A novel construction of acetamides from rhodium-catalyzed aminocarbonylation of DMC with nitro compounds

Article abstract of DOI:10.1039/d1cc00047k

Dimethyl carbonate (DMC), an environment-friendly compound prepared from CO₂, shows diverse reactivities. In this communication, an efficient procedure using DMC as both a C1 building block and solvent in the aminocarbonylation reaction with nitro compounds has been developed. W(CO)₆acts both a CO source and a reductant here.

Full text of DOI:10.1039/d1cc00047k

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A novel construction of acetamides from
rhodium-catalyzed aminocarbonylation of
DMC with nitro compounds†
Cite this: Chem. Commun., 2021,
57, 1955
Received 4th January 2021,
Accepted 19th January 2021
bc
Zhi-Peng Bao,a Ren-Guan Miao,a Xinxin Qi*a and Xiao-Feng Wu
*
DOI: 10.1039/d1cc00047k
rsc.li/chemcomm
Dimethyl carbonate (DMC), an environment-friendly compound
On the other hand, since the pioneering work of Heck and
prepared from CO2, shows diverse reactivities. In this communica- co-workers,7 the transition-metal-catalyzed carbonylation reaction
tion, an efficient procedure using DMC as both a C1 building block experienced impressive progress during the last few decades, and
and solvent in the aminocarbonylation reaction with nitro com- has drawn much attention in both academic and industrial
pounds has been developed. W(CO)6 acts both a CO source and a fields.8 This reaction has been extensively applied as one of the
reductant here.
most powerful and direct protocols for the production of
carbonyl-containing compounds. The model case is the Monsanto
Dimethyl carbonate (DMC) is a non-toxic and biodegradable process for the industrial manufacturing of acetic acid, an efficient
compound, which is well-known as a green solvent in organic rhodium-catalyzed carbonylation reaction of methanol.9 In this
synthesis.1 Many methods have been explored for the preparation process, HI is used as a cocatalyst that usually causes some serious
of DMC during these years,2 and one of the most significant and equipment corrosion problem. Recently, Han, Liu and their co-
attractive strategies is using CO2 as a feedstock,3 by insertion of CO2 workers demonstrated a new route for carbonylative synthesis of
into oxirane and then reaction with methanol. Meanwhile, DMC aryl acetates from aryl methyl ethers catalyzed by RhCl3 in the
plays an important role as a versatile and appealing reactant in presence of LiI and LiBF4.10 Moreover, the investigation of a new
industry and fine chemistry for multiple applications. DMC can act protocol for the construction of carbonyl-containing compounds
as a methoxycarbonylating and methylating reagent with various is highly desired. In our continuous study of DMC in the
nucleophiles.4 Generally, diazomethane, methyl iodide, methyl transition-metal-catalyzed carbonylation reactions,11 we herein
tosylate, methyl triflate, and dimethyl sulfate are commonly used wish to describe the first example based on the use of DMC as
methylation reagents. Most of them suffer from several disadvan- both a C1 building block and solvent in the rhodium-catalyzed
tages such as being explosive, toxic/corrosive, expensive and so on. aminocarbonylation reaction for the synthesis of acetamides
Besides, in these methylation reactions, a stoichiometric amount of with abundant and more stable nitro compounds as a nitrogen
base is usually required, affording the corresponding inorganic surrogate. To our knowledge, nitro compounds combined with
salts that have some disposal issues. In this perspective, DMC could DMC as a carbon coupling partner in the aminocarbonylation
be used as a safe and environmentally benign alternative without reaction remain unexplored. The integration of DMC in
special cautions for conventional toxic dimethyl sulfate and expen- rhodium-catalyzed aminocarbonylation reactions would open a
sive methyl iodide.5,6 It does not produce undesired inorganic salts novel and sustainable pathway for the construction of acetamides.
compared to methylation with dimethyl sulfate or methyl iodide.
