Palladium Catalyzed Aminocarbonylation of Benzylic Ammonium Triflates with Nitroarenes: Synthesis of Phenylacetamides

Article abstract of DOI:10.1002/adsc.202001561

A palladium catalyzed reductive aminocarbonylation of benzylic ammonium triflates with nitroarenes for the synthesis of phenylacetamides was developed. Using Pd(acac)₂/DPPF catalyst system, a range of different substituted phenylacetamides were prepared in moderate to good yields from benzylic ammonium triflates and nitroarenes through Csp³?N bond cleavage. A variety of alkyl, aryl, and halide substituents on both substrates can be used, and many useful functional groups can be tolerated. (Figure presented.).

Full text of DOI:10.1002/adsc.202001561

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DOI: 10.1002/adsc.202001561
Palladium Catalyzed Aminocarbonylation of Benzylic Ammonium
Triflates with Nitroarenes: Synthesis of Phenylacetamides
Li-Miao Yang,a Shan-Shan Li,a You-Ya Zhang,a Jin-Liang Lu,a Jing-Tong Deng,a
Ai-Jun Ma,a Xiang-Zhi Zhang,a Shu-Yu Zhang,b,* and Jin-Bao Penga,*
a
School of Biotechnology and Health Sciences, Wuyi University, Jiangmen, Guangdong 529020, People’s Republic of China
E-mail: pengjb_05@126.com
b
Shanghai Key Laboratory for Molecular Engineer of Chiral Drugs & School of Chemistry and Chemical Engineering, Shanghai
Jiao Tong University, Shanghai, 200240, People’s Republic of China
E-mail: zhangsy16@sjtu.edu.cn
Manuscript received: December 15, 2020; Revised manuscript received: February 1, 2021;
Version of record online: Februar 18, 2021
Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.202001561
over anilines. Thus, aminocarbonylation with nitro-
Abstract: A palladium catalyzed reductive amino-
carbonylation of benzylic ammonium triflates with
arenes has been of commonly studied in recent years.[6]
Several research groups, including Beller,[6a]
nitroarenes for the synthesis of phenylacetamides
Driver,[6b–d] Hu,[6e] and Wu,[6f] developed transition
was developed. Using Pd(acac)2/DPPF catalyst
metal catalyzed aminocarbonylations of various carbon
system, a range of different substituted phenyl-
coupling partners (such as alkenes, arenes, aryl halides,
acetamides were prepared in moderate to good
as well as arylboronic acids) with nitroarenes and CO
yields from benzylic ammonium triflates and nitro-
arenes through Csp3À N bond cleavage. A variety of
(or CO surrogates). For example, Hu and co-workers
developed a reductive aminocarbonylation of aryl
alkyl, aryl, and halide substituents on both sub-
halides with nitroarenes under nickel catalysis.[6e] Wu
strates can be used, and many useful functional
group developed a palladium-catalyzed aminocarbony-
groups can be tolerated.
lation of arylboronic acids with nitroarenes.[6f] Re-
cently, Cheung and Ma reported a Ni-mediated amino-
carbonylation of arylboronic acids with nitroarenes.[6g]
Keywords: Aminocarbonylation;
Benzylic
However, the existing literatures on carbonylation of
nitroarenes mainly focused on Csp2À X bonds (Sche-
me 1a), only a few examples had been reported on
Ammonium Triflates; Nitroarenes; Phenylacetamides
Amide represents one of the most important structural
motifs in life science and is ubiquitous in fine
chemicals, bioactive molecules (e.g., peptides and
proteins), natural products and pharmaceuticals.[1]
Amide is also important intermediate in organic
chemistry.[2] Traditional method for the construction of
amide motifs is based on the amidation reaction of
carboxylic acids with anilines or amines as amino
sources.[3] Alternatively, transition-metal-catalyzed
aminocarbonylation with amines provides a direct and
step economic method for amide synthesis from
organic halides.[4] On the other hand, the direct use of
air-stable nitroarenes as nitrogen sources is becoming
more and more attractive due to their low cost and
wide availability. In addition, since anilines are mainly
derived from the reduction of their corresponding
nitroarenes,[5] the direct use of nitroarenes in amide
synthesis also features their redox-economic advantage
Scheme 1. Aminocarbonylation with Nitroarenes.
