Direct amide synthesis: via Ni-mediated aminocarbonylation of arylboronic acids with CO and nitroarenes

Article abstract of DOI:10.1039/c9cc06638a

Herein we describe an alternative and unconventional approach of an aminocarbonylation reaction to access aryl amides from readily available and low-cost arylboronic acids and nitroarenes. Nickel metal can serve as both reductant and catalyst in this direct aminocarbonylation. This protocol exhibits a good functional group compatibility and allows a variety of aryl amides to be synthesized, including several drug-like molecules.

Full text of DOI:10.1039/c9cc06638a

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Direct amide synthesis via Ni-mediated
aminocarbonylation of arylboronic acids with
CO and nitroarenes†
Cite this: Chem. Commun., 2019,
55, 13709
Received 26th August 2019,
Accepted 18th October 2019
ab
Ni Shen,ab Chi Wai Cheung
*
and Jun-An Ma*ab
DOI: 10.1039/c9cc06638a
rsc.li/chemcomm
Herein we describe an alternative and unconventional approach of
an aminocarbonylation reaction to access aryl amides from readily
available and low-cost arylboronic acids and nitroarenes. Nickel
metal can serve as both reductant and catalyst in this direct
aminocarbonylation. This protocol exhibits a good functional group
compatibility and allows a variety of aryl amides to be synthesized,
including several drug-like molecules.
Amides are among the most important compounds in pharma-
ceutical, agrochemical, and materials chemistry.1,2 The amida-
tion of carboxylic acids with amines in the presence of coupling
reagents has long been the traditional method to synthesize
amides.3 Meanwhile, the aminocarbonylation reaction represents
an alternative attractive protocol for amide synthesis.4 As a result, a
myriad of amides could be easily accessed by simply assembling the
readily available carbon monoxide (CO) or its surrogates, carbon
electrophiles, and amine substrates in the presence of transition
metal catalysts (Scheme 1a). To further extend the scope and utility
Scheme 1 Various modes of aminocarbonylation for amide synthesis.
in amide synthesis, various aminocarbonylation reactions using surrogates have emerged as an appealing research area due to the
unconventional coupling substrates, such as carbon nucleophiles low cost, high stability, and high accessibility of nitroarenes.10–15 In
or nitrogen electrophiles, have also been explored (Scheme 1b).4f,5 particular, aminocarbonylation with nitroarenes is among the
For example, Wu and co-workers first described the Pd-catalyzed most commonly studied approaches towards amide synthesis in
aminocarbonylation of nucleophilic arylboronic acids using recent years. Among them, the Beller,10 Driver,11 Hu,12 and Wu
N-chloroamines as electrophilic nitrogen substrates.6 Soon groups13 presented seminal aminocarbonylation methods via
after, the groups of Jiao7 and Ma8 reported the Pd-catalyzed the three-component reactions with nitroarenes, CO or its
aminocarbonylation of arylboronic acids with amines using Cu(II) surrogates, and a diverse set of carbon coupling partners such as
salts or oxygen as oxidants. Most recently, Szostak and co-workers arenes,11 alkenes,10,13 and aryl halides.12 Strikingly, the amino-
disclosed the analogous oxidative Pd-catalyzed aminocarbonylation carbonylation reaction of nitroarenes with arylboronic acids
of arylsilanes with amines.9 On the other hand, the C–N bond remains underdeveloped, even though arylboronic acids have
forming reactions using electrophilic nitroarenes as arylamine been extensively utilized in the C–C and C-heteroatom cross-
coupling reactions.
a Department of Chemistry, Tianjin Key Laboratory of Molecular Optoelectronic
Sciences, and Tianjin Collaborative Innovation Center of Chemical Science &
Engineering, Tianjin University, Tianjin 300072, People’s Republic of China.
E-mail: zhiwei.zhang@tju.edu.cn, majun_an68@tju.edu.cn
Herein we report our efforts in developing an alternative
direct aminocarbonylation based on arylboronic acids and CO
by using nitroarenes as nitrogen electrophiles (Scheme 1c).
