Copper-Catalyzed C5-H Sulfenylation of Unprotected 8-Aminoquinolines Using Sulfonyl Hydrazides

Article abstract of DOI:10.1021/acs.joc.8b01658

The synthesis of C5-sulfenylated 8-aminoquinolines using unprotected 8-aminoquinolines and sulfonyl hydrazides is achieved via the catalysis of CuI. The reactions are hypothesized to proceed via the Cu(I)-Cu(II)-Cu(I) catalytic processes induced by aerobic oxidation and single-electron transfer on the Cu(II)-8-aminoquinoline complex. This work discloses an unprecedented step-efficient method for the synthesis of C5-sulfenylated 8-aminoquinolines bearing a useful free NH₂ group.

Full text of DOI:10.1021/acs.joc.8b01658

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Note
Copper-Catalyzed C5-H Sulfenylation of Unprotected
8-Aminoquinolines Using Sulfonyl Hydrazides
Qing Yu, Yiming Yang, Jie-Ping Wan, and Yunyun Liu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01658 • Publication Date (Web): 06 Aug 2018
Downloaded from http://pubs.acs.org on August 6, 2018
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Copper-Catalyzed C5-H Sulfenylation of Unprotected
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8-Aminoquinolines Using Sulfonyl Hydrazides
Qing Yu, Yiming Yang, JieꢀPing Wan, Yunyun Liu*
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College of Chemistry and Chemical Engineering, Jiangxi Normal University,
Nanchang 330022, P. R. China
Email: chemliuyunyun@jxnu.edu.cn
Abstract
The synthesis of C5ꢀsulfenylated 8ꢀaminoquinolines using unprotected
8ꢀaminoquinolines and sulfonyl hydrazides is achieved via the catalysis of CuI. The
reactions are hypothesized to proceed via the Cu(I)ꢀCu(II)ꢀCu(I) catalytic processes
induced by the aerobic oxidation and the single electron transfer (SET) on the
Cu(II)ꢀ8ꢀaminoquinoline complex, respectively. This work discloses an
unprecedented step efficient method for the synthesis of C5ꢀsulfenylated
8ꢀaminoquinolines bearing useful free NH2 group.
By acting as directing group (DG), the 8ꢀaminoquinoline has shown marvellous
function in assisting the activation of numerous C(sp)ꢀH, C(sp2)ꢀH, C(sp3)ꢀH bonds in
amides via transition metal catalysis.1 Notably, alongside the impressive application
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as DG in CꢀH activation, the 8ꢀaminoquline itself has been identified as a useful
aromatic CꢀH bond donor in the remote activation of the C5 position when the amino
group is acylated. Because of the inherent privilege of the 8ꢀaminoquiline as main
fragment in many natural products and lead compounds (Fig. 1),2 the remote CꢀH
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Figure 1 Some 8ꢀaminoquinolineꢀbased natural products and lead compounds
bond activation and functionalization of the quinoline CꢀH bond directed by the
8ꢀamido group has rapidly gained splendid progress. During the past several years, a
large number of catalytic and synthetic methods on the remote CꢀH transformation
have been realized as reliable tools for the synthesis of diversified 8ꢀquinoquinoline
derivatives. For example, for the CꢀC bond construction, the C5ꢀH
perfluoroalkylation,3 alkylation,4 as well as allylation5 have been accomplished by
different groups. On the other hand, the examples on the formation of C5ꢀheteroatom
bond, as known in literature, cover the CꢀH halogenation,6 amination,7 nitration,8
azidation,9 acyloxylation,10 and etherification.11 Notably, as important advances, the
remote 8ꢀamidoquinoline CꢀH activation reactions enabling the formation of new
CꢀS/CꢀSe bonds, including chalcogenation,12 thio/selenocyanation13 and
sulfonylation14 have been also realized. According to these results, the C5ꢀH bond
functionalization of 8ꢀaminoquinolines is inarguably a powerful tool in the synthesis
of C5ꢀsubstituted 8ꢀaminoquinoline libraries of enriched diversity. However, one
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common and mandatory precondition in all these known reactions is that the amino
group must be prior acylated so that the expected CꢀH bond transformation can
smoothly take place (Scheme 1A). Such operation is thus a restriction for the
synthesis of those useful Nꢀunsubstituted or Nꢀalkyl 8ꢀaminoquinolines (see Fig. 1)
because of the low step economy associated with the additional experiments of the
prior Nꢀacylation as well as the later deprotection. In this context, a catalytic or
synthetic method allowing the direct C5ꢀH bond activation on the unprotected
8ꢀaminoquinolines is thus authentically desirable.
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Scheme 1 C5ꢀH Sulfenylation: Nꢀacyl 8ꢀaminoquinolines vs unprotected
8ꢀaminoquinolines
A) Prevous: acyl PG-assisted C-5 functionalization
H
FG
FG precursor
catalyst
N
N
HN
HN
COR
COR
mandatory PG
B) this work: PG-free C5-H sulfenylation
H
SAr
ArSO2NHNH2
copper cat.
