR (500 MHz, CDCl )
3
3
1.3, 21.8, 117.9, 126.1, 126.4, 128.9, 129.1, 130.0, 133.3, 134.4, 137.8,
δ: 8.76 (s, 1H), 8.45 (q, J = 10.0 Hz, 2H), 8.10 (d, J = 10.0 Hz, 1H),
8.06 (d, J = 10.0 Hz, 1H), 8.01 (d, J = 10.0 Hz, 1H), 7.95 (d, J = 5.0
Hz, 1H), 7.88 (d, J = 10.0 Hz,1H), 7.58−7.65 (m, 4H); 2.54 (s, 3H);
39.2, 139.3, 139.6, 146.1, 157.2; IR (KBr) ν 2920, 1320, 1166, 820,
max
−1
+
98, 612, 465 cm ; HRMS (ESI): M + H found 298.0908;
13
1
C H NO S requires 298.0910.
C{ H} NMR(125 MHz,CDCl ) δ: 20.7, 117.8, 123.7, 126.4, 127.5,
1
7
16
2
3
6
-Methyl-2-tosylquinoline (3d). White solid, mp 144−146 °C,
127.9, 128.9, 129.2, 129.5, 130.0, 130.7, 132.1, 133.4, 135.3, 137.8,
1
yield: 79% (46.9 mg). H NMR (500 MHz, CDCl ) δ: 8.26(d, J = 10.0
Hz, 1H), 8.15 (d, J = 5.0 Hz, 1H), 8.07 (d, J = 10.0 Hz, 1H), 8.03 (d, J
139.7, 146.1, 157.2; IR (KBr) ν 3858, 3637, 2901, 1636, 1297, 679
3
max
−1
+
cm ; HRMS (ESI): M + H found 334.0895; C H NO S requires
20 16 2
=
2
2
1
10.0 Hz,2H), 7.61 (d, J = 5.0 Hz, 2H), 7.33 (d, J = 10.0 Hz, 2H),
334.0896.
.55 (s, 3H), 2.40 (s, 3H); 13C{ H} NMR (125 MHz, CDCl ) δ: 21.6,
1
3
6-Methyl-2-(pyridin-3-ylsulfonyl)quinoline (3l). White solid, mp
1
1.8, 117.7, 126.4, 128.9, 129.0, 129.7, 130.0, 133.3, 136.4, 137.8,
39.6, 144.6, 146.1, 157.4; IR (KBr) ν 2962, 1319, 1260, 1128, 792,
00, 607 cm ; HRMS (ESI): M + H found 298.0895; C H NO S
requires 298.0896.
156−157 °C, yield: 85% (48.2 mg). H NMR (400 MHz, CDCl ) δ:
3
max
9.25 (s, 1H), 8.74 (d, J = 4.0 Hz, 1H), 8.36 (d, J = 8.0 Hz, 1H), 8.23
(d, J = 12.0 Hz, 1H), 8.12 (d, J = 8.0 Hz, 1H), 7.94 (d, J = 8.0 Hz,
1H), 7.56 (d, J = 12.0 Hz, 2H), 7.42 (dd, J = 8.0, 4.0 Hz, 1H), 2.48 (s,
−1
+
7
17 16 2
3H); 13C{ H} NMR (100 MHz, CDCl ) δ: 20.8, 116.3, 122.6, 125.4,
1
2
-((4-tert-Butylphenyl)sulfonyl)-6-methylquinoline (3e). White
3
1
solid, mp 201−202 °C, yield: 93% (63.1 mg). H NMR(400 MHz,
CDCl ) δ: 8.17 (d, J = 8.0 Hz, 1H), 8.07 (d, J = 8.0 Hz, 1H), 8.01 (d, J
128.0, 128.8, 132.6, 134.8, 135.7, 137.0, 139.1, 145.0, 148.9,
3
152.9.,155.4; IR (KBr) ν
798, 600 cm ; HRMS (ESI): M + H found 285.0704; C H N O S
max
2961, 1568, 1376, 1165, 1081, 1020,
−1
+
=
(
12.0 Hz, 1H), 7.97 (d, J = 8.0 Hz, 2H), 7.53 (d, J = 8.0 Hz, 2H), 7.45
15 13 2 2
d, J = 8.0 Hz, 2H), 2.46 (s, 3H), 1.22 (s, 9H); 13C{ H} NMR (100
1
requires 285.0706.
