Ligand-Promoted RhIII-Catalyzed Thiolation of Benzamides with a Broad Disulfide Scope

Article abstract of DOI:10.1002/anie.201903511

A ligand-promoted Rh^III-catalyzed C(sp²)?H activation/thiolation of benzamides has been developed. Using bidentate mono-N-protected amino acid ligands led to the first example of Rh^III-catalyzed aryl thiolation reactions directed by weakly coordinating directing amide groups. The reaction tolerates a broad range of amides and disulfide reagents.

Full text of DOI:10.1002/anie.201903511

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Accepted Article
Title: Ligand-Promoted Rh(III)-Catalyzed Thiolation of Benzamides with
a Broad Scope of Disulfides Reagents
Authors: Yan-Shang Kang, Ping Zhang, Min-Yan Li, You-Ke Chen,
Hua-Jin Xu, Jing Zhao, Wei-Yin Sun, Jin-Quan Yu, and Yi Lu
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201903511
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10.1002/anie.201903511
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Ligand-Promoted Rh(III)-Catalyzed Thiolation of Benzamides with
a Broad Scope of Disulfide Reagents
Yan-Shang Kang,† Ping Zhang,† Min-Yan Li,‡ You-Ke Chen,† Hua-Jin Xu,† Jing Zhao,† Wei-Yin Sun,†,*
Jin-Quan Yu,‡,* Yi Lu†,*
Abstract:
A
ligand-promoted
Rh(III)-catalyzed
C(sp2)–H
activation/thiolation of benzamides has been developed. Using the
bidentate mono-N-protected amino acid ligands allows the first
example of weakly coordinating directing amide groups directed
Rh(III)-catalyzed aryl thiolation reactions. The reaction tolerates a
broad scope of amides and disulfide reagents.
It is well known that thiol moieties are widely existed in natural
products,[1] pharmaceutical intermediates[2] and polymer
materials[3] and play important roles in modifying their physical
and biological properties. In the past few decades, thiolation
chemistry has been recognized as a prominent branch of
synthetic organic chemistry in consequence of unremitting
exploration and practice.[4] One of the most effective protocols to
introduce thiol motifs is the Ullmann coupling reactions coupling
aryl/vinyl halides and thiols/thioethers in the presence of
palladium[5] or other transition metal catalysts. Recently, lots of
efforts have been made in transition metal catalyzed C–H
thiolation reactions. Seminal work reported by Yu and co-workers
demonstrated that a strongly coordinating pyridine directing group
facilitated the Cu-mediated direct thiolation of 2-phenylpyridine
with high ortho-selectivity (Scheme 1a).[6] Daugulis’ group later
improved this protocol to the sulfonation of benzonic acid
derivatives using 8-aminoquinoline auxiliaries as bidentate
directing groups(Scheme 1b).[7] Other strongly coordinating
directing groups, including pyrimidine,[8] together with some other
chelating groups,[9] were also successfully used in the C–H
thiolation reactions. While the previous strategies are promising,
to date, C–H activation/thiolation reactions using weakly
coordinating directing groups are still rare because of the strong
coordination of sulfur to catalytic centers.[10] Herein, we report a
mono-N-protected amino acid (MPAA) promoted weakly
Scheme 1. Transition-metal-catalyzed C–H thiolation reactions.
Introduced by Yu and coworkers in 2008, MPAAs have
proven to be privileged ligands in Pd(II)-catalyzed
enantioselective C–H activation.[11] Since then, MPAAs exhibited
extraordinary potentials in controlling the products’ configuration
and accelerating the reaction rate in Pd-catalyzed C–H activation
reactions.[12] However, MPAA promoted other metal catalyzed C–
H activations are still quite rare.[13] In 2016, Liu’s group developed
a Ni-catalyzed C–H activation/thiolation reaction enabled by
amino acid auxiliary as a bidentate directing group.[14] Inspired by
this work, and encouraged by our previous work focusing on the
ligand-promoted Rh(III)-catalyzed olefination,[15] arylation[16] and
amination[17] of N-pentafluorophenyl benzamides, we intended to
apply this weakly coordinating monodentate directing group to
Rh(III)-catalyzed ortho-C–H thiolation reaction with the assistance
of amino acid derivatives, supposing that the coordination of
amino acid ligand to the rhodium center could suppress the
catalyst deactivation caused by the strong sulfur coordination.
With this consideration in mind, we firstly conducted 18 ligands
study for the Rh(III)-catalyzed coupling of amide 1aa and phenyl
disulfide 2a, using 5 mol% [RhCp*Cl2]2, 20 mol% ligand, and 1.5
equiv. of Ag2O in dichloromethane (DCM) at 70 °C for 12 h (Table
1). Among all of the tested N-Fmoc amino acids, Fmoc-leucine
and Fmoc-isoleucine afforded higher yields than the others (entry
coordinating
amide
directed
Rh(III)-catalyzed