N
N
NH2
NH2
no PG, the first example
Sulfonyl hydrazides are bench stable chemicals showing universal application
in organic synthesis. In previous works, sulfonyl hydrazides have been found as
practical donors of various organic fragments such as sulfonyl, sulfenyl, aryl,
hydrazide and carbene precursor.15 Besides introducing novel reaction pathways
enabling sophisticated syntheses, another notable advantage of the sulfonyl
hydrazides is their friendliness to operators as odourless alternatives of thiols.16 On
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the basis of our recent efforts in developing step economical CꢀH activation and
functionalization reactions,17 we report herein the first direct C5ꢀH sulfenylation of
unprotected 8ꢀaminoquinolines by employing sulfonyl hydrazides as the sulfenylating
reagents (Scheme 1B).
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At the beginning, the reaction between 8ꢀaminoquinoline 1a and tosyl
hydrazide 2a was selected for initial investigation. By running this reaction in the
presence of 15 mol% CuI in pꢀxylene, the C5ꢀsufenylated product 3a was acquired
with low yield (entry 1, Table 1). Employing Na2CO3 as a base additive led to the
yield of 3a with dramatic improvement (entry 2, Table 1). Respectively varying the
amount of CuI as well as Na2CO3 both provided the target product with inferior yield
(entries 3ꢀ6, Table 1). Further screening on copper catalysts such as CuBr, CuBr2,
Cu(OAc)2, CuCl2 and CuO showed that all these copper species were not practical for
the expected reaction (entries 7ꢀ11, Table 1). The parallel experiments using different
base additives, including DBU, Et3N, NaHCO3 and NaOAc proved that they were all
not proper additives since either lower yield or no expected product formation was
observed (entries 12ꢀ15, Table 1). The subsequent work in running the reaction in
different media suggested that no expected reaction took place in polar solvents such
DMSO or DMF, and lower yield was obtained in the entry using toluene, possibly
because of the quick evaporation of the solvent at the reflux temperature (entries
16ꢀ18, Table 1). Finally, heightening or lowering the reaction temperature both
resulted in 3a with lower yield (entries 19ꢀ20, Table 1).
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Table 1 Optimization on the conditions for the C5ꢀH sulfenylation of
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8ꢀaminoquinolinea
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entry catalyst
solvent
base
ꢀ
temp (oC) yield (%)b
1
CuI
pꢀxylene
120
13
67
38
35
33
8
2
CuI
pꢀxylene Na2CO3 120
pꢀxylene Na2CO3 120
pꢀxylene Na2CO3 120
pꢀxylene Na2CO3 120
pꢀxylene Na2CO3 120
pꢀxylene Na2CO3 120
pꢀxylene Na2CO3 120
3c
4d
5e
6f
CuI
CuI
CuI
CuI
7
CuBr
CuBr2
trace
trace
nr
8
9
Cu(OAc)2 pꢀxylene Na2CO3 120
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CuCl2
CuO
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
pꢀxylene Na2CO3 120
pꢀxylene Na2CO3 120
trace
nr
pꢀxylene DBU
pꢀxylene Et3N
120
120
20
32
nr
pꢀxylene NaHCO3 120
pꢀxylene NaOAc 120
nr
DMF
Na2CO3 120
Na2CO3 120
Na2CO3 reflux
nr
DMSO
toluene
nr
18
23
37
pꢀxylene Na2CO3 110
pꢀxylene Na2CO3 130
aReaction condition: 1a (0.2 mmol) , 2a (0.4 mmol) , copper catalyst (0.03 mmol),
o
base (0.6 mmol) in solvent ( 2.0 mL), stirred at 120 C for 12 h under air atmosphere;
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b
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nr = no expected reaction. Yield of isolated product based on 1a. CuI (0.02 mmol).
dCuI (0.04 mmol). eNa2CO3 (0.4 mmol). fNa2CO3 (0.8 mmol).
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In order to explore the synthetic scope of this CꢀH sulfenylation reaction, a
class of different aryl functionalized sulfonyl hydrazides 2 were employed to react
with unprotected 8ꢀaminoquinolines 1. As shown in Table 2, the results indicated that
this sulfenylation protocol tolerated well to aryl sulfonyl hydrazides containing
diverse functional groups, including those ones with different electron effects and
locations. In the reaction using paraꢀsubstituted phenyl sulfonyl hydrazides, the
substrates containing electron withdrawing group usually afforded products with
lower yields than equivalent reactions employing sulfonyl hydrazides containing
electron donating substitutent (3aꢀ3h, Table 1). On the other hand, phenyl sulfonyl
hydrazides possessing orthoꢀsbustitution provided the products with lower yields than
those paraꢀsubstituted substrates (3a, 3e vs 3i, 3j, Table 2), indicating the presence of
negative steric hindrance. As for the reactions employing fused aryl functionalized
substrates, similar negative effect of the electron withdrawing group was also found
(3k vs 3l, Table 2). In addition, when the 3ꢀmethyl 8ꢀaminoquinline was used to react
with various aryl sulfonyl hydrazides, related products were also acquired with
moderate to good yields (3mꢀ3q, Table 2). Notably, the Nꢀalkylated
8ꢀaminoquinolines could also take part in this C5ꢀsulfenylation reaction, but the
products were afforded with much lower yield (3r, 3s, Table 2), suggesting that the
free NH2 group in the quinoline substrate was positive for this sulfenylation process.
