Intermolecular C?H Amidation of (Hetero)arenes to Produce Amides through Rhodium-Catalyzed Carbonylation of Nitrene Intermediates

Article abstract of DOI:10.1002/anie.201903656

Amide bond formation is one of the most important reactions in organic chemistry because of the widespread presence of amides in pharmaceuticals and biologically active compounds. Existing methods for amides synthesis are reaching their inherent limits. Described herein is a novel rhodium-catalyzed three-component reaction to synthesize amides from organic azides, carbon monoxide, and (hetero)arenes via nitrene-intermediates and direct C?H functionalization. Notably, the reaction proceeds in an intermolecular fashion with N₂ as the only by-product, and either directing groups nor additives are required. The computational and mechanistic studies show that the amides are formed via a key Rh-nitrene intermediate.

Full text of DOI:10.1002/anie.201903656

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Accepted Article
Title: Intermolecular C–H Amidation of (Hetero)arenes to Produce
Amides through Rhodium-Catalyzed Carbonylation of Nitrene
Intermediate
Authors: Si-Wen Yuan, Hui Han, Yan-Lin Li, Xueli Wu, Xiaoguang Bao,
Zheng-Yang Gu, and Ji-Bao Xia
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201903656
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Intermolecular C–H Amidation of (Hetero)arenes to Produce Amides
through Rhodium-Catalyzed Carbonylation of Nitrene Intermediate
Si-Wen Yuan[a],+, Hui Han[a],+, Yan-Lin Li[a], Xueli Wu[c], Xiaoguang Bao[c],*, Zheng-Yang Gu[a,b],*, and Ji-
Bao Xia[a],*
Dedicated to Professor Li-Xin Dai on the occasion of his 95 birthday
Abstract: Amide bond formation is one of the most important
reactions in organic chemistry due to the widespread presence of
amides in pharmaceuticals and biologically active compounds. But
existing methods for amides synthesis are reaching their inherent
limits. In this communication, we describe a novel rhodium-catalyzed
three-component reaction to synthesize amides from organic azides,
carbon monoxide, and (hetero)arenes via nitrene intermediate and
direct C–H functionalization. Notably, the reaction proceeds in an
intermolecular and green fashion with N2 as the only by-product,
without directing groups and any additive. The computational and
mechanistic studies showed that the amides are formed through the
key Rh-nitrene intermediate.
and T3P (n-propylphosphonic acid anhydride), etc. Development
of catalytic amidation reactions has drawn long-standing
attention to chemists.[5] In the last few decades, transition-metal-
catalyzed carbonylation of aryl halides and related compounds
with carbon monoxide (CO) and amines via aryl–metal species
has rapidly evolved to have tremendous impact since the
pioneering work of Heck and co-workers in 1974 (Scheme 1b).[6]
Then, many excellent works have been achieved by the groups
of Beller,[7] Buchwald,[8] Jiao,[9] Li[10] and others.[11] This strategy
has become a powerful tool to synthesize amides, owing to the
unique ability of CO serving as an excellent carbonyl source. But
the current methods are reaching their inherent limits, and it is
necessary to develop new methods for amide synthesis.
Nitrene intermediates are among the most promising agents
for selective introduction of nitrogen in molecules.[12] The
chemistry of metal-nitrene intermediate has attracted significant
attention due to the high reactivity in various nitrogen transfer
reactions such as addition reactions,[13] radical coupling
reactions,[14] as well as C–H activation reactions.[15] Organic
azides have been identified as convenient nitrene precursors,
which do not require any external oxidant and release N2 as the
only by-product. Our group has been interested in developing
transition-metal-catalyzed C–H carbonylations to construct
carbonyl compounds.[16] We hypothesize that C–H amidation of
arenes would be realized with CO and azides through metal-
nitrene intermediate, which has not been explored yet (Scheme
1c). The product amide could be obtained via two possible
Amide linkages not only constitute one of the most essential
connections in peptides and proteins, but also have an important
role in pharmaceutical and chemical industries.[1] They are the
basis for some of the most widely used synthetic polymers.
Recently, applications of amide molecules have significantly
increased in the areas of materials, agrochemicals, drugs and
biologically active compounds.[2] Furthermore, amides are one of
the most reliable and useful synthetic intermediates for
accessing other types of compounds, such as amines, isonitriles,
hetorocycles.[3] Therefore, the developments of green, waste-
free, and novel catalytic methods for amide synthesis are in
great demand.
Traditionally, the most common method for the synthesis of
amides is condensation reaction of amines with carboxylic acids
using various coupling reagents (Scheme 1a).[4] The breadth
and reliability of these reactions has made it a mainstay in the
synthetic organic repertoire for the assembly of amides.
