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Letter

pubs.acs.org/acscatalysis

Nickel-Catalyzed Reductive Transamidation of Secondary Amides

with Nitroarenes
Chi Wai Cheung, Marten Leendert Ploeger, and Xile Hu*
Laboratory of Inorganic Synthesis and Catalysis, Institute of Chemical Sciences and Engineering, Ecole Polytechnique Fédérale de
Lausanne (EPFL), ISIC-LSCI, BCH 3305, Lausanne 1015, Switzerland
*
S Supporting Information

ABSTRACT: Transmidation is an attractive method for

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amide synthesis. However, transamidation of secondary amides

is challenging. Here, we describe a reductive transamidation
method that employs readily available nitro(hetero)arenes as
the nitrogen sources, zinc or manganese as reductant, and
Downloaded via 132.255.20.2 on September 26, 2019 at 02:27:33 (UTC).

simple nickel salt and ligand as a catalyst system. The scope of

amides includes both alkyl and aryl secondary amides, with
high functional group compatibility.
KEYWORDS: transamidation, nickel catalysis, reductive coupling, amide synthesis, nitroarenes

A mides are ubiquitous in nature and are among the most

important functional molecules in industries.1,2 The
prevalence and stability of amides make them attractive
reagents in organic synthesis.3 Among various transformations
of amides, transamidation is particularly useful, because it
provides a direct and rapid means to diversify amides. However,
the amide C−N bond is very strong and difficult to cleave,
because of the resonance stabilization.1,4,5 While efficient
catalytic methods are available for the transamidation of
primary amides,3a,6 secondary transamidation remains challeng-
ing, because this process is mostly thermoneutral and has a
tendency to give an equilibrium mixture of reagent and product
amides (see Figure 1a).7,8
Figure 2. Proposed mechanisms for Ni-catalyzed reductive amidation
and transamidation with nitroarene.
Recently, Garg and co-workers reported a two-step approach
to effect transamidation of secondary aryl9 and alkyl10 amides
(see Figure 1b). By activating the amides with tert-
butyloxycarbonyl (Boc) group, using di-tert-butyl carbonate
(Boc2O), transamidation with amines was achieved using nickel
catalysis. Szostak and co-workers showed that transamidation of
similar Boc-activated aryl amides with alkylamines and
arylamines could be obtained using 3 equiv of Et3N as a
promoter11 and Pd12 catalysis, respectively (Figure 1b). These
recent developments have considerably advanced the trans-
amidation methodology.
We13,14 and other researchers15 have recently reported
amination and amidation reactions using nitroarenes as the
nitrogen sources. Compared to anilines, nitroarenes are more
attractive nitrogen sources, because of their lower cost, easier
accessibility, and higher stability.13−15 Here, we describe a
method for transamidation with nitroarenes under reductive

Received: August 23, 2017

Figure 1. Various methods of transamidation. Revised: September 14, 2017
Published: September 18, 2017

© 2017 American Chemical Society 7092 DOI: 10.1021/acscatal.7b02859

ACS Catal. 2017, 7, 7092−7096
ACS Catalysis Letter

Table 1. Optimization of Reductive Transamidation of Boc- Chart 1. Scope of Reductive Transamidation with Boc-
Activated Secondary Alkyl Amide Activated Secondary Alkyl Amides (Conditions Are
Described in Detail in the Supporting Information; Isolated
Yields Are Reported)

entry variation from “standard conditions” yielda (%)

1 none 80
2 L2 instead of L1 63
3 L3 instead of L1 78
4 L4 instead of L1 60
5 L5 instead of L1 67
6 L6 instead of L1 61
7 L7 instead of L1 55
8 Ni(diglyme)Br2 instead of Ni(glyme)Cl2 71
9 NiCl2 instead of Ni(glyme)Cl2 70
10 FeBr2 (10 mol %) instead of Ni(glyme)Cl2 25
11 CoBr2 (10 mol %) instead of Ni(glyme)Cl2 27
12 CuBr2 (10 mol %) instead of Ni(glyme)Cl2 9
13 Mn(OTf)2 (10 mol %) instead of Ni(glyme)Cl2 7
14 Mn instead of Zn 47
15 PhNO2 (1.3 equiv) instead of (1.5 equiv) 66
16 No Ni(glyme)Cl2 6
17 no TMSCl <5
18 PhNH2 instead of PhNO2 28
19 PhNH2 instead of PhNO2b <5
a
GC yield using n-dodecane as an internal standard. bZn (3 equiv)
instead of (5 equiv), no TMSCl was added, Zn(OTf)2 (2 equiv) is
added (as the source of Zn2+, after 2a was reduced by Zn).