However, no such CꢀS bond forming reaction was observed when methyl sulfonyl
hydrazide was employed to react with 1a under the standard condition. On the basis
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of 8ꢀaminoquinoline’s reaction, an entry employing aniline and tosyl hydrazide was
also conducted, but no expected sulfonylation reaction occured. Notably, no other
regioisomeric product was oberved in the above reactions, indicating the ideal
regioselectibity of this CꢀH sulfenylation protocol.
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Table 2 Scope on the 8ꢀfree amino and Nꢀalkyl 8ꢀaminoquinoline C5 sulfenylationa,b
aReaction condition: 1 (0.2 mmol), 2 (0.4 mmol), CuI (0.03 mmol), Na2CO3 (0.6
o
mmol) in pꢀxylene ( 2.0 mL), stirred at 120 C for 12 h under air atmosphere.
bIsolated yield based on 1.
Since no protection was required in the synthesis of sulfenylated products 3, the
presence of the free NH2 group in products provided a good platform for the synthesis
of different Nꢀsubstituted derivatives. For example, the Nꢀacyl 5ꢀsulfenyl
8ꢀaminoquinolines 5 can be easily accessed via the Et3N promoted acylation by using
products 3 and acyl chloride 4 (Scheme 2).
Scheme 2 Synthesis of Nꢀacyl C5ꢀsulfenyl 8ꢀaminoquinolines
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In order to gain information on reaction mechanism, related control
experiments were carried out. We first examined the reaction of Nꢀacylated
8ꢀaminoquinoline 6 with tosyl hydrazide 2a under the standard conditions, but the
expected C5ꢀsulfenylation on 6 didn’t occur, implying that the free NH2 group was
crucial for the titled reaction (Eq 1). In addition, the model reaction carried out in the
presence of TEMPO and BHT showed that the formation of the target product was
evidently inhibited, supporting that free radical reaction pathway was involved (Eqs 2
and 3, Scheme 3). Subsequently, the reaction employing 8ꢀaminoquinoline 1a with
stoichiometrical CuI was peformed. But no reaction took place, suggesting against the
presence of an iodinated intermediate (Eq 4, Scheme 3). On the other hand, subjecting
solely tosyl hydrazide 2a to the standard conditions provided mixed
benzenesulfonothioate 6a and disulfide 7a (Eq 5, Scheme 3), suggesting that
compounds of type 6 and 7 were possible intermediates. Based on the results from the
above experiment, the benzenesulfonothioate 6a and disulfide 7a were than subjected
to react with 8ꢀaminoquinoline, respectively. As expected, both reactions provided
product 3a (Eq 6 and 7, Scheme 3).
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Scheme 3 Control experiments
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On the basis of the reaction outcome from the synthetic reactions and control
experiments, a possible mechanism is proposed for the reaction (Scheme 4). First, the
sulfonyl hydrazide undergoes
a
featured reductive coupling to provide
benzenesulfonothioate 6.16c,d Meanwhile, the aerobic heating enables the oxidation of
Cu(I) to Cu(II) which can incorporate 8ꢀaminoquinolines 1 to provide Cu(II)ꢀcomplex
A with the assistance of a base like in those well documented Cu(II)ꢀcatalyzed C5ꢀH
functionalization of 8ꢀamidoquinolines.6ꢀ14 The presence of Cu(II) species then
initiates SET on A to provide free radical intermediate B, and the Cu(I) is
simultaneously regenerated. On the other hand, intermediate 6 gets further reduced to
yield disulfide 7 in the presence of sulfonyl hydrazide. 16d,e The arylthio free radical 8
resulting from the homoꢀcleavage of disulfide then quickly reacts with B to yield
another Cu(II)ꢀcomplex C. Subsequently, C is further transformed into D via
intramolecular proton transfer. Finally, the products 3 are provided from D, and the
Cu(II) is released for further catalytic cycle.
Scheme 4 The proposed reaction mechanism
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In summary, by employing CuI/base catalytic system, we accomplished the first
C5ꢀH sulfenylation reaction of unprotected 8ꢀaminoquinolines wherein sulfonyl
hydrazides are employed as the sulfenylating reagents. The direct reaction of the free
NH2 functionalized quinolines shows incomparable advantages by affoding products
containing the free NH2 group without requiring any additional operation of
protection or deprotection. This present work offers a uniquely step economical
platform to access 8ꢀaminoquinoline derivatives with divergent Nꢀsubstitution.
Experimental Section
General experimental information
All of the reactions were performed under air atmosphere. Besides tosyl hydrazide,
other sulfonyl hydrazides18 as well as the substituted 8ꢀaminoquinolines3e, 19 used in
the experiments were synthesized following literature process. All other chemical
reagents and solvents were obtained from commercial sources and used directly
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without further treatment. The 1H and 13C NMR were recorded in 400 MHz apparatus
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in CDCl3 or DMSOꢀd6, and the frequencies for H NMR and C NMR test are 400
MHz and 100 MHz, respectively. The chemical shifts are reported in ppm with TMS
as internal standard. Melting points were tested in an Xꢀ4A instrument without
correcting temperature. The HRMS were obtained under ESI model in a MS
spectrometer equipped with TOF analyzer.