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reductive aminocarbonylation of Csp3À X bonds with
nitroarenes for the synthesis of amides. In 2019,
Mankad and co-worker reported a copper-catalyzed
aminocarbonylation of alkyl iodides and nitroarenes to
access N-aryl alkylamides (Scheme 1b).[6h]
On the other hand, benzylammonium salts have
recently been widely used as a class of valuable C-
electrophiles in various organic transformations own-
ing to their features of good reactivity, readily
availability as well as thermal stability.[7] With a
continuous interest in carbonylation of nitroarenes,[8]
we herein report a palladium catalyzed aminocarbony-
lation of benzylic ammonium triflates with nitroarenes
employing Mo(CO)6 as a solid CO source (Sche-
me 1c). Notably, this is the first example of reductive
aminocarbonylation of nitroarenes through palladium
catalyzed Csp3À N bond cleavage.[9]
Table 1. Optimization of the Reaction Conditions.[a]
Entry [Pd]
Ligand Sol.
Base
Yield (%)[b]
1
2
Pd(acac)2 DPPP Tol.
Pd(PPh3)4 DPPP Tol.
K2CO3 22
K2CO3 11
3
4
Pd(acac)2 DPPP CH2Cl2 K2CO3 30
Pd(acac)2 DPPB DMSO K2CO3 43
5
6
7
Pd(acac)2 DPPP DMF
Pd(acac)2 DPPP Dioxane K2CO3 71
Pd(acac)2 DPPP THF K2CO3 64
K2CO3 51
8
9
Pd(acac)2 DPPP CH3CN K2CO3 73
Pd(acac)2 DPPP CH3CN Cs2CO3 60
10
11
12
13
Pd(acac)2 DPPP CH3CN t-BuOK
Pd(acac)2 DPPP CH3CN NEt3
Pd(acac)2 DPPF CH3CN K2CO3 75
6
17
Initially, the air and thermally stable benzyltrimeth-
ylammonium triflate 1a and 4-nitrotoluene 2a were
selected as model substrates for this aminocarbonyla-
tion reaction. To our delight, using Mo(CO)6 as a solid
CO source and K2CO3 as the base, the desired phenyl-
acetamide 3aa was successfully obtained in 22% yield
using the Pd(acac)2/DPPP catalyst system in toluene
(Table 1, entry 1). Subsequently, a series of commer-
cially available palladium catalyst precusors were
examined in this reaction, and Pd(acac)2 was found to
be optimal (see Table S1). Other palladium catalysts
led to lower yields, 3aa was obtained in 11% yields
when Pd(PPh3)4 was used as the catalyst (Table 1,
entry 2). The choice of solvents affected the yields
significantly. Reactions in polar solvents gave higher
yields than those in non-polar solvents (Table 1, entries
Pd(acac)2 PPh3
CH3CN K2CO3 trace
14[c] Pd(acac)2 DPPF CH3CN K2CO3 85
15[c,d] Pd(acac)2 DPPF CH3CN K2CO3 77
[a] Reaction conditions: Benzyltrimethylammonium triflate 1a
(0.5 mmol), 4-nitrotoluene 2a (0.75 mmol), [Pd] (5 mol%),
ligand (10 mol% for monodentate ligand, 5 mol% for
bidentate ligand), Mo(CO)6 (0.5 mmol.), base (2.0 equiv.),
°
solvent (2 mL), 130 C, 16 h.
[b] Isolated yields.
[c] H2O (4.0 equiv.) was added.
[d] TEBAC (20 mol%) was added. DPPP: 1,3-Bis(diphenylpho-
sphino)propane. DPPF: 1,1’-Bis(diphenylphosphino)ferro-
cene. TEBAC: Benzyl triethyl ammonium chloride.
