Copper-Promoted Thiolation of C(sp2)–H Bonds Using a 2-Amino Alkylbenzimidazole Directing Group

Article abstract of DOI:10.1002/ejoc.201700147

A copper-promoted thiolation of C(sp²)–H bonds with disulfides was achieved by using 2-amino alkylbenzimidazole (MBIP amine) as a new and removable N,N-bidentate directing group. This strategy gives a variety of functionalized thioethers in moderate to excellent yields in a simple and efficient way. Importantly, the substrate scope is not limited to aromatic amides; diverse alkenyl amides are also compatible. Furthermore, this synthetic approach provides a potentially feasible way to achieve structural modification of related benzimidazole-containing compounds through direct C–H activation.

Full text of DOI:10.1002/ejoc.201700147

A Journal of
Accepted Article
Title: Copper-Promoted Thiolation of C(sp2)-H Bonds Using an 2-
Amino Alkylbenzimidazole Directing Group
Authors: Mao-Ping Song, Shuang-Liang Liu, Xue-Hong Li, Tan-Hao
Shi, Guang-Chao Yang, Hai-Li Wang, and Jun-Fang Gong
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201700147
Link to VoR: http://dx.doi.org/10.1002/ejoc.201700147
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10.1002/ejoc.201700147
European Journal of Organic Chemistry
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Copper-Promoted Thiolation of C(sp2)-H Bonds Using an 2-Amino
Alkylbenzimidazole Directing Group
Shuang-Liang Liu,[a] Xue-Hong Li,[a] Tan-Hao Shi,[a] Guang-Chao Yang,[a] Hai-Li Wang,[a] Jun-Fang
Gong,*[a] and Mao-Ping Song*[a]
Abstract: A copper-promoted thiolation of C(sp2)-H bonds with
disulfides has been achieved by using 2-amino alkylbenzimidazole
(MBIP-amine) as a novel and removable N,N-bidentate directing
group. This strategy affords a variety of functionalized thioethers in
accomplished.[9]
Copper, known as abundant first-row transition metal, has
also been proved to be highly efficient catalyst for diverse C−H
bond functionalization.[10] As early as 2006, Yu reported the
pioneering work of Cu-mediated direct thiolation of aryl C-H
bonds employing pyridine as a directing group.[11] Afterwards,
Qing realized the same auxiliary assisted Cu-mediated
methylthiolation using DMSO as the sulfur source.[12] Later in
2012, Daugulis reported the seminal work of Cu-promoted direct
C(sp2)-S bond formation assisted by the removable 8-
aminoquinoline directing group. In addition, they demonstrated
that the picolinic acid directing group was also effective but at
least stoichiometric amount of Cu(II) was required (Scheme
1a).[13] Following this, Liu and coworkers developed the
supplementary work by replacing disulfides with thiols as
coupling partners.[14] To the best of our knowledge, there is no
precedent of auxiliary-assisted, copper-catalyzed/mediated
direct thiolation of alkene C-H bonds so far.
moderate to excellent yields in
a simple and efficient way.
Importantly, the substrate scope is not limited to aromatic amides,
diverse alkenyl amides are also well accomplished. Furthermore, the
synthetic approach provides a potential feasible way for the structure
modification of the related benzimidazole-containing compounds via
direct C-H activation.
Introduction
Thioethers are ubiquitous motifs in various biological and
medicinal molecules.[1] For example, they are frequently found in
drugs which show therapeutic efficacy for diabetes, AIDS,
arthritis, and depression.[2] In addition, thioethers have extensive
application in functional materials and synthetic chemistry.[3]
Traditionally, preparation of thioethers mainly depended on the
cross coupling of organic halides with thiols/disulfides or addition
of thiols/disulfides across unsaturated C−C bonds.[4] However,
these methods are often confronted with problems such as
prefunctionalization, narrow substrate scope, special reaction
conditions and the potential of catalyst poisoning. Therefore, the
development of more efficient synthetic routes would be of prime
value.
In the past decades, transition metal-catalyzed, directing
group-accelerated direct C-H activation has emerged as an
efficient and atom-economic tool for the formation of C-C and C-
X bonds.[5] However, due to the strong coordination ability of
sulfur atom to the metals, which may lead to the deactivation of
the catalysts, synthesis of thioethers employing this strategy was
relatively rare. In 2014, this type of C-H activation/C-S bond
formation was achieved under expensive palladium[6] and
rhodium[7] catalysis. Almost simultaneously, nickel-catalyzed
direct sulfenylation of non-acidic C-H bonds has been intensively
studied which showed broad substrate scope and excellent
yields, but complicated reaction conditions were always
required.[8] Very recently, the first cobalt-catalyzed thiolation of
indole in the 2-position assisted by pyrimidine was successfully
Scheme 1. Copper promoted C(sp2)-H thiolation using bidentate directing
groups.
[a]
College of Chemistry and Molecular Engineering, Henan Key
laboratory of Chemical Biology and Organic Chemistry, Zhengzhou
University, Zhengzhou 450001, P. R. China
E-mail: mpsong@zzu.edu.cn.
gongjf@zzu.edu.cn.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/ejoc.
Figure 1. A drug containing 2-amino alkylbenzimidazole skeleton.
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10.1002/ejoc.201700147
European Journal of Organic Chemistry
FULL PAPER
Benzimidazole skeleton exists in
many important
Results and Discussion
pharmaceutical molecules, such as the famous drugs Deleobuvir
(Figure 1),[15] Nexium, Micardis and so on. However, its
application in C-H activation has never been explored. Herein,
we report the 2-(1-methyl-1H-benzo[d]imidazol-2-yl)isopropyl-
amine (MBIP-amine), which can be easily synthesized from 2-
aminoisobutyric acid and N-methyl-1,2-phenylenediamine, as a
N,N-bidentate directing group for copper-promoted C(sp2)-S
bond formation (Scheme 1b).
The reaction of benzamide derivative 1a and diphenyl disulfide
2a was chosen as a model to optimize the reaction conditions
(Table 1 and Table S1 in the Supporting Information). The
dithiolated product 3a, whose molecular structure (Figure 2,
CCDC 1505428) was determined by X-ray crystallography,
Table 1. Optimization of the reaction conditions.[a]
Entry
Cu salt
Solvent
DMSO
DMSO
Time (h)
10
Base
Yield[b] (%)
50
Cu(OAc)2
Cu(OAc)2
1
2
/
/
10
50[c]
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
10
10
10
10
10
10
10
10
8
37[d]
39[e]
45[f]
30[g]
38[h]
35[i]
42[j]
41[k]
50
3
/
4
/
5
/
6
/
7
/
8
/
9
/
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
/
/
6
44
/
12
8
34
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
DMSO
toluene
DMF
/
13
/
8
32
/
8
23
DMAc
NMP
/
8
27
Cu(OAc)2
CuCl
/
DMSO
DMSO
DMSO
DMSO
8
trace
trace
0
/
Cu2(OH)2CO3
CuBr2
8
/
8
/
Cu(OTf)2
Cu(OAc)2
8
0
/
8
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
Na2C2O4
NaHCO3
Na2CO3
NaOAc
KOAc
CsOAc
CsOAc
CsOAc
44
8
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
33
8
47
8
69
8
65
8
Cu(OAc)2
81
40[l]
80[m]
Cu(OAc)2
8
Cu(OAc)2
8
[a] Reaction conditions: 1a (0.2 mmol), 2a (0.5 mmol), Cu(OAc)2 (0.5 equiv), base (1.0 equiv), solvent (1.5 mL), 135 oC, air. [b] Isolated yield. [c] Cu(OAc)2 (0.8
equiv). [d] Cu(OAc)2 (0.3 equiv). [e] under Ar. [f] under O2. [g] 125 oC. [h] 2a (0.4 mmol). [i] 2a (0.6 mmol). [j] DMSO (1.0 mL). [k] DMSO (2.0 mL). [l] CsOAc (0.5
equiv). [m] CsOAc (1.5 equiv).
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10.1002/ejoc.201700147
European Journal of Organic Chemistry
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could be obtained in 50% isolated yield in the presence of 0.5
equiv of Cu(OAc)2 with 2.5 equiv of 2a in DMSO (1.5 mL) under
air at 135 oC for 10 h (entry 1). Increasing the amount of
Cu(OAc)2 did not result in any improvement in the yield (entry 2),
while decreasing the amount of Cu(OAc)2 led to a reduced yield
(37%, entry 3). The influences of the reaction atmosphere,
temperature, the amounts of disulfide 2a and DMSO as well as
reaction time on the model reaction were briefly investigated
(entries 4-13). Unfortunately, the yields were no higher than 50%
in all cases. However, a shorter reaction time of 8 h could
provide the same isolated yield of 3a (entry 11 vs entry 1). Using
other solvents such as toluene, DMF, DMAc or NMP instead of
DMSO gave significantly lower reactivity (13-32% yields, entries
14-17). Besides Cu(OAc)2 some other Cu salts including CuCl,
Cu2(OH)2CO3, CuBr2 and Cu(OTf)2 were also tested and
Cu(OAc)2 was found to be the only effective one (entries 18-21).
Then the effect of different bases were examined (entries 22-25).
We were delighted to find that the addition of NaOAc could
afford a better yield (69%, entry 25). Further screening of the
acetates (entries 26-29) showed that 1.0 equiv of CsOAc gave
the best yield (81%, entry 27).
electronic variations of functional groups on the phenyl were
compatible (50-86% yields), among which electron-rich
substrates showed higher reactivity than the electron-poor ones
(3f-3h vs 3b-3e). The sterically hindered m-substituted
benzamides participated smoothly, affording the corresponding
disulfenylation products in moderate yields (35% and 63%,
respectively, 3i and 3j). In addition, -naphthalyl substrate
provided the desired monothiolated product in 55% yield (3k).
Pleasingly, reactions of the heterocyclic substrates also
proceeded efficiently (3l-3n). In particular, the 5-membered
heterocyclic substrates led to the formation of both mono- and
dithilolated products in excellent combined yields (>90%, 3m
and 3n), which were not achieved in previous reports. Finally, in
the case of the piperonylic acid substrate, the expected
dithiolated product was obtained in 57% yield (3o).
The tolerance of disulfides was then evaluated and the results
are summarized in Table 3. We were pleased to find that diaryl
disulfides bearing either electron-donating or electron-
withdrawing group afforded the corresponding dithiolated
products in good yields (64-80%, 4a-4d). In addition to the
substituted diphenyl disulfides, the heteroaromatic bis(2-methyl-
3-furyl) disulfide was also reactive in this reaction, giving the
desired product 4e in 53% yield. Moreover, the scope of the
disulfides was not limited to aromatic disulfides. When aliphatic
disulfides were used, high yields could also be obtained (66%
and 84%, respectively, 4f and 4g). Notably, diphenyl diselenide
could result in the diselenylated product 4h in 55% yield.