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General Procedure for the C5 sulfenylation of 8-aminoquinolines
In a 25 mL round bottom flask equipped with a condenser were charged with
8ꢀaminoquinoline 1 (0.2 mmol), sulfonyl hydrazide 2 (0.4 mmol), Na2CO3 (0.6 mmol)
o
and pꢀxylene (2 mL). The resulting mixture was stirred at 120 C for 12 h. Upon
completion (TLC), the reaction was allowed to cool down to room temperature, and 5
mL water was added into the vessel. The heterogeneous mixture was extracted with
ethyl acetate (3 ×10 mL). The combined organic phase was dried over Na2SO4. After
filtration, the acquired solution was collected and the solvent was removed at reduced
pressure. The acquired residue was subjected to silica gel column chromatography to
give pure products by using mixed petroleum ether and dichloromethane (VPET
:
VDCM = 1:1) as eluent.
5-(p-Tolylthio)quinolin-8-amine (3a). Black liquid; 35.6 mg, 67% yield; 1H NMR
(400 MHz, CDCl3): δ 8.75 (dd, J = 4.0, 1.6 Hz, 1 H), 8.60 (dd, J = 8.4, 1.6 Hz, 1 H),
7.72 (d, J = 7.8 Hz, 1 H), 7.39 (dd, J = 8.4, 4.0 Hz, 1 H), 6.98ꢀ6.88 (m, 5 H), 5.32 (s, 2
H), 2.23 (s, 3 H); 13C NMR (100 MHz, CDCl3): δ 147.4, 145.9, 138.9, 137.3, 135.8,
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134.9, 134.8, 130.6, 129.6, 126.6, 122.3, 115.1, 109.5, 20.8; ESIꢀHRMS Calcd for
C16H15N2S [M+H]+ 267.0950, found 267.0956.
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5-(Phenylthio)quinolin-8-amine (3b).12a Black liquid; 30.0 mg, 60% yield; H NMR
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(400 MHz, CDCl3): δ 8.76 (dd, J = 4.0, 1.4 Hz, 1 H), 8.59 (dd, J = 8.4, 1.4 Hz, 1 H),
7.73 (d, J = 7.8 Hz, 1 H), 7.39 (dd, J = 8.4, 4.2 Hz, 1 H), 7.13 (t, J = 7.6 Hz, 2 H),
7.03 (t, J = 7.2 Hz, 1 H), 6.98 (d, J = 7.4 Hz, 2 H), 6.91 (d, J = 7.8 Hz, 1 H), 5.27 (s, 2
H); 13C NMR (100 MHz, CDCl3): δ 147.5, 146.1, 139.6, 138.9, 137.7, 134.8, 130.7,
128.8, 126.1, 124.9, 122.4, 114.2, 109.5.
5-((4-Methoxyphenyl)thio)quinolin-8-amine (3c). Black liquid; 33.0 mg, 58% yield;
1H NMR (400 MHz, CDCl3): δ 8.75 (dd, J = 4.2, 1.6 Hz, 1 H), 8.05 (dd, J = 8.2, 1.6
Hz, 1 H), 7.47 (d, J = 8.0 Hz, 1 H), 7.39 (dd, J = 8.2, 4.2 Hz, 1 H), 7.18 (d, J = 8.8 Hz,
2 H), 7.06 (d, J = 8.6 Hz, 1 H), 6.79 (d, J = 8.0 Hz, 2 H), 5.72 (s, 2 H), 3.75 (s, 3 H);
13C NMR (100 MHz, CDCl3): δ 158.5, 147.5, 146.2, 136.1, 133.5, 132.7, 130.0, 128.9,
126.7, 121.9, 115.1, 114.8, 55.4; ESIꢀHRMS Calcd for C16H15N2OS [M+H]+
283.0900, found 283.0904.
5-((4-Fluorophenyl)thio)quinolin-8-amine (3d). Black liquid; 27.5 mg, 51% yield;
1H NMR (400 MHz, CDCl3): δ 8.76 (dd, J = 4.0, 1.4 Hz, 1 H), 8.57 (dd, J = 8.4, 1.4
Hz, 1 H), 7.71 (d, J = 7.8 Hz, 1 H), 7.41 (dd, J = 8.4, 4.2 Hz, 1 H), 7.00ꢀ6.96 (m, 2 H),
6.92ꢀ6.83 (m, 3 H), 5.33 (s, 2 H); 13C NMR (100 MHz, CDCl3): δ 160.9 (d, 1JCꢀF = 243
Hz), 147.5, 146.1, 138.8, 137.4, 134.6, 134.4, 130.5, 128.2 (d, 3JCꢀF = 7 Hz), 122.4,
2
115.9 (d, JCꢀF = 22 Hz), 114.7, 109.4; ESIꢀHRMS Calcd for C15H12FN2S [M+H]+
271.0700, found 271.0698.
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5-((4-Chlorophenyl)thio)quinolin-8-amine (3e). Brown soild; 34.5 mg, 60% yield;
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mp 123ꢀ124 C; 1H NMR (400 MHz, CDCl3): δ 8.76 (dd, J = 4.0, 1.4 Hz, 1 H), 8.51
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(dd, J = 8.4, 1.4 Hz, 1 H), 7.71 (d, J = 7.8 Hz, 1 H), 7.39 (dd, J = 8.4, 4.0 Hz, 1 H),
7.09 (d, J = 8.4 Hz, 2 H), 6.91ꢀ6.87 (m, 3 H), 5.32 (s, 2 H); 13C NMR (100 MHz,
CDCl3): δ 147.6, 146.4, 139.0, 138.2, 137.8, 134.5, 130.7, 130.5, 128.9, 127.3, 122.6,
113.5, 109.4; ESIꢀHRMS Calcd for C15H12ClN2S [M+H]+ 287.0404, found 287.0410.
