Cobalt-Catalyzed Direct C-H Thiolation of Aromatic Amides with Disulfides: Application to the Synthesis of Quetiapine

Article abstract of DOI:10.1021/acs.orglett.8b02812

A direct C(sp²)-H thiolation of aromatic amides with disulfides was developed. The coupling reaction proceeds between the thioether radical and cobaltacycle intermediate. This method exhibits a relatively broad substrate scope and high functional group compatibility. A mechanistic study indicates that the cobalt(IV) intermediate is probably formed during the course of the reaction. The thiolation product can be transformed to Quetiapine, which is an atypical antipsychotic agent approved for the treatment of schizophrenia and bipolar disorder.

Full text of DOI:10.1021/acs.orglett.8b02812

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Cobalt-Catalyzed Direct C−H Thiolation of Aromatic Amides with
Disulfides: Application to the Synthesis of Quetiapine
Mingliang Li and Jun “Joelle” Wang*
Department of Chemistry and Shenzhen Grubbs Institute, Southern University of Science and Technology, Shenzhen 518055,
China
S
* Supporting Information
ABSTRACT: A direct C(sp2)−H thiolation of aromatic amides with disulfides was developed. The coupling reaction proceeds
between the thioether radical and cobaltacycle intermediate. This method exhibits a relatively broad substrate scope and high
functional group compatibility. A mechanistic study indicates that the cobalt(IV) intermediate is probably formed during the
course of the reaction. The thiolation product can be transformed to Quetiapine, which is an atypical antipsychotic agent
approved for the treatment of schizophrenia and bipolar disorder.
ransition-metal-catalyzed coupling of radical species with
Ta cyclic metallacycle intermediate has emerged as a useful
pathway for C−H bond activation.1−4 Nevertheless, there are
rare reports utilizing this methodology for construction of the
C−X bond (X = N, O, S).2,3b The coupling of a radical with a
cyclic metallacycle intermediate is a single-electron oxidation
process [Mn → M(n+1)], which provides a high-valent metal
complex with unusual electronic and steric properties for
promoting further synthetic transformation.5 It can be said that
this method opens up an interesting avenue for C−H bond
activation via a newfangled mechanism, in which a transition
metal catalyst undergoes an unusual cyclic pathway [Mn →
M(n+1) → M(n−1) → Mn].3−5 Additionally, applying the radical
coupling to C−H bond activation could effectively expand the
type of coupling partners to radical precursors and would
accomplish rarely reported C−X bond formation (X = P, Si,
B).
fore, transition-metal-catalyzed C(sp2)−S bond formation has
recently received increasing attention.10−13 However, there are
limited examples for cobalt-catalyzed C(sp2)−H thiolation.14
In 2016, Glorius and co-workers developed the cobalt-
catalyzed chelation-assisted direct thiolation of indole deriva-
tives with thiophenols (Scheme 1a).14b Yet this methodology
Scheme 1. Cobalt-Catalyzed C(sp2)−H Thiolation
Among transition-metal-catalyzed C−H activations, the C−
X (X = N, O, S) bond formation is always accomplished by the
reductive elimination of the key C−M−X intermediate, which
is afforded via ligand exchange, transmetalation, oxidative
addition, or metal-carbene formation with a cyclic metallacycle
intermediate.6To date, there are a few reports aimed at C−X
bond formation via the radical coupling of cyclic metallacycle
species, especially in the area of employing a cobalt catalyst. In
previous work, the cobalt(III) complex was found to couple
with TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy) effectively
in delivering a cobalt(IV) intermediate.7 To further understand
the interaction between a cyclic metallacycle intermediate and
radical species, we turned our attention to the cobalt-catalyzed
C(sp2)−H bond activation using a radical precursor as the
coupling partner.
The C(sp2)−S bonds widely exist in organic functionalized
materials, pharmaceuticals, and bioactive molecules.8,9 There-
Received: September 3, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02812
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a b
,
cannot be expanded to the aromatic amides and required the
use of an expensive cobalt catalyst [Cp*Co(CO)I2]. There-
fore, we aim to accomplish the cobalt-catalyzed direct C−H
thiolation of aromatic amides via the coupling of cobaltacycle
intermediates with a thioether radical derived from disulfides in
the presence of peroxide (Scheme 1b).
Scheme 2. Scope of Aromatic Amides
We initially explored the coupling of 2-(2-methyl-
benzamido)pyridine 1-oxide (1a) with 1,2-diphenyldisulfane
(2a). To our delight, the thiolation product 3a could be
obtained in 42% yield in the presence of Co(OAc)2·4H2O (20
mol %), NaOAc (2.0 equiv), and DTBP (di-tert-butyl
peroxide) (2.0 equiv) in toluene (Table S1, entry 1). When
the catalyst loading of Co(OAc)2·4H2O was decreased to 10
mol %, the yield was improved to 74% (Table S1, entry 5).
