Ruthenium(II)-catalyzed C-H arylation of N,N-dialkyl thiobenzamides with boronic acids by sulfur coordination in 2-MeTHF

Article abstract of DOI:10.1021/acs.orglett.0c02410

We report ruthenium(II)-catalyzed ortho-C-H arylation of N,N-dialkylthiobenzamides with boronic acids. The method employs [RuCl2(p-cym)]2 in the presence of Cu(OTf)2 and Ag2O oxidant. The reaction represents the first example of Ru-catalyzed C-H arylation directed by sulfur-containing groups and a rare example of C-H arylation directed by the versatile thiobenzamide moiety. As a further advantage, the method is performed in sustainable and eco-friendly 2-MeTHF as a solvent.

Full text of DOI:10.1021/acs.orglett.0c02410

pubs.acs.org/OrgLett
Letter
Ruthenium(II)-Catalyzed C−H Arylation of N,N-Dialkyl
Thiobenzamides with Boronic Acids by Sulfur Coordination in
2‑MeTHF
Jin Zhang,* Ying Liu, Qiangqiang Jia, Yue Wang, Yangmin Ma, and Michal Szostak*
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ABSTRACT: We report ruthenium(II)-catalyzed ortho-C−H
arylation of N,N-dialkylthiobenzamides with boronic acids. The
method employs [RuCl2(p-cym)]2 in the presence of Cu(OTf)2
and Ag2O oxidant. The reaction represents the first example of Ru-
catalyzed C−H arylation directed by sulfur-containing groups and
a rare example of C−H arylation directed by the versatile
thiobenzamide moiety. As a further advantage, the method is
performed in sustainable and eco-friendly 2-MeTHF as a solvent.
ver the past two decades, C−H bond activation has
catalyzed α-C−H arylation of N-heterocycles directed by the
bulky thioamide group by the Yu group and related methods
are noteworthy.11 The You group has made significant
progress in Pd- and Rh-catalyzed C−H arylation of the
electron-rich ferrocene scaffold directed by thioketones.12
Kuninobu, Kanai, and co-workers devised Ir-catalyzed C−H
borylation of aryl sulfides by Lewis acid−Lewis base
interaction, including modifiable thiomethyl linkage.13 Miura
reported Rh(III)-catalyzed C−H olefination of bulky thio-
amides.14 The Pd(II)-catalyzed arylation of thienyl thioamides
has been developed by Murai.15,16
In sharp contrast, very few methods using sulfur directing
groups with Ru catalysis have been reported. Jeganmohan
established sulfoxide-directed C−H hydroarylation of aromatic
sulfoxides by Ru(II) with oxygen serving as a directing group,17
while Urriolabeitia reported hydroarylation of alkynes using
benzylthioethers as the directing group.18 Despite the major
advantages of ruthenium as an inexpensive, functional group
tolerant, orthogonal, and operationally simple catalyst
system,19−23 Ru-catalyzed C−H arylations directed by sulfur-
containing groups remain elusive.
O
emerged as one of the most powerful synthetic methods
for the rapid assembly of molecules.1 However, while the vast
majority of C−H functionalization methods have been
accomplished using N-directing groups,2 including amide-
based weak coordination through N-amidate assistance, the
use of sulfur to direct C−H cleavage remains severely
underdeveloped.3
In general, sulfur directing groups are easier to convert to
other functional groups than their nitrogen-based congeners.4
Furthermore, sulfur-based functional groups are recognized as
privileged scaffolds in pharmaceuticals and are broadly present
in natural products, agrochemicals, medicinal chemistry, and
organic optoelectronic materials.5 It is estimated that 25% of
drugs contain sulfur as the key component, emphasizing the
importance of developing new strategies for the construction of
sulfur-containing lead compounds.6 In this context, thioamides
are particularly attractive as amide bond bioisosteres (Figure
1).7,8
Electronically, the thioamide bond (C(S)−N) features
higher rotational barrier than the amide bond (C(O)−N) by
ca. 5 kcal/mol (approximately 22 kcal/mol in thioamides) as a
consequence of nN → π*C=S resonance and the large radius of
sulfur. Furthermore, the thioamide C=S bond is weaker than
the corresponding C=O bond in amides (140 kcal/mol vs 180
kcal/mol) bond, while the sulfur atom is significantly less
electronegative than oxygen. Overall, the properties of
thioamides together with the known affinity of sulfur to
metals9 render C−H functionalization of thioamides a major
challenge.