MHz, CDCl ) δ: 20.7, 30.0, 34.2, 116.9, 125.1, 125.3, 127.7, 127.9,
8-Methyl-2-(thiophen-2-ylsulfonyl)quinoline (3m). White solid,
3
1
1
2
29.0, 132.2, 135.3, 136.7, 138.5, 145.1, 156.3, 156.5; IR (KBr) ν
962, 1319, 1261, 1096, 797, 647, 614 cm ; HRMS (ESI): M + H
mp 147−148 °C, yield: 57%, (32.9 mg); H NMR (500 MHz, CDCl )
max
3
−1
+
δ:8.35 (d, J = 10.0 Hz, 1H), 8.19 (d, J = 5.0 Hz, 1H), 7.91 (d, J = 5.0
Hz, 1H), 7.75 (d, J = 5.0 Hz, 1H), 7.71 (d, J = 5.0 Hz, 1H), 7.62 (d, J
= 5.0 Hz, 1H), 7.54 (t, J = 5.0 Hz, 1H), 7.14 (t, J = 5.0 Hz, 1H), 2.75
found 340.1378; C H NO S requires 340.1380.
20
21
2
2
-((4-Methoxyphenyl)sulfonyl)-6-methylquinoline (3f). White
1
13
1
solid, mp 140−142 °C, yield: 90%, (53.6 mg). H NMR (400
MHz,CDCl ) δ: H NMR (400 MHz, CDCl ) δ 8.16 (d, J = 8.0 Hz,
(s, 3H); C{ H} NMR (125 MHz, CDCl ) δ: 17.6, 116.3, 125.5,
3
1
3
3
127.5, 129.0, 130.2, 131.0, 135.2, 138.5, 138.8, 143.8, 145.8, 156.9; IR
−
1
1
H), 8.05 (d, J = 8.0 Hz, 1H), 7.98 (d, J = 8.0 Hz, 3H), 7.52 (d, J = 8.0
(KBr) ν 2963, 2361, 1261, 1095, 801, 649, 604 cm ; HRMS (ESI):
max
13
1
+
Hz, 2H), 6.90 (d, J = 8.0 Hz, 2H), 3.75 (s, 3H), 2.46 (s, 3H); C{ H}
M + H found 290.0316; C H NO S requires 290.0318.
14
12
2 2
3
2-(Dodecylsulfonyl)quinoline (3n). White solid, mp 168−169 °C,
1
yield: 58%, (41.8 mg). H NMR (400 MHz, CDCl ) δ: 8.32 (d, J = 8.0
3
Hz, 1H), 8.02 (t, J = 8.0 Hz, 2H), 7.82 (d, J = 8.0 Hz, 1H), 7.71 (t, J =
8.0 Hz, 1H), 7.54 (t, J = 8.0 Hz, 1H), 3.13−3.05 (m, 1H), 2.95−2.87
(m, 1H), 1.89−1.81 (m, 1H), 1.58−1.47 (m, 1H), 1.38−1.26 (m, 2H),
13
1
1.13 (s, 16H), 0.78 (t, J = 4.0 Hz, 3H); C{ H} NMR(100 MHz,
CDCl ) δ:13.1, 20.9, 21.6, 27.6, 28.1, 28.3, 28.4, 28.5, 30.8, 53.9, 114.7,
3
Hz, 1H), 7.61 (d, J = 8.0 Hz, 2H), 7.20 (t, J = 8.0 Hz, 2H), 2.54 (s,
126.7, 127.0 127.1, 128.2, 129.7, 137.2, 146.4, 164.0. IR (KBr) ν
2923, 1592, 1470, 1044, 840, 752, 632 cm ; HRMS (ESI): M + H
max
H); 13C{ H} NMR (100 MHz, CDCl ) δ: 20.7, 115.3 (d, J
1
= 22.5
−1
+
3
3
C−F
Hz), 116.5, 125.4, 127.9, 128.9, 130.8 (d, JC−F = 9.6 Hz,), 132.4, 134.1,
36.9, 138.8, 145.0, 155.9, 164.8(JC−F = 254.7 Hz); 19F NMR (376
MHz, CDCl ) δ:-103.5. IR (KBr) ν 2922, 1584, 1323, 1229, 1134,
found 262.2160; C H NO S requires 362.2162.