Table 3. Scope of disulfides in disulfenylation.[a]
O
SR
O
MBIP
MBIP
Cu(OAc)2, CsOAc
DMSO, 135 oC, 8 h
N
N
RSSR
H
H
SR
1a
2
4
Figure 2. Molecular structure of the compound 3a.
R
O
S
O
S
O
S
MBIP
MBIP
With the optimized reaction conditions in hand, the scope of
the benzamides was firstly explored (Table 2). It was found that
4a
N
H
, R = F, 72%
N
H
4b, R = Cl, 64%
4c, R = CH3, 76%
S
4d
, R = OMe, 80%
Table 2. Scope of benzamides.[a]
O
O
SPh
O
4e, 53%
R
MBIP
MBIP
Cu(OAc)2, CsOAc
DMSO, 135 oC, 8 h
N
N
H
PhSSPh
R
R
H
SePhO
SR
O
SPh
MBIP
2a
MBIP
1
3
N
N
H
H
[b]
4f
, R = Et, 66%
SPh
O
SePh
4h
SPh
O
SPh O
SPh
O
SR
4g
, R = nBu, 84%
MBIP
MBIP
MBIP
MBIP
, 55%
N
H
N
N
N
H
H
O
H
[a] Reaction conditions: 1a (0.2 mmol), 2 (0.5 mmol), Cu(OAc)2 (0.5 equiv),
S
SPh
SPh
3a, 81%
SPh
R
SPh
F3C
SPh
CsOAc (0.2 mmol), DMSO (1.5 mL), air, 135 oC, 8 h. Isolated yields. [b] 12 h.
O
3b, R = F, 67%
3c
[b]
3d
3e
, 61%
, 50%
, R = Cl, 66%
The monothiolation was successfully achieved when o-toluic
acid amide (1p) was utilized as the coupling partner (Table 4). It
was found that a little concentrated system gave the desired
product 5a in higher yield in the reaction of 1p with phenyl
disulfide (80%, see Table S2 in the Supporting Information).
Then various disulfides were examined. Evidently, halogen
substituted diaryl disulfides were compatible, giving moderate
yields (5b and 5c). Diaryl disulfides with electron-donating group
proceeded more smoothly as expected (5d and 5e). In addition,
the heteroaromatic bis(2-methyl-3-furyl) disulfide was also
suitable, affording 5f in 57% yield. Moreover, thioalkylation
products 5g and 5h were isolated in good yields (70% and 66%,
respectively). Finally, the monoselenylated product 5i could be
obtained in 50% yield when 1p reacted with phenyl diselenide.
SPh
O
SPh
O
O
SPh O
MBIP
MBIP
MBIP
MBIP
N
N
H
N
N
H
H
H
R
SPh
SPh
SPh
3f, R = CH3, 80%
3g
NO2
OMe
, R = OMe, 78%
3k, 55%[c]
SPh
3h, R = tBu, 86%
3i,
3j
, 63%
35%
O
O
SPh
O
PhS
MBIP
MBIP
MBIP
[c]
N
N
N
3m
, X = O, 96%
3ma 3mb
) = 7:1
H
H
H
X
N
mono(
3n, X = S, 91%[c]
mono(3na):di(3nb) = 4:5
):di(
SPh
SPh
O
PhS
O
3l
, 64%
3o
, 57%
[a] Reaction conditions: 1 (0.2 mmol), 2a (0.5 mmol), Cu(OAc)2 (0.5 equiv),
CsOAc (0.2 mmol), DMSO (1.5 mL), air, 135 oC, 8 h. Isolated yields. [b] 4 h. [c]
1.0 mL DMSO.
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10.1002/ejoc.201700147
European Journal of Organic Chemistry
FULL PAPER
in the case of α-alkyl substituted and α-phenyl substituted
acrylamides. The sterically more congested α,β-dimethyl
substituted acrylamide could also be tolerated, affording the
tetrasubstituted thiolated alkene 6i in a good yield (62%).
Unfortunately, in the case of β-isopropyl substituted acrylamide
and conjugated alkenes, such as sorbic acid and cinnamic acid
substrates (1y, 1z and 1aa, see the Supporting Information),
trace or no desired products were observed. Furthermore, the
scope of disulfide towards α-phenyl substituted acrylamide was
investigated. For p-tolyl disulfide and p-methoxyphenyl disulfide,
the dithiolated products 6k and 6l were obtained in good yields
(68% and 76%, respectively). Interestingly, the p-fluorophenyl
disulfide provided the mixture adducts 6m in a 66% combined
yield, while the p-chloro one only resulted in monothiolation (6n,
79% yield). Finally, when dibutyl disulfide was used, the mono-
and disulfenylation mixture products 6o were obtained in 54%
yield with a ratio of 1 to 3.2.
Table 4. Scope of disulfides in monosulfenylation.[a]
O
O
MBIP
MBIP
Cu(OAc)2, CsOAc
DMSO, 135 oC, 8 h
N
N
RSSR
H
H
SR
1p
2
5
O
S
O
O
O
MBIP
MBIP
MBIP
MBIP
N
N
N
H
N
H
H
H
S
S
S
OMe
R
[b]
5a
, 80%
O
5e
5d
, 88%
5b, R = F, 62%
, R = Cl, 44%
, 71%
O
5c
O
O
After substrate investigation, we conducted further elaboration
of the products. As outlined in Scheme 2, 6n could be selectively
oxidized to vinyl sulfinyl (7a, 82%, rt) or vinyl sulfone (7b, 80%,
50 oC) under H2O2 in AcOH.[16] Since both vinyl sulfinyl and vinyl
sulfone were deemed important building blocks in synthetic
chemistry,[17] these transformations further demonstrated the
practicability of our methodology.
MBIP
MBIP
MBIP
MBIP
N
H
N
N
H
N
H
H
S
S
S
SePh
nBu
O
5f
, 57%
5g
, 70%
5i
5h
, 50%
, 66%
[a] Reaction conditions: 1p (0.2 mmol), 2 (0.5 mmol), Cu(OAc)2 (0.5 equiv),
CsOAc (0.2 mmol), DMSO (1.0 mL), air, 135 oC, 8 h. Isolated yields. [b] 12 h.
It’s worthwhile to point out that our methodology is also
applicable to more challenging alkene substrates. As shown in
Table 5, cycloalkene-amides showed much high reactivity
towards diaryl disulfides, producing the expected thiolated
products 6a, 6c-6e in high yields (80-92%). Notably,
cyclopentene-amide could also couple with dibutyl disulfide
efficiently, delivering the desired product 6b in 75% yield, which
offered an atom-economic way to dialkyl sulfides. In addition,
chain-alkene-amides were compatible as well. For acrylamide, a
mixture of mono- and dithiolated products 6f (39%) were
obtained. In contrast, either the monothiolated products 6g (62%)
and 6h (22%) or the dithiolated product 6j (76%) were isolated
Scheme 2. Synthetic utility of 6n.
The MBIP group could be smoothly removed and recovered
via a N-Boc protection and hydrazinolysis sequence (Scheme
3).[18] For example, treatment of 3ma with Boc2O afforded the
corresponding product 8 in 90% yield. Subsequent microwave
irradiation reaction provided Boc-protected MBIP 9 and N-acyl
hydrazide 10 in 89% and 80% yield, respectively.
Table 5. Scope of alkene substrates.[a]
Scheme 3. Removal of the directing group.
To explore the reaction mechanism, some control experiments
were performed (Scheme 4). The intermolecular kinetic isotope
effect value of 1.7 was observed (Scheme 4a), and the parallel
reactions gave a KIE value of 2.5, indicating that the C-H
activation could be involved in the rate-determining step
(Scheme 4b). Furthermore, radical scavenger reactions were
conducted (Scheme 4c). The addition of radical scavengers
[a] Reaction conditions: 1q-1x (0.2 mmol), 2 (0.5 mmol), Cu(OAc)2 (0.5 equiv),
CsOAc (0.2 mmol), DMSO (1.0 mL), air, 135 oC, 8 h. Isolated yields.
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10.1002/ejoc.201700147
European Journal of Organic Chemistry
FULL PAPER
such as TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy, 5.0 equiv)
led to substantially reduced yield and BHT (2,6-di-tert-butyl-4-
methylphenol, 1.0 equiv) inhibited the reaction completely.
However, the addition of 1,1-diphenylethylene had a slight
influence on the reaction. In short, these results showed that
radicals were probably not involved in the current thiolation. We
assumed that the addition of TEMPO or BHT might consume
copper, which in turn made the thiolation process depressed.
Moreover, p-toluenethiol could react with 1a to deliver the
dithiolated product 4c in 65% isolated yield under the standard
conditions (Scheme 4d). It was also found that p-toluenethiol
could be oxidized to p-tolyl disulfide 2d in the absence of 1a
(Scheme 4e).
Experimental Section
General Methods: 1H NMR, 13C NMR and 19F NMR spectra were
recorded on Bruker DPX 400 or Bruker DPX 600 instruments using TMS
as an internal standard. HRMS were determined on an Agilent 1290-
6540 UHPLC Q-Tof HR-MS System or a Waters Q-Tof Micro MS/MS
System ESI spectrometer. Melting points were measured on a WC-1
instrument and are uncorrected. The multiplicities are reported as
follows: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, dd =
doublet of doublets. Unless otherwise noted, materials were obtained
from commercial suppliers without further purification. CsOAc was dryed
under infrared drying oven. Anhydrous Cu(OAc)2 were purchased from
Alfa Aesar.
SPh O
H(D) O
2a
(D)H
(D)H
MBIP
General Procedure for the Copper-Promoted Thiolation of C(sp2)-H
Bonds: To a 10 mL Schlenk tube, 1 (0.2 mmol), 2 (0.5 mmol), Cu(OAc)2
(18.1 mg, 0.1 mmol), CsOAc (38.4 mg, 0.2 mmol) and DMSO (1.5 mL)
were added. The tube was heated at 135 oC for 8 hours under air. After
cooling to room temperature, the reaction mixture was diluted with ethyl
acetate and filtered through a celite pad. Then, the solvent was removed
under reduced pressure. The residue was purified by preparative TLC on
silica gel plates using petroleum ether/EtOAc as the eluent to give the
target product.