C–H
activation/thiolation of benzamides.
[a]
Y.-S. Kang, P. Zhang, Y.-K. Chen, Dr. H.-J. Xu, Prof. Dr. J. Zhao,
Prof. Dr. W.-Y. Sun, Prof. Dr. Y. Lu
Coordination Chemistry Institute, State Key Laboratory of
Coordination Chemistry, School of Chemistry and Chemical
Engineering, Nanjing National Laboratory of Microstructures,
Collaborative Innovation Center of Advanced Microstructures,
Nanjing University, Nanjing 210023, China.
E-mail: sunwy@nju.edu.cn; luyi@nju.edu.cn
[b]
Dr. M.-Y. Li, Prof. Dr. J.-Q. Yu
Department of Chemistry, The Scripps Research Institute, 10550 N.
Torrey Pines Road, La Jolla, California 92037, USA.
E-mail: yu200@scripps.edu
Supporting information for this article is given via a link at the end of
the document.
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1, 2). Further tuning of the steric hinderance of protecting group
for leucine showed that large groups led to a higher ratio of mono-
/di- thiolation products (entries 1, 9). However, no suitable ligand
was found to improve the mono-/di- ratio to a satisfactory level.
Some bulky phosphine ligands and quinolone-based ligands have
been studied as well, and we found that MPAAs were the
privileged ligands to accelerate this reaction (Table S2). On the
contrary, Boc-leucine afforded exclusive dithiolated product when
the temperature was increased to 90 °C (entry 11). When the Boc-
group was absent, tert-leucine led to dramatically decrease of
yield into 10% (entry 18), suggesting that an electron-withdrawing
N-protecting group is critical to the catalyst turnover by
suppressing catalyst poisoning. Besides, amino acids with
hydrophilic side chain are unfavorable to the reaction (entries 15-
17). Control experiment showed that only 5% monothiolated
product was observed without ligand, indicating the important
roles of amino acid ligands in stabilizing the catalytic centers and
promoting the C–H activation (entry 19). Further optimization of
solvents and oxidants revealed that DCM and Ag2O were the best
choice for the thiolation reaction (See supporting information, SI).
Reducing catalyst loading to 2.5 mol% decreased the yield to 73%
(34% mono- and 39% di-).
well tolerated to afford the products (3o-3p) in satisfactory yields.
The strong coordinating pyridine amide provided desired product
3q in a yield of 60% with 20 mol% catalyst loading. Unique
dithiolated products with good to excellent yields were obtained
for the substrates with either electron-donating or electron-
withdrawing groups at the para-position of the benzene ring (3aa-
3al). For the substrates with less hindered meta-substituted
groups, the dithiolated products could not be ignored (3am-3ao),
reaching up to 15%. Once the steric hindrance of the substituted
groups was further reduced, the di-substituted products become
the only product (3ap). We also prepared 3a on gram-scale to
demonstrate the synthetical utility of this transformation. The
auxiliary can be readily removed by BF3·Et2O in ethanol, to afford
the corresponding ethyl esters in good yields (see the Supporting
Information).
Table 2. Scope with respect to benzamide substrates.a, b
Table 1. Ligand screening.a, b
[a] Conditions: 1aa (0.1 mmol), 2a (0.1 mmol), [RhCp*Cl2]2 (5 mol %), Ag2O
(0.15 mmol), Ligand (20 mol %) and dry DCM (2 mL) under N2, 12 h, 70 °C; [b]
The yield was determined by 1H NMR analysis of crude product using CH2Br2
as an internal standard; [c] Under N2, 12 h, 90 °C.
[a] Conditions: 1 (0.1 mmol), 2a (0.1 mmol), [RhCp*Cl2]2 (5 mol %), Boc-Leucine
(20 mol %), Ag2O (0.15 mmol) and DCM (2 mL) under N2, 12 h, 90 oC. [b] Yields
of isolated products are given. [c] [RhCp*Cl2]2 (10 mol %).
With the optimized conditions in hand, we further
investigated the scope of the substrates. Overall, the thiolation
reaction possesses high functional-group tolerance, and the
compatibility of halogen groups made it possible for the
subsequent valuable transformations. When methyl, fluoro or
trifluoromethyl groups occupied the ortho-position of benzamides,
monothiolated products were obtained as the exclusive products
(3a-3c). As for meta-substituted benzamides bearing bulky
substituents, selective C–H thiolation occurred at the less
sterically hindered position and gave monothiolated products in
excellent yields (3f-3m). Notably, the heterocyclic amides were
We next studied the substrate scope of disulfides. To our
delight, both electron-rich and electron-deficient substrates
showed high reactivity under the optimized conditions. Various
functional groups, such as methyl, methoxy, halogen and nitro
groups were compatible with the optimized condition (4b-4g).
Moreover, the reaction of benzamides bearing aliphatic disulfide
proceeded smoothly to give the desired products in good yields