5-((4-Bromophenyl)thio)quinolin-8-amine (3f). Brown soild; 34.0 mg, 52% yield;
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mp 129ꢀ130 oC; H NMR (400 MHz, CDCl3): δ 8.76 (dd, J = 4.0, 1.4 Hz, 1 H), 8.52
(dd, J = 8.4, 1.4 Hz, 1 H), 7.71 (d, J = 7.8 Hz, 1 H), 7.40 (dd, J = 8.4, 4.0 Hz, 1 H),
7.23 (d, J = 8.6 Hz, 2 H), 6.91 (d, J = 7.8 Hz, 1 H), 6.82 (d, J = 8.6 Hz, 2 H), 5.35 (s,
2 H); 13C NMR (100 MHz, CDCl3): δ 147.6, 146.4, 138.9, 137.8, 134.5, 131.8, 130.5,
127.5, 122.6, 118.5, 113.3, 109.4; ESIꢀHRMS Calcd for C15H12BrN2S [M+H]+
330.9899, found 330.9893.
5-((4-Nitrophenyl)thio)quinolin-8-amine (3g). Red solid; 33.0 mg, 55% yield; mp
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87ꢀ88 C; H NMR (400 MHz, CDCl3): δ 8.81ꢀ8.78 (m, 1 H), 8.44 (d, J = 8.0 Hz, 1
H), 7.97 (d, J = 8.0 Hz, 2 H), 7.73 (d, J = 7.8 Hz, 1 H), 7.42 (dd, J = 8.0, 4.0 Hz, 1 H),
7.01ꢀ6.93 (m, 3H), 5.44 (s, 2 H); 13C NMR (100 MHz, CDCl3): δ 150.0, 147.8, 147.1,
145.0, 138.8, 138.3, 134.0, 130.5, 125.2, 124.0, 122.9, 110.8, 109.4; ESIꢀHRMS
Calcd for C15H12N3O2S [M+H]+ 298.0645, found 298.0650.
4-((8-Aminoquinolin-5-yl)thio)benzonitrile (3h). Red solid; 27.0 mg, 49% yield;
o
mp 181ꢀ182 C; 1H NMR (400 MHz, CDCl3): δ 8.79 (dd, J = 4.2, 1.6 Hz, 1 H), 8.46
(dd, J = 8.6, 1.6 Hz, 1 H), 7.73 (d, J = 7.8 Hz, 1 H), 7.43 (dd, J = 8.6, 4.2 Hz, 1 H),
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7.39ꢀ7.36 (m, 2 H), 6.95 (t, J = 7.8 Hz, 3 H), 5.46 (s, 3 H); 13C NMR (100 MHz,
DMSOꢀd6): δ 149.1, 147.9, 147.6, 139.1, 138.5, 133.7, 133.1, 130.5, 125.8, 123.6,
119.3, 108.9, 107.4, 107.3; ESIꢀHRMS Calcd for C16H12N3S [M+H]+ 278.0746, found
278.0748.
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5-(o-Tolylthio)quinolin-8-amine (3i). Black solid; 28.0 mg, 53% yield; mp 85ꢀ86 oC;
1H NMR (400 MHz, CDCl3): δ 8.76 (dd, J = 4.0, 1.2 Hz, 1 H), 8.52 (dd, J = 8.6, 1.0
Hz, 1 H), 7.68 (d, J = 7.8 Hz, 1 H), 7.38 (dd, J = 8.4, 4.2 Hz, 1 H), 7.14 (d, J = 7.2 Hz,
1 H), 6.98ꢀ6.92 (m, 2 H), 6.85 (t, J = 7.6 Hz, 1 H), 6.44 (d, J = 7.8 Hz, 1 H), 5.16 (s, 2
H), 2.48 (s, 3 H); 13C NMR (100 MHz, CDCl3): δ 147.5, 145.9, 138.9, 138.5, 137.5,
134.8, 130.7, 129.9, 126.3, 125.7, 124.7, 122.4, 109.7, 20.0; ESIꢀHRMS Calcd for
C16H15N2S [M+H]+ 267.0950, found 267.0952.
5-((2-Chlorophenyl)thio)quinolin-8-amine (3j). Black solid; 31.5 mg, 55% yield;
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mp 127ꢀ128 C; H NMR (400 MHz, CDCl3): δ 8.77 (d, 1 H), 8.51 (dd, J = 8.4, 1.4
Hz, 1 H), 7.74 (d, J = 7.8 Hz, 1 H), 7.40 (dd, J = 8.4, 4.0 Hz, 1 H), 7.33 (dd, J = 7.8,
1.0 Hz, 1 H), 6.99ꢀ6.93 (m, 2 H), 6.89ꢀ6.84 (m, 1 H), 6.35 (dd, J = 8.0, 1.4 Hz, 1 H),
5.35 (s, 2 H); 13C NMR (100 MHz, CDCl3): δ 147.6, 146.6, 138.9, 138.3, 134.6, 130.8,
130.2, 129.4, 127.0, 126.5, 125.5, 122.7, 112.3, 109.6; ESIꢀHRMS Calcd for
C15H12ClN2S [M+H]+ 287.0404, found 287.0408.