(D)H
(D)H
MBIP
standard conditions
N
N
H
H
a)
10 min, 16%
kH/kD = 1.7
SPh
H(D)
H(D)
3a/[D3]-3a
H(D)
1a/[D5]-1a
standard conditions
b)
c)
1a or [D5]-1a
2a
3a or [D3]-3a
kH/kD = 2.5
Additive
Yield
TEMPO (1.0 equiv)
TEMPO (5.0 equiv)
63%
11%
0
80%
74%
standard conditions
1a
1a
2a
3a
N-(2-(1-Methyl-1H-benzo[d]imidazol-2-yl)propan-2-yl)-2,6-
additive
BHT
(1.0 equiv)
bis(phenylthio)benzamide (3a): Rf 0.5 (Petroleum ether/EtOAc = 2/1).
White solid (82.6 mg, 81% yield). M.p. 177-181 °C. 1H NMR (400 MHz,
CDCl3) δ 7.73-7.69 (m, 1H), 7.66 (s, 1H) 7.45-7.38 (m, 4H), 7.33-7.20 (m,
Ph2C=CH2 (1.0 equiv)
Ph2C=CH2 (5.0 equiv)
9H), 7.15-7.09 (m, 1H), 7.07-7.03 (m, 2H), 3.94 (s, 3H), 2.08 (s, 6H). 13
C
standard conditions
d)
e)
4c
without 2d
NMR (100 MHz, CDCl3) δ 165.7, 156.8, 140.8, 140.2, 137.5, 135.0,
134.8, 132.1, 130.3, 129.9, 129.4, 127.7, 122.7, 122.2, 119.7, 109.2,
55.2, 32.1, 25.5. HRMS (positive ESI; m/z): [M+H]+ calcd for
C30H28N3OS2+: 510.1668, found 510.1671.
SH
2.5 equiv
65%
S
S
standard conditions
without 1a
SH
4-Fluoro-N-(2-(1-methyl-1H-benzo[d]imidazol-2-yl)-propan-2-yl)-2,6-
bis(phenylthio)benzamide (3b): Rf 0.5 (Petroleum ether/EtOAc = 2/1).
White solid (70.7 mg, 67% yield). M.p. 108-110 °C. 1H NMR (400 MHz,
CDCl3) δ 7.96 (s, 1H), 7.76-7.71 (m, 1H), 7.52-7.45 (m, 4H), 7.40-7.23 (m,
9H), 6.52 (d, J = 8.8 Hz, 2H), 3.97 (s, 3H), 2.12 (s, 2H). 13C NMR (100
MHz, CDCl3) δ 165.0, 162.6 (d, JC-F = 250.5 Hz), 156.8, 140.7, 138.9,
138.8, 137.5, 133.6, 132.7, 129.7, 128.7, 122.8, 122.3, 119.6, 114.6 (d,
2d, 25%
Scheme 4. Control experiments.
Although the mechanism is unclear at this moment, based on
our own observations and previous reports,[6],[19] especially
Stahl’s work on mechanisms of copper(II)-mediated C-H
oxidations,[19e] a C,N,N-pincer type Cu(III) intermediate involved
concerted metalation-deprotonation (CMD) pathway may be
reasonable (see Figure S2 in the Supporting Information).
JC-F = 24.1 Hz), 109.3, 55.2, 32.2, 25.4. 19F NMR (376 MHz, CDCl3) δ
+
109.84. HRMS (positive ESI; m/z): [M+H]+ calcd for C30H27FN3OS2
:
528.1574, found 528.1576.
4-Chloro-N-(2-(1-methyl-1H-benzo[d]imidazol-2-yl)-propan-2-yl)-2,6-
bis(phenylthio)benzamide (3c): Rf 0.5 (Petroleum ether/EtOAc = 2/1).
White solid (71.8 mg, 66% yield). M.p. 115-120 °C. 1H NMR (400 MHz,
CDCl3) δ 7.98 (s, 1H), 7.76-7.71 (m, 1H), 7.51-7.45 (m, 4H), 7.38-7.27 (m,
9H), 6.86 (s, 2H), 3.97 (s, 3H), 2.11 (s, 6H). 13C NMR (100 MHz, CDCl3)
δ 164.9, 156.8, 140.7, 137.7, 137.5, 136.7, 135.6, 133.2, 133.0, 129.7,
128.6, 128.1, 122.8, 122.3, 119.6, 109.3, 55.2, 32.2, 25.3. HRMS
(positive ESI; m/z): [M+H]+ calcd for C30H27ClN3OS2+: 544.1279, found
544.1282.
Conclusions
In summary, we have developed a novel and removable
N,N-bidentate directing group which facilitated the thiolation
of C(sp2)-H bonds smoothly in the presence of Cu(OAc)2.
This protocol has the advantages of simple reaction
conditions and broad substrate scope, affording diverse
functionalized thioethers in an efficient way. Importantly, this
is the first example of copper-promoted, auxiliary-assisted
thiolation of alkenes. In addition, our strategy provides a
potential feasible way to access structure modification of the
bioactive benzimidazole-containing compounds via direct C-
H activation. Further mechanistic studies and applications of
the MBIP DG are currently underway in our laboratory.
N-(2-(1-Methyl-1H-benzo[d]imidazol-2-yl)propan-2-yl)-2,6-
bis(phenylthio)-4-(trifluoromethyl)benzamide (3d): Rf 0.5 (Petroleum
ether/EtOAc = 2/1). White solid (70.5 mg, 61% yield). M.p. 160-164 °C.
1H NMR (400 MHz, CDCl3) δ 8.17 (s, 1H), 7.75-7.69 (m, 1H), 7.52-7.44
(m, 4H), 7.40-7.27 (m, 9H), 7.13 (s, 2H), 3.97 (s, 3H), 2.14 (s, 6H). 13C
NMR (100 MHz, CDCl3) δ 164.5, 156.7, 141.2, 140.6, 137.5, 133.1,
132.8, 132.2, 131.8, 129.8, 128.7, 125.0 (q, JC-F = 3.6 Hz), 123.0 (q, JC-F
= 271.9 Hz), 122.9, 122.4, 119.6, 109.3, 55.4, 32.1, 25.2. 19F NMR (376
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700147
European Journal of Organic Chemistry
FULL PAPER
MHz, CDCl3) δ 63.22. HRMS (positive ESI; m/z): [M+H]+ calcd for
122.0, 119.6, 119.1, 112.9, 109.1, 56.3, 55.1, 31.9, 25.4. HRMS (positive
ESI; m/z): [M+H]+ calcd for C31H30N3O2S2+: 540.1774, found 540.1777.
C31H27F3N3OS2+: 578.1542, found 578.1546.
N-(2-(1-Methyl-1H-benzo[d]imidazol-2-yl)propan-2-yl)-4-
N-(2-(1-Methyl-1H-benzo[d]imidazol-2-yl)propan-2-yl)-2-(phenylthio)-
1-naphthamide (3k): Rf 0.5 (Petroleum ether/EtOAc = 1/1). White solid
(49.7 mg, 55% yield). M.p. 62-65 °C. 1H NMR (400 MHz, CDCl3) δ 7.98
(d, J = 5.6 Hz, 1H), 7.92 (s, 1H), 7.79 (d, J = 5.2 Hz, 1H), 7.74 (d, J = 5.6
Hz, 1H), 7.64 (d, J = 5.2 Hz, 1H), 7.54-7.47 (m, 2H), 7.38 (d, J = 5.2 Hz,
2H), 7.34-7.17 (m, 7H), 3.92 (d, J = 2.0 Hz, 3H), 2.15 (d, J = 1.6 Hz, 6H).
13C NMR (100 MHz, CDCl3) δ 167.0, 156.8, 140.7, 137.9, 137.4, 135.9,
132.5, 131.0, 130.7, 129.78, 129.76, 129.5, 129.3, 128.1, 127.6, 127.2,
126.7, 125.2, 122.8, 122.3, 119.6, 109.2, 55.2, 32.1, 25.7. HRMS
(positive ESI; m/z): [M+H]+ calcd for C28H26N3OS+: 452.1791, found
452.1794.
(methylsulfonyl)-2,6-bis(phenylthio)benzamide
(3e):
Rf
0.5
(Petroleum ether/EtOAc = 1/1). White solid (58.8 mg, 50% yield). M.p.
212-215 °C. 1H NMR (400 MHz, CDCl3) δ 8.34 (s, 1H), 7.75-7.69 (m, 1H),
7.54-7.47 (m, 4H), 7.40-7.23 (m, 11H), 3.97 (s, 3H), 2.82 (s, 3H), 2.16 (s,
2H). 13C NMR (100 MHz, CDCl3) δ 164.3, 156.6, 141.74, 141.69, 140.5,
138.9, 137.5, 133.5, 132.1, 130.0, 129.1, 126.0, 123.0, 122.5, 119.5,
109.4, 55.4, 44.1, 32.2, 25.2. HRMS (positive ESI; m/z): [M+H]+ calcd for
C31H30N3O3S3+: 588.1444, found 588.1449.
4-Methyl-N-(2-(1-methyl-1H-benzo[d]imidazol-2-yl)-propan-2-yl)-2,6-
bis(phenylthio)benzamide (3f): Rf 0.5 (Petroleum ether/EtOAc = 1/1).
Colorless oil (83.8 mg, 80% yield). 1H NMR (400 MHz, CDCl3) δ 7.73-
7.68 (m, 1H), 7.51 (s, 1H), 7.42-7.36 (m, 4H), 7.33-7.18 (m, 9H), 6.93 (s,
2H), 3.92 (s, 3H), 2.14 (s, 3H), 2.03 (s, 6H). 13C NMR (100 MHz, CDCl3)
δ 165.9, 156.8, 140.8, 140.2, 138.6, 137.4, 135.3, 134.2, 131.9, 131.5,
129.4, 127.4, 122.7, 122.1, 119.6, 109.2, 55.1, 32.1, 25.6, 21.2. HRMS
(positive ESI; m/z): [M+H]+ calcd for C31H30N3OS2+: 524.1825, found
524.1829.
N-(2-(1-Methyl-1H-benzo[d]imidazol-2-yl)propan-2-yl)-3,5-
bis(phenylthio)isonicotinamide (3l): Rf 0.5 (Petroleum ether/EtOAc =
1/1). White solid (49.7 mg, 64% yield). M.p. 108-111 °C. 1H NMR (400
MHz, CDCl3) δ 8.20 (s, 2H), 8.15 (s, 1H), 7.74-7.67 (m, 1H), 7.49-7.42 (m,
4H), 7.36-7.23 (m, 9H), 3.94 (s, 3H), 2.07 (s, 6H). 13C NMR (100 MHz,
CDCl3) δ 163.4, 156.5, 150.1, 146.0, 140.6, 137.5, 133.1, 132.4, 130.9,
129.7, 128.3, 122.9, 122.4, 119.6, 109.3, 55.4, 32.1, 25.3. HRMS
(positive ESI; m/z): [M+H]+ calcd for C29H27N4OS2: 511.1626, found
511.1625.