3–8). This might be resulted from the better solubility hydrogen source, played a significant role in the
of the quaternary ammonium salt 1a in polar solvents. reductive carbonylation of nitroarenes. The yield of
When the reaction was performed in MeCN, 3aa was 3aa was improved to 62% when 4 equiv. of water was
obtained in 73% yields (Table 1, entry 8). Then, differ- added in the reaction (Table 1, entry 14). However, the
ent solvents were examined in this reaction. The yield addition of phase transfer catalysts such as TEBAC
of 3aa decreased to 60% when Cs2CO3 was used as failed to improve the yield (Table 1, entry 15, see
base (Table 1, entry 9). Other bases such as t-BuOK or details in SI). In addition, when the reaction an
NEt3 led to even lower yields (Table 1, entries 10 and atmosphere of CO
11, see details in SI). The ratio of quaternary
Having established the optimized reaction condi-
ammonium salt 1a and 4-nitrotoluene 2a also played tions (Table 1, entry 14), the generality of this amino-
an important role in this reaction. Reducing the amount carbonylation reaction was examined with various
of nitroarene decreased the yield of 3aa (see Table S5). nitroarenes and quaternary ammonium salts. As sum-
The screening of ligands revealed that a phosphine marized in Scheme 2, we first investigated the nitro-
ligand is required for this transformation, no desired arene scope with benzyltrimethylammonium triflate
product was obtained when the reaction was performed 1a. Generally, various nitroarenes were well tolerated,
without phosphine ligand (see details in SI). Bidentate providing the desired products in moderate to good
phosphine ligands were suitable, the yield was slightly yields (34–90% yields). Nitrobenzenes with either
improved to 75% when DPPF was used (Table 1, electron-donating group (3ac–3ai), electron-withdraw-
entry 12). Monodentate phosphine ligands were ineffi- ing groups (3aj–3al) or multi-substituents (3am–3ap)
cient for this transformation, no or only trace amount reacted smoothly under the standard reaction condi-
of product was detected (Table 1, entry 13, see details tions to give the desired phenylacetamides 3 in
in SI). Further sceening of reaction temperature and moderate to good yields. The steric hindrance of the
reaction time did not improve the reaction yield. substituents on the nitrobenzene affected the yields
Notably, the addition of water, which serves as the significantly (3aa and 3ac vs 3ad). Gratifyingly,
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Scheme 3. Substrate Scope of Tetraalkylammonium Triflates.
drance of the substituents on benzyltrimeth-
ylammonium triflates also affected the yields signifi-
cantly (3ba and 3ca vs 3da). Furthermore,
tetraalkylammonium triflates with naphthalene and
thiophene were suitable substrates as well, which
produced the corresponding products 3la, 3ma and
3na in 75%, 74% and 67% yields, respectively.
Scheme 2. Substrate Scope of Nitroarenes.
In order to gain a better understanding of the
many kinds of functional groups, including ether (3af reaction pathway of this aminocarbonylation reaction,
and 3ag), amine (3ah), thioether (3ai), ester (3al), the following control experiments were carried out
and halides (3aj, 3am–3ap), were compatible in this (Scheme 4). Four possible reduction intermediates of
aminocarbonylation reaction and produced the corre- nitrobenzene (isocyanatobenzene, aniline, nitrosoben-
sponding products without breaking the CÀ X bonds. zene and azobenzene) were used to react with
Besides, when 1-nitronaphthalene was used in this benzyltrimethylammonium triflate 1a under standard
reaction, the corresponding phenylacetamide 3aq was conditions. Firstly, no desired phenylacetamide 3aa
obtained in 79% yields. Moreover, this aminocarbony-
lation reaction also works well for nitroheteroarene.
For instance, 8-nitroquinoline and indole-substituted
nitrobenzene reacted smoothly with 1a and produced
the corresponding phenylacetamides 3ar and 3as in
76% and 43% yields, respectively.
Subsequently, a series of different tetraalkylammo-
nium salts were reacted with 4-nitrotoluene to examine
the generality of the other coupling partner for this
aminocarbonylation reaction. As illustrated in
Scheme 3,
various
substituted
benzyltrimeth-
ylammonium triflates were tolerated in this reaction
and produced the desired products in moderate to good
yields (32%–91%). Both electron-donating group
(3ba–3ha) and electron-withdrawing group (3ia–3ka)
substituted benzyltrimethylammonium triflates were
well tolerated. In general, substrates with electron-
donating group gave better yields than those with
electron-withdrawing group. Again, the steric hin-
Scheme 4. Control Experiments.