To probe the catalytic system of DMC with nitro compounds,
nitrobenzene was used as an initial substrate for establishing
this aminocarbonylation reaction (Table 1). The reaction was
performed in DMC with Rh2(CO)4Cl2 as catalyst, DPPP as a
ligand, NaI as an additive, Mo(CO)6 as the CO source, and
Na3PO4 as base in the presence of H2O at 120 1C for 24 h. To our
delight, the desired acetamide product 2b was obtained in 75%
yield (Table 1, entry 1). We next studied the catalyst effects, and
the use of Rh2(OAc)4 and [Cp*RhCl2]2 afforded acetamide in
lower yields (Table 1, entries 2 and 3). However, compared to
rhodium catalysts, Pd(OAc)2 and Ni(OTf)2 had very low efficiency
a Department of Chemistry, Zhejiang Sci-Tech University, Hangzhou, Zhejiang
310018, People’s Republic of China. E-mail: xinxinqi@zstu.edu.cn
b Dalian National Laboratory for Clean Energy, Dalian Institute of Chemical
Physics, Chinese Academy of Sciences, 116023, Dalian, Liaoning, China.
E-mail: xwu2020@dicp.ac.cn
c
¨
¨
Leibniz-Institut fur Katalyse e.V. an der, Institution Universitat Rostock,
Albert-Einstein-Straße 29a, Rostock 18059, Germany. E-mail: xiao-
feng.wu@catalysis.de
† Electronic supplementary information (ESI) available: General comments,
general procedure, analytic data and NMR spectra. See DOI: 10.1039/d1cc00047k on this catalytic system, only a trace amount of the target product
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Table 1 Screening of reaction conditionsa
DPPP
Entry Catalyst (mol%) (mol%) Base (equiv.) NaI (mol%) Yield (%)
1
2
3
4
5
6
7
8
Rh2(CO)4Cl2 (5) 10
Rh2(OAc)4 (5) 10
[Cp*RhCl2]2 (5) 10
Na3PO4 (1)
Na3PO4 (1)
Na3PO4 (1)
Na3PO4 (1)
Na3PO4 (1)
Na3PO4 (1)
Na3PO4 (1)
K3PO4 (1)
30
30
30
30
30
30
30
30
75
70
55
o1
o1
80
70
o1
20
85
84
0
75
84
78
81
89
96
Pd(OAc)2 (10)
Ni(OTf)2 (10)
10
10
Rh2(CO)4Cl2 (5) 15
Rh2(CO)4Cl2 (5) 20
Rh2(CO)4Cl2 (5) 15
Rh2(CO)4Cl2 (5) 15
Rh2(CO)4Cl2 (5) 15
Rh2(CO)4Cl2 (5) 15
Rh2(CO)4Cl2 (5) 15
Rh2(CO)4Cl2 (5) 15
Rh2(CO)4Cl2 (5) 15
9
Na2HPO4 (1) 30
Na3PO4 (1.5) 30
Na3PO4 (2)
10
11
12
13
14
15
16b
17c
18d
30
0
Na3PO4 (1.5)
Na3PO4 (1.5) 20
Na3PO4 (1.5) 50
Na3PO4 (1.5) 30
Na3PO4 (1.5) 30
Na3PO4 (1.5) 30
Na3PO4 (1.5) 30
Rh2(CO)4Cl2 (2)
Rh2(CO)4Cl2 (2)
Rh2(CO)4Cl2 (2)
Rh2(CO)4Cl2 (2)
6
6
6
6
a
Reaction conditions: nitrobenzene 1a (0.5 mmol), DMC (1.5 mL),
catalyst (5 mol%), DPPP (10 mol%), NaI (30 mol%), Mo(CO)6 (1.5 equiv.),
Na3PO4 (1 equiv.), H2O (1 equiv.), 120 1C, 24 h. GC yield, with hexadecane
b
c
d
as the internal standard. H2O (2 equiv.). W(CO)6 (1.5 equiv.).