21
32
2
1
2-((3-Chloropropyl)sulfonyl)quinoline (3o). White solid, mp 151−
1
152 °C, yield: 72%, (38.7 mg). H NMR (400 MHz, CDCl ) δ: 8.46
3
max
3
−1
+
8
21, 682, 587 cm ; HRMS (ESI): M + H found 302.0644;
(d, J = 8.0 Hz, 1H), 8.22 (d, J = 8.0 Hz, 1H), 8.12 (d, J = 8.0 Hz, 1H),
7.95 (d, J = 8.0 Hz, 1H), 7.87 (t, J = 8.0 Hz, 1H), 7.73 (t, J = 8.0 Hz,
C H FNO S requires 302.0646.
1
6
13
2
1
3
1
2
-((4-Chlorophenyl)sulfonyl)-6-methylquinoline (3h). White solid,
1H), 3.69−3.76 (m, 4H), 2.33−2.40 (m, 2H); C{ H} NMR (100
1
mp 121−122 °C, yield: 85% (51.3 mg). H NMR (500 MHz, CDCl )
δ: 8.31 (d, J = 10.0 Hz, 1H), 8.18 (d, J = 10.0 Hz, 1H), 8.10 (d, J =
MHz, CDCl ) δ: 25.6, 42.8, 49.2, 116.9, 127.9, 129.2, 129.4, 130.1,
3
3
131.3, 139.0, 147.1, 156.6; IR (KBr) ν 3877, 3751, 3612, 2901,
max
−1
+
1
(
0.0 Hz, 2H), 8.06 (d, J = 5.0 Hz, 1H), 7.65 (d, J = 5.0 Hz, 2H), 7.53
1613, 649, 427 cm ; HRMS (ESI): M + H found 270.0362;
C H ClNO S requires 270.0364.
d, J = 10.0 Hz, 2H), 2.59 (s, 3H); 13C{ H} NMR (125 MHz, CDCl )
1
3
12 13
2
δ: 21.8, 117.6, 126.4, 129.0, 129.3, 129.9, 130.5, 133.5, 137.7, 137.9,
2-(Phenylsulfonyl)quinoline (3p). White solid, mp 160−161 °C,
1
1
39.9, 140.4, 146.1, 156.8; IR (KBr) ν 2998, 1637, 1357, 1100, 860,
67 cm ; HRMS (ESI): M + H found 318.0362; C H ClNO S
yield: 74%, (39.8 mg); H NMR (400 MHz, CDCl ) δ: 8.29 (d, J =
max
3
−1
+
5
12.0 Hz, 1H), 8.13 (d, J = 8.0 Hz, 1H), 8.07 (t, J = 8.0 Hz, 3H), 7.79
16
13
2
requires 318.0364.
(d, J = 8.0 Hz, 1H), 7.70 (t, J = 8.0 Hz, 1H), 7.57 (t, J = 8.0 Hz, 1H),
E
DOI: 10.1021/acs.joc.6b00475
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1
1H), 7.59 (t, J = 10.0 Hz, 1H), 7.53 (t, J = 10.0 Hz, 2H); 13
7
.52 (t, J = 8.0 Hz, 1H), 7.45 (t, J = 8.0 Hz, 2H); 13C{ H} NMR (100
C
MHz, CDCl ) δ: 116.7, 126.7, 127.8, 128.01, 128.07, 128.2, 129.3,
NMR(125 MHz, CDCl ) δ: 118.6, 123.6, 129.1, 129.2, 129.7, 131.6,
3
3
1
1
2
29.9, 130.0, 132.7, 137.7, 138.1, 146.4, 157.0; IR(KBr) ν 2925,
133.9, 134.6, 137.7, 138.8, 145.9, 158.5; IR (KBr) ν 2910, 1743,
max
max
−1
+
−1
+
321, 1165, 1129, 1020, 756, 639 cm ; HRMS (ESI): M + H found
70.0595; C H NO S requires 270.0597.