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was observed when 1-isocyanato-4-methylbenzene was
used as substrate, which excluded the possibility of
isocyanate as a intermediate in this reaction (Scheme 4,
a). On the other hand, when aninline, nitrosobenzene
and azobenzene were subjected to the optimized
reaction conditions, the corresponding products were
obtained successfully (Scheme 4, b–d). These observa-
tions indicate that aniline, nitrosobenzene and azoben-
zene might serve as possible intermediates in the
aminocarbonylation reaction.
Based on the above experimental results and
previous relevant reports, a plausible reaction pathway
for this aminocarbonylation of benzyltrimeth-
ylammonium triflates is proposed in Scheme 5. First,
the reaction is initiated by oxidative addition of the in-
situ generated Pd(0) to benzyltrimethylammonium
triflate 1 to give a benzyl-palladium complex A or A’.
Then, coordination and migratory insertion of CO,
which was released from Mo(CO)6, generates the acyl
palladium intermediate B. Subsequently, ligand sub-
stitution of complex B with amine 4, which is
generated from the reduction of nitroarene by Mo(CO)6
in the presence of water,[10] affords intermediate C.
Reductive elimination of C leads to the desired product
3 and releases Pd(0) species for the next catalytic
cycle.
Experimental Section
General Information. Unless otherwise noted, all reactions
were carried out under a nitrogen atmosphere. All reagents were
from commercial sources and used as received without further
purification. All solvents were dried by standard techniques and
distilled prior to use. Column chromatography was performed
on silica gel (200–300 meshes) using petroleum ether (bp. 60~
1
°
90 C) and ethyl acetate as eluent. NMR spectra were recorded
on a Bruker Avance operating at for H NMR at 500 MHz, 13C
1
NMR at 126 MHz and 19F NMR at 471 MHz and spectral data
were reported in ppm relative to tetramethylsilane (TMS) as
internal standard and CDCl3 (1H NMR δ 7.27, 13C NMR δ 77.0)
as solvent. All coupling constants (J) are reported in Hz. The
following abbreviations were used to describe peak splitting
patterns when appropriate: s=singlet, d=doublet, dd=double
doublet, ddd=double doublet of doublets, t=triplet, dt=
double triplet, q=quatriplet, m=multiplet, br=broad.
Benzyltrimethylammonium triflate 1 were prepared according
to the previously reported procedures.[11]
General Procedure. Under nitrogen atmosphere, 1a
(0.5 mmol), 2a (0.75 mmol), Pd(acac)2 (5 mol%), DPPF
(5 mol%), Mo(CO)6 (1 equiv.) and K2CO3 (2 equiv.) were added
to an oven-dried 15 mL In-Ex tube. Then, H2O (4 equiv.) and
CH3CN (2 mL) were added to the reaction. The tube was sealed
°
and the mixture was stirred at 130 C for 13 h. After the reaction
was completed, the reaction mixture was filtered and concen-
trated under vacuum. The crude product was purified by column
chromatography on silica gel to afford the corresponding
product 3aa to 3na.
In summary, we have developed a reductive amino-
carbonylation of benzylic ammonium triflates with
nitroarenes through palladium catalyzed CÀ N bond
cleavage. Using Pd(acac)2/DPPF catalyst system, a
range of different substituted phenylacetamides were
prepared in moderate to good yields from benzylic
ammonium triflates and nitroarenes. A variety of alkyl,
aryl, and halide substituents on both substrates can be
used, and many useful functional groups can be
tolerated
Acknowledgements
Financial supports from the NSFC (21801225), the Guangdong
Province Universities and Colleges Pearl River Scholar Funded
Scheme (2019), the High-level Talent Research Start-up Project
(2018TP018) and Science Foundation for Young Teachers
(2019td02) of Wuyi University, and the Department of Educa-
tion of Guangdong Province (2020KCXTD036) are gratefully
acknowledged
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