Lewis Acid/Br?nsted Acid Controlled Pd(II)-Catalyzed Chemodivergent Functionalization of C(sp2)-H Bonds with N-(Arylthio)i(a)mides

Article abstract of DOI:10.1021/acs.orglett.8b01281

An efficient and chemodivergent palladium-catalyzed thiolation (C-S) and imidation (C-N) of directing group-assisted C-H bonds have been accomplished employing N-(arylthio)imides in combination with either Br?nsted acid or Lewis acid, respectively. Notable features of the developed methodologies include excellent diversity, high functional group tolerance, wide substrate scope, and use of a single N-S reagent. Importantly, the developed hypothesis was also successfully extended to the amidation of C-H bonds. A plausible mechanistic pathway was proposed based on the preliminary mechanistic study.

Full text of DOI:10.1021/acs.orglett.8b01281

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Lewis Acid/Brønsted Acid Controlled Pd(II)-Catalyzed
Chemodivergent Functionalization of C(sp2)−H Bonds with
N‑(Arylthio)i(a)mides
Manthena Chaitanya and Pazhamalai Anbarasan*
Department of Chemistry, Indian Institute of Technology Madras, Chennai-600036, India
S
* Supporting Information
ABSTRACT: An efficient and chemodivergent palladium-catalyzed thiolation (C−S) and imidation (C−N) of directing group-
assisted C−H bonds have been accomplished employing N-(arylthio)imides in combination with either Brønsted acid or Lewis
acid, respectively. Notable features of the developed methodologies include excellent diversity, high functional group tolerance,
wide substrate scope, and use of a single N−S reagent. Importantly, the developed hypothesis was also successfully extended to
the amidation of C−H bonds. A plausible mechanistic pathway was proposed based on the preliminary mechanistic study.
Scheme 1. Metal-Catalyzed Functionalization of C−H Bond
to C−N and C−S Bonds
electivity is a fundamental challenge in organic synthesis,
Sand it has been the prime focus to achieve the maximum
synthetic efficiency in various synthetic sequences. Among
these, chemoselective transformations have provided a
significant advantage to simplify the synthetic strategies for
complex molecules, due to the efficiency to target a specific site
in a polyfunctionalized target.1 In this context, transition-metal-
catalyzed direct functionalization of an abundant C−H bonds
has seen exponential growth in recent decades,2 where high
regioselectivity for ortho C−H bonds was achieved with a
directing group. However, chemoselectivity in the C−H bond
functionalization has been scarcely studied.
Particularly, transition-metal-catalyzed C−S and C−N bond
formations via functionalization of C−H bonds have gained
significant attention.3 For instance, direct functionalization of
C−H bonds to C−S bonds include metal-free4 and transition-
metal-catalyzed5 thiolation employing various electrophilic
sulfenylating reagents such as diaryldisulfide, N-(arylthio)-
succinimide, etc. On the other hand, the transition-metal-
catalyzed amination of C−H bonds was developed under either
oxidative conditions with amines6 or the directed C−H
amination employing electrophilic nitrogen sources having a
weak N−X bond,7 such as chloramines, hydroxyl amines, and
azides, under redox neutral conditions (Scheme 1a). However,
no unified approach for the construction of either a C−S or C−
N bond from a C−H bond employing a single electrophilic
reagent has been demonstrated in the literature. Herein, we
disclose a unified approach for palladium-catalyzed thiolation
and i(a)midation of a C−H bond employing N-(arylthio)i(a)-
mide as a suitable reagent in the presence of either a Brønsted
acid (BA) or Lewis acid (LA), respectively.
in which the sulfur and nitrogen are attached to a good leaving
group (LG).6,7 We envisioned N-(arylthio)i(a)mides (N−S
reagent) in combination with either a BA or LA as a suitable
reagent for the divergent functionalization of C−H bonds to
either C−S or C−N bonds. It was anticipated that a BA and LA
would coordinate with the amide oxygen and sulfur of 1,
respectively, and as a consequence either the i(a)mide or
arylthio moiety could selectively act as a good leaving group to
drive the chemodivergent functionalization (Scheme 1b).
Successful development of these reactions would provide
ready access to either C−S or C−N bonds from a single
reagent, viz N-(arylthio)i(a)mides in the metal-catalyzed C−H
bond functionalization (Scheme 1c).
The literature strategies for the functionalization of C−H
bonds to C−S and C−N bonds utilize an electrophilic reagent
Received: April 23, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01281
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Based on the hypothesis, palladium-catalyzed and BA-
mediated thiolation of C−H bond was investigated employing
2-phenylpyridine 2a as a model substrate. The initial reaction of
2-phenylpyridine 2a and 2 equiv of N-(phenylthio)phthalimide
1a in the presence of 5 mol % of Pd(OAc)2 and 20 equiv of
acetic acid in toluene at 100 °C did not afford the expected
thiolation product 3a (Table 1, entry 1). Gratifyingly, switching
Scheme 2. Palladium-Catalyzed Arylthiolation of Arenes
Table 1. Optimization of Palladium-Catalyzed Divergent
a
Functionalization of C−H Bond with N−S Reagent
b
yield (%)
temp
(°C)
time
(h)
entry
additive (X equiv)
solvent
3a
4a
1
2
3
4
AcOH (20)
toluene
AcOH
AcOH
AcOH
AcOH
toluene
toluene
toluene
toluene
100
100
80
18
18
18
18
18
18
36
36
36
36
−
53
−
−
−
−
−
−
20
−
−
−
−
5
120
120
100
120
120
120
120
63
74
80
−
−
−
c
5
d
6
AcOH (20)
CuI (0.5)
AgOAc (0.5)
CuBr (0.5)
7
8
−
53
77
9
a
1
All are isolated yields. † Yield based on H NMR. ‡ 1 mmol scale
10
Cu(OAc)2·H2O (0.5) toluene
−
reaction.