In this Letter, we report the first ruthenium(II)-catalyzed
ortho-C−H arylation of N,N-dialkyl thiobenzamides with
boronic acids. The method affords privileged biaryl scaffolds
containing biorelevant thioamide bond moiety using inex-
pensive and commercially available reagents and catalysts. As a
Received: July 21, 2020
Very few methods for C−H functionalization using sulfur-
directing groups have been developed to date. Zhang
established thioethers as directing groups in C−H olefination
and arylation by Pd(II) catalysis.10 The development of Pd-
https://dx.doi.org/10.1021/acs.orglett.0c02410
© XXXX American Chemical Society
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A

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Table 1. Optimization of Ru(II)-catalyzed C−H Arylation of
a
Thiobenzamides
b
entry
oxidant
additive
base
solvent
yield (%)
c
1
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
Cu(OTf)2
Cu(OTf)2
Cu(NTf2)2
Cu(OTf)2
Cu(OTf)2
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
2-MeTHF
2-MeTHF
2-MeTHF
2-MeTHF
2-MeTHF
2-MeTHF
77
43
<2
77
45
16
c
2
c
3
4
5
6
7
8
9
10
11
12
13
14
15
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
NaHCO3
Na2CO3
Cs2CO3
LiOAc
NaOAc
KOAc
2-MeTHF
2-MeTHF
2-MeTHF
2-MeTHF
2-MeTHF
2-MeTHF
2-MeTHF
2-MeTHF
2-MeTHF
<2
<2
43
<2
<2
22
<2
29
<2
CsOAc
K3PO4
16
17
18
19
20
Ag2O
Cu(OAc)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
2-MeTHF
2-MeTHF
2-MeTHF
2-MeTHF
2-MeTHF
<2
<2
<2
18
<2
Ag2CO3
AgOAc
BQ
Figure 1. (a) Thioamide resonance. (b) Challenges in C−H arylation
of thioamides and this work. (c) Examples of thioamides.
further advantage, the method is performed in sustainable and
eco-friendly 2-MeTHF as a solvent, which emerges as the
preferred biomass-derived solvent for C−H functionalization
processes.24 We anticipate that this study will facilitate the
development of Ru-catalyzed C−H functionalizations directed
by weaker coordinating sulfur-based groups.
21
22
23
24
25
26
27
28
29
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
CH3CN
DMF
DMSO
DMA
toluene
DCE
THF
<2
<2
<2
<2
20
25
67
<2
<2
Our study commenced with optimization of the reaction
conditions for the direct C−H arylation of N-pyrrolidynyl-
thiobenzamide (Table 1). Within our program on amide bond
activation25 and Ru catalysis,26 we were attracted in probing
the capacity of the powerful Ru-catalysis platform for the direct
C−H functionalization of thiobenzamides. We recognized that
the switch of N-thioamidate to S-thioamide coordination in N,N-
dialkyl thiobenzamides27 might address the challenge of catalyst
poisoning by irreversible coordination to sulfur,28 while at the
same time preventing hydrolysis and nucleophilic addition
through the iminothiolate intermediate. Because another
challenge of using sulfur directing groups stems from facile
desulfurization by ruthenium-hydride catalysts,9c we opted for
a functional group tolerant Ru(II) catalysis platform.19
After very extensive optimization, we determined that the
combination of [RuCl2(p-cymene)]2 (5 mol %), Cu(OTf)2
(2.0 equiv), Ag2O (2.0 equiv), and K2CO3 (2.0 equiv) in 2-
MeTHF at 120 °C promoted the desired arylation of N-
pyrrolidynyl-thiobenzamide with phenylboronic acid in 77%
yield (Table 1, entry 1). Importantly, the product was obtained
with exclusive monoarylation selectivity (mono/di > 20:1),
which is often a major complicating issue in Pd-catalyzed
arylations.
dioxane
i-PrOH
d
30
Ag2O
Ag2O
Ag2O
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
K2CO3
K2CO3
K2CO3
2-MeTHF
2-MeTHF
2-MeTHF
56
<2
78
e
31
f
32
a
Conditions: amide (R′,R″ = pyrrolidine, 1.0 equiv), [RuCl2(p-
cymene)]2 (5 mol %), PhB(OH)2 (1.5 equiv), oxidant (2 equiv),
additive (2.0 equiv), base (2 equiv), solvent (0.25 M, 120 °C, argon,
20 h. Determined by H NMR and/or GC. AgSbF6 (20 mol %).
12 h. 80 °C. 140 °C.
b
c
1
d
e
f
results are worth noting (see the Supporting Information for
details). The use of AgSbF6 is not required, while Cu(OTf)2 is
the preferred Cu(II) additive (entries 1−6). Among various
bases examined, the use of K2CO3 is critical, while Cs2CO3
gave a moderate yield of the desired product (entries 7−16).
Ag2O is the preferred Ru(0)/(II) oxidant, with Ag2CO3,
AgOAc, and BQ showing little to no conversion (entries 17−
20). Interestingly, among the range of solvents examined, 2-
MeTHF is the preferred solvent, showing higher conversion
than related THF, likely because of higher solubility of the
catalyst system (entries 21−29). Optimization of the reaction
time revealed approximately 50% conversion after 12 h,
consistent with the slow cyclometalation process (entry 30).