5-(Naphthalen-2-ylthio)quinolin-8-amine (3k). Black liquid; 39.0 mg, 64% yield;
1H NMR (400 MHz, CDCl3): δ 8.75 (dd, J = 4.0, 1.4 Hz, 1 H), 8.60 (dd, J = 8.4, 1.4
Hz, 1 H), 7.78 (d, J = 7.8 Hz, 1 H), 7.71 ꢀ7.68 (m, 1 H), 7.62 (d, J = 8.6 Hz, 1 H),
7.53ꢀ7.50 (m, 1 H), 7.36ꢀ7.31 (m, 4 H), 7.17 (dd, J = 8.6, 1.8 Hz, 1 H), 6.93 (d, J =
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7.8 Hz, 1 H), 5.32 (s, 2 H); 13C NMR (100 MHz, CDCl3): δ 147.5, 146.2, 139.0, 137.7,
137.1, 134.8, 133.8, 131.4, 130.7, 128.4, 127.7, 126.9, 126.5, 125.2, 124.9, 123.8,
122.5, 114.1, 109.6; ESIꢀHRMS Calcd for C19H15N2S [M+H]+ 303.0950, found
303.0954.
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5-(Quinolin-8-ylthio)quinolin-8-amine (3l). Black solid; 29.0 mg, 48% yield; mp
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139ꢀ140 C; 1H NMR (400 MHz, CDCl3): δ 9.02 (d, J = 2.8 Hz, 1 H), 8.80 (s, 1 H),
8.18ꢀ8.12 (m, 2 H), 7.63 (d, J = 8.4 Hz, 1 H), 7.55 (d, J = 8.0 Hz, 1 H), 7.50ꢀ7.45 (m,
2 H), 7.28 (t, J = 7.8 Hz, 1 H), 7.17 (d, J = 8.4 Hz, 1 H), 6.93 (d, J = 7.4 Hz, 1 H),
5.85 (s, 2 H); 13C NMR (100 MHz, CDCl3): δ 149.3, 148.3, 147.6, 145.2, 137.1, 136.4,
136.2, 135.1, 129.7, 128.6, 126.8, 124.8, 124.3, 124.2, 122.3, 121.7, 115.3, 107.2;
ESIꢀHRMS Calcd for C18H14N3S [M+H]+ 304.0903, found 304.0906.
6-Methyl-5-(phenylthio)quinolin-8-amine (3m). Black liquid; 34.5 mg, 65% yield;
1H NMR (400 MHz, CDCl3): δ 8.80ꢀ8.61 (m, 2 H), 7.35 (dd, J = 8.4, 4.2 Hz, 1 H),
7.11 (t, J = 7.6 Hz, 2 H), 7.01 (t, J = 7.2 Hz, 1 H), 6.89 (t, 3 H), 5.19 (s, 2 H), 2.56 (s,
3 H); 13C NMR (100 MHz, CDCl3): δ 146.6, 145.5, 145.3, 139.2, 138.0, 134.6, 131.6,
128.8, 125.4, 124.5, 122.5, 112.4, 112.3, 22.1; ESIꢀHRMS Calcd for C16H15N2S
[M+H]+ 267.0950, found 267.0948.
6-Methyl-5-(p-tolylthio)quinolin-8-amine (3n). Black liquid; 36.0 mg, 64% yield;
1H NMR (400 MHz, CDCl3): δ 8.75ꢀ8.67 (m, 2 H), 7.37 (dd, J = 8.4, 4.0 Hz, 1 H),
6.94 (d, J = 8.0 Hz, 3 H), 6.79 (d, J = 8.0 Hz, 2 H), 5.19 (s, 2 H), 2.57 (s, 3 H), 2.23 (s,
3 H); 13C NMR (100 MHz, CDCl3) : δ 146.5, 145.3, 145.2, 137.9, 135.6, 134.8, 134.3,
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131.6, 129.6, 125.5, 122.4, 113.0, 112.4, 22.1, 20.8; ESIꢀHRMS Calcd for C17H17N2S
[M+H]+ 281.1107, found 281.1110.
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5-((4-Methoxyphenyl)thio)-6-methylquinolin-8-amine (3o). Black solid; 33.0 mg,
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57% yield; mp 83ꢀ84 C; 1H NMR (400 MHz, CDCl3): δ 8.76 (dd, J = 8.6, 1.4 Hz, 1
H), 8.69 (dd, J = 4.0, 1.4 Hz, 1 H), 7.38 (dd, J = 8.6, 4.0 Hz, 1 H), 6.92ꢀ6.84 (m, 3 H),
6.73ꢀ6.67 (m, 2 H), 5.17 (s, 2 H), 3.71 (s, 3 H), 2.58 (s, 3 H); 13C NMR (100 MHz,
CDCl3): δ 157.4, 146.5, 145.2, 144.9, 138.0, 134.8, 131.5, 129.8, 127.4, 122.4, 114.6,
112.4, 55.3, 22.2; ESIꢀHRMS Calcd for C17H17N2OS [M+H]+ 297.1056, found
297.1058.