Most recently, Wu and co-workers described the Pd-catalyzed
aminocarbonylation of arylboronic acids with nitroarenes
using Mo(CO)6 as a CO surrogate and K2CO3 as a base.16 Our
complementary method highlights the use of more sustainable
b Joint School of NUS & TJU, International Campus of Tianjin University,
Fuzhou 350207, People’s Republic of China
† Electronic supplementary information (ESI) available: Experimental and spectral
data. See DOI: 10.1039/c9cc06638a
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Table 1 The optimization of aminocarbonylationa
Entry
Metal (equiv.)
Additives (equiv.)
Yieldb (%)
1
2
3
4
5
6
7
8
Ni (4)
Ni (4)
Ni (4)
Mn (4)
Co, Mg, or Zn (4)
Ni (4)
Ni (3)
Ni (3)
Ni (3)
Ni (3)
Ni (3)
Ni (3)
Ni (3)
Ni (3)
Ni (3)
Ni (3)
TMSCl (3), PPh3 (1.5)
TMSBr (3), PPh3 (1.5)
TMSI (3), PPh3 (1.5)
TMSCl (3), PPh3 (1.5)
TMSCl (3), PPh3 (1.5)
TMSCl (3), dppp (1)
TMSCl (3), PPh3 (1)
TMSCl (3), PPh3 (1), NaI (2)
TMSCl (3), PPh3 (1), NaBr (2)
TMSCl (3), PPh3 (1), NaI (1)
TMSCl (3), PPh3 (1), NaI (2)
TMSCl (3), PPh3 (1), NaI (2)
TMSCl (3), PPh3 (1), NaI (2)
TMSCl (3), PPh3 (1), NaI (2)
TMSCl (3), PPh3 (1), NaI (2), CoCl2 (10 mol%)
TMSCl (3), PPh3 (1), NaI (2), CuCl2 (10 mol%)
TMSCl (3), PPh3 (1), NaI (2), PdCl2 (10 mol%)
62
33
52
20
0–5
60
63
85
62
76
72c
81d
0e
9
10
11
12
13
14
15
16
17
46f
66
61
48
Ni (3)
a
General procedure: 1a (0.75 mmol), 2a (0.5 mmol), CO (balloon), metal powder, additives (ligand, halotrimethylsilane, metal salt), DMA (1.5 mL),
b
c
d
e
135 1C, 16 h. Isolated yield. Dimethylformamide was used instead of DMA. N-Methylpyrrolidine was used instead of DMA. Mo(CO)6
(2 equiv.) was used instead of CO. Co2(CO)8 (2 equiv.) was used instead of CO.
f
and inexpensive CO and Ni metal as the carbonyl source and of metal salts such as Co, Cu, and Pd, 3a was formed in
reductant, respectively. Additional base is not required in this moderate yields (48–66%, entries 15–17), indicating that the
protocol, thus allowing the synthesis of a broader range of aryl trace metals possibly present in Ni metal are unlikely the
amides, including several drug-like amide molecules.
catalysts for aminocarbonylation.
We commenced our study on aminocarbonylation using
We applied the optimized reaction conditions (Table 1, entry 8) to
4-tolylboronic acid (1a) and 4-nitrotoluene (2a) as the model study the scope of the aminocarbonylation of arylboronic acids and
substrates (Table 1). In the presence of CO, Ni metal powder CO with nitroarenes (Scheme 2). Electron-rich (3a–3e), electron-
(4 equiv.), chlorotrimethylsilane (TMSCl, 3 equiv.), and triphenyl- neutral (3f), and electron-deficient arylboronic acids (3g, 3h) all
phosphine (PPh3, 1 equiv.), 1a (1.5 equiv.) and 2a (1 equiv.) reacted to form the corresponding aryl amides in good to high
reacted in dimethylacetamide (DMA) solvent at 135 1C to deliver yields (60–91%). In this context, the amide 3e derived from sterically
the desired amide 3a in 62% yield (entry 1). In this context, hindered 2,5-dimethylphenylboronic acid could be synthesized with-
Ni powder likely reacted as both reductant and mediator, PPh3 out significant diminishment of yield. In addition, a wide range of
likely acts as the ligand for Ni-mediated reaction, and TMSCl nitroarenes were tolerated in this protocol. Electron-neutral (3i),
served as the deoxygenating reagent of nitroarene.12,14 The use of electron-rich (3j–3s), and electron-deficient nitroarenes (3t–3ad) were
bromotrimethylsilane (TMSBr) or iodotrimethylsilane (TMSI) in suitable reaction partners. While the electron-neutral and electron-