W(CO)6 (2 equiv.).
could be detected (Table 1, entries 4 and 5). Notably, a higher
yield could be observed with 15 mol% of DPPP (Table 1, entry 6),
while when using 20 mol% of DPPP, the yield dropped (Table 1,
entry 7). Next, different bases were checked, resulting in product
2a in much lower yields when K3PO4 and Na2HPO4 were
employed as base (Table 1, entries 8 and 9). By increasing the
amount of Na3PO4 to 1.5 and 2 equivalents, the corresponding
product was produced in 85% and 84% yields (Table 1, entries 10
Scheme 1 Substrate scope of nitro compounds.a aReaction conditions:
nitro compounds (0.5 mmol), DMC (1.5 mL), Rh2(CO)4Cl2 (2 mol%), DPPP
(6 mol%), NaI (30 mol%), W(CO)6 (2 equiv.), Na3PO4 (1.5 equiv.), H2O (2 equiv.),
120 1C, 24 h. Isolated yield.
and 11). Remarkably, NaI played an important role in this desired products were produced in more than 90% yields.
aminocarbonylation system, and a methyl iodide molecule could Nitroarenes with electron-donating groups, including methyl,
be detected in GC, suggesting that DMC might transform into N,N-dimethyl, thiomethyl, methoxy, phenoxy, and tosylate
CH3I with the assistance of NaI. However, no aminocarbonyla- groups afforded the acetamide products in good to excellent
tion reaction occurred in the absence of NaI (Table 1, entry 12). yields (2b–2i). Those substrates with ortho-substitution resulted
Further screening showed that 30 mol% of NaI seemed to be the in the product with lower yield compared to para- and meta-
best (Table 1, entries 10 vs. 13 and 14). Subsequently, when the substitution probably due to the steric effects (2d vs. 2b, 2c).
catalyst loading was decreased to 2 mol% along with 6 mol% of Electron-withdrawing groups such as trifluoro and acetyl
DPPP, a slightly lower yield of 2b was obtained (Table 1, entry groups were also well compatible in this aminocarbonylation
15). Considering the price of rhodium catalysts, 2 mol% loading reaction; the corresponding acetamides were successfully
was further employed, and a better result was achieved by using obtained in 93% and 94% yields (2j and 2k). Moreover, nitroar-
2 equivalents of H2O (Table 1, entry 16). Finally, it should be enes with halo groups, involving fluoro, chloro, and bromo groups
mentioned that the CO surrogate affected the yield significantly; were well tolerated to provide the target products in excellent
2b with 89% and 96% yield was formed by using W(CO)6 as the yields (2l–2p). 2-Nitro-1,10-biphenyl, 1-nitronaphthalene, and
CO source (Table 1, entries 17 and 18). And lower yield was 3-nitro-9H-fluorene substrates were further studied, and the
obtained when CO gas (1 bar) was applied.
desired amide products were isolated in 91%, 88%, and 96%
With the best reaction conditions in hand, we next turn our yields (2q–2s). In addition, this catalytic system could work
attention to the substrate scope of this aminocarbonylation smoothly with heteroaryl groups, and the corresponding
reaction towards various nitro compounds. As illustrated in acetamides were obtained in good to excellent yields (2t–2w).
Scheme 1, a wide range of nitro compounds were tolerated well Remarkably, substrates with two nitro groups, for examples, 1,3-
under the standard reaction conditions, and most of the dinitrobenzene and 2,20-dinitro-1,10-biphenyl, were still reactive,
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delivering the diacetamide products in good yields (2x and 2y). It is conditions (Scheme 2, eqn (e)). The acetamide product 2a was
noteworthy that besides nitroarenes, aliphatic nitro compounds formed in 32–53% yields, which demonstrated that 1a0–1e0 are
were shown to be suitable nitrogen sources as well. Those possible nitrogen intermediates in this aminocarbonylation
substrates with propyl, tert-butyl, and cyclic groups reacted reaction, and W(CO)6 acts both a CO source and a reductant.
smoothly with DMC and gave the acetamide products in moderate
to high yields (2aa–2ac).