However, the production of large quantities of waste is the major
concern using stoichiometric activating agents, such as thionyl
chloride, EDC (1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide),
[a]
S.-W. Yuan, H. Han, Y.-L. Li, Dr. Z.-Y. Gu, Prof. Dr. J.-B. Xia
State Key Laboratory for Oxo Synthesis and Selective Oxidation,
Suzhou Research Institute of LICP, Lanzhou Institute of Chemical
Physics (LICP), Chinese Academy of Sciences, Lanzhou 730000,
China
E-mail: jibaoxia@licp.cas.cn
[b]
Dr. Z.-Y. Gu
College of Textiles and Clothing & Key Laboratory for Advanced
Technology in Environmental Protection of Jiangsu Province,
Yancheng Institute of Technology, Jiangsu, 224003, China
E-mail: zhengyang.gu@qq.com
[c]
[+]
X. Wu, Prof. Dr. X. Bao
College of Chemistry, Chemical Engineering and Materials
Science, Soochow University, Suzhou, 215123, China
E-mail: xgbao@suda.edu.cn
These authors contributed equally to this work.
Supporting information for this article is given via a link at the end
of the document.
Scheme 1. Comparison of the different approaches to amides synthesis.
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10.1002/anie.201903656
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pathways. One is via isocyanate I derived from metal-nitrene
and CO, follewed by reaction with arenes. Isocyanates have
been obtaiend from azides and CO under high temperatrue or
via metal-catalysis.[17] The other pathway is through aryl metal
intermediate II derived from arenes and metal–nitrene, followed
by reaction with CO. This strategy provides a simple catalytic
approach to amides from readily available compounds. Herein,
and 60%). Trace amount of product could be detected when N-
Boc or N-Ac substituted indole was used (3y and 3z). Notably,
the free (NH) indole could be tolerated for this reaction
generating the C–H amidation product 3d in 53% yield. It should
be noted that urea product was not detected by reaction with N–
H of indole. Other substituted N-methylindoles were compatible
to this reaction giving the desired products in good yields, such
as 1,2-dimethylindole, 1-methyl-2-phenylindole, and 5-bromo-1-
methylindole (3e-g, 70-89%). Free (NH) indoles bearing
electron-donating groups (Me, OMe) at different positions could
produce the desired products 3h-k in excellent yields (82-95%).
When 5-(benzyloxy)-1H-indole 1l was used, the product 3l could
be isolated in 64% yield. However, 2-phenyl, 7-F, and 4-Cl
substituted indoles displayed lower reactivity than other indoles
and the desired product 3m-o could be obtained in 43-57%
yields. Poor reactivity was also observed with indole 1p bearing
electron-withdrawing group, and product 3p was obtained in
38% yield. Besides indoles, N-methylpyrrole and pyrrole were
found to be appropriate substrates for this reaction, which could
react to generate the corresponding products in moderated to
we report
a novel rhodium-catalyzed C–H amidation to
synthesize amides simply from arenes, CO, and organic azides
via nitrene intermediate, and it provides an efficient strategy for
the synthesis of amides with broad range of substrates (Scheme
1d).
We started our research by investigating C–H amidation of
N-methylindole (1a) with CO (balloon pressure) and
benzenesulfonyl azide (2a) in the presence of various metal
catalysts. To our delight, the desired amidation product 3a was
obtained in 20% yield with 5 mol % Co2(CO)8 as catalyst in
MeCN at 80 °C (Table 1, entry 1). Trace amount of product
could be detected with other metal catalysts, such as
Fe2Cp2(CO)4, Ni(cod)2, and Cu(OAc)2 (Table 1, entries 2-4).
Better results were observed using PdCl2 and Pd(OAc)2 (Table 1, good yields (3q and 3r). Good yields were also obtained when
entries 5 and 6). However, trace amount of product was
obtained with Rh2(OAc)4 (Table 1, entry 7). It was found that the
yield of product 3a could be increased to 92% when [Rh(cod)Cl]2
was used (Table 1, entry 10). The reaction showed low reactivity
at room temperature (Table 1, entry 11). We further examined
other solvents, and moderate to good yields could be obtained
(Table 1, entries 12-15). When the catalyst loading was reduced
to 2.5 mol %, the yield of 3a decreased to 60% (Table 1, entry
16).
using azulenes as substrates (3s and 3t). Last but not least,
electron-rich arenes also displayed good reactivity in this
reaction.
For
example,
N,N-dimethylaniline,
N,N,3-
trimethylaniline, 1-phenylpyrrolidine, and 1-phenylpiperidine all
worked well, and the corresponding chemoselective C–H
amidation products could be isolated in good yields (3u-x, 59-
80%). Unfortunately, trace amount of products could be detected
with toluene, anisole, and even 1,3,5-trimethoxybenzene as
substrates under current conditions (3aa and 3ab).
