Rhodium-Catalyzed Transarylation of Benzamides: C-C Bond vs C-N Bond Activation

Article abstract of DOI:10.1021/acscatal.9b05214

A rhodium-catalyzed transarylation of benzamides via selective C-C bond activation with arylboronic acids was described, which was distinct from the conventional metal-catalyzed C-N bond activation. This transformation exhibited good functional group compatibility with yields up to 88%, offering a practical approach for the construction and functionalization of benzamides. Preliminary experimental and computational studies revealed the selectivity of metal insertion into the C-C bond or the C-N bond was greatly affected by substituents on the amide's N atom.

Full text of DOI:10.1021/acscatal.9b05214

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Letter
Rhodium-Catalyzed Transarylation of
Benzamides: C-C Bond vs C-N Bond Activation
Yang Long, Zhishan Su, Yanling Zheng, Shiyu He, Jing Zhong, Haifeng Xiang, and Xiangge Zhou
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.9b05214 • Publication Date (Web): 25 Feb 2020
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Rhodium-Catalyzed Transarylation of Benzamides: C-C Bond vs C-N
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Bond Activation
Yang Long, Zhishan Su, Yanling Zheng, Shiyu He, Jing Zhong, Haifeng Xiang and Xiangge Zhou*
College of Chemistry, Sichuan University, 29 Wangjiang Road, Chengdu 610064, P. R. China
ABSTRACT: A rhodium-catalyzed transarylation of benzamides via selective C-C bond activation with arylboronic acids was de-
scribed, which was distinct from the conventional metal-catalyzed C-N bond activation. This transformation exhibited good func-
tional group compatibility with yields up to 88%, offering a practical approach for the construction and functionalization of ben-
zamides. Preliminary experimental and computational studies revealed the selectivity of metal insertion into C-C bond or C-N bond
was greatly affected by substituents on amide’s N atom.
KEYWORDS: Amide, C-C activation, C-N activation, arylation, rhodium catalysis, DFT
Transition metal-catalyzed C-C bond activation is one of im-
portant and thorny research areas in organic chemistry over the
past few decades. Compared with the well-developed C-H bond
activation, C-C bond activation is facing more difficulties: the
stability of C-C  bond; the difficulty for a metal to interact with
a C-C bond that is usually surrounded by more dominant C-H
bonds; the incompatibility of other functional groups etc.1 How-
ever, C-C bond activation still draws significant attention owing
to its ubiquitous presence in nature, which may pave more pow-
erful and straightforward pathways to reconstruct molecular
skeletons. In recent years, transition metal-catalyzed C-C bond
activation has been reported in succession, especially focusing
on small ring compounds driven by relief of strain force.2 Mean-
while, ketone, alcohol, amine and nitrile compounds have also
been employed as unstrained substrates.3 However, other im-
portant scaffolds are still underdeveloped.4
Amide is one of the most important structural motifs found
in peptides, pharmaceutically molecules, agrochemicals and
functional materials.5 Recently, remarkable progress has been
made in the metal-catalyzed C(O)-N bond activation of amides,
while the direct C(O)-C bond activation is rarely reported.6 By
precisely regulating the substituents on N atom, various func-
tionalization of amides via C-N bond activation could be real-
ized.6g Typically, these reactions are divided into two ap-
proaches including non-decarbonylation and decarbonylation
pathways, wherein the amine group acts as leaving group in
both (Scheme 1A). Although decarbonylation process could
fulfill the scission of C(O)-C bond macroscopically, this trans-
formation always results in the inevitable loss of carbonyl unit
and deconstruction of amide structure, along with the liberation
of stoichiometric amount of hazardous carbon monoxide.
On the other hand, to the best of our knowledge, selective
metal insertion into C(O)-C bond instead of C(O)-N bond with
the retention of benzamide scaffold has not been reported yet.
Inspired by the reports about the effects of substituents on am-
ide’s N atom on the selective C-N bond activation, in continua-
tion of our work on C-C and C-H bond activation,7 we herein
report a general approach for catalytic selective activation of
C(O)-C(aryl) bond of benzamides by introducing proper direct-
ing and steric groups onto N atom to guide the transition metal
exclusive insertion into the target C-C bond and exchange aryl
groups with arylboronic acids (Scheme 1B).