After surveying various cobalt catalysts [e.g., CoCl2, CoBr2,
and Co(acac)2], CoBr2 was found to give the best yield of 83%
(Table S1, entries 6−8). In the absence of DTBP, no desired
product was obtained (Table S1, entry 10). The reaction yield
was decreased to 18% when the reaction was carried out
without NaOAc (Table S1, entry 10). Other bases proved to
be less efficient (Table S1, entries 13−16). No product was
obtained with silver salts such as Ag2CO3, Ag2O, AgNO3, and
AgOAc as the oxidant (Table S1, entries 17−20). Under the
optimized reaction conditions, the desired product could be
afforded in 90% yield in the presence of CoBr2 (10 mol %),
NaOAc (2.0 equiv), and DTBP (2.0 equiv) in dry toluene
(Table S1, entry 25). Apart from the pyridine N-oxide, other
directing groups including bidentate or monodentate were
inefficient, and 2-methyl-N-(quinolin-8-yl)benzamide only
provided the corresponding product in 9% yield under the
optimized conditions (Table S2).
a
Reactions conditions: CoBr2 (10 mol %), NaOAc (2.0 equiv), DTBP
(2.0 equiv), amide 1 (0.25 mmol), and 1,2-diphenyldisulfane (2a)
(0.625 mmol) were stirred in dry toluene (1 mL) at 130 °C for 18 h.
b
c
d
Isolated yield. Co(acac)2 (20 mol %). Reactions conditions: CoBr2
With the optimized reaction conditions in hand, we next
explored the scope of aromatic amides (Scheme 2). A variety
of ortho-substituted benzamide derivatives provided the
thiolation products in moderate-to-good yields (3a−d). It is
noteworthy that the thiolation reaction only occurred at the
C−H bond rather than the C−X (X = F, Cl, Br) bonds (3b−
d), which offers opportunities for further subsequent trans-
formation of the thiolation product. 2,3-Disubstituted or 2,4-
disubstituted aromatic amides all proceeded well to give the
corresponding products except the 4-fluoro-2-methyl benza-
mide derivative (3e−m). The monothiolation product 3n
could also be obtained when 2-benzamidopyridine 1-oxide
(1n) was used as a coupling partner. Interestingly, 2-(1-
methyl-1H-indole-2-carboxamido)pyridine 1-oxide (1o) could
also afford the desired product 3o in fair yield.
Next, we turned our attention to the scope of disulfide
substrates (Scheme 3). An array of 1,2-diaryldisulfides was able
to efficiently couple with benzamide 1a to give the
corresponding products (4a−i). The 1,2-diaryldisulfides with
either electron-withdrawing or electron-donating groups at the
phenyl ring all proceeded well to give the corresponding
products in moderate-to-good yields (4a−f). It is noteworthy
that this method was compatible with some functional groups
such as F, Cl, Br, CF3, Me, and OMe. Interestingly, disulfides
with bulky substituents such as mesityl, 2,4,6-triisopropyl-
phenyl, and naphthalen-2-yl also worked well, giving the
corresponding products 4g, 4h, and 4i in 86%, 79%, and 85%
yields, respectively. The disulfides with a heteroaromatic
moiety could also afford the corresponding products in
medium yields (4j−k). Furthermore, 1,2-dibenzyldisulfane
could also deliver the desired product in synthetically useful
yield (4l). The relatively low yield was probably caused by the
(5 mol %), Ni(OAc)2 (20 mol %), PPh3 (40 mol %), CsOAc (2.0
equiv), DTBP (2.0 equiv), amide 1n (0.25 mmol), and 1,2-
diphenyldisulfane 2a (0.625 mmol) were stirred in dry toluene (1
mL) at 130 °C for 24 h.
undesired transformation of the BnS radical in the presence of
DTBP.
To gain insight into the reaction mechanism, we conducted
the H/D exchange experiments. When the reaction was carried
out with benzamide 1a and D2O in the presence of CoBr2 (10
mol %) and NaOAc (2.0 equiv) in dry toluene, no H/D
exchange was observed by 1H NMR [see Supporting
Information (SI) IV, eq 1]. However, 15% of 1a was
deuterated with the addition of DTBP (2.0 equiv) (Scheme
4a), which revealed that the reversible C−H bond cleavage was
probably caused by the active cobalt(III) catalyst. Other KIE
(kinetic isotope effect) experiments were performed with two
independent reactions and the value was found to be 1.20,
indicating that the C−H bond cleavage is probably not
involved in the rate-determining step (Scheme 4b). Fur-
thermore, a series of radical trap experiments were carried out
with the addition of radical scavengers (Scheme 4c). The
reaction yield of 1a with 2a was decreased to 13% in the
presence of TEMPO (2,2,6,6-tetramethylpiperidine oxide)
(1.0 equiv), and no desired product was observed with the
addition of 4.0 equiv of TEMPO or 1,1-diphenylethylene.