Then, we investigated the scope of organic azides 2. It was
found that benzenesulfonyl azides with electron-donating group
(OMe) showed good reactivity, leading to the desired products
4b in 75% yield. Generally, the halogen-substituted
benzenesulfonyl azides (F, Cl, Br, I) were well tolerated, and the
corresponding products could be obtained in relatively good
yields (4c-f, 77-87%). The reaction of naphthalene-2-sulfonyl
azide showed a lower reactivity, delivering the product 4g in
55% yield. The heterocyclic 3-pyridylsulfonyl azide also worked
well and the product 4h could be obtained in 82% yield. Besides
arylsulfonyl azides, alkylsulfonyl azides, such as benzylsulfonyl
azide, butane-1-sulfonyl azide, propane-1-sulfonyl azide,
ethanesulfonyl azide, propane-2-sulfonyl azide, and 1-
vinylcyclopropane-1-sulfonyl azide also exhibited good
reactivities in this transformation, producing the target products
4i-n in 65-95% yields. Unfortunately, when we tested
azidobenzene or (azidomethyl)benzene for this reaction, trace
amount of the products could be detected (4o and 4p).
Table 1. Optimization of the catalytic C–H amidation of heteroarenes[a]
Entry
Catalyst
Solvent
Yield (%)[b]
Temp. (℃)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16[d]
Co2(CO)8
Fe2Cp2(CO)4
Ni(cod)2
Cu(OAc)2
PdCl2
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
toluene
THF
80
80
80
80
80
80
80
80
80
80
25
80
80
80
80
80
20
trace
trace
trace
65
85
trace
40
Pd(OAc)2
Rh2(OAc)4
Cp*Rh(MeCN)3
(Cp*RhCl2)2
[Rh(cod)Cl]2
[Rh(cod)Cl]2
[Rh(cod)Cl]2
[Rh(cod)Cl]2
[Rh(cod)Cl]2
[Rh(cod)Cl]2
[Rh(cod)Cl]2
30
92 (88)[c]
10
65
60
70
80
1,4-dioxane
DMF
MeCN
The motif of sulfonamide is
a core structure widely
distributed in many antibiotics, such as antidiabetic drug
Glibenclamide, one of the top 200 most prescribed medication in
US in 2016. To demonstrate the synthetic utility of our method,
an analogue 9 of Glibenclamide was synthesized concisely from
readily available chemicals (Scheme 2). Sulfonyl azide 8 was
prepared efficiently by condensation of acyl chloride 5 with
amine, followed by Friedel-type sulfonylation and azidation. The
desired product 9 was then obtained in 81% yield by C–H
amidation of 1a under the standard conditions.
60
[a] Reaction conditions: 1a (0.5 mmol), 2a (0.6 mmol), CO (balloon), catalyst
(5 mol %), solvent (2 mL), 12 h. [b] Determined by 1H NMR analysis using
1,1,2,2-tetrachloroethane as an internal standard. [c] Isolated yield. [d] 2.5
mol % [Rh(cod)Cl]2.
With the optimal reaction conditions in hand, we first
investigated the scope of various heteroarenes and arenes 1
(Table 2). It was gratifying to observe that N-Bn and N-Ph
substituted indoles exhibited moderate reactivity (3b and 3c, 55%
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Table 2. Substrate scope of Rh-catalyzed C–H amidation of (hetero)arenes with CO and azides[a]
[a] Reaction conditions: 1 (0.5 mmol), 2 (0.6 mmol), CO (balloon), [Rh(cod)Cl]2 (5 mol %), MeCN (2 mL), 80 °C, 12 h, isolated yield was provided. [b] With
Pd(OAc)2 (5 mol %).
Then, several control experiments were performed to
understand the reaction mechanism. We carried out a stepwise
reaction of p-toluenesulfonyl azide (2a) with CO for 4 hours
under standard reaction conditions, followed by addition of N-
methylindole (1a) for 8 hours, affording product 3a and by-
product p-toluenesulfonamide 10 in 53% and 25% yields,
respectively (Scheme 3a). When we tried the reaction of by-
product 10 with 1a under standard conditions, trace amount of
product 3a could be detected, demonstrating that 10 was not the
intermediate (Scheme 3b). We used the [Rh(CO)2Cl]2 as the
catalyst, and product 3a could be obtained in 90% NMR-yield,
indicating that [Rh(CO)2Cl]2 might be the on-cycle catalyst
(Scheme 3c). The reactions of arenes with tosylisocyanate were
performed with or without [Rh(CO)2Cl]2. Excellent yields were
obtained for both reactions and reaction rate was accelerated
with [Rh(CO)2Cl]2, indicating that isocyanate could be the
possible intermediate (details see Figure S1).