Scheme 1. Benzamides’ C-N Bond and C-C Bond Activation
Reactions
Analogous to the transamidation process of amides,8 this re-
action looks like a transarylation process, which not only offers
a strategy for the less developed amide’s C(O)-C bond activa-
tion reaction, but also complements traditional benzamides’
synthetic methods owing to its potential advantages including
easily available reagents, circumventing the need for protecting
groups and complex ligands etc.5 Furthermore, similar aryl-ex-
changed reactions of ketones were reported by Wang,9 John-
son10 and coworkers recently by using quinolinyl group as di-
recting group through C-C bond activation. However, in the
case of amide substrate, there exist several challenges such as:
(1) selective metal insertion into C(O)-C(aryl) bond is more dif-
ficult, especially in the presence of competitive C-N and C-H
bonds; (2) undesired decarbonylation after oxidative addition
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would lose carbonyl unit and deconstruct the amide structure;
(3) tolerance of various functional groups.
Table 1. Experimental and Computational Study of N-sub-
stituents’ Effect on Selective C-N bond and C-C Bond Acti-
vation.a,b
7
8
9
Entry
1
-NR1R2
Insertion
C-C
Gc
10.8
18.8
8.6
Gd
Yieldse
84% (83%)f
0%
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8.0
C-N
C-C
32%
2
3
4
1.5
4.6
3.0
C-N
C-C
10.1
13.3
17.9
16.6
19.6
11.8
44%
46%
C-N
C-C
36%
Figure 1. Configuration of N-substituted benzamides. ORTEP
representation of 1a (CCDC 1944056) and 5a (CCDC 1944055)
with thermal ellipsoids at a 30% probability level. H atoms are
omitted for clarity.
45%
C-N
C-C
34%
68%
5
4.4
Initially, benzamide substrates bearing primary or phenyl
substituted amino group failed to afford the desired C-C bond
activation products, which aroused us to introduce directing
group, such as pyridyl or pyrimidyl group, onto amide’s N atom.
N-coordination might make metal closer to the target C-C bond
and stabilize the five-membered ring intermediate. Considering
that the secondary amides would favor the trans configuration
with the directing group being far away from the C(O)-C(aryl)
bond (Figure 1A),11 the tertiary amides, which might adopt cis
configuration if installation of proper steric groups on N atom
and would force the transition metal in close proximity to the
C(O)-C(aryl) bond, were designed and synthesized (Figure 1B).
Indeed, the tertiary benzamide substrates 1a and 5a, which con-
tained diisopropylphenyl group and pyridyl or pyrimidyl group
respectively, were in the desired cis configuration, and their
structures were confirmed by single crystal X-ray diffraction
determination (Figure 1C).12
Then, we began our investigation by evaluating the effects of
different substituents on the N atom of tertiary benzamides (1a-
8a), together with 4-methoxyphenylboronic acid (1b) as sub-
strate and Rh(acac)(CO)2 as catalyst. Meanwhile, DFT methods
were also employed to locate the C-C bond and C-N bond in-
sertion transition states in oxidative addition step respectively
for 1a-8a.13 Their relative activation energy G and activation
energy differences G listed in Table 1 were adopted to eval-
uate roughly the selectivity of metal in oxidative addition pro-
cess.
After extensive screening different N-substituents, we were
delighted to find the judiciously designed N-(2,6-diiso-
propylphenyl)-N-(pyridine-2-yl)benzamide (1a) could fulfil the
proposed transarylation transformation and gave 84% yield
without formation of C-N bond activation product (entry 1).
Computational results indicated that the activation energy G
of C-C insertion for 1a was 10.8 kcal/mol, 8.0 kcal/mol lower-
ing than that of C-N insertion, which might account for the ex-
clusive selectivity of activation on C-C bond. Steric effect of R2
group was an important factor affecting the selectivity. When
replacing R2 group to other less steric groups, including phenyl
(entry 2), methyl substituted (entry 3) and ethyl substituted (en-
try 4) phenyl groups, the poorer selectivity along with smaller
G values (1.5 to 4.6 kcal/mol) were obtained, resulting in the
C-N
16.2
21%
C-C
C-N
C-C
C-N
C-C
C-N
12.8
11.7
30.2
35.7
29.3
25.4
0%
60%
0%
0%
0%
0%
6
7
8
-1.1
5.5
-3.9
aThe yield of amine (d) was monitored as the yield of C-N bond
activation. Reactions were carried out under nitrogen atmos-
phere with a (0.1 mmol), 1b (0.25 mmol), Rh(acac)(CO)2 (10
mol%), Na2CO3 (1.2 equiv) in 1,4-dioxane (1 mL) at 140 C for
24 h. Relative Gibbs free energy (kcal/mol) of Rh-complexes
and the corresponding transition states associated with C-C or
C-N bond insertion reactions, which was obtained at the
B3LYP-D3(BJ)/[6-31G*, Lanl2dz](SMD, 1,4-dioxane) theo-
retical level. dRelative Gibbs free energy of the transition state
in C-C insertion reaction was set to zero. eNMR yields of c and
d by using CH2Br2 as internal standard. fIsolated yield.