These results suggest that a free-radical pathway could be
involved in the reaction. The key cobalt(IV) intermediate
generated by coupling of a thioether radical with a cobaltacycle
intermediate derived from C−H activation of 1a was detected
B
DOI: 10.1021/acs.orglett.8b02812
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a b
,
Scheme 3. Scope of Disulfides
Scheme 5. Plausible Mechanism
cobaltation to afford cobaltacycle species III. Subsequently,
radical coupling of intermediate III with the thioether radical
generated from disulfides in the presence of DTBP provides
cobalt(IV) intermediate IV, which was detected by ESI-MS
(see SI IV). Finally, reductive elimination of IV followed by
protonation furnishes the desired product 3a and cobalt(II)
catalyst to complete the catalytic cycle. The rate-determining
step could be the reductive elimination of intermediate IV.
To demonstrate the synthetic usefulness, we applied this
newly established method in synthesizing Quetiapine, which is
an atypical antipsychotic agent approved for the treatment of
schizophrenia and bipolar disorder.15 The traditional synthetic
route for accessing Quetiapine was based on the cross-coupling
of benzenethiols with aryl halides,15a,16 while our synthetic
strategy was based on the direct C−H thiolation of benzamides
(Scheme 6). The thiolation of 2-benzamidopyridine 1-oxide
a
Reactions conditions: CoBr2 (10 mol %), NaOAc (2.0 equiv), DTBP
(2.0 equiv), amide 1a (0.25 mmol), and disulfides 2 (0.625 mmol)
b
were stirred in dry toluene (1 mL) at 130 °C for 18 h. Isolated yield.
c
d
CoBr2 (20 mol %). Co(acac)2 (20 mol %), 140 °C.
Scheme 4. Mechanistic Experiments
Scheme 6. Synthesis of Quetiapine
by mass spectroscopic analysis of the reaction mixtures after 2
h.
(1n) with 1,2-diphenyldisulfane afforded the desired product
3n on gram scale. Then, benzoic acid derivative 5 was obtained
by hydrolysis of amide 3o. Subsequently, Curtius rearrange-
ment of the compound 5 and treatment with phenols delivered
carbamate 6, which underwent polyphosphoric acid promoted
cyclization and subsequent pseudohalogenation to give triflate
7. Finally, the desired Quetiapine product was obtained by
nucleophilic substitution of the piperazine derivative with
triflate 7.
Based on the aforementioned mechanistic investigations and
literature examples,4 a proposed mechanism is illustrated in
Scheme 5. Initially, coordination of benzamide 1a with a
cobalt(II) catalyst and a subsequent ligand exchange delivered
intermediate I, which was detected by ESI-MS (see SI IV).
Next, the cobalt(II) complex is oxidized by DTBP to generate
cobalt(III) intermediate II, which undergoes a reversible C−H
C
DOI: 10.1021/acs.orglett.8b02812
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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In conclusion, we have developed a cobalt-catalyzed direct
C(sp2)−H thiolation of aromatic amides with disulfides. This
reaction exhibits a relatively extensive substrate scope and high
functional group compatibility. Disulfides with bulky sub-
stituents such as mesityl or 2,4,6-triisopropylphenyl are also
found to be compatible under these reaction conditions.
Mechanistic study indicates that the C(sp2)−S bond is
probably formed by the coupling of a cobaltacycle intermediate
with a thioether radical and subsequent reductive elimination.
In addtion, this direct C(sp2)−H thiolation of aromatic amides
with disulfides was successfully applied as the key step in the
synthesis of Quetiapine. Further extension of this method
toward drug synthesis is ongoing in our laboratory.
ASSOCIATED CONTENT
* Supporting Information
■
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ACS Publications website at DOI: 10.1021/acs.or-
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: wang.j@sustc.edu.cn.
ORCID
Jun “Joelle” Wang: 0000-0001-9723-4054
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
This work is supported by Shenzhen Basic Research Program
(JCYJ20170817112532779 and JCYJ20170412152435366)
and the Shenzhen Nobel Prize Scientists Laboratory Project
(C17783101).
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DOI: 10.1021/acs.orglett.8b02812
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