1307, 1139, 814, 690 cm ; HRMS (ESI): M + H found 347.9701;
C H BrNO S requires 347.9703.
15
12
2
15 11
2
3
-Methyl-2-(phenylsulfonyl)quinoline (3q). White solid, mp 146−
3-Iodo-2-tosylquinoline (3y). White solid, mp 138−139 °C, yield:
1
1
1
(
7
48 °C, yield: 78%, (44.1 mg). H NMR (500 MHz, CDCl ) δ: 8.09
d, J = 5.0 Hz, 3H), 7.90 (d, J = 5.0 Hz, 1H), 7.78 (d, J = 5.0 Hz, 1H),
.71−7.65 (m, 2H), 7.60(q, J = 5.0 Hz, 3H), 2.90 (s, 3H); C{ H}
NMR (125 MHz, CDCl ) δ: 18.8, 126.7, 128.5, 128.6, 129.0, 129.1,
70% (57.2 mg). H NMR (500 MHz, CDCl ) δ:8.88 (s, 1H), 8.00 (d,
3
3
J = 10.0 Hz, 2H), 7.92 (d, J = 10.0 Hz, 1H), 7.75 (t, J = 10.0 Hz, 2H),
13
1
7.67 (t, J = 10.0 Hz, 1H), 7.39 (d, J = 10.0 Hz, 2H), 2.50 (s, 3H);
13
1
C{ H} NMR (125 MHz, CDCl ) δ: 21.7, 79.9, 126.3, 129.3, 129.82,
3
3
1
3
2
29.4, 129.8, 129.9, 133.5, 138.8, 139.8, 144.6, 156.9; IR (KBr) ν
129.85, 130.0, 130.1, 131.2, 134.5, 144.7, 144.8, 150.5, 156.3; IR (KBr)
νmax 2927, 1687, 1301, 1064, 738, 641 cm ; HRMS (ESI): M + H
max
−1
+
−1
+
049, 1588, 1364, 527, 501, 416 cm ; HRMS (ESI): M + H found
84.0738; C H NO S requires 284.0740.
16
14
2
found 409.9718; C H INO S requires 409.9720.
16 13
2
4
-Methyl-2-(phenylsulfonyl)quinoline (3r). White solid, mp 145−
6-Nitrophenyl-2-tosylquinoline (3z). White solid, mp 170−171 °C,
1
1
1
46 °C, yield: 92% (52.1 mg). H NMR (400 MHz, CDCl ) δ:8.06 (t,
yield: 60% (39.4 mg). H NMR (400 MHz, CDCl ) δ: 8.28 (d, J = 8.0
3
3
J = 8.0 Hz, 3H), 7.96 (s, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.67 (t, J = 8.0
Hz, 1H), 8.12 (d, J = 8.0 Hz, 1H), 8.04 (d, J = 8.0 Hz, 2H), 7.63 (d, J
Hz, 1H), 7.57 (t, J = 8.0 Hz, 1H), 7.51 (t, J = 8.0 Hz, 1H), 7.44 (t, J =
= 8.0 Hz, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.46 (t, J = 8.0 Hz, 3H), 2.59
.0 Hz, 2H), 2.70 (s, 3H); 13C{ H} NMR(100 MHz,CDCl ) δ:18.1,
1
13
1
8
1
1
(s, 3H); C{ H} NMR (100 MHz, CDCl ) δ: 17.5, 116.6, 125.6,
3
3
17.1, 122.8, 127.7, 127.92, 127.95, 128.0, 129.5, 130.0, 132.6, 138,2,
46.1, 146.9, 156.6; IR (KBr) ν 2962, 1312, 1110, 777, 687, 622
cm ; HRMS (ESI): M + H found 284.0753; C H NO S requires
128.9,129.13, 129.17, 130.9, 131.1, 132.1, 137.9, 138.3, 138.9,146.4,
−
1
max
156.7 ;IR (KBr) ν 3078, 2907, 1666, 1301, 1051, 723 cm ; HRMS
max
−1
+
+
16
14
2
(ESI): M + H found 329.0603; C H N O S requires 329.0605.
16 13
2
4
2
84.0754.