b
c
occurrence of competitive C-N bond activation side reactions.
Moreover, pyridyl group seemed to be more suitable directing
group for this reaction than pyrimidyl group (entries 5-6), and
the smaller G values of pyrimidyl group might be caused by
the greater effects on N atom’s electron deficiency.6 In addition,
changing the directing group to phenyl group made the activa-
tion energy G for both C-C bond and C-N bond insertions up
to about 30 kcal/mol, thus retarding the reactions (entries 7-8).
Above all, from the experimental and computational point of
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view, the optimal reaction conditions consist of benzamide (0.1
ester substituents, thus avoiding the installation of protecting
groups owing to their incompatibility in traditional methods.
Furthermore, when substrate bearing two different amide units
was treated (22c), the central metal exclusively inserted into the
target C(O)-C(aryl) bond, rather than C-N bonds or C(O)-
C(methyl) bond. In addition, coupling with di- and trisubsti-
tuted arylboronic acids delivered the corresponding poly substi-
tuted amides in moderate to good yields (23c-30c).
mmol), arylboronic acid (0.25 mmol), Rh(acac)(CO)2 (10
mol%), Na2CO3 (1.2 equiv) in 1,4-dioxane (1 mL) at 140 C for
24 h under nitrogen atmosphere (see Supporting Information for
details).
Table 2. Scope of Arylboronic Acids.a,b
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Scheme 2. Synthetic Applications
aReaction conditions: 1a (0.1 mmol),
Rh(acac)(CO)2 (10 mol%), Na2CO3 (1.2 equiv) in 1,4-dioxane
(1 mL) at 140 C for 24 h under nitrogen atmosphere. bIsolated
yields.
b (0.25 mmol),
The utility of this transarylation reaction was further exam-
ined. Firstly, a scaled-up reaction was carried out, affording 1c
in 68% yield, indicating its feasibility on a more synthetically
useful scale (Scheme 2A). Subsequent reduction of transaryla-
tion product could deliver tertiary amine (Scheme 2B).15 In ad-
dition, replacing arylboronic acid to arylboronates with 5 equiv
water could also afford the desired product 15c in 69% yield,
illustrating the compatibility of the system with water and aryl-
boronates (Scheme 2C), and the bromo atom of the product 15c
enabled the reaction to be further concatenated with other cou-
pling reactions for late-stage functionalization (Scheme 2D).
More importantly, the combination of this transarylation pro-
cess and transamidation process could realize the complete mu-
tual conversion of amide units within two steps. For example,
the reaction between 1a and commercially available aryl-
boronic acid 31b smoothly provided the transarylation product
31c, which could be further converted to 1f,12 an important an-
titumor agent, through a transamidation process with 4-chlo-
roaniline (Scheme 2E).8e
At last, in order to gain insight into the possible reaction path-
way, a series of control experiments were carried out as shown
in Scheme 3. Initially, no reaction occurred when secondary
amides (9a or 10a) were treated as substrates, convincing the
importance of chelation and steric effect of substituents on N
atom (Scheme 3A). Meanwhile, the biaryl product (1g) was not
detected in this transformation, which illustrated that C-C bond
oxidative addition might occur prior to transmetalation process
(Scheme 3B).9-10 In addition, the fate of the leaving phenyl
group of substrate was also investigated. GC-MS analysis of the
With the optimized reaction conditions in hand, the scope of
arylboronic acids was examined as shown in Table 2. In general,
the transformation exhibited broad substrate scope, good func-
tional group tolerance and selective activation on C(O)-C(aryl)
bond. For the steric effects, m, p-methoxy group substituted
phenylboronic acids gave the desired products in good yields
about 80% (1c, 2c), while o-methoxy substituted product (3c)
was obtained in a moderate yield 65%, suggesting that steric
hinderance on phenylboronic acid might have a slight inhibition
on the yield. Meanwhile, various alkyl-substituted substrates
were well-tolerated during reaction, affording the correspond-