4-Methoxy-N-(2-(1-methyl-1H-benzo[d]imidazol-2-yl)propan-2-yl)-2,6-
bis(phenylthio)benzamide (3g): Rf 0.5 (Petroleum ether/EtOAc = 2/1).
Colorless oil (84.2 mg, 78% yield). 1H NMR (400 MHz, CDCl3) δ 7.76-
7.69 (m, 1H), 7.54 (s, 1H), 7.47-7.39 (m, 4H), 7.36-7.22 (m, 9H), 6.52 (s,
2H), 3.95 (s, 3H), 3.55 (s, 3H), 2.05 (s, 6H). 13C NMR (100 MHz, CDCl3)
δ 165.8, 160.0, 156.8, 140.9, 137.4, 136.6, 134.3, 132.6, 132.3, 129.5,
127.9, 122.7, 122.1, 119.6, 115.3, 109.2, 55.3, 55.0, 32.1, 25.7. HRMS
(positive ESI; m/z): [M+H]+ calcd for C31H30N3O2S2+: 540.1774, found
540.1778.
N-(2-(1-Methyl-1H-benzo[d]imidazol-2-yl)propan-2-yl)-3-
(phenylthio)furan-2-carboxamide
(3ma):
Rf
0.6
(Petroleum
ether/EtOAc = 1/1). White solid (65.8 mg, 84% yield). M.p. 87-92 °C. 1H
NMR (400 MHz, CDCl3) δ 7.98 (s, H), 7.80-7.74 (m, 1H), 7.53-7.48 (m,
2H), 7.40-7.33 (m, 4H), 7.32-7.23 (m, 3H), 6.09 (d, J = 2.0 Hz, 1H), 3.86
(s, 3H), 2.02 (s, 6H). 13C NMR (100 MHz, CDCl3) δ 157.6, 156.6, 143.5,
141.6, 141.1, 137.3, 132.8, 132.7, 129.4, 128.5, 125.8, 122.7, 122.1,
119.8, 113.8, 109.1, 54.2, 31.8, 26.7. HRMS (positive ESI; m/z): [M+H]+
calcd for C22H22N3O2S+: 392.1427, found 392.1435.
4-(tert-Butyl)-N-(2-(1-methyl-1H-benzo[d]imidazol-2-yl)propan-2-yl)-
2,6-bis(phenylthio)benzamide (3h): Rf 0.5 (Petroleum ether/EtOAc =
2/1). White solid (97.3 mg, 86% yield). M.p. 210-213 °C. 1H NMR (400
MHz, CDCl3) δ 7.73-7.68 (m, 1H), 7.40 (s, 1H), 7.38-7.34 (m, 4H), 7.32-
7.18 (m, 9H), 7.15 (s, 2H), 3.92 (s, 3H), 2.01 (s, 6H), 1.10 (s, 6H). 13C
NMR (100 MHz, CDCl3) δ 165.9, 156.7, 153.2, 140.9, 138.5, 137.4,
135.5, 133.8, 131.1, 129.3, 128.8, 127.3, 122.6, 122.1, 119.7, 109.2,
55.0, 34.9, 32.1, 30.8, 25.6. HRMS (positive ESI; m/z): [M+H]+ calcd for
C34H36N3OS2+: 566.2294, found 566.2297.
N-(2-(1-Methyl-1H-benzo[d]imidazol-2-yl)propan-2-yl)-3,5-
bis(phenylthio)furan-2-carboxamide (3mb): Rf 0.7 (Petroleum
ether/EtOAc = 1/1). White solid (12.0 mg, 12% yield). M.p. 208-211 °C.
1H NMR (400 MHz, CDCl3) δ 7.78-7.73 (m, 1H), 7.71 (s, 1H), 7.55-7.50
(m, 2H), 7.40-7.34 (m, 3H), 7.33-7.21 (m, 8H), 6.20 (s, 1H), 3.84 (s, 3H),
1.99 (s, 6H). 13C NMR (100 MHz, CDCl3) δ 157.1, 156.4, 146.4, 143.1,
141.1, 137.2, 133.6, 133.5, 131.9, 129.6, 129.4, 128.9, 128.6, 127.6,
122.7, 122.1, 120.0, 119.8, 109.1, 54.3, 31.8, 26.8. HRMS (positive ESI;
m/z): [M+H]+ calcd for C28H26N3O2S2+: 500.1461, found 500.1471.
N-(2-(1-Methyl-1H-benzo[d]imidazol-2-yl)propan-2-yl)-3-nitro-2,6-
bis(phenylthio)benzamide (3i): Rf 0.3 (Petroleum ether/EtOAc = 2/1).
Yellow oil (38.8 mg, 35% yield). 1H NMR (400 MHz, CDCl3) δ 8.26 (s, 1H),
7.73-7.68 (m, 1H), 7.60-7.56 (m, 2H), 7.54 (d, J = 8.8 Hz, 1H), 7.46-7.41
(m, 3H), 7.35-7.27 (m, 5H), 7.23-7.18 (m, 2H), 7.14-7.08 (m, 1H), 6.98 (d,
J = 8.8 Hz, 1H), 3.94 (s, 3H), 2.10 (s, 6H). 13C NMR (100 MHz, CDCl3) δ
163.7, 156.6, 150.8, 143.5, 142.9, 140.5, 137.5, 134.9, 134.8, 130.7,
130.1, 129.7, 129.6, 129.2, 129.0, 127.2, 125.3, 125.0, 122.9, 122.4,
119.6, 109.3, 55.4, 32.1, 24.9. HRMS (positive ESI; m/z): [M+H]+ calcd
for C30H27N4O3S2+: 555.1519, found 555.1521.
N-(2-(1-Methyl-1H-benzo[d]imidazol-2-yl)propan-2-yl)-3-
(phenylthio)thiophene-2-carboxamide (3na): Rf 0.6 (Petroleum
ether/EtOAc = 1/1). White solid (33.4 mg, 41% yield). M.p. 109-114 °C.
1H NMR (600 MHz, CDCl3) δ 8.60 (s, H), 7.77-7.71 (m, 1H), 7.51 (d, J =
5.4 Hz, 1H), 7.33-7.29 (m, 2H), 7.27-7.17 (m, 6H), 7.08 (d, J = 4.8 Hz,
1H), 3.59 (s, 3H), 1.88 (s, 6H). 13C NMR (100 MHz, CDCl3) δ 160.0,
156.1, 141.4, 140.9, 137.0, 135.2, 134.7, 129.7, 129.6, 128.1, 127.2,
122.4, 122.1, 121.9, 119.8, 109.0, 54.1, 31.2, 27.4. HRMS (positive ESI;
m/z): [M+H]+ calcd for C22H22N3OS2+: 408.1199, found 408.1210.
3-Methoxy-N-(2-(1-methyl-1H-benzo[d]imidazol-2-yl)propan-2-yl)-2,6-
bis(phenylthio)benzamide (3j): Rf 0.6 (Petroleum ether/EtOAc = 1/1).
Colorless oil (68.0 mg, 63% yield). 1H NMR (400 MHz, CDCl3) δ 7.66 (d,
J = 4.8 Hz, 1H), 7.49 (d, J = 5.6 Hz, 1H), 7.31 (s, 1H), 7.27-7.19 (m, 9H),
7.17 (t, J = 4.8 Hz, 2H), 7.09 (t, J = 4.8 Hz, 1H), 7.05 (t, J = 4.8 Hz, 1H),
6.93 (d, J = 5.6 Hz, 1H), 3.83 (s, 3H), 3.77 (s, 3H), 1.98 (s, 6H). 13C NMR
(100 MHz, CDCl3) δ 165.5, 160.6, 156.6, 148.6, 140.8, 138.2, 137.6,
137.4, 136.9, 129.2, 129.1, 128.8, 128.0, 126.4, 125.8, 122.9, 122.6,
N-(2-(1-Methyl-1H-benzo[d]imidazol-2-yl)propan-2-yl)-3,5-
bis(phenylthio)thiophene-2-carboxamide (3nb): Rf 0.7 (Petroleum
ether/EtOAc = 1/1). White solid (51.6 mg, 50% yield). M.p. 53-55 °C. 1H
NMR (600 MHz, CDCl3) δ 8.53 (s, 1H), 7.77-7.70 (m, 1H), 7.40-7.36 (m,
2H), 7.35-7.19 (m, 11H), 7.04 (d, J = 1.8 Hz, 1H), 3.62 (s, 3H), 1.87 (s,
6H). 13C NMR (100 MHz, CDCl3) δ 159.5, 156.1, 142.2, 141.4, 140.3,
137.7, 137.0, 134.8, 134.7, 130.6, 129.7, 129.5, 128.6, 128.3, 128.1,
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10.1002/ejoc.201700147
European Journal of Organic Chemistry
FULL PAPER
127.5, 122.5, 121.9, 119.8, 109.0, 54.3, 31.3, 27.2. HRMS (positive ESI;
m/z): [M+H]+ calcd for C28H26N3OS3+: 516.1233, found 516.1234.
133.8, 129.4, 123.6, 122.8, 122.3, 119.6, 115.4, 109.3, 107.4, 55.2, 32.3,
+
25.6, 11.9. HRMS (positive ESI; m/z): [M+H]+ calcd for C28H28N3O3S2
:
518.1567, found 518.1570.
N-(2-(1-Methyl-1H-benzo[d]imidazol-2-yl)propan-2-yl)-4,6-
bis(phenylthio)benzo[d][1,3]dioxole-5-carboxamide (3o): Rf 0.5
(Petroleum ether/EtOAc = 1/1). Colorless oil (63.1 mg, 57% yield). 1H
NMR (400 MHz, CDCl3) δ 7.71-7.64 (m, 1H), 7.56 (s, 1H), 7.37-7.07 (m,
13H), 6.82 (s, 1H), 5.95 (s, 2H), 3.87 (s, 3H), 2.00 (s, 6H). 13C NMR (100
MHz, CDCl3) δ 165.2, 156.7, 150.1, 148.4, 140.7, 139.7, 137.4, 136.5,
135.4, 130.4, 129.3, 129.1, 128.8, 127.0, 126.5, 125.8, 122.7, 122.1,
119.6, 114.5, 111.7, 109.2, 102.1, 55.1, 32.0, 25.4. HRMS (positive ESI;
m/z): [M+H]+ calcd for C31H28N3O3S2+: 554.1567, found 554.1570.