Furthermore, C−H activation at the electron-rich α-position
of the pyrrolidine ring was not observed,11 consistent with the
high activity for aromatic C−H activation. Several optimization
B
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Finally, the temperature screen revealed that the reaction was
less efficient at 100 °C, while minor improvement in the
efficiency was observed at 140 °C (entries 31−32). It is worth
noting that the optimized conditions are quite distinct from
Ru(II)-catalyzed C−H arylation of benzamides,26a wherein the
generation of TfOH was found to be critical to promote the
reaction. We hypothesize that in the present case the
carboxylate base assists in breaking the S−Ru coordination;27
however, the involvement of a Ru(II) carboxylate system
cannot be excluded at this point.19,23
observed in the case of meta-substituted thiobenzamides
(3ha−3ia), including electron-deficient chloro-substituted
arene (3ia). Moreover, the reaction could be extended to
polyaromatic substrates, such as naphthalene (3ja), and
heterocyclic substrates, such as thiophene (3ka). At this
point, ortho-substitution is not tolerated.19 Importantly, in all
cases, only the mono-C−H arylation product was observed.
The scope of the reaction with respect to the boronic acid
component is also broad (Scheme 2). Electronically differ-
Next, the scope of this novel C−H arylation process of
thiobenzamides was examined (Scheme 1). We found that the
Scheme 2. C−H Arylation of Tertiary Thiobenzamides:
a
Scope of Nucleophiles
Scheme 1. C−H Arylation of Tertiary Thiobenzamides:
a b
,
Scope of Thiobenzamides
a
See Scheme 1. See the Supporting Information for details.
entiated boronic acids, including electron-rich (3ab−3ac) and
electron-deficient (3ad−3ag) nucleophiles were well tolerated.
Noteworthy is the functional group tolerance to biorelevant
fluoro motifs (3ae) and the use of sensitive halide substituents,
such as chloro (3ag), bromo (3ah), and iodo (3ai), that could
be utilized in subsequent functionalization. Moreover, longer
alkyl chains on the aryl boronic acid (3aj) and biaryl-based
boronic acids (3ak) are well compatible with this reaction.
Next, we were curious to investigate the impact of the N-
substitution on the thiobenzamide scaffold on this C−H
functionalization (Scheme 3). Pleasingly, this reaction well
accommodates challenging N,N-acyclic thiobenzamides, such
as N,N-dimethyl (3la) and N,N-diethyl (3ma) without
competing dealkylation, including even the sterically hindered
N,N-di-isopropylbenzamide (3na), albeit in a lower yield.
Moreover, a privileged cyclic N-piperidynyl ring is also well
tolerated (3na). At the present stage, ortho-substituted
substrates are not compatible. This is a general feature of
Ru(II)/(0)-catalysis enabling high monoarylation selectivi-
ty.19,26j We hypothesize that catalyst poisoning is less likely in
this case because of switchable N-thioamide/N-thioamidate
coordination. We believe that the role of Cu(OTf)2 is to
facilitate the formation of a cationic Ru(II) species.21,23 The
proposed mechanism involves triflate-promoted ortho-cyclo-
ruthenation, transmetalation, reductive elimination, and
Ru(0)/(II) reoxidation pathway.
a
Conditions: thioamide (R′,R″ = pyrrolidine, 1.0 equiv), [RuCl2(p-
cymene)]2 (5 mol %), PhB(OH)2 (1.5 equiv), Ag2O (2 equiv),
Cu(OTf)2 (2 equiv), K2CO3 (2 equiv), 2-MeTHF (0.25 M), 120 °C,
b
20 h. Isolated yields. X-ray structure of (3fa) and (3ja).
Crystallographic data have been deposited under CCDC 2011649
and 2011650. See the Supporting Information for details.
scope of this reaction is broad and supersedes all current
methods for the stoichiometric and catalytic arylation of the
thiobenzamide moiety. The scope includes electron-neutral
(3aa), electron-rich (3ba−3ca), and electron-deficient (3da−
3fa) thiobenzamide substrates. It is noteworthy that the
reaction tolerates readily modifiable halide substituents, such
as chloro (3fa) and bromo (3ga). Full regioselectivity is
Preliminary mechanistic studies were carried out to gain
insight into this intriguing C−H activation process (Scheme
4). (1) Intermolecular competition experiments with differ-
ently substituted thioamides revealed that electron-deficient
thioamides react preferentially, consistent with a concerted
C
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Scheme 3. C−H Arylation of Tertiary Thiobenzamides:
Scheme 4. Mechanistic Studies and Gram Scale Arylation
a
Scope of Thioamides
a
See Scheme 1. See the Supporting Information for details.