(4h-4k). Interestingly, disulfides bearing allyl group was also
coupled with 1a to give monothiolated product 4j in 58% yield, and
no olefination product was observed under the optimized
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condition. However, Di-tert-butyl sulfide was an exception to give
low yield probably due to the steric hindrance. Additionally,
heteroarmatic disulfides showed moderate reactivity to afford the
corresponding products (4l-4n), including the strong coordinating
coupling partner 2, 2’-dipyridiyldisulfide (4n). Notably, the
analogous of disulfides, both diphenyl diselenide and benzoyl
peroxide, were successfully converted into the desired products
in satisfactory yields (4o and 4p).
Boc-leucine on the rate profile, which revealed that the ligand
accelerates the rate of this thiolation reaction dramatically (Figure
S2).
Table 2. Scope with respect to disulfides.a,b
Scheme 2. Radical trapping experiment.
A plausible catalytic cycle for this transformation is depicted.
The initial step is the coordination of the substrate to the [RhIII]
catalytic center, followed by the ortho-C–H bond activation to form
a
five-membered rhodacycle intermediate A. Afterward,
intermediate A may release the target product 4b and species B
via a nucleophilic addition with diphenyldisulfide (path a).
Alternatively, intermediate A undergoes an oxidative addition with
diphenyldisulfide, followed by reductive elimination to provide the
product 4b and species B (path b). Afterwards species B goes
through another C–H activation pathway to afford the rhodacycle
intermediate D. Finally, reductive elimination of the rhodacycle
intermediate D generates 4b together with [RhI] species which is
then oxidized to the [RhIII] species with Ag2O to complete the
catalytic cycle.
[a] Conditions: 1a (0.1 mmol), 2 (0.1 mmol), [RhCp*Cl2]2 (5 mol %), Boc-Leucine
(20 mol %), Ag2O (0.15 mmol) and DCM (2 mL) under N2, 12 h, 90 oC. [b] Yields
of isolated products are given. [c] 70 oC.
To gain insights into the reaction mechanism, detailed
radical scavenger studies have been conducted as shown in
Scheme 2. The reaction was not significantly inhibited in the
presence of TEMPO or 1,4-dinitrobenzene (electron-transfer
scavenger), excluding the single electron transfer (SET) pathway
in this reaction. Furthermore, intermolecular kinetic isotope effect
(KIE) value of 1.70 and the parallel KIE value of 1.54 were
observed in a series of control experiments, suggesting that the
ortho-C–H bond activation might be the rate-determining step. To
gain further insight into this reaction, we examined the effect of
Scheme 3. Proposed reaction mechanism.
In summary, we developed a ligand-promoted Rh-catalyzed
thiolation reaction of aryl C–H bonds with disulfides using a
weakly coordinating amide auxiliary. This transformation
exhibited a broad substrate scope and good functional group
tolerance with the assistance of the N-protected amino acid ligand
which is employed to facilitate the catalytic cycles.
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Experimental Section
To a 25 mL Schlenk-type sealed tube equipped with a magnetic stirring
bar was added the substrate (0.1 mmol), [RhCp*Cl2]2 (3.1 mg, 0.005 mmol),
disulfides (0.1 mmol), Ag2O (34.8 mg, 0.15 mmol), Boc-leucine (4.6 mg,
20 mol %) and dry DCM (2.0 mL) under N2 atmosphere. The tube was
capped and heated to 90 °C for 12 h. After cooled to room temperature,
the reaction mixture was filtered through a pad of Celite. The filtrate was
concentrated in vacuo to afford crude product, which was purified by flash
column chromatography on silica gel to give the pure product.
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We gratefully acknowledge the National Natural Science
Foundation of China (grant no. 21671097 and 21331002) and the
Fundamental Research Funds for the Central Universities for
financial support.
Keywords: weakly coordinating directing group • thilolation •
disulfide • amino acid • rhodium
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This article is protected by copyright. All rights reserved.

10.1002/anie.201903511
Angewandte Chemie International Edition
COMMUNICATION
COMMUNICATION
Yan-Shang Kang,† Ping Zhang,† Min-
Yan Li,‡ You-Ke Chen,† Hua-Jin Xu,†
Jing Zhao,† Wei-Yin Sun,†,* Jin-Quan
Yu,‡,* Yi Lu†,*
A
mono-N-protected amino acid
ligand successfully promoted
weakly coordinating directing group
directed Rh(III)-catalyzed aryl
a
thiolation reactions with a broad scope
of amides and disulfide reagents.
Page No. – Page No.
Ligand-Promoted Rh(III)-Catalyzed
Thiolation of Benzamides with a
Broad Scope of Disulfide Reagents
This article is protected by copyright. All rights reserved.