place of TMSCl only gave 3a in 33% and 52% yields, respectively rich nitroarenes reacted to give the amide products in generally high
(entries 2 and 3). In addition, when Mn metal was used as a to excellent yields (B70–90%), the reactions with electron-deficient
reductant in lieu of Ni, 3a was formed in 20% yield (entry 4), nitroarenes usually afforded the amides in good to high yields
while the use of Co, Mg, or Zn metal did not induce the reaction (B50–70%). Nevertheless, mono-, di- and tri-substituted nitroarenes
at all (entry 5), suggesting the indispensable role of nickel in the all reacted smoothly. Notably, the aminocarbonylation with sterically
reaction. Moreover, the use of bidentate ligand, 1,3-bis(diphenyl- bulky 2,4-dimethyl-1-nitrobenene delivered the corresponding amide
phosphino)propane (dppp, 1 equiv.), gave 3a in 60% yield (entry 6). in 82% yield (3s). Moreover, various nitroheteroarenes could be
By lowering the loadings of Ni and PPh3 to 3 equiv. and 1 equiv., incorporated in the amides, including benzodioxole (3ae), benzothio-
respectively, 3a was still formed in 63% yield (entry 7). Interestingly, phene (3af), benzofuran (3ag), and N-benzyl indole (3ah). Further-
by adding 2 equivalents of NaI as additive, the yield of amide more, a variety of functional groups were tolerated on both
improved significantly to 85% (entry 8). In stark contrast, when arylboronic acid and nitroarene substrates, such as thioether (3n),
NaBr was used instead of NaI or when 1 equivalent of NaI was used, chloro (3g, 3x–3z), flouro (3h, 3t–3ab), cyano (3ac), and keto groups
the yields dropped accordingly (entries 9 and 10). DMA was a (3ad). Notably, this protocol allowed for the synthesis of various types
superior solvent to other polar aprotic solvents such as dimethyl- of fluorine-containing aryl amides, which are ubiquitous structural
formamide and N-methylpyrrolidine (entries 11 and 12). Moreover, motifs in medicinal and agrochemical chemistry.
CO was a more effective carbonyl source than Mo(CO)6 and
The application of this aminocarbonylation protocol was
Co2(CO)8 (entries 13 and 14). In the presence of catalytic amounts demonstrated by the synthesis of several drug-like amide molecules.
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Scheme 4 Probing nitrogen-based species for aminocarbonylation.
reaction to less reduced nitrogen-based species (5a, 5b), followed
by intermediately-reduced species (5c, 5d), and eventually to the
more reduced species (5e).14a,20 5e is most likely the ultimate
nitrogen-containing species for reaction. 5e reacted to give the
amide in slightly lower yields than 5d, presumably due to the
lower stability of 5d than 5e at the high reaction temperature.
The addition of NaI was found to promote the efficiency of
aminocarbonylation and significantly enhance the yield of
amide (Table 1, entries 7 and 8). A possible role of NaI is to
generate I2, which can also induce the formation of iodoarene,
such that both I2 and iodoarene could promote the amino-
carbonylation [Scheme S1, (i), ESI†]. Iodide could coordinate to
Ni(II) species to form NiIII2, which liberates I2 under high
temperature.21 Arylboronic acid then reacts with I2 to form
iodoarene,22 which further reacts with Ni metal and nitroarene
to give amide.12 However, when I2 was used instead of KI, the
reaction was less efficient, giving the amide product in much
less yield [Scheme S1, (ii), ESI†]. Moreover, no iodoarene was
formed in the Ni(II)-mediated reaction between arylboronic acid
and I2 [Scheme S1, (iii), ESI†]. These results suggested that the
in situ formation of iodine or iodoarene does not take place to
trigger aminocarbonylation.