2,6-Bis(ethylthio)-N-(2-(1-methyl-1H-benzo[d]imidaz-ol-2-yl)propan-
2-yl)benzamide (4f): Rf 0.6 (Petroleum ether/EtOAc = 1/1). White solid
(54.6 mg, 66% yield). M.p. 53-58 °C. 1H NMR (600 MHz, CDCl3) δ 7.70
(d, J = 7.8 Hz, 1H), 7.36 (s, 1H), 7.33 (d, J = 7.8 Hz, 1H), 7.31-7.23 (m,
5H), 4.02 (s, 3H), 2.93 (q, J = 7.2 Hz, 4H), 2.14 (s, 6H), 1.27 (t, J = 7.2
Hz, 6H). 13C NMR (100 MHz, CDCl3) δ 166.3, 157.0, 141.2, 140.9, 137.4,
134.7, 129.2, 128.4, 122.7, 122.1, 119.7, 109.2, 55.0, 32.3, 28.9, 25.7,
14.3. HRMS (positive ESI; m/z): [M+H]+ calcd for C22H28N3OS2
:
+
414.1668, found 414.1671.
2,6-Bis((4-fluorophenyl)thio)-N-(2-(1-methyl-1H-benzo[d]imidazol-2-
yl)propan-2-yl)benzamide (4a): Rf 0.4 (Petroleum ether/EtOAc = 2/1).
Colorless oil (78.6 mg, 72% yield). H NMR (400 MHz, CDCl3) δ 8.02 (s,
2,6-Bis(butylthio)-N-(2-(1-methyl-1H-benzo[d]imidazol-2-yl)propan-2-
yl)benzamide (4g): Rf 0.4 (Petroleum ether/EtOAc = 2/1). Colorless oil
(78.9 mg, 84% yield). 1H NMR (400 MHz, CDCl3) δ 7.72-7.67 (m, 1H),
7.36 (s, 1H), 7.34-7.21 (m, 6H), 4.01 (s, 3H), 2.90 (t, J = 7.6 Hz, 4H),
2.13 (s, 6H), 1.63-1.54 (m, 4H), 1.44-1.33 (m, 4H), 0.86 (t, J = 7.2 Hz,
6H). 13C NMR (100 MHz, CDCl3) δ 166.3, 157.0, 141.0, 140.9, 137.4,
135.0, 129.2, 128.1, 122.7, 122.1, 119.7, 109.2, 55.0, 34.6, 32.3, 31.2,
25.7, 22.0, 13.6. HRMS (positive ESI; m/z): [M+H]+ calcd for
C26H36N3OS2+: 470.2294, found 470.2300.
1
1H), 7.73-7.68 (m, 1H), 7.49-7.43 (m, 4H), 7.36-7.27 (m, 3H), 7.10 (dd, J
= 8.4 Hz, 7.6 Hz, 1H), 7.06-6.98 (m, 4H), 6.97-6.92 (m, 2H), 3.98 (s, 3H),
2.14 (s, 6H). 13C NMR (100 MHz, CDCl3) δ 165.5, 162.7 (d, JC-F = 247.2
Hz), 156.9, 140.7, 139.2, 137.5, 135.7, 135.1 (d, JC-F = 8.2 Hz), 129.9,
129.3 (d, JC-F = 3.4 Hz), 129.2, 122.9, 122.3, 119.5, 116.6 (d, JC-F = 21.8
Hz), 109.3, 55.2, 32.2, 25.3. 19F NMR (376 MHz, CDCl3) δ -112.92.
HRMS (positive ESI; m/z): [M+H]+ calcd for C30H26F2N3OS2+: 546.1480,
found 546.1485.
N-(2-(1-Methyl-1H-benzo[d]imidazol-2-yl)propan-2-yl)-2,6-
2,6-Bis((4-chlorophenyl)thio)-N-(2-(1-methyl-1H-benzo[d]imidazol-2-
yl)propan-2-yl)benzamide (4b): Rf 0.5 (Petroleum ether/EtOAc = 2/1).
Yellow oil (69.6 mg, 64% yield). 1H NMR (400 MHz, CDCl3) δ 8.02 (s, 1H),
7.71-7.66 (m, 1H), 7.38-7.22 (m, 11H), 7.20-7.13 (m, 1H), 7.12-7.06 (m,
2H), 3.95 (s, 3H), 2.10 (s, 6H). 13C NMR (100 MHz, CDCl3) δ 165.4,
156.8, 141.0, 140.6, 137.5, 134.6, 133.9, 133.4, 133.3, 131.0, 130.1,
129.6, 122.9, 122.4, 119.6, 109.3, 55.2, 32.2, 25.2. HRMS (positive ESI;
m/z): [M+H]+ calcd for C30H26Cl2N3OS2+: 578.0889, found 578.0895.
bis(phenylselanyl)benzamide (4h): Rf 0.6 (Petroleum ether/EtOAc =
1/1). White solid (66.4 mg, 55% yield). M.p. 192-195 °C. 1H NMR (400
MHz, CDCl3) δ 7.84 (s, 1H), 7.67-7.63 (m, 1H), 7.52-7.46 (m, 4H), 7.27-
7.16 (m, 9H), 7.06-7.02 (m, 2H), 6.91 (dd, J = 8.4 Hz, 7.2 Hz, 1H), 3.88 (s,
3H), 2.04 (s, 6H). 13C NMR (100 MHz, CDCl3) δ 166.8, 156.8, 141.0,
140.8, 137.5, 134.5, 131.7, 131.3, 130.3, 130.2, 129.6, 128.1, 122.8,
122.2, 119.7, 109.3, 55.2, 32.2, 25.4. HRMS (positive ESI; m/z): [M+H]+
calcd for C30H28N3OSe2+: 606.0557, found 606.0564.
N-(2-(1-Methyl-1H-benzo[d]imidazol-2-yl)propan-2-yl)-2,6-bis(p-
2-Methyl-N-(2-(1-methyl-1H-benzo[d]imidazol-2-yl)propan-2-yl)-6-
(phenylthio)benzamide (5a): Rf 0.5 (Petroleum ether/EtOAc = 1/1).
White solid (66.5 mg, 80% yield). M.p. 88-93 °C. 1H NMR (400 MHz,
CDCl3) δ 7.73-7.64 (m, 2H), 7.35-7.10 (m, 11H), 3.92 (s, 3H), 2.42 (s,
3H), 2.06 (s, 6H). 13C NMR (100 MHz, CDCl3) δ 167.4, 156.9, 140.7,
140.5, 137.4, 136.3, 136.1, 132.0, 130.7, 130.6, 129.7, 129.4, 129.2,
126.9, 122.8, 122.2, 119.6, 109.2, 54.9, 32.1, 25.4, 19.4. HRMS (positive
ESI; m/z): [M+H]+ calcd for C25H26N3OS+: 416.1791, found 416.1793.
tolylthio)benzamide (4c): Rf 0.5 (Petroleum ether/EtOAc
= 2/1).
Colorless oil (81.7 mg, 76% yield). 1H NMR (600 MHz, CDCl3) δ 7.75-
7.71 (m, 1H), 7.61 (s, 1H), 7.34 (d, J = 8.4 Hz, 4H), 7.33-7.25 (m, 3H),
7.12 (d, J = 7.8 Hz, 4H), 7.04 (t, J = 7.8 Hz, 1H), 6.91 (d, J = 7.8 Hz, 2H),
3.98 (s, 3H), 2.30 (s, 6H), 2.11 (s, 6H). 13C NMR (100 MHz, CDCl3) δ
165.8, 156.8, 140.9, 138.6, 138.2, 137.5, 136.0, 133.0, 130.5, 130.3,
129.7, 128.7, 122.7, 122.1, 119.6, 109.3, 55.2, 32.2, 25.6, 21.2. HRMS
(positive ESI; m/z): [M+H]+ calcd for C32H32N3OS2+: 538.1981, found
538.1986.
2-((4-Fluorophenyl)thio)-6-methyl-N-(2-(1-methyl-1H
benzo[d]imidazol-2-yl)propan-2-yl)benzamide (5b): Rf 0.5 (Petroleum
ether/EtOAc = 1/1). White solid (53.8 mg, 62% yield). M.p. 156-159 °C.
1H NMR (600 MHz, CDCl3) δ 7.93 (s, 1H), 7.68 (d, J = 7.2 Hz, 1H), 7.40-
7.36 (m, 2H), 7.35-7.27 (m, 3H), 7.18 (t, J = 7.2 Hz, 1H), 7.12 (d, J = 7.8
Hz, 1H), 7.04 (d, J = 7.8 Hz, 1H), 7.00-6.94 (m, 2H), 3.96 (s, 3H), 2.43 (s,
2,6-Bis((4-methoxyphenyl)thio)-N-(2-(1-methyl-1H-benzo[d]imidazol-
2-yl)propan-2-yl)benzamide (4d): Rf 0.6 (Petroleum ether/EtOAc = 1/1).
White solid (91.2 mg, 80% yield). M.p. 204-206 °C. 1H NMR (600 MHz,
CDCl3) δ 7.78-7.71 (m, 2H), 7.44 (d, J = 9.0 Hz, 4H), 7.36-7.23 (m, 3H),
6.98 (t, J = 7.8 Hz, 1H), 6.87 (d, J = 8.4 Hz, 4H), 6.74 (d, J = 7.8 Hz, 2H),
4.01 (s, 3H), 3.78 (s, 6H), 2.16 (s, 6H). 13C NMR (100 MHz, CDCl3) δ
165.9, 160.1, 156.9, 140.9, 137.5, 137.3, 136.5, 135.9, 129.5, 126.8,
123.7, 122.8, 122.2, 119.6, 115.1, 109.3, 55.4, 55.2, 32.3, 25.7. HRMS
(positive ESI; m/z): [M+H]+ calcd for C32H32N3O3S2+: 570.1880, found
570.1883.
3H), 2.12 (s, 6H). 13C NMR (100 MHz, CDCl3) δ 167.3, 162.3 (d, JC-F
=
245.9 Hz), 156.9, 140.6, 139.9, 137.5, 135.9, 133.8 (d, JC-F = 8.1 Hz),
133.0, 130.8 (d, JC-F = 3.2 Hz), 129.7, 129.41, 129.35, 122.9, 122.3,
119.6, 116.4 (d, JC-F = 21.8 Hz), 109.2, 54.9, 32.1, 25.3, 19.4. 19F NMR
(376 MHz, CDCl3) δ -114.28. HRMS (positive ESI; m/z): [M+H]+ calcd for
C25H25FN3OS+: 434.1697, found 434.1701.
N-(2-(1-Methyl-1H-benzo[d]imidazol-2-yl)propan-2-yl)-2-((2-
2-((4-Chlorophenyl)thio)-6-methyl-N-(2-(1-methyl-1H-
methylfuran-3-yl)methyl)-6-((2-methylfuran-3-yl)thio)benzamide (4e):
Rf 0.4 (Petroleum ether/EtOAc = 2/1). White solid (54.8 mg, 53% yield).
