Direct α-Chalcogenation of Aliphatic Carboxylic Acid Equivalents

Article abstract of DOI:10.1021/acs.orglett.9b02424

A novel approach to α-chalcogenation of aliphatic carboxylic acids has been developed by means of transforming them as the corresponding benzazoles. The catalyst system, consisting of Cu^I, DMSO, and a base, operates through a unique mechanism t

Full text of DOI:10.1021/acs.orglett.9b02424

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Direct α‑Chalcogenation of Aliphatic Carboxylic Acid Equivalents
Aniket Gupta, Ajijur Rahaman, and Sukalyan Bhadra*
Inorganic Materials and Catalysis Division, Academy of Scientific and Innovative Research, CSIR-Central Salt and Marine Chemicals
Research Institute, G. B. Marg, Bhavnagar 364002, Gujarat, India
S
* Supporting Information
ABSTRACT: A novel approach to α-chalcogenation of aliphatic
carboxylic acids has been developed by means of transforming
them as the corresponding benzazoles. The catalyst system,
consisting of CuI, DMSO, and a base, operates through a unique
mechanism to access a range of practically significant thio- and
selenoethers that are otherwise challenging to achieve. The
applicative potentials have been exemplified by utilizing the
resultant chalcogenated compounds as the precursor for the
synthesis of biologically pertinent molecules and synthetic
intermediates.
he selective functionalization of a specific C−H bond
Tplays a central role to access targeted molecular scaffolds
in modern organic synthesis.1 Despite the many successes, the
catalytic functionalization of relatively inert C−H bonds of
alkanes appears to be an arduous challenge to synthetic
chemists.2 In general, these C−H functionalizations rely on the
directed strategy in which a chelating directing group of the
substrate assists to hold the transition metal catalyst close to
the cleavable C−H bond.2a−e Essentially, the C−H bond
positioned at an appropriate distance (typically at the β-, γ-, or
even δ-position) with respect to the directing group is
activated via the formation of thermodynamically favored
five- or six-membered metallacycle intermediates, by using
primarily palladium catalysts3 and others.4 Nevertheless, the
proximal α-functionalization of common substrates, e.g.,
carboxylic acids, amides, imines, etc., via a directed strategy
was not achieved presumably due to the requirement of a
strained four-membered metallacycle intermediate.5 In this
paper, we describe a novel approach that enables the direct α-
functionalization of aliphatic carboxylic acid equivalents.
Chalcogenated acetic acids, in particular, α-thiolated acetic
acid derivatives, are prevalent in a myriad of biological systems,
approved drugs, and functional materials.6 Thus, their
synthesis via the regiospecific installation of a thio-based
substituent (C−S) at an unactivated C−H bond of aliphatic
carboxylic acid equivalents is a noteworthy transformation of
fundamental importance, but there are several hitches,
including the reported catalyst retarding effect of sulfur
compounds.7 To date, a number of methods have appeared
to access β- and γ-thiolated carboxylic acids via the classical
directed strategy.8 However, the direct synthesis of α-thiolated
carboxylic acid equivalents has remained elusive.
would be rather activated by the azole, thereby facilitating the
required chalcogenation process. This was further supported
by our recent finding of a C−H methoxylation process under
palladium catalysis.9 We herein report a novel α-chalcogena-
tion strategy (ArS−C and ArSe−C) of 2-alkylbenzazoles, as
synthons of aliphatic carboxylic acids, by means of a copper-
based catalyst system (Scheme 1).
Scheme 1. C(sp3)−H Chalcogenations of Aliphatic
Carboxylic Acid Equivalents
To accomplish the title transformation, we have conceived
another approach. We envisioned that if aliphatic carboxylic
acids were converted into the corresponding 2-alkylazoles, the
α-position with respect to the heterocycle in the 2-alkyl chain
Received: July 12, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02424
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
We commenced our investigation by studying the reaction
between 2-benzylbenzoxazole (1a) and diphenyldisulfide (2)
in the presence of CuBr2 and K3PO4 under aerial conditions
(Table 1 and Table S1, Supporting Information). However,
aromatic rings. In general, monothiolated compounds were
formed as the single product with few cases of bis-thiolated
compounds. The extent of mono- and bis-thiolation depends
upon the steric crowding of the two coupling partners (e.g.,
4aa vs 4na or 4pa vs 4xa). However, alkylthio substituents
could not be installed under the optimized condition.