-Bromo-2-(phenylsulfonyl)quinoline (3s). yellow solid, mp 180−
1-(Phenylsulfonyl)isoquinoline (3aa). White solid, mp 159−161
1
5
°C, yield: 71% (38.2 mg). H NMR (400 MHz, CDCl ) δ: 9.07 (d, J =
3
1
1
82 °C, yield: 65% (45.0 mg): H NMR (400 MHz, CDCl ) δ: 8.69
4.0 Hz, 1H), 8.33 (d, J = 4.0 Hz, 1H), 8.01 (d, J = 8.0 Hz, 2H), 7.81
(d, J = 4.0 Hz, 1H), 7.69 (t, J = 4.0 Hz, 3H), 7.56 (t, J = 8.0 Hz, 1H),
3
(
d, J = 8.0 Hz, 1H), 8.22 (d, J = 8.0 Hz, 1H), 8.06 (d, J = 8.0 Hz, 3H),
7.47 (t, J = 8.0 Hz, 2H); 13C{ H} NMR (100 MHz, CDCl ) δ: 123.3,
1
7
7
1
1
.85 (d, J = 8.0 Hz, 1H), 7.57 (d, J = 8.0, 1H), 7.54 (d, J = 8.0, 1H),
3
.47 (t, J = 8.0 Hz, 2H); 13C{ H} NMR (100 MHz, CDCl ) δ: 117.8,
1
124.0, 124.2, 126.5, 127.8, 128.1, 128.2, 130.1, 132.6, 136.7, 138.0,
3
20.8, 127.3, 128.11, 128.15, 129.2, 130.1, 131.7, 132.9, 137.6, 137.7,
139.5, 155.9; IR (KBr) ν 1496, 1298, 1139, 1081, 720, 684, 591
max
−1
+
47.0, 157.9; IR (KBr) ν 2961, 1507, 1328, 1284, 1078, 812, 684
cm ; HRMS (ESI): M + H found 270.0581; C H NO S requires
max
15 12 2
−1
+
cm ; HRMS (ESI): M + H found 347.9701; C H BrNO S requires
270.0583.
15
11
2
3
47.9703.
-Methoxy-2-(phenylsulfonyl)quinoline (3t). White solid, mp
2-(Phenylsulfonyl)pyridine (3ab). White solid, mp 95−96 °C,
1
6
yield: 72%, (31.5 mg). H NMR (400 MHz, CDCl ) δ: 8.44 (d, J = 4.0
3
1
1
47−149 °C, yield: 90% (53.8 mg), H NMR (400 MHz, CDCl )
Hz, 1H), 7.96 (t, J = 8.0 Hz, 1H), 7.76 (t, J = 8.0 Hz, 1H), 7.71 (d, J =
8.0 Hz, 2H), 7.34 (d, J = 8.0 Hz, 3H), 7.18 (d, J = 4.0 Hz, 1H);
3
δ: 8.15 (d, J = 12.0 Hz, 1H), 8.06 (t, J = 8.0 Hz, 3H,), 7.98 (d, J = 8.0
13
1
Hz, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.44 (t, J = 4.0 Hz, 2H), 7.34 (d, J =
C{ H} NMR(100 MHz, CDCl ) δ: 117.3, 123.6, 123.8, 127.8,
3
.0 Hz, 1H), 7.01 (s, 1H), 3.86 (s, 3H); 13C{ H} NMR (100 MHz,
1
8
128.10, 128.13, 130.1, 137.1, 148.7; IR (KBr) ν 3052, 1574, 1419,
max
−1
+
CDCl ) δ: 54.7, 103.5, 117.2, 123.3, 126.7, 127.8, 128.0, 128.3, 129.4,
1088, 837, 788 cm ; HRMS (ESI): M + H found 220.0439;
C H NO S requires 220.0441.
3
1
30.8, 132.5, 135.8, 142.6, 158.8; IR (KBr) ν 2926, 1316, 1166,
max
11 10
2
−1
+
1
073, 1024, 802, 601 cm ; HRMS (ESI): M + H found 300.0701;
C H NO S requires 300.0703.
1
6
14
3
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.6b00475.