Next, we switched our attention to the halogen effect of
nickel(II) halides on aminocarbonylation. NiIICl2 could be
formed via the reduction of nitroarene with Ni metal and
TMSCl. NiIICl2 could then undergo halide substitution with
NaI to form NiIII2. Several control experiments based on these
Ni(II) salts were studied. In the absence of NaI, NiIICl2 mediated
the reaction under otherwise identical conditions to deliver the
amide in 14% yield (Scheme 5(a)). The addition of NaI pro-
moted the NiIICl2-mediated reaction to afford the amide in 48%
yield (Scheme 5(b)). Furthermore, the direct use of NiIII2 even
significantly enhanced the reaction to generate the amide
quantitatively (Scheme 5(c)). The results strongly indicated that
NaI facilitates the in situ formation of NiIII2 to mediate the
aminocarbonylation much more efficiently.
Scheme 2 The scope of aminocarbonylation. Isolated yields are shown.
Under this protocol, three benzoxazole-based antibacterial agents
4a,17 4b,17 and 4c,18 as well as a fluoro-containing antibacterial
agent 4d,19 could be synthesized using the commercially available
or readily available arylboronic acids and nitro(hetero)arenes
(Scheme 3).
During the reaction, Ni metal acts as a reductant to reduce
nitroarenes to various nitrogen-containing species, including
nitrosoarene, N-aryl hydroxylamine, azoxyarene, azoarene, and
1,2-diaryl hydrazine,20 whilst Ni is oxidized to Ni(II) species. To
probe their roles in aminocarbonylation, the reactions of these
nitrogen-based species with 4-tolylboronic acid 1a and CO under
otherwise identical conditions were examined (Scheme 4). Nitroso-
benzene (5a), N-phenyl hydroxylamine (5b), azoxybenzene (5c),
azobenzene (5d), and 1,2-diphenyl hydrazine (5e) all reacted to
give the amide 3i in moderate to good yields (48–77%). Most
likely, nitrobenzene is reduced successively by Ni in the course of
Based on the above results, we proposed a plausible mechanism
of this aminocarbonylation reaction (Scheme S2, ESI†). Ni metal
(Ni(0)) reduces nitroarene successively to 1,2-diaryl hydrazine20
in the presence of TMSCl as a deoxygenating additive12,14
[Scheme S2(a), ESI†]. Meanwhile, Ni(0) is oxidized to Ni(II) salts,
Scheme 3 Applications in medicinal chemistry.
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in which the counter anion could be chloride or O-centered
ligands [trimethylsilanolate (TMS-OÀ), hydroxide (OHÀ)]] originated
from the reduction process of nitroarene. Ni(II) salts then undergo
ligand substitution with NaI to form NiIII2, which further reacts
with PPh3 to form ligated NiIII2 complexes 6 [Scheme S2(b),
ESI†]. We speculated that the formation of complex 6 could
prevent Ni precipitation with O-centered ligands.23 The good
leaving group ability of iodide23 also enables rapid iodide dis-
sociation from 6, providing a vacant site to effect transmetala-
tion of arylboronic acid via the activation with TMS-OÀ or OHÀ,
as well as to effect the subsequent CO insertion to form acyl-NiII
intermediate 7 [Scheme S2(c), ESI†]. 1,2-Diaryl hydrazine bears a
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and likely splits readily into amino radicals, which then react
with 7 to give NiIII(acyl)(amino) complex 8 [Scheme S2(d), ESI†].
Finally, 7 undergoes reductive elimination to afford the amide
product, while the co-product Ni(I) species could disproportionate
to regenerate NiIII2 and Ni(0).25 The detailed reaction mechanism
will be subjected to a future dedicated study.
In summary, we have disclosed an alternative aminocarbonyla-
tion method for amide synthesis using readily available carbon
monoxide, arylboronic acids, and nitroarenes as reaction sub-
strates. Nickel metal serves as both a reductant and mediator in
this protocol. Diverse aryl amines could be synthesized, including
several drug-like molecules. Further advancement of the reaction
protocol, especially the endeavour to use safer carbon monoxide
surrogates instead of the more toxic carbon monoxide, are under-
way in our laboratory.
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We acknowledged the National Natural Science Foundation
of China (No. 21532008, 21772142, 21901181, and 21971186)
and Tianjin University for financial support.
¨
¨
˙
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Conflicts of interest
There are no conflicts to declare.
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Notes and references
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