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1.37 Å while the N…H distance is shortened to 1.27 Å. The
predicted energy barrier of HAA in the triplet state is very high
3
(27.1 kcal/mol relative to separated INT2 and 1d). For the HAA
in the singlet state, the optimized TS was shown as 1TS3, in
which the C…H distance is lengthened to 1.29 Å while the N…H
distance is shortened to 1.45 Å. Although the predicted ΔG≠ in
singlet state is much lower than the corresponding triplet state,
the overall energy barrier for path b is still higher than that of
path a. Therefore, computational results suggest that the
generation of isocyanate is more favorable via CO attack to the
nitrene moiety after the formation of the key Rh–nitrene
intermediate. Based on the mechanistic and computational
studies, the plausible reaction pathway was proposed in
Scheme 4.
In summary, we have developed a novel rhodium-catalyzed
C–H amidation to synthesize amides simply from readily
available (hetero)arenes, CO, and organic azides via nitrene
intermediate. This protocol provides a simple and effective
strategy for the synthesis of amides with a range of substrates.
No directing group on arenes and any additive are needed in
this reaction. The mechanistic and computational studies
showed that the formation of amides was through Rh−nitrene
intermediate.
Scheme 2. The modification of Glibenclamide.
Scheme 3. Control experiments.
Computational studies were carried out to obtain an in-
depth understanding on the reaction mechanism.[18] The initial
catalyst precursor, Rh(cod)Cl, could undergo ligand exchange
with CO molecules to afford the complex of Rh(CO)2Cl, which is
exothermic by 7.1 kcal/mol. Thus, the thermodynamically more
stable Rh(I) complex, Rh(CO)2Cl, was employed for the
computational study. Initially, the azide, TsN3 (2a), could
coordinate with the Rh(I) catalyst model to form a complex INT1.
Next, the transition state (TS) of the dissociation of N2 from INT1
to generate the key Rh–nitrene intermediate is located as TS1,
in which the cleavage N–N bond distance is lengthened to 1.84
Å (Figure 1). The calculated energy barrier for the elimination of
N2 is 31.3 kcal/mol relative to INT1. The triplet state of the
formed Rh–nitrene intermediate (3INT2) is found to be the
ground state, which is 6.5 kcal/mol lower in energy than the
corresponding singlet state (1INT2). Subsequently, two possible
mechanistic pathways were considered. For the proposed path a,
the transition states of CO attack to the nitrene moiety of both
Figure 1. Energy profiles (in kcal/mol) for the formation of the Rh-nitrene
intermediate and subsequent CO attack to the nitrene moiety to form
isocyanate. Bond lengths are shown in Å.
3
1
3
1INT2 and INT2 were located as TS2 and TS2, respectively,
which are very close in energy. The predicted ΔG≠ for this
3
pathway is ca. 12 kcal/mol relative to separated CO and INT2.
The resulted Rh(I)-isocyanate complex (1INT3)19 is very
exothermic. Alternatively, another substrate, indole (1d), might
react with the nitrene moiety of the formed Rh–nitrene
intermediate via H-atom abstraction (HAA) pathway prior to CO
attack (path b). For the triplet state, the optimized TS of the
intermolecular HAA from C3–H bond of indole was shown as
3TS3 in Figure 2, in which the C…H distance is lengthened to
Figure 2. Energy profiles (in kcal/mol) for the HAA pathway after the formation
of the Rh-nitrene intermediate. Bond lengths are shown in Å.
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Acknowledgements
We are grateful to the financial support NSFC (21772208,
21702212, 21633013, 21642004), NSFC of Jiangsu Province
(BK20161260), Joint Open Fund of Jiangsu Collaborative
Innovation Center for Ecological Building Material and
Environmental Protection Equipments and Key Laboratory for
Advanced Technology in Environmental Protection of Jiangsu
Province (JH201863), and Hundred-Talented Program of the
Chinese Academy of Sciences. We thank professor Sen-Miao
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Keywords: carbonylation • C–H functionalization • amide •
rhodium • nitrene
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[18] See Supporting Information for computational details.
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10.1002/anie.201903656
Angewandte Chemie International Edition
COMMUNICATION
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COMMUNICATION
Si-Wen Yuan[a],+, Hui Han[a],+, Yan-Lin
Li[a], Xueli Wu[c], Xiaoguang Bao[c],*,
Zheng-Yang Gu[a,b],*, Ji-Bao Xia[a],
*
Page No. – Page No.
Intermolecular C–H Amidation of
(Hetero)arenes to Produce Amides
through Rhodium-Catalyzed
A novel rhodium-catalyzed three-component reaction has been developed to
synthesize amides from organic azides, carbon monoxide, and (hetero)arenes via
nitrene intermediate and direct C-H functionalization. No directing group on arenes
and any additive are needed in this reaction.
Carbonylation of Nitrene Intermediate
This article is protected by copyright. All rights reserved.