a
Table 1. Optimization of the Reaction Condition
With the success of thiolations, we subsequently applied this
approach to analogous selenylation reactions (Scheme 3). It
soon turned out that the Cu-based system was equally effective
for the phenylselenylation of 2-benzylazoles with diphenylde-
selenide even at ambient temperature (25 °C). The new
selenylated compounds are believed to function as important
intermediates in the synthesis of complex structures.
entry
S source
[Cu]
additive
4aa (%)
5 (%)
To gain insight into the mechanism, several experiments
were carried out (see the Supporting Information). The
presence of a radical quencher, e.g., 2,2,6,6-tetramethylpiper-
idine-N-oxyl (TEMPO) or 2,6-di-tert-butyl-4-methylphenol
(BHT) (1.5 equiv each), completely suppressed product
formation, suggesting the involvement of radical species.13
We speculated that 2-alkylbenzazoles might act as an
electron donor that transfers a single electron to the copper
catalyst in a manner similar to that of aryl ketones as described
by Lei et al.11 To validate this assumption, EPR experiments
were conducted (see the Supporting Information). When the
reaction between 1a and CuI in DMSO was monitored by
EPR, a the intensity of the signal at g = 2.166 for CuII increased
steadily with time. However, no signal for CuII was observed
when the reaction was performed in the presence of K3PO4.
These results suggest that CuII generated in situ, via the
oxidation of CuI by DMSO, was rapidly reduced to CuI
through single-electron transfer (SET) from 1a in the presence
of K3PO4. Next, we carried out the reaction of 1a with CuBr2
in DMF in the absence and presence of K3PO4. The EPR of
the reaction without K3PO4 revealed that the initial signal for
CuII remained unchanged while that of CuII entirely
disappeared over time for the reaction with K3PO4. Moreover,
the reactive DMSO radical was also detected by a low-
temperature EPR experiment (see the Supporting Informa-
tion).14 These experiments not only confirmed our postulation
but also evidenced that DMSO had served as the oxidant for
the CuI to CuII transition in this reaction.11
When benzylic substrates holding conjugated functions, e.g.,
amides, ester, carboxylic acid, imine, phenyl, etc., were
subjected to thiolation, either very little or no desired thiolated
products were obtained (see the Supporting Information). We
speculate that the carbo-radicals formed in the case of 2-
alkylazoles are rather stabilized by the azole ring. Furthermore,
a stabilized thio radical, e.g., arylthio radicals, might be
required for a successful thiolation, because the attempted
thiolations by employing either a free alkylthiol or
dialkyldisulfide led to the formation of undesired thiolated
compounds presumably via the C(sp3)−H bond oxidation in
the alkylthio substituent (Scheme 4).
1
2
3
4
5
6
2
2
3
3
3
3
3
3
CuBr2
CuBr2
CuBr2
CuI
CuI
CuI
air
−
−
0
38
49
79
80
84
0
80
25
16
8
<5
0
−
b
picolinic acid
c
−
−
−
d
7
8
CuI
−
14
0
e
7
a
Reaction conditions: 1a (0.5 mmol), 2 or 3a (1.1 mmol), Cu salt (20
mol %), K3PO4 (1.0 mmol), DMSO (6 mL), N2 atmosphere, 90 °C, 8
b
c
h. With 20 mol % 2-picolinic acid, 12 h. With 10 mol % CuI.
d
e
Without K3PO4. For 24 h. BO = benzoxazole.
ketone 5 was the sole product due to a known copper-
catalyzed benzylic oxygenation process (entry 1).10 To
circumvent this problem and inspired by the report of Lei et
al. that DMSO can be utilized as a mild and selective oxidant
for CuI species, we carried out the thiolation under inert
conditions that provided 4aa in an isolable quantity (entry
2).11 Because thiols are known to dimerize into the
corresponding disulfide upon heating in DMSO, we used
thiophenol (3) directly and found that 4aa was formed in a
slightly improved yield (entry 3).12 Replacing CuBr2 with CuI
resulted in significant enhancement of the product yield (entry
4). The use of 2-picolinic acid among the other N-,O-ligands
provided comparable yields with regard to the ligand-free
reaction (entry 5). Gratifyingly, the yield was further improved
by reducing the copper loading up to 10 mol % (entry 6). Any
additional modification of the reaction parameters gave an
inferior result in terms of the yield of 4aa (see Table S1).