M.p. 69-72 °C. 1H NMR (600 MHz, CDCl3) δ 7.97 (s, 1H), 7.76-7.70 (m,
1H), 7.37-7.27 (m, 5H), 7.02 (t, J = 8.0 Hz, 1H), 6.68 (d, J = 8.0 Hz, 2H),
6.38 (d, J = 2.0 Hz, 2H), 4.03 (s, 3H), 2.34 (s, 6H), 2.20 (s, 6H). 13C NMR
(100 MHz, CDCl3) δ 165.5, 157.5, 156.9, 141.4, 140.8, 137.5, 137.0,
benzo[d]imidazol-2-yl)propan-2-yl)benzamide (5c): Rf 0.5 (Petroleum
ether/EtOAc = 1/1). White solid (39.6 mg, 44% yield). M.p. 164-167 °C.
1H NMR (600 MHz, CDCl3) δ 7.90 (s, 1H), 7.70-7.63 (m, 1H), 7.35-7.11
(m, 10H), 3.93 (s, 3H), 2.43 (s, 3H), 2.07 (s, 6H). 13C NMR (100 MHz,
CDCl3) δ 167.2, 156.9, 140.9, 140.5, 137.4, 136.2, 135.1, 132.8, 131.7,
131.3, 131.0, 130.1, 129.5, 129.3, 122.9, 122.4, 119.6, 109.2, 54.9, 32.1,
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10.1002/ejoc.201700147
European Journal of Organic Chemistry
FULL PAPER
25.2, 19.4. HRMS (positive ESI; m/z): [M+H]+ calcd for C25H25ClN3OS+:
450.1401, found 450.1404.
3H), 2.05 (s, 6H). 13C NMR (100 MHz, CDCl3) δ 167.9, 156.9, 140.8,
140.6, 137.5, 135.7, 133.5, 131.7, 131.3, 129.6, 129.5, 129.4, 128.8,
127.5, 122.9, 122.3, 119.6, 109.2, 54.9, 32.1, 25.3, 19.7. HRMS (positive
ESI; m/z): [M+H]+ calcd for C25H26N3OSe+: 464.1236, found 464.1239.
2-Methyl-N-(2-(1-methyl-1H-benzo[d]imidazol-2-yl)propan-2-yl)-6-(p-
tolylthio)benzamide (5d): Rf 0.5 (Petroleum ether/EtOAc = 1/1). White
solid (61.0 mg, 71% yield). M.p. 182-185 °C. 1H NMR (600 MHz, CDCl3)
δ 7.65 (s, 1H), 7.60 (d, J = 7.8 Hz, 1H), 7.25-7.13 (m, 5H), 7.05 (t, J = 7.8
Hz, 1H), 7.01-6.96 (m, 3H), 6.93 (d, J = 7.8 Hz, 1H), 3.84 (s, 3H), 2.31 (s,
3H), 2.17 (s, 3H), 1.98 (s, 6H). 13C NMR (100 MHz, CDCl3) δ 167.4,
156.9, 140.7, 139.6, 137.5, 137.4, 135.8, 133.3, 131.9, 131.8, 130.1,
129.5, 129.3, 129.1, 122.8, 122.2, 119.6, 109.2, 54.9, 32.1, 25.5, 21.1,
19.4. HRMS (positive ESI; m/z): [M+H]+ calcd for C26H28N3OS+: 430.1948,
found 430.1950.
N-(2-(1-Methyl-1H-benzo[d]imidazol-2-yl)propan-2-yl)-2-
(phenylthio)cyclopent-1-enecarboxamide (6a): Rf 0.5 (Petroleum
ether/EtOAc = 1/1). White solid (63.4 mg, 81% yield). M.p. 152-156 °C.
1H NMR (400 MHz, CDCl3) δ 7.76-7.70 (m, 1H), 7.63 (s, 1H), 7.57-7.51
(m, 2H), 7.39-7.21 (m, 6H), 3.91 (s, 3H), 2. 84-2.74 (m, 2H), 2.41-2.31 (m,
2H), 2.00 (s, 6H), 1.94-1.84 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 164.5,
157.3, 148.5, 141.0, 137.3, 134.6, 132.4, 128.9, 128.8, 128.4, 122.6,
122.1, 119.7, 109.1, 54.0, 38.6, 33.8, 31.9, 26.4, 21.9. HRMS (positive
ESI; m/z): [M+H]+ calcd for C23H26N3OS+: 392.1791, found 392.1794.
2-((4-Methoxyphenyl)thio)-6-methyl-N-(2-(1-methyl-1H-
benzo[d]imidazol-2-yl)propan-2-yl)benzamide (5e): Rf 0.6 (Petroleum
ether/EtOAc = 1/1). White solid (78.4 mg, 88% yield). M.p. 79-83 °C. 1H
NMR (600 MHz, CDCl3) δ 7.81 (s, 1H), 7.70 (d, J = 7.8 Hz, 1H), 7.40 (d,
J = 8.4 Hz, 2H), 7.36-7.24 (m, 3H), 7.11 (t, J = 7.9 Hz, 1H), 7.03 (d, J =
7.8 Hz, 1H), 6.89 (d, J = 7.8 Hz, 1H), 6.84 (d, J = 8.4 Hz, 2H), 3.98 (s,
3H), 3.76 (s, 3H), 2.41 (s, 3H), 2.13 (s, 6H). 13C NMR (100 MHz, CDCl3)
δ 167.5, 159.7, 157.0, 140.7, 138.2, 137.5, 135.6, 135.1, 135.0, 129.2,
128.3, 127.8, 124.8, 122.8, 122.3, 119.6, 115.0, 109.2, 55.3, 54.9, 32.2,
31.3, 25.5, 19.3. HRMS (positive ESI; m/z): [M+H]+ calcd for
C26H28N3O2S+: 446.1897, found 446.1900.
2-(Butylthio)-N-(2-(1-methyl-1H-benzo[d]imidazol-2-yl)propan-2-
yl)cyclopent-1-enecarboxamide (6b): Rf 0.5 (Petroleum ether/EtOAc =
1/1). White solid (55.7 mg, 75% yield). M.p. 93-96 °C. 1H NMR (400 MHz,
CDCl3) δ 7.76-7.71 (m, 1H), 7.51 (s, 1H), 7.32-7.20 (m, 3H), 3.88 (s, 3H),
2.87-2.77 (m, 4H), 2.76-2.70 (m, 2H), 2.02-1.93 (m, 8H), 1.66-1.58 (m,
2H), 1.51-1.39 (m, 2H), 0.93 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz,
CDCl3) δ 164.6, 157.2, 147.5, 141.2, 137.2, 129.0, 122.4, 121.9, 119.7,
109.0, 53.8, 37.6, 33.7, 32.1, 31.8, 31.6, 26.7, 21.9, 21.8, 13.6. HRMS
(positive ESI; m/z): [M+H]+ calcd for C21H30N3OS: 372.2110, found
372.2107.
2-Methyl-N-(2-(1-methyl-1H-benzo[d]imidazol-2-yl)propan-2-yl)-6-((2-
methylfuran-3-yl)thio)benzamide (5f): Rf 0.5 (Petroleum ether/EtOAc =
1/1). White solid (47.8 mg, 57% yield). M.p. 79-85 °C. 1H NMR (600 MHz,
CDCl3) δ 7.88 (s, 1H), 7.61 (d, J = 7.8 Hz, 1H), 7.27-7.15 (m, 4H), 7.01 (t,
J = 7.8 Hz, 1H), 6.88 (d, J = 7.8 Hz, 1H), 6.69 (d, J = 8.4 Hz, 1H), 6.29 (d,
N-(2-(1-Methyl-1H-benzo[d]imidazol-2-yl)propan-2-yl)-2-
(phenylthio)cyclohex-1-enecarboxamide (6c): Rf 0.5 (Petroleum
ether/EtOAc = 1/1). White solid (64.9 mg, 80% yield). M.p. 163-166 °C.
1H NMR (400 MHz, CDCl3) δ 7.74-7.70 (m, 1H), 7.50 (s, 1H), 7.43-7.39
(m, 2H), 7.34-7.21 (m, 6H), 3.89 (s, 3H), 2.53-2.44 (m, 2H), 2.17-2.13 (m,
2H), 1.94 (s, 6H), 1.73-1.60 (m, 4H). 13C NMR (100 MHz, CDCl3) δ 168.6,
157.0, 141.0, 137.8, 137.3, 134.0, 132.6, 131.5, 129.1, 127.2, 122.6,
122.0, 119.6, 109.1, 54.2, 31.8, 31.2, 28.6, 26.2, 23.3, 21.8. HRMS
(positive ESI; m/z): [M+H]+ calcd for C24H28N3OS+: 406.1948, found
406.1950.
J = 1.2 Hz, 1H), 3.90 (s, 3H), 2.30 (s, 3H), 2.25 (s, 3H), 2.05 (s, 6H). 13
C
NMR (100 MHz, CDCl3) δ 167.4, 157.1, 157.0, 141.3, 140.6, 137.4,
136.4, 135.5, 135.3, 129.1, 127.4, 124.6, 122.9, 122.4, 119.5, 115.5,
109.3, 107.9, 54.9, 32.2, 25.5, 19.3, 11.9. HRMS (positive ESI; m/z):
[M+H]+ calcd for C24H26N3O2S+: 420.1740, found 420.1742.
2-(Ethylthio)-6-methyl-N-(2-(1-methyl-1H-benzo[d]-imidazol-2-
yl)propan-2-yl)benzamide (5g): Rf 0.5 (Petroleum ether/EtOAc = 1/1).
White solid (51.5 mg, 70% yield). M.p. 172-174 °C. 1H NMR (400 MHz,
CDCl3) δ 7.70-7.67 (m, 1H), 7.65 (s, 1H), 7.35-7.19 (m, 5H), 7.08 (d, J =
7.2 Hz, 1H), 3.99 (s, 3H), 2.92 (q, J = 7.2 Hz, 2H), 2.39 (s, 3H), 2.13 (s,
6H), 1.26 (t, J = 7.6 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 167.8, 157.0,
140.8, 140.2, 137.5, 135.6, 132.9, 128.9, 128.6, 128.4, 122.8, 122.2,
119.6, 109.2, 54.8, 32.2, 29.2, 25.5, 19.4, 14.4. HRMS (positive ESI; m/z):
[M+H]+ calcd for C21H26N3OS+: 368.1791, found 368.1780.