■
7
-Methyl-2-(phenylsulfonyl)quinoline (3u). White solid, mp 144−
1
*
S
1
(
8
=
45 °C, yield: 85% (48.0 mg). H NMR (400 MHz, CDCl ) δ: 8.23
3
d, J = 8.0 Hz, 1H), 8.06 (d, J = 8.0 Hz, 3H), 7.86 (s, 1H), 7.68 (d, J =
.0 Hz, 1H), 7.51 (t, J = 4.0 Hz, 1H), 7.45 (t, J = 8.0 Hz, 2H),7.40 (d, J
8.0 Hz, 1H), 2.46 (s, 3H); 13C{ H} NMR (100 MHz, CDCl ) δ:
1
3
1
13
H and C NMR spectra of compounds 3a−3ab (PDF)
2
0.8, 115.8, 125.9, 126.2, 126.7, 127.9, 128.0, 128.1, 130.5, 132.6,
1
6
37.2, 138.2, 140.6, 146.7, 156.9; IR (KBr) ν 2962, 1322, 852, 719,
max
−1
+
86, 587 cm ; HRMS (ESI): M + H found 284.0752; C H NO S
16 14 2
AUTHOR INFORMATION
■
*
requires 284.0754.
Corresponding Author
E-mail: chunlianhe6688@163.com.
8
-Methyl-2-(phenylsulfonyl)quinoline (3v). White solid, mp 106−
1
1
(
07 °C, yield: 82% (46.4 mg). H NMR (400 MHz, CDCl ) δ: 8.25
d, J = 8.0 Hz, 1H), 8.11(t, J = 8.0 Hz, 3H), 7.60 (d, J = 8.0 Hz, 1H),
3
Notes
13
1
7
.55−7.41 (m, 5H), 2.57 (s, 3H); C{ H} NMR (100 MHz, CDCl )
3
The authors declare no competing financial interest.
δ: 17.4, 116.7, 125.5, 128.83, 128.89, 129.0, 129.4, 130.9, 133.6, 138.4,
1
38.8, 138.9, 146.3, 157.1; IR (KBr) ν 3018, 2916, 1477, 1468,
max
−1
+
ACKNOWLEDGMENTS
1
302, 517 cm ; HRMS (ESI): M + H found 284.0752; C H NO S
■
(
1
6
14
2
requires 284.0754.
We thank the National Natural Science Foundation of China
no. 21176063) and Scientific Research Fund of Hunan
Provincial Education Department (no. 12A085) for financial
support.
6
-Chloro-2-(phenylsulfonyl)quinoline (3w). White solid, mp 173−
1
1
74 °C, yield 76% (46.0 mg). H NMR (400 MHz, CDCl ) δ: 8.20 (d,
3
J = 8.0 Hz, 1H), 8.15 (d, J = 12.0 Hz, 1H), 8.06 (d, J = 8.0 Hz, 2H),
8
.02 (d, J = 8.0 Hz, 1H), 7.79 (d, J = 2.4 Hz, 1H), 7.64 (dd, J = 12.0,
8
.0 Hz, 1H), 7.55 (t, J = 8.0 Hz, 1H), 7.47 (t, J = 8.0 Hz, 2H);
1
3
1
REFERENCES
C{ H} NMR (100 MHz, CDCl ) δ: 118.6, 126.3, 129.12, 129.17,
■
3
1
29.4, 131.9, 132.1, 133.9, 135.3, 137.8, 138.8, 145.8, 158.4; IR (KBr)
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−1
+
νmax 2947, 1531, 1301, 927, 816, 501 cm ; HRMS (ESI): M + H
found 304.0205; C H ClNO S requires 304.0208.
15
11
2
6
-Bromo-2-(phenylsulfonyl)quinoline (3x). Yellow solid, mp 180−
1
1
82 °C, yield: 72% (49.8 mg). H NMR (500 MHz,CDCl ) δ: 8.26 (d,
3
J = 10.0 Hz, 1H), 8.20 (d, J = 5.0 Hz, 1H), 8.12 (d, J = 10.0 Hz, 2H),
.01 (s, 1H), 7.98 (d, J = 15.0 Hz, 1H), 7.80 (dd, J = 9.5 Hz, 7.0 Hz,
8
F
DOI: 10.1021/acs.joc.6b00475
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
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DOI: 10.1021/acs.joc.6b00475
J. Org. Chem. XXXX, XXX, XXX−XXX