conditions (Figure 1c). Both Boc-activated secondary alkyl and

aryl amides are suitable substrates. Broad scope and high
functional group tolerance are demonstrated.
In our previous work on Ni-catalyzed amidation of esters
with nitroarenes,14 we identified diazoarene as the most
probable intermediate, which was formed by reduction of a
nitroarene with zinc in the presence of chlorotrimethylsilane
(TMSCl). This intermediate then reacted with a Ni(0) species
to give a Ni(II) nitrene-type species, which then reacted with
an ester to give an amide (see Figure 2). An analogous Ni-
catalyzed reductive transamidation with nitroarenes might be
developed if amides can be used as the substrates in place of
esters (see Figure 2). This replacement is not trivial, because
amides are normally more inert than esters.
Inspired by the two-step approach of transamidation of Garg
et al.,9,10 we initially focused on transamidation of Boc-activated
N-benzyl decanoamide (1a) with nitrobenzene (2a). The
conditions for amidation of esters with nitroarenenes14 were
the starting point of optimization. After screening various
reaction parameters, the optimized conditions were found to
involve N-methyl-2-pyrrolidone (NMP) as a solvent, Ni-
(glyme)Cl2 (10 mol %) as a catalyst, 1,10-phenanthroline
(L1, phen, 10 mol %) as a ligand, Zn powder (5 equiv) as a
reductant, and chlorotrimethylsilane (TMSCl, 1.5 equiv) as an
additive (see Table 1, entry 1). The optimal loading of 2a was
1.5 equiv, and the reaction was completed after 16 h at 100 °C.
After an acidic workup, the desired amide product, N-phenyl
7093
a
120 °C. bNi(glyme)Cl2 (15 mol %), phen (15 mol %). c130 °C.
decanoate, was obtained in 80% yield (Table 1, entry 1). Table
1, as well as Table S1 in the Supporting Information, list the
yields obtained when the reaction parameters were systemically
varied. Whereas the influence of ligands in the yields of reaction
was small (L2−L7, Table 1, entries 2−7), both the Ni catalyst
and TMSCl were essential (Table 1, entries 16 and 17). Other
anhydrous Ni salts such as Ni(diglyme)Br2 and NiCl2 could be
used as catalysts, leading to slightly lower yields (Table 1,
entries 8 and 9). However, FeBr2, CoBr2, CuBr2, and
Mn(OTf)2 (where OTf = triflate) were all greatly inferior
catalysts (Table 1, entries 10−13). The use of Mn reductant
instead of Zn resulted in a lower yield (Table 1, entry 14).
Because some reduction of nitrobenzene to aniline was
occurring as a side reaction, a slight excess (1.5 equiv) of
nitrobenzene was needed. Lowering the loading of nitro-
benzene led to a diminished yield (Table 1, entry 15). When
DOI: 10.1021/acscatal.7b02859
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ACS Catalysis Letter

Table 2. Optimization of Reductive Transamidation of Boc- Chart 2. Scope of Reductive Transamidation with Boc-
Activated Secondary Aryl Amide Activated Secondary Aryl Amides (Conditions Are
Described in Detail in the Supporting Information; Isolated
Yields Are Reported)

entry variation from “standard conditions” yielda (%)

1 conditions ofTable1, entry 1 were used 63
2 no variation 88
3 L1 instead of L8 69
4 L2 instead of L8 68
5 L3 instead of L8 54
6 L4 instead of L8 60
7 L5 instead of L8 77
8 L7 instead of L8 64
9 TMSCl instead of TMSI 84
10 TMSBr instead of TMSI 83
11 TMSI (0.5 equiv) instead of (1 equiv) 83
12 FeBr2 (10 mol %) instead of Ni(glyme)Cl2 61
13 CoBr2 (10 mol %) instead of Ni(glyme)Cl2 46
14 CuBr2 (10 mol %) instead of Ni(glyme)Cl2 19
15 MnCl2 (10 mol %) instead of Ni(glyme)Cl2 12
16 no Ni(glyme)Cl2 15
17 no TMSI 62
18 PhNH2 instead of PhNO2 36
a
GC yield using n-dodecane as an internal standard.