cyclometalation/deprotonation (Scheme 4A).19a (2) Experi-
ments with differently substituted boronic acids indicated that
electron-deficient boronic acids react preferentially (Scheme
4B), consistent with boron coordination during transmetala-
tion.29 (3) The following order of the directing group reactivity
has been established: pyrrolidine > N,N-Me2 > N,N-i-Pr2
consistent with the steric effect of S-coordination. (4)
Deuterium incorporation revealed reversible C−H cyclo-
ruthenation (Scheme 4D). (5) Most intriguingly, competition
experiments established exquisite selectivity for the C−H
arylation of thiobenzamide (S−Ru coordination) vs benzamide
(O−Ru coordination) (Scheme 4E, box). The observed
selectivity bodes well for the future expansion of Ru(II)-
catalyzed C−H functionalization protocols enabled by weaker
coordinating sulfur-containing groups.
To assess the robustness of this C−H activation protocol, we
conducted a gram scale reaction (Scheme 4F). The reaction
readily afforded the C−H arylation product in 75% yield (0.99
g), demonstrating potential for future applications in the
synthesis of privileged biaryl thiobenzamide motifs.
The structures of two ortho-arylated products were
confirmed by X-ray crystallography (Scheme 1 and the
Supporting Information).25 The thioamide bond in (3fa)
shows planar N−C(S) bond (τ = 5.7°, χN = 1.4°). The N−
C(S) and C=S bond lengths are 1.310 and 1.666 Å,
respectively. Compared with a representative ortho-aryl N,N-
dialkylamide (N−C(O) = 1.353 Å; C=O = 1.235 Å), it is
evident that amide to thioamide replacement results in a much
elongated C=X bond (X = S, O), while nN → π*C=S resonance
is reflected by the short N−C(S) bond. The structural
parameters of the naphthalene biaryl product (3ja) are similar
to those of (3fa). The structure confirms arylation at the less
electron-rich 3-naphthyl position.
In conclusion, we have developed a new method for the
ruthenium(II)-catalyzed ortho-C−H arylation of N,N-dialkyl
thioben zamides with boronic acids. The method exploits
weaker sulfur coordination to accomplish the challenging C−H
arylation using thiobenzamide as versatile, biorelevant, and
sulfur-containing directing group. The use of Ru(II) catalysis
has experienced tremendous growth in the past decade owing
to the low price, versatility, and functional group tolerance;
however, its application to the sulfur-containing directing
groups has lagged behind. We anticipate that this study will
facilitate the development of new methods for Ru-catalyzed
C−H functionalizations directed by sulfur-based donors.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c02410.
Procedures, characterization data, crystallographic data
of 3fa and 3ja (PDF)
D
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AUTHOR INFORMATION
Corresponding Authors
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■
Jin Zhang − College of Chemistry and Chemical Engineering,
Key Laboratory of Chemical Additives for China National Light
Industry, Shaanxi University of Science and Technology, Xi’an
710021, China; orcid.org/0000-0002-6616-7087;
Email: zhangjin@sust.edu.cn
Michal Szostak − College of Chemistry and Chemical
Engineering, Key Laboratory of Chemical Additives for China
National Light Industry, Shaanxi University of Science and
Technology, Xi’an 710021, China; Department of Chemistry,
Rutgers University, Newark, New Jersey 07102, United States;
orcid.org/0000-0002-9650-9690; Email: michal.szostak@
rutgers.edu
̈
(3) (a) Sambiagio, C.; Schonbauer, D.; Blieck, R.; Dao-Huy, T.;
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̈
J.; Besset, T.; Maes, B. U. W.; Schnurch, M. A Comprehensive
Authors
Ying Liu − College of Chemistry and Chemical Engineering, Key
Laboratory of Chemical Additives for China National Light
Industry, Shaanxi University of Science and Technology, Xi’an
710021, China
Qiangqiang Jia − State Key Laboratory of Plateau Ecology and
Agriculture, Qinghai University, Xining 810016, China
Yue Wang − College of Chemistry and Chemical Engineering,
Key Laboratory of Chemical Additives for China National Light
Industry, Shaanxi University of Science and Technology, Xi’an
710021, China
Yangmin Ma − College of Chemistry and Chemical Engineering,
Key Laboratory of Chemical Additives for China National Light
Industry, Shaanxi University of Science and Technology, Xi’an
710021, China
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Complete contact information is available at:
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
J.Z. thanks the CSC (No. 201808610096). Support was
provided by the Foundation for Young Scholars of SUST (No.
BJ12-26). M.S. thanks Rutgers University and the NSF (CHE-
1650766).
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3204−3210. (c) Nareddy, P.; Jordan, F.; Szostak, M. Ruthenium(II)-
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