6-Methyl-5-((4-nitrophenyl)thio)quinolin-8-amine (3p). Light yellow solid; 32.0
mg, 51% yield; mp 208ꢀ209 oC; H NMR (400 MHz, DMSOꢀd6): δ 8.74 (dd, J = 4.0,
1
1.6 Hz, 1 H), 8.45 (dd, J = 8.6, 1.6 Hz, 1 H), 8.04 (d, J = 8.0 Hz, 2 H), 7.53 (dd, J =
8.6, 4.0 Hz, 1 H), 7.06 (d, J = 8.0 Hz, 2 H), 6.99 (s, 1 H), 6.58 (s, 2 H), 2.48 (s, 3 H);
13C NMR (100 MHz, DMSOꢀd6): δ 149.8, 148.4, 146.9, 145.9, 144.9, 137.6, 133.4,
131.2, 125.4, 124.8, 123.6, 111.3, 106.0, 22.1; ESIꢀHRMS Calcd for C16H14N3O2S
[M+H]+ 312.0801, found 312.0804.
6-Methyl-5-(naphthalen-2-ylthio)quinolin-8-amine (3q). Red solid; 40.0 mg, 63%
yield; mp 170ꢀ171 oC; 1H NMR (400 MHz, CDCl3): δ 8.75ꢀ8.68 (m, 2 H), 7.69 (d, J =
7.2 Hz, 1 H), 7.62 (d, J = 8.6 Hz, 1 H), 7.48 (d, J = 7.2 Hz, 1 H), 7.36ꢀ7.30 (m, 3 H),
7.18ꢀ7.09 (m, 3 H), 6.94 (s, 1 H), 5.23 (s, 2 H), 2.59 (s, 3 H); 13C NMR (100 MHz,
CDCl3): δ 146.6, 145.6, 145.5, 138.0, 136.8, 134.7, 133.9, 131.6, 131.2, 128.4, 127.7,
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126.8, 126.4, 125.0, 124.4, 122.7, 122.6, 112.5, 112.2, 22.2; ESIꢀHRMS Calcd for
C20H17N2S [M+H]+ 317.1107, found 317.1108.
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N-Methyl-5-(p-tolylthio)quinolin-8-amine (3r). Light yellow solid; 12.0 mg, 21%
yield; mp 121ꢀ122 oC; 1H NMR (400 MHz, CDCl3): δ 8.69 (dd, J = 4.2, 1.6 Hz, 1 H),
8.58 (dd, J = 8.4, 1.6 Hz, 1 H), 7.79 (d, J = 8.0 Hz, 1 H), 7.37 (dd, J = 8.4, 4.2 Hz, 1
H), 6.98ꢀ6.84 (m, 4 H), 6.62 (d, J = 8.0 Hz, 1 H), 6.47 (s, 1 H), 3.07 (s, 3 H), 2.23 (s,
3 H); 13C NMR (100 MHz, CDCl3): δ 147.5, 146.8, 138.9, 138.1, 136.2, 134.8, 134.6,
130.3, 129.6, 126.3, 122.4, 112.1, 103.8, 29.8, 20.8; ESIꢀHRMS Calcd for C17H17N2S
[M+H]+ 281.1107, found 281.1106.
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N-Ethyl-5-(p-tolylthio)quinolin-8-amine (3s). Light yellow solid; 14.5 mg, 25%
o
yield; mp 91ꢀ92 C; 1H NMR (400 MHz, CDCl3): δ 8.70 (dd, J = 4.2, 1.6 Hz, 1 H),
8.58 (d, J = 8.4 Hz, 1 H), 7.77 (d, J = 8.0 Hz, 1 H), 7.38 (dd, J = 8.4, 4.2 Hz, 1 H),
6.98ꢀ6.87 (m, 4 H), 6.65 (d, J = 8.0 Hz, 1 H), 6.41 (s, 1 H), 3.39 (q, J = 7.2 Hz, 2 H),
2.23 (s, 3 H), 1.43 (t, J = 7.2 Hz, 3 H); 13C NMR (100 MHz, CDCl3): δ 146.7, 146.4,
138.1, 136.2, 134.7, 130.4, 129.6, 126.2, 122.3, 112.0, 104.2, 37.7, 20.8, 14.5;
ESIꢀHRMS Calcd for C18H19N2S [M+H]+ 295.1263, found 295.1262.
General Procedure for the N-acylation of 5-sulfenylated 8-aminoquinolines 3
Acyl chloride 4 (1.5 mmol) was added dropwise to a solution of compound 3 ( 1.0
o
mmol) and Et3N (1.2 mmol) in CH2Cl2 (2 mL) at 0 C. The mixture was stirred
overnight at room temperature. Then the mixture was diluted with CH2Cl2 (10 mL),
and the resulting mixture was washed successively with water, saturated NaHCO3
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solution, and brine. The organic layer was dried over Na2SO4, and the solvent was
then removed under reduced pressure. The resulting residue was purified by silica gel
column chromatography eluted with mixted petroleum ether and dichloromethane
(VPET: VDCM = 1:1) to afford products 5.