Control experiments revealed that the thiolation does not
proceed in the absence of any base (entry 7). Without CuI, the
reaction becomes sluggish, giving 4aa only in traces even after
a prolonged period (entry 8). These findings point out that
CuI together with a base, e.g., K3PO4, in DMSO constitutes
conceivably the most essential component of the catalyst
system.
Next, via application of the optimized reaction condition, a
series of 2-alkyl- and 2-benzylbenzazoles with varied
substitution patterns were consistently converted into the
corresponding α-thiolated derivatives in synthetically useful
yields (Scheme 2). Furthermore, a diverse range of functional
groups, including fluoro, chloro, methyl, methoxy, bromo,
nitro, amine, pyridyl, etc., were tolerant to the reaction
condition. Notably, the competitive thiolation at the cross-
coupling sensitive C(aryl)−Br and C(aryl)−Cl bonds was
entirely repressed. For 2-benzylbenzazoles, the thiolation
occurred regiospecifically at the C(sp3)−H bonds adjacent to
the azole rings without any concomitant thiolation at the
On the basis of these studies, we propose a mechanistic
pathway outlined in Scheme 5. In a catalytic cycle, the CuI
catalyst is initially oxidized by DMSO to give a CuII species,
which upon a base-mediated SET from 2-alkylazole 1
regenerates the CuI species.15 The carbo-radical thus produced
from 1 reacts readily with the in situ-formed disulfide to furnish
α-thiolated product 4. We believe that a similar mechanism is
also operational for the selenylation reaction.
Finally, the synthetic practicality of the new approach was
established by a gram-scale synthesis (from 1.26 g, 6 mmol of
B
DOI: 10.1021/acs.orglett.9b02424
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Letter
a
Scheme 2. Copper-Catalyzed Thiolation of 2-Alkylbenzoxazoles and Benzothiazoles
a
b
Reaction conditions: 1 (0.5 mmol), 3 (1.1 mmol), CuI (10 mol %), K3PO4 (1.0 mmol), DMSO (3 mL), N2 atmosphere, 90 °C, 6−10 h. Twelve
c
d
e
f
g
hours. Two hours. Fourteen hours. With 20% CuI and 20% picolinic acid. Three hours. Twenty-four hours. BT = benzothiazole.
a
Scheme 3. Scope of C(sp3)−H Phenylselenylation
Scheme 4. Plausible Mechanistic Pathway
1a) of 4ad (1.45 g, 61%). Subsequently, 4ad was transformed
into α-thilolated carboxylic acid 7, which was further converted
into a bioactive sphingosine 1-phosphate antagonist 8 that is
capable of preventing glaucoma, dry eye, and angiogenesis-
related diseases.9,16 Additional applications were demonstrated
via the conversion to a sulfone 9 and a ketal 10 giving access to
important benzothiazole derivatives, which can be successively
transformed into a ketone or an aldehyde by a literature
method.17
a
Reaction conditions: 1 (0.5 mmol), Ph2Se2 (0.65 mmol), CuI (10
mol %), K3PO4 (1 mmol), DMSO (3 mL), N2 atmosphere, 25 °C, 6
h. Two hours. Ten hours.
b
c
C
DOI: 10.1021/acs.orglett.9b02424
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Organic Letters
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Scheme 5. Transformations of α-Thiolated Compounds
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: sbhadra@csmcri.res.in.
ORCID
Sukalyan Bhadra: 0000-0003-1266-0930
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank DST (Grant DST/INSPIRE/04/2015/
002248), CSIR (for a fellowship to A.R.), “Analytical and
Environmental Science Division and Centralized Instrument
Facility” of CSIR-CSMCRI for instrument facilities, and Dr. E.
Suresh of CSIR-CSMCRI for X-ray crystallographic analysis.
CSIR-CSMCRI Communication 070/2019.
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