Based on the above results and previous literature report,9,10
a plausible reaction mechanism is proposed in Scheme 3. First,
In order to gain more insight into the reaction mechanism in the presence of a base, NaI will react with the soft electro-
for acetamide synthesis, several control experiments were conducted philic methyl group of DMC to give CH3I, which further under-
(Scheme 2). First, when TEMPO (2,2,6,6-tetramethylpiperidinooxy, went an oxidative addition with RhCl(CO)2(dppp) I to afford
2 equiv.) was used as a radical scavenger under the standard complex II, followed by the CO coordination and insertion to
reaction conditions, no target product 2b could be observed produce acetyl intermediate III. Acetyl iodide is then formed
(Scheme 2, eqn (a)). However, employing 1,1-DPE (1,1- and the active rhodium species I will be released upon reduc-
diphenylethylene,
2 equiv.) and BHT (2,4-di-tert-butyl-4- tive elimination from complex III. Afterwards, a nucleophilic
methylphenol, 2/5 equiv.) as the radical-trapping reagents, the attack of amine (generated from nitro compounds) to the acetyl
desired product 2b was obtained in 73%, and 73%/72% yields iodide molecule gave the final acetamide products.
(Scheme 2, eqn (a)), which indicate that a free radical pathway
To further reveal the potential utility of this aminocarbony-
might not be involved. When methyl iodide and methanol were lation protocol, an active pharmaceutical compound was
further treated with 1b under the standard conditions, the final synthesized. Under the standard reaction conditions, the non-
product 2b was detected in 31% and 0% yield (Scheme 2, steroidal anti-inflammatory drug Phenacetin was prepared in
eqn (b) and (c)), suggesting that methyl iodide might be the almost quantitative yield from the corresponding 1-ethoxy-4-
key intermediate in this catalytic system. Here, it is important nitrobenzene (Scheme 4, eqn (a)), which provides a new synthetic
to note that methyl iodide can be detected in our optimization route for Phenacetin. Moreover, the reaction for Phenacetin
process when the yield of amide was low. When anisole was synthesis in one mmol-scale catalyzed by lower loading of
also used as a methyl source, no expected acetamide 2b was Rh2(CO)4Cl2 (1 mol%) still worked very well to produce the
produced (Scheme 2, eqn (d)). The reduction of nitro compounds Phenacetin product in 92% yield (Scheme 4, eqn (b)). Addition-
can generate several nitrogen-containing intermediates.12 To get ally, to extend the scope of this aminocarbonylation reaction, the
more information about the nature of nitro compounds in this late-stage modification of natural molecules was carried out. By
catalytic system, nitrosobenzene (1a0), N-phenyl hydroxylamine using D-10-camphorsulfonyl chloride and dehydroabietylamine
(1b0), azobenzene (1c0), 1,2-diphenyl hydrazine (1d0), and aniline as starting materials, followed by the reaction with 4-nitrophenol
(1e0) were reacted with DMC under the standard reaction and 4-nitrobenzoyl chloride, respectively; the resulting inter-
mediates 4 and 6 reacted smoothly via the present pathway
under standard reaction conditions to give the corresponding
acetamide derivatives 5 and 7 in 70% and 95% isolated yields
(Scheme 4, eqn (c) and (d)). These positive outcomes shed light
on the potential application of this method in drug synthesis and
discovery.
Scheme 2 Mechanistic studies.a aGC yields, with hexadecane as the
internal standard.
Scheme 3 Proposed reaction mechanism.
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We are grateful for the financial support from the Natural
Science Foundation of Zhejiang Province (LY21B020010)
and the Fundamental Research Funds of Zhejiang Sci-Tech
University (2020Q038).
Conflicts of interest
There are no conflicts to declare.
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In summary, a new route for the synthesis of acetamides has
been developed via a general and practical rhodium-catalyzed
aminocarbonylation reaction of DMC with nitro compounds.
In this aminocarbonylative transformation, DMC acted as not
only a C1 building block but also a reaction medium, whereas
NaI served as a cocatalyst to promote the conversion of DMC to
CH3I. With W(CO)6 as the CO source and reductant, a wide
range of nitro compounds could be efficiently transferred to the
10 Q. Mei, Y. Yang, H. Liu, S. Li, H. Liu and B. Han, Sci. Adv., 2018,
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over, Phenacetin synthesis and last-stage modification of natural
products were achieved via this aminocarbonylation strategy.
This work provides a new synthetic pathway for the preparation
of acetamides and highlights the application of DMC as both an
active reagent and solvent in carbonyl-containing compound
construction.
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1958 | Chem. Commun., 2021, 57, 1955ꢀ1958
This journal is The Royal Society of Chemistry 2021