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N-(5-(p-Tolylthio)quinolin-8-yl)benzamide (5a). White solid; 68.0 mg, 92% yield;
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mp 170ꢀ171 C; 1H NMR (400 MHz, CDCl3): δ 10.83 (s, 1 H), 8.91 (dd, J = 8.2, 1.0
Hz, 1 H), 8.88ꢀ8.82 (m, 2 H), 8.71 (d, J = 8.4 Hz, 1 H), 8.09 (d, J = 7.6 Hz, 2 H), 7.85
(dd, J = 8.0, 0.8 Hz, 1 H), 7.63ꢀ7.51 (m, 6 H), 7.54ꢀ7.45 (m, 2 H), 7.06ꢀ7.01 (m, 4 H),
2.27 (s, 3 H); 13C NMR (100 MHz, CDCl3): δ 165.5, 148.4, 139.5, 136.2, 135.6, 135.0,
135.0, 134.9, 133.6, 132,0, 129.9, 129.1, 128.9, 128.5, 127.3, 124.4, 122.3, 116.4,
20.9; ESIꢀHRMS Calcd for C23H19N2OS [M+H]+ 371.1213, found 371.1218.
N-(6-Methyl-5-(phenylthio)quinolin-8-yl)benzamide (5b). White solid; 66.0 mg, 89%
o
yield; mp 187ꢀ188 C; 1H NMR (400 MHz, CDCl3): δ 10.84 (s, 1 H), 8.99 (s, 1 H),
8.84ꢀ8.77 (m, 2 H), 8.11ꢀ8.07 (m, 2 H), 7.61ꢀ7.53 (m, 3 H), 7.46 (dd, J = 8.4, 4.2 Hz,
1 H), 7.14 (t, J = 7.4 Hz, 2 H), 7.04 (t, J = 7.4 Hz, 1 H), 6.94ꢀ6.89 (m, 2 H), 2.72 (s, 3
H); 13C NMR (100 MHz, CDCl3): δ 165.6, 147.5, 145.4, 138.5, 138.0, 135.8, 135.2,
134.9, 132.1, 130.7, 129.0, 128.9, 127.4, 125.9, 125.0, 122.7, 120.1, 119.2, 22.6;
ESIꢀHRMS Calcd for C23H19N2OS [M+H]+ 371.1213, found 371.1219.
N-(6-Methyl-5-((4-nitrophenyl)thio)quinolin-8-yl)acetamide (5c). Yellow solid;
o
63.5 mg, 90% yield; mp 193ꢀ194 C; 1H NMR (400 MHz, CDCl3): δ 9.93 (s, 1 H),
8.86 (s, 1 H), 8.79 (d, J = 4.0 Hz, 1 H), 8.66 (d, J = 8.0 Hz, 1 H), 7.99 (d, J = 8.0 Hz,
2 H), 7.49 (dd, J = 8.0, 4.0 Hz, 1 H), 6.95 (d, J = 8.0 Hz, 2 H), 2.67 (s, 3 H), 2.40 (s, 3
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H); 13C NMR (100 MHz, CDCl3): δ 169.1, 147.9, 147.7, 146.1, 145.2, 138.0, 136.6,
134.4, 130.2, 125.2, 124.2, 123.0, 119.0, 117.0, 25.2, 22.4; ESIꢀHRMS Calcd for
C18H16N3O3S [M+H]+ 354.0907, found 354.0912.
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Supporting Information
13
1H and C NMR spectra for all products 3 and 5. This material is available free of
charge via the Internet at http://pubs.acs.org.
Acknowledgements
This work is financially supported by the National Natural Science Foundation of
China (21562024).
References
1 (a) Daugulis, O.; Roane, J.; Tran, L. D. Bidentate, monoanionic auxiliaryꢀdirected
functionalization of carbonꢀhydrogen bonds. Acc. Chem. Res. 2015, 48, 1053ꢀ1064. (b)
Corbet, M.; De Campo, F. 8ꢀAminoquinoline: a powerful directing group in
metalꢀcatalyzed direct functionalization of CꢀH bonds. Angew. Chem. Int. Ed. 2013,
52, 9896ꢀ9898. (c) Rouquet, G.; Chatani, N. Catalytic functionalization of C(sp2)ꢀH
and C(sp3)ꢀH bonds by using bidentate directing groups. Angew. Chem. Int. Ed. 2013,
52, 11726ꢀ11743. (d) Wan, J.ꢀP.; Li, Y.; Liu, Y. Annulation based on 8ꢀaminoquinoline
assisted C–H activation: an emerging tool in Nꢀheterocycle construction. Org. Chem.
Front. 2016, 3, 768ꢀ772. (e) Castro, L. C. M.; Chatani, N. Nickel
catalysts/N,N′ꢀbidentate directing groups: An excellent partnership in directed CꢀH
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activation reactions. Chem. Lett. 2015, 44, 410ꢀ421. (f) Chen, Z.; Wang, B.; Zhang, J.;
Yu, W.; Liu, Z.; Zhang, Y. Transition metalꢀcatalyzed CꢀH bond functionalizations by
the use of diverse directing groups. Org. Chem. Front. 2015, 2, 1107ꢀ1295.
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