2-((4-Methoxyphenyl)thio)-N-(2-(1-methyl-1H-benzo-[d]imidazol-2-
yl)propan-2-yl)cyclohex-1-enecarboxamide (6d): Rf 0.5 (Petroleum
ether/EtOAc = 2/1). White solid (80.1 mg, 92% yield). M.p. 153-155 °C.
1H NMR (400 MHz, CDCl3) δ 7.78-7.70 (m, 1H), 7.51 (s, 1H), 7.44-7.37
(m, 2H), 7.32-7.21 (m, 3H), 6.88-6.81 (m, 2H), 3.89 (s, 3H), 3.78 (s, 3H),
2.42 (t, J = 6.0 Hz, 2H), 2.04 (t, J = 5.6 Hz, 2H), 1.96 (s, 6H), 1.69-1.53
(m, 4H). 13C NMR (100 MHz, CDCl3) δ 168.7, 159.7, 157.1, 141.0, 137.3,
135.7, 135.3, 133.4, 123.4, 122.6, 122.0, 119.5, 114.6, 109.2, 55.4, 54.1,
31.9, 30.8, 28.4, 26.4, 23.2, 21.9. HRMS (positive ESI; m/z): [M+H]+
calcd for C25H30N3O2S+: 436.2053, found 436.2055.
2-(Butylthio)-6-methyl-N-(2-(1-methyl-1H-benzo[d]-imidazol-2-
yl)propan-2-yl)benzamide (5h): Rf 0.5 (Petroleum ether/EtOAc = 1/1).
White solid (52.2 mg, 66% yield). M.p. 64-66 °C. 1H NMR (400 MHz,
CDCl3) δ 7.72-7.61 (m, 2H), 7.35-7.17 (m, 5H), 7.05 (d, J = 7.2 Hz, 1H),
3.98 (s, 3H), 2.89 (t, J = 7.2 Hz, 2H), 2.37 (s, 3H), 2.11 (s, 6H), 1.63-1.51
(m, 2H), 1.43-1.32 (m, 2H), 0.85 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz,
CDCl3) δ 167.8, 157.0, 140.7, 140.0, 135.6, 133.3, 128.9, 128.5, 128.3,
122.8, 122.3, 119.6, 109.2, 54.8, 34.9, 32.2, 31.3, 25.5, 22.0, 19.3, 13.6.
HRMS (positive ESI; m/z): [M+H]+ calcd for C23H30N3OS+: 396.2104,
found 396.2109.
N-(2-(1-Methyl-1H-benzo[d]imidazol-2-yl)propan-2-yl)-6-(phenylthio)-
3,4-dihydro-2H-pyran-5-carboxamide (6e): Rf 0.5 (Petroleum
ether/EtOAc = 1/1). White solid (66.0 mg, 81% yield). M.p. 175-177 °C.
1H NMR (600 MHz, CDCl3) δ 7.83 (s, 1H), 7.70 (d, J = 7.8 Hz, 1H), 7.46
(d, J = 7.8 Hz, 2H), 7.36-7.22 (m, 6H), 4.04 (t, J = 4.8 Hz, 2H), 3.88 (s,
3H), 2.51 (t, J = 6.0 Hz, 2H), 1.97-1.91 (m, 8H). 13C NMR (100 MHz,
CDCl3) δ 166.9, 157.3, 152.9, 141.0, 137.2, 131.9, 131.7, 129.0, 127.7,
122.5, 122.0, 119.6, 111.6, 109.1, 69.6, 54.0, 31.8, 26.4, 23.5, 21.6.
HRMS (positive ESI; m/z): [M+H]+ calcd for C23H26N3O2S+: 408.1740,
found 408.1743.
2-Methyl-N-(2-(1-methyl-1H-benzo[d]imidazol-2-yl)propan-2-yl)-6-
(phenylselanyl)benzamide (5i): Rf 0.5 (Petroleum ether/EtOAc = 1/1).
White solid (46.2 mg, 50% yield). M.p. 180-182 °C. 1H NMR (600 MHz,
CDCl3) δ 7.88 (s, 1H), 7.68 (d, J = 7.2 Hz, 1H), 7.52-7.48 (m, 2H), 7.35-
7.18 (m, 7H), 7.13 (d, J = 4.8 Hz, 2H), 3.95 (s, 3H), 2.44 (s, 3H), 2.10 (s,
(Z)-N-(2-(1-Methyl-1H-benzo[d]imidazol-2-yl)propan-2-yl)-3-
(phenylthio)acrylamide (6fa): Rf 0.4 (Petroleum ether/EtOAc = 1/1).
White solid (14.8 mg, 21% yield). M.p. 78-82 °C. 1H NMR (600 MHz,
DMSO-d6) δ 8.64 (s, 1H), 7.59 (d, J = 7.8 Hz, 1H), 7.46 (d, J = 7.8 Hz,
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10.1002/ejoc.201700147
European Journal of Organic Chemistry
FULL PAPER
1H), 7.43 (d, J = 7.8 Hz, 2H), 7.38 (t, J = 7.2 Hz, 2H), 7.31 (t, J = 7.2 Hz,
1H), 7.23-7.16 (m, 3H), 6.18 (d, J = 9.6 Hz, 1H), 3.76 (s, 3H), 1.73 (s, 6H).
13C NMR (150 MHz, DMSO-d6) δ 165.3, 157.6, 143.0, 141.8, 137.5,
137.3, 130.0, 129.8, 127.9, 122.0, 121.6, 119.1, 116.9, 110.0, 52.8, 31.6,
27.9. HRMS (positive ESI; m/z): [M+H]+ calcd for C20H22N3OS+: 352.1478,
found 352.1486.
7.8 Hz, 2H), 6.99-6.91 (m, 4H), 3.73 (s, 3H), 2.35-2.26 (m, 6H), 1.92 (s,
6H). 13C NMR (150 MHz, CDCl3) δ 166.6, 156.6, 144.4, 140.9, 137.7,
137.4, 137.3, 136.8, 136.6, 132.3, 132.2, 130.1, 129.7, 129.4, 129.2,
128.9, 128.43, 128.41, 122.6, 122.1, 119.7, 109.1, 54.6, 31.7, 26.0,
+
21.22, 21.18. HRMS (positive ESI; m/z): [M+H]+ calcd for C34H34N3OS2
:
564.2138, found 564.2142.
N-(2-(1-Methyl-1H-benzo[d]imidazol-2-yl)propan-2-yl)-3,3-
3,3-Bis((4-methoxyphenyl)thio)-N-(2-(1-methyl-1H-benzo[d]imidazol-
bis(phenylthio)acrylamide (6fb): Rf 0.5 (Petroleum ether/EtOAc = 1/1).
White solid (16.5 mg, 18% yield). M.p. 215-219 °C. 1H NMR (600 MHz,
DMSO-d6) δ 8.41 (s, 1H), 7.58-7.54 (m, 1H), 7.52-7.32 (m, 10H), 7.22-
7.13 (m, 2H), 5.83 (s, 1H), 3.71 (s, 3H), 1.64 (s, 6H). 13C NMR (150 MHz,
DMSO-d6) δ 164.0, 157.8, 141.8, 137.3, 136.3, 134.3, 132.5, 131.2,
2-yl)propan-2-yl)-2-phenylacrylamide (6l):
Rf 0.5 (Petroleum
ether/EtOAc = 1/1). White solid (90.6 mg, 76% yield). M.p. 90-93 °C. 1H
NMR (600 MHz, CDCl3) δ 7.75-7.70 (m, 1H), 7.49 (d, J = 7.2 Hz, 2H),
7.37 (t, J = 7.8 Hz, 2H), 7.33 (t, J = 7.2 Hz, 1H), 7.28-7.24 (m, 3H), 7.23
(s, 1H), 7.20 (d, J = 8.4 Hz, 2H), 6.93 (d, J = 8.4 Hz, 2H), 6.75 (d, J = 8.4
Hz, 2H), 6.68 (d, J = 8.4 Hz, 2H), 3.79-3.76 (m, 6H), 3.75 (s, 3H), 1.93 (s,
6H). 13C NMR (150 MHz, CDCl3) δ 166.6, 159.6, 159.4, 156.7, 142.9,
141.0, 138.2, 137.3, 136.9, 134.3, 134.2, 128.9, 128.5, 128.3, 124.2,
123.8, 122.6, 122.1, 119.6, 114.1, 114.0, 109.1, 55.3, 54.6, 31.7, 26.0.
HRMS (positive ESI; m/z): [M+H]+ calcd for C34H34N3O3S2+: 596.2036,
found 596.2040.
130.6, 130.4, 130.01, 129.97, 129.2, 122.0, 121.6, 119.1, 110.0, 55.4,
+
31.6, 27.9. HRMS (positive ESI; m/z): [M+H]+ calcd for C26H26N3OS2
:
460.1512, found 460.1517.
(Z)-2-Methyl-N-(2-(1-methyl-1H-benzo[d]imidazol-2-yl)propan-2-yl)-3-
(phenylthio)acrylamide (6g): Rf 0.4 (Petroleum ether/EtOAc = 1/1).
White solid (45.3 mg, 62% yield). M.p. 165-168 °C. 1H NMR (400 MHz,
CDCl3) δ 8.01 (s, 1H), 7.76-7.70 (m, 1H), 7.53-7.48 (m, 2H), 7.39-7.23 (m,
6H), 6.81 (d, J = 1.2 Hz, 1H), 3.92 (s, 3H), 2.15 (d, J = 0.8 Hz, 3H), 2.02
(s, 6H). 13C NMR (100 MHz, CDCl3) δ 166.2, 157.4, 140.8, 138.9, 138.1,
130.8, 129.2, 127.5, 123.7, 122.7, 122.2, 119.6, 109.2, 54.2, 32.0, 25.8,
19.7. HRMS (positive ESI; m/z): [M+H]+ calcd for C21H24N3OS+: 366.1635,
found 366.1637.
(Z)-3-((4-Fluorophenyl)thio)-N-(2-(1-methyl-1H-benzo[d]imidazol-2-
yl)propan-2-yl)-2-phenylacrylamide (6ma): Rf 0.5 (Petroleum
ether/EtOAc = 1/1). Colorless oil (41.0 mg, 46% yield). 1H NMR (600
MHz, CDCl3) δ 7.61 (d, J = 7.8 Hz, 1H), 7.51-7.47 (m, 2H), 7.46-7.37 (m,
5H), 7.30-7.20 (m, 4H), 7.03 (t, J = 8.4 Hz, 2H), 6.95 (s, 1H), 3.86 (s, 3H),
1.96 (s, 6H). 13C NMR (150 MHz, CDCl3) δ 165.5, 162.6 (d, JC-F = 246.6
Hz), 156.7, 143.2, 141.0, 137.7, 137.3, 133.3 (d, JC-F = 8.1 Hz), 133.0 (d,
JC-F = 3.3 Hz), 130.3, 129.1, 129.0, 128.3, 122.6, 122.0, 119.7, 116.3 (d,
JC-F = 21.9 Hz), 109.1, 54.4, 31.8, 26.4. 19F NMR (376 MHz, CDCl3) δ -
113.43, HRMS (positive ESI; m/z): [M+H]+ calcd for C26H25FN3OS:
446.1702, found 446.1701.