a
Reaction conditions: 2a (0.2 mmol, 1 equiv), 1 (0.4 mmol, 2 equiv),
b
Pd(OAc)2, additive, toluene (1 mL), temp, time. Py = 2-Pyridinyl. All
are isolated yields. 10 mol % of Pd(OAc)2. N-(Phenylthio)-
succinimide 1b was used instead of 1a.
c
d
moderate to good yields. It is important to note that various
functional groups such as OAc, OTs, and carbamate on the
arene moiety were well tolerated and gave products 3j−3l in
63%, 50%, and 73% yields, respectively.
to acetic acid as a solvent afforded 3a in 53% yield, where the
complete decomposition of 1a was observed (Table 1, entry 2).
This successfully demonstrates the significance of acetic acid in
C−S bond formation and the unique activation of 1a.
Similarly, various substituents such as methyl, methoxy, and
fluoro on the pyridine-directing group were also well tolerated
and gave the thiolated products 3m−3o in good yields. In
addition, other directing groups such as quinoline, isoquinoline,
pyrimidine, and pyrazole were also proven to be good directing
groups in the C−H bond thiolation. Next, the effect of various
substituents on the arylthio moeity of 1b under the optimized
conditions was examined (Scheme 2). Thiolating reagents
derived from methyl, methoxy, and halogenated thiophenol, as
well as 2-naphthylthiol furnished the corresponding products
3t−3x in good yields.
Subsequently, the methodology was extended to the
thiolation of the C(sp2)−H bond of alkenes. To our delight,
reaction of 2-(cyclohexen-1-yl)pyridine 5a with 1b under the
optimized conditions afforded the thiolated product 6a in 77%
yield, and it is worth noting that this is the first report on the
thiolation of alkenes (Scheme 3). Subsequently, various
substituted cyclohexenylpyridine and cycloalkenylpyridines
were examined, which afforded products 6b−6g in good yields.
1,1-Disubstituted alkenes also showed compatibility to furnish
products 6h−6i in moderate yields. Furthermore, the reaction
of 5a with various thiolating reagents gave products 6j−6n in
excellent yields.
Subsequently, decreasing the temperature led to only 5% of
3a, but increasing the temperature to 120 °C gave the product
3a in 63% yield (Table 1, entries 3 and 4). Changing the
loading of Pd(OAc)2 to 10 mol % gave the product 3a in 74%
yield at 120 °C (Table 1, entry 5). Interestingly, a similar result
was observed using N-(phenylthio)succinimide 1b as the
reagent in toluene at 100 °C with 20 equiv of AcOH (Table
1, entry 6). Successively, Pd-catalyzed and LA-mediated
imidation of C−H bond was studied. The reaction of 2a with
1a provided the product 4a in 20% yield in the presence of 5
mol % of Pd(OAc)2 and 0.5 equiv of CuI in toluene at 120 °C,
and importantly, no thiolation product was observed (Table 1,
entry 7). Next, to improve the yield of imidation, various
copper and silver based Lewis acids were examined, and the
best yield (77%) was achieved with 0.5 equiv of Cu(OAc)2·
H2O (Table 1, entries 7−10; see Supporting Information (SI)).
After identifying the optimal conditions for the divergent
functionalization of the C−H bond either to C−S or C−N
bonds by simple switching of a BA or LA, the scope and
generality of the palladium-catalyzed thiolation was envisaged.
Initially, the effect of various groups on the arene moiety was
investigated with 1b, since it gave comparable reactivity and
yield under mild conditions (Scheme 2). Electron-neutral and
-donating groups on the arene gave the corresponding thiolated
products 3b−3e in good yields. Similarly, formation of halogen-
containing arylthiolated products 3f−3h were achieved in
After the successful demonstration of Pd-catalyzed and BA-
mediated thiolation of C−H bonds, the scope and generality of
the Pd/Cu cocatalyzed imidation of arenes were investigated
(Scheme 4). Simple alkyl, electron-donating, and halogen-
containing arenes gave imidated products 4a−4h in ∼70%
yield. Importantly, enolizable ketone, carbonate, and carba-
B
DOI: 10.1021/acs.orglett.8b01281
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Next, the utility of the developed transformation was
demonstrated through orthogonal functionalization and in-
direct amination of the C−H bond. Thus, synthesis of the
orthogonally functionalized product 8 was accomplished via the
Pd-catalyzed and AcOH-mediated thiolation of the C−H bond
of 2a to 3a, followed by the Pd/Cu cocatalyzed imidation in
32% yield for two steps (Scheme 6a). Furthermore, the imide
Scheme 3. Palladium-Catalyzed Arylthiolation of Alkenes
Scheme 6. Synthetic Utility
a
1
All are isolated yields. † Yield based on H NMR.