ing products in good yields up to 88% (4c-9c). Trimethylsilyl
(10c) and dimethylamino (11c) groups also provided the desir-
able yields 80% and 82% respectively. Substrates with halogen
atom substituents reacted smoothly in moderate yields ranging
from 59% to 79%, indicating the feasibility of combining with
conventional cross-coupling methods (12c-16c). More im-
portantly, arylboronic acids bearing electron-deficient groups,
such as cyano (17c) and trifluoromethyl (18c) groups, which
were inactive in quinolinyl ketone’s aryl interconversion reac-
tion,9 resulted in 67% and 54% yields, respectively. It is worth
noting that neither of the previously reported rhodium insertion
into the C-H bond of the aldehyde (19c),14 the C-C bond of the
ketone (20c)3d or the C-O bond of the ester (21c)6g was observed
in the case of arylboronic acids containing aldehyde, acetyl or
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Figure. 2. DFT-computed pathway for transarylation of benzamides and DFT calculations was obtained at the B3LYP-D3(BJ)/[6-
31G*, Lanl2dz](SMD, 1,4-dioxane) theoretical level.
exchange process was exergonic by 2.1 kcal mol-1. Subse-
quently, -aryl elimination of IM3 via TS3 gave IM4,16 and
the reaction mixture revealed that benzene (1h) was obtained in
73% yield, which was in 0.88 molar ratio to transarylation prod-
uct 1c, indicating that -aryl elimination16 might be involved in
transmetalation process (Scheme 3C). According to Hartwig’s
work,16a the H source of benzene would be from the hydroxyl
hydrogen of boronic acid, and our deuterium-labeling experi-
ments further convinced that. Following treatment of 11c with
PhB(OD)2 and 1,4-dioxane-D8 respectively, the deuterated ra-
tios of the corresponding hydrogen of 2h were approximately
81% and 0%, respectively, providing the evidence for the pro-
ton exchange between phenyl group and arylboronic acid rather
than solvent (Scheme 3D).
IM4 recombined with CO ligand to give IM5. The final reduc-
tive elimination, which required an activation energy of 28.4
kcal mol-1, afforded IM6 (via TS4) and closed the catalytic cy-
cle.
In conclusion, we developed an example of Rh-catalyzed
transarylation of benzamides to afford the aryl exchanged ben-
zamides with arylboronic acids. Screening of the amide N-sub-
stituents experimentally and computationally made Rh(I) cata-
lyst exclusively insert into C(O)-C(aryl) bond rather than con-
ventional C(O)-N bond. In addition, this transformation pro-
vided a novel and practical methodology to construct amides,
with broad substrate scope, good functional group tolerance and
high selectivity. Further studies on amide’s functionalization
are ongoing in our research group.
Scheme 3. Control Experiments
ASSOCIATED CONTENT
AUTHOR INFORMATION
Corresponding Author
* Email: zhouxiangge@scu.edu.cn
Notes
The authors declare no competing financial interest.
Supporting Information
Detailed experimental procedures, characterization data, copies of
1H, 13C and 19F NMR spectra of products are reported in the Sup-
porting Information. This material is available free of charge via
the Internet at http://pubs.acs.org.
ACKNOWLEDGMENT
We are grateful to the National Natural Science Foundation of
China (grant nos. 21472128) and Sichuan Science and Technology
Program (NO. 2018JY560) for financial support. We also
acknowledge Comprehensive training platform of specialized la-
boratory, College of chemistry, Sichuan University for HRMS
analysis, Prof. Daibing Luo for single crystal measurements and
Prof Pengchi Deng for NMR analysis.
Based on our work and literatures,1-3,9-10,16 DFT calculations
were performed to further probe the mechanism of this trans-
formation, and the plausible reaction pathway was shown in
Figure 2. The reaction started from ligand exchange between
IM6 and substrate 1a to give catalyst-substrate complex 1a-
COM, which directly facilitated the C(O)-C(aryl) bond oxida-
tive addition to generate IM1 via 1a-TS-a. Then ligand substi-
tution converted IM1 to IM2, and IM2 underwent proton ex-
change to deliver IM3 via TS2 and release benzene. The proton
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