(Z)-2-Benzyl-N-(2-(1-methyl-1H-benzo[d]imidazol-2-yl)propan-2-yl)-3-
(phenylthio)acrylamide (6h): Rf 0.4 (Petroleum ether/EtOAc = 1/1).
White solid (19.4 mg, 22% yield). M.p. 66-68 °C. 1H NMR (600 MHz,
CDCl3) δ 7.72 (d, J = 7.8 Hz, 1H), 7.47 (d, J = 7.2 Hz, 2H), 7.38-7.21 (m,
11H), 7.09 (s, 1H), 6.91 (s, 1H), 3.77 (s, 2H), 3.50 (s, 3H), 1.82 (s, 6H).
13C NMR (150 MHz, CDCl3) δ 165.6, 156.7, 141.0, 140.9, 138.2, 137.7,
137.2, 130.6, 129.3, 128.9, 128.7, 127.6, 127.1, 127.0, 122.5, 122.0,
119.7, 109.1, 54.0, 40.1, 31.3, 26.5. HRMS (positive ESI; m/z): [M+H]+
calcd for C27H28N3OS+: 442.1948, found 442.1953.
3,3-Bis((4-fluorophenyl)thio)-N-(2-(1-methyl-1H-benzo[d]imidazol-2-
yl)propan-2-yl)-2-phenylacrylamide (6mb): Rf 0.6 (Petroleum
ether/EtOAc = 1/1). White solid (24.2 mg, 20% yield). M.p. 87-92 °C. 1H
NMR (600 MHz, CDCl3) δ 7.72-7.67 (m, 1H), 7.52-7.47 (m, 3H), 7.39 (t, J
= 6.6 Hz, 2H), 7.37-7.33 (t, J = 7.2 Hz, 1H), 7.29-7.22 (m, 5H), 6.99-6.94
(m, 2H), 6.90 (t, J = 9.0 Hz, 2H), 6.84 (t, J = 9.0 Hz, 2H), 3.76 (s, 3H),
1.94 (s, 6H). 13C NMR (150 MHz, CDCl3) δ 166.2, 162.6 (d, JC-F = 246.9
Hz), 162.4 (d, JC-F = 246.6 Hz), 156.6, 144.0, 140.8, 137.3, 136.6, 134.6
(d, JC-F = 8.2 Hz), 134.0 (d, JC-F = 8.3 Hz), 128.8, 128.64, 128.62, 128.4
(d, JC-F = 3.1 Hz), 128.1 (d, JC-F = 3.4 Hz), 122.8, 122.3, 119.6, 115.7 (d,
JC-F = 21.8 Hz), 115.6 (d, JC-F = 21.9 Hz), 109.2, 54.6, 31.7, 25.7. 19F
NMR (376 MHz, CDCl3) δ -113.21, -113.62. HRMS (positive ESI; m/z):
[M+H]+ calcd for C32H28F2N3OS2+: 572.1642, found 572.1645.
(Z)-2-Methyl-N-(2-(1-methyl-1H-benzo[d]imidazol-2-yl)propan-2-yl)-3-
(phenylthio)but-2-enamide (6i): Rf 0.4 (Petroleum ether/EtOAc = 1/2).
White solid (47.1 mg, 62% yield). M.p. 86-88 °C. 1H NMR (400 MHz,
CDCl3) δ 7.74-7.69 (m, 1H), 7.48 (s, 1H), 7.42-7.37 (m, 2H), 7.33-7.20 (m,
6H), 3.89 (s, 3H), 2.05 (d, J = 1.2 Hz, 3H), 1.95 (s, 6H), 1.92 (d, J = 1.2
Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 169.3, 157.0, 140.9, 137.3, 137.0,
134.4, 131.1, 129.14, 129.07, 127.0, 122.6, 122.1, 119.6, 109.1, 54.3,
31.8, 26.0, 20.1, 17.8. HRMS (positive ESI; m/z): [M+H]+ calcd for
C22H26N3OS+: 380.1791, found 380.1799.
(Z)-3-((4-Chlorophenyl)thio)-N-(2-(1-methyl-1H-benzo[d]imidazol-2-
yl)propan-2-yl)-2-phenylacrylamide
(6n):
Rf
0.5
(Petroleum
N-(2-(1-Methyl-1H-benzo[d]imidazol-2-yl)propan-2-yl)-2-phenyl-3,3-
bis(phenylthio)acrylamide (6j): Rf 0.5 (Petroleum ether/EtOAc = 1/1).
White solid (81.4 mg, 76% yield). M.p. 108-112 °C. 1H NMR (600 MHz,
CDCl3) δ 7.73-7.69 (m, 1H), 7.53 (d, J = 7.2 Hz, 2H), 7.38 (t, J = 7.2 Hz,
2H), 7.33 (t, J = 7.2 Hz, 2H), 7.29-7.23 (m, 5H), 7.22-7.11 (m, 6H), 7.04
(d, J = 7.8 Hz, 2H), 3.74 (s, 3H), 1.93 (s, 6H). 13C NMR (150 MHz, CDCl3)
δ 166.4, 156.6, 144.7, 140.9, 137.3, 136.7, 136.0, 133.5, 133.2, 132.2,
132.0, 128.8, 128.54, 128.51, 128.4, 127.6, 127.3, 122.7, 122.1, 119.7,
109.1, 54.6, 31.7, 25.9. HRMS (positive ESI; m/z): [M+H]+ calcd for
C32H30N3OS2+: 536.1825, found 536.1827.
ether/EtOAc = 1/1). White solid (73.9 mg, 79% yield). M.p. 168-171 °C.
1H NMR (600 MHz, CDCl3) δ 7.63-7.58 (m, 1H), 7.49-7.37 (m, 7H), 7.34
(s, 1H), 7.32-7.19 (m, 5H), 6.97 (s, 1H), 3.85 (s, 3H), 1.96 (s, 6H). 13C
NMR (150 MHz, CDCl3) δ 165.4, 156.7, 141.8, 140.9, 137.6, 137.2,
136.3, 134.0, 132.1, 130.9, 129.4, 129.1, 129.0, 128.4, 122.6, 122.1,
119.7, 109.1, 54.4, 31.8, 26.4. HRMS (positive ESI; m/z): [M+H]+ calcd
for C26H25ClN3OS+: 462.1407, found 462.1405.
(Z)-3-(Butylthio)-N-(2-(1-methyl-1H-benzo[d]imida-zol-2-yl)propan-2-
yl)-2-phenylacrylamide (6oa): Rf 0.5 (Petroleum ether/EtOAc = 1/1).
White solid (10.6 mg, 13% yield). M.p. 158-163 °C. 1H NMR (600 MHz,
CDCl3) δ 7.63 (d, J = 5.2 Hz, 1H), 7.43 (t, J = 5.2 Hz, 2H), 7.41-7.34 (m,
3H), 7.28-7.19 (m, 3H), 6.98 (s, 1H), 6.82 (s, 1H), 3.83 (s, 3H), 2.72 (t, J
= 4.8 Hz, 2H), 1.92 (s, 6H). 1.67-1.62 (m, 2H), 1.47-1.39 (m, 2H), 0.91 (t,
J = 4.8 Hz, 3H). 13C NMR (150 MHz, CDCl3) δ 165.7, 156.8, 143.4, 141.0,
138.4, 137.1, 129.8, 129.0, 128.9, 127.9, 122.5, 122.0, 119.7, 109.0,
N-(2-(1-Methyl-1H-benzo[d]imidazol-2-yl)propan-2-yl)-2-phenyl-3,3-
bis(p-tolylthio)acrylamide (6k): Rf 0.6 (Petroleum ether/EtOAc = 1/1).
White solid (76.7 mg, 68% yield). M.p. 85-91 °C. 1H NMR (600 MHz,
CDCl3) δ 7.72 (d, J = 6.0 Hz, 1H), 7.51 (d, J = 7.8 Hz, 2H), 7.39-7.30 (m,
3H), 7.28-7.24 (m, 3H), 7.23 (s, 1H), 7.17 (d, J = 7.8 Hz, 2H), 7.02 (d, J =
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10.1002/ejoc.201700147
European Journal of Organic Chemistry
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54.2, 36.3, 32.2, 31.8, 26.6, 21.8, 13.6. HRMS (positive ESI; m/z): [M+H]+
calcd for C24H30N3OS: 408.2110, found 408.2108.
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CDCl3) δ 7.72 (d, J = 7.2 Hz, 1H), 7.42 (d, J = 7.8 Hz, 2H), 7.36 (t, J = 7.2
Hz, 2H), 7.31 (t, J = 7.2 Hz, 1H), 7.29-7.21 (m, 3H), 6.98 (s, 1H), 3.71 (s,
3H), 2.88 (t, J = 7.8 Hz, 2H), 2.65 (t, J = 7.2 Hz, 2H), 1.95 (s, 6H). 1.62
(quint, J = 7.2 Hz, 2H), 1.48 (quint, J = 7.2 Hz, 2H), 1.40 (sext, J = 7.2
Hz, 2H), 1.28 (sext, J = 7.2 Hz, 2H), 0.91-0.83 (m, 6H). 13C NMR (150
MHz, CDCl3) δ 167.0, 156.7, 144.3, 140.9, 137.2, 136.1, 128.9, 128.3,
128.0, 122.6, 122.1, 119.7, 109.1, 54.4, 34.1, 33.5, 31.9, 31.6, 26.1, 22.1,
21.8, 13.7, 13.6. HRMS (positive ESI; m/z): [M+H]+ calcd for
C28H38N3OS2: 496.2456, found 496.2454.
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Key Topic* C-H Activation
Shuang-Liang Liu, Xue-Hong Li, Tan-
Hao Shi, Guang-Chao Yang, Hai-Li
Wang, Jun-Fang Gong,* and Mao-Ping
Song*
Page No. – Page No.
A convenient and efficient copper-promoted thiolation of (hetero)arene and alkene
C–H bonds with disulfides was achieved with ample substrate scope by using a
novel and removable 2-amino alkylbenzimidazole (MBIP-amine) directing group.
Copper-Promoted Thiolation of
C(sp2)-H Bonds Using an 2-Amino
Alkylbenzimidazole Directing Group
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