Scheme 4. Pd/Cu Cocatalyzed Imidation of C−H Bond
in 4a, 4c, 4e, and 4o was transformed to the amine by reaction
with hydrazine hydrate in up to 62% overall yield,
demonstrating a two-step approach to amination of C−H
bonds (Scheme 6b).
To gain insight into the reaction mechanism, a series of
control experiments, as well as variable temperature FTIR and
NMR studies, were performed (Scheme 7). Treatment of 2a
Scheme 7. Mechanistic Investigation
mates were well tolerated under the optimized conditions and
afforded products 4i−4k in good yields. Substituted pyridines,
isoquinoline, and pyrazole-directed imidation gave products
4l−4o in good yields. Notably, the optimized conditions are
also suitable for the synthesis of imidated alkene 4p via
imidation of the C−H bond of alkene.
Next, the extension of the developed methodology for the
amidation of the C−H bond was envisaged. Among the various
reagents examined, the reaction of N-(phenylthio)benzamide
1c (2 equiv) with 2-phenylpyridine 2a (1 equiv) under the
optimized conditions afforded the amidated product 7 in 30%
yield, along with the formation of dithiolated product 3′ in 24%
yield (Scheme 5). This reaction indicated that the hypothesis
could be extended to the amidation of the C−H bond.
and 1b in the presence of 5 mol % of palladacycle A as the
catalyst, synthesized from 2a and Pd(OAc)2 and 20 equiv of
AcOH, furnished the product 3a in 89% yield. Similarly,
formation of the imidation product 4a was also observed in
70% yield from 2a under the optimized conditions with 5 mol
% of palladacycle A.
Scheme 5. Pd/Cu Cocatalyzed Amidation of C−H Bond
On the other hand, a stoichiometric reaction of palladcycle A
with 4 equiv of 1b and 40 equiv of AcOH afforded the product
3a in 28% yield. Surprisingly, no reaction was observed with
palladacycle A under the imidation conditions with 4 equiv of
1a. Expecting that the dimeric palladacycle A may be relatively
C
DOI: 10.1021/acs.orglett.8b01281
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
stable under the reaction conditions, as well as to release the
product from the catalyst, the addition of an equimolar amount
of additives such as pyridine, PPh3, and NaOAc was examined.
However, significant improvement was not observed in either
the thiolation or imidation reactions. Interestingly, addition of
2l under the imidation conditions with A gave a mixture of
imidated products 4a and 4l in 26% yield. These results suggest
that (i) dimeric palladacycle A may be the resting state of the
catalyst, (ii) the active monomeric catalyst may be generated
from A, and (iii) a bulky nucleophile such as 2-arylpyridine is
essential to release the product from a palladium complex.
Next, variable temperature FTIR and NMR studies of 1b
with acetic acid and 1a with Cu(OAc)2 were studied to
understand their mode of interaction. Interestingly, a significant
shift in CO stretching frequency from 1731 to 1717 cm−1
was observed in the FTIR with acetic acid and the same was
absent with Cu(OAc)2 (see SI). It was supported by the
downfield shift of the carbonyl carbon (175.2 ppm to 175.7
to allow the synthesis of arylthiolated and imidated products in
good yields. In addition, the developed methodology was
successfully extended to the amidation of an aryl C−H bond.
Notably, utility of the developed methodology was demon-
strated through the orthogonal functionalization and a two-step
amination of C−H bonds. Furthermore, a possible mode of
activation of N-(arylthio)imides with a BA/LA and a plausible
mechanism was also proposed based on the preliminary
mechanistic investigation.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b01281.
1
Experimental details, characterization data, H and 13C
NMR spectra of isolated compounds (PDF)
1
ppm) in the 13C NMR with AcOH. In the H NMR, no
significant change in the aromatic signal was observed with
AcOH. On the other hand, a downfield shift of aromatic
protons (6.74−6.93 ppm to 6.83−7.01 ppm) was observed with
Cu(OAc)2. In addition, a downfield shift in the sulfur attached
quaternary carbon of phenyl was also observed in the 13C
NMR. These observations suggest that the AcOH protonates
the imide oxygen and Cu(OAc)2 coordinates with the sulfur.
Based on the preliminary studies mentioned above and
earlier reports on the thiolation and imidation of C−H bonds,3b
a plausible mechanism was proposed for the developed
transformations (Scheme 8). The reaction starts with the
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: anbarasansp@iitm.ac.in.
ORCID
Pazhamalai Anbarasan: 0000-0001-6049-5023
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Indian Institute of Technology Madras (Project
No. CHY/16-17/840/RFIR/ANBA) for financial support.
M.C. thanks CSIR, New Delhi for a fellowship.
Scheme 8. Plausible Mechanism
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