aniline was used instead of 2a, the yield was <30% (Table 1,
entries 18 and 19), which was consistent with the previous
result, indicating diazobenzene rather than aniline as the
intermediate in the analogous amidation reaction of esters.14
The optimization conditions in Table 1 could be applied for
the transamidation of various secondary alkyl amides bearing a
Boc group (Chart 1). Both nonfunctionalized and function-
alized alkyl groups on the amide reaction partners could be
tolerated (P-1−P-7, 3a−3o). Heterocyclic groups such as
quinoline (3a), benzothiophene (3b), pyrazole (3c), benzox-
azole (3d), and indole (3e) could also be included in the
nitroarene partners. Sterically encumbered, ortho-substituted
nitroarene was also a suitable substrate (3o). Functional
groups, including olefins (3i, 3j), chloroalkyl (3l), chloroaryl
(3m), ketone (3n), ether (P-5, 3g), thio (P-6, 3h), and
trifluoromethyl groups (P-7), were compatible. In some of
these transamidation reactions, amines originated from the
starting amide reagents could be observed after the workup.
Apparently, these amines, likely in the deprotonated forms, did
not interfere the transamidation, again suggesting that the
reactions did not involve anilines as intermediates. While
amides bearing primary alkyl substituents transamidate
smoothly, the use of amides bearing more sterically bulky
secondary alkyl groups were problematic, because of difficulties
in the preparation of bulky Boc-activated amide substrates or
the low yields of transamidation products.
When the optimal conditions for transamidation of Boc-
activated alkyl amide (Table 1) was applied for the trans-
amidation of a secondary aryl amide, N-Boc,N-benzyl
benzamide (1b), with 2a, the yield of N-phenyl benzamide
7094
a
Ni(glyme)Cl2 (7.5 mol %), terpy (7.5 mol %). bNi(glyme)Cl2 (15
mol %), terpy (15 mol %), 120 °C. cNi(glyme)Cl2 (15 mol %), terpy
(15 mol %), TMSI (1.5 equiv), 130 °C. d120 °C. eNi(glyme)Cl2 (15
mol %), terpy (15 mol %), TMSI (1.5 equiv), 120 °C. fNi(glyme)Cl2
(15 mol %), terpy (15 mol %), TMSI (2 equiv), 140 °C.
was 63% (Table 2, entry 1). Further optimization showed that
by replacing Zn with Mn (5 equiv), TMSCl with
iodotrimethylsilane (TMSI, 1 equiv), and phen with
2,2’:6′,2″-terpyridine (L8, terpy, 10 mol %), and by lowering
the temperature to 80 °C, the amide product could be obtained
in 88% yield (Table 2, entry 2). Table 2, as well as Table S2 in
the Supporting Information, list the yields obtained when the
reaction parameters were systemically varied. Again, the Ni
catalyst and TMSI additive were essential (Table 2, entries 16
and 17). The use of bidentate (L1−L5) and monodentate
ligands (L7) was less efficient in transamidation (Table 2,
entries 3−8). The use of TMSCl, bromotrimethylsilane
(TMSBr), and a lower loading of TMSI (0.5 equiv) resulted
in slight diminishment in yields (Table 2, entries 9−11). Ni was
again a superior catalyst in the transamidation of aryl amides,
while the use of other metal catalysts (Fe, Co, Cu, Mn) led to
significant decreases in yield (Table 2, entries 12−15). When
aniline was used instead of 2a, the yield was only 36% (Table 2,
DOI: 10.1021/acscatal.7b02859
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ACS Catalysis
Figure 3. Comparison studies of transamidation methods.
Figure 4. Studies of the nitrogen-containing intermediate in Ni-
catalyzed reductive transamidation of Boc-activated secondary alkyl
and aryl halides with nitrobenzene.
entry 18), consistent with the previous result that indicated
diazobenzene rather than aniline as the intermediate in the
analogous amidation reaction of esters.14
The optimal conditions were then applied for the trans-
amidation of various secondary aryl amides bearing a Boc group
(Chart 2). Electron-neutral (4a), electron-deficient (4e, 4h),
and electron-rich (4f, 4j, 4k) aryl amides were all suitable
reaction partners. Similarly, electron-withdrawing groups (4a−
4c, 4f, 4g), electron-donating groups (4e, 4k, 4l), sterically
demanding ortho group (4k), as well as heteroaryl groups (4d,
4j) in the nitroarenes were compatible. Various primary N-alkyl
groups (P-1, P-8−P-10) in the starting amides also were
7095
Letter
tolerated. Notably, N-phenyl benzoate (P-11) without the
activation by Boc group transamidated smoothly (4j).
To demonstrate the complementarity of this reductive
amidation protocol to other existing transamidation methods,
some direct comparison experiments were conducted (Figure
3). Considerably higher yields were obtained using the current
methods when compared to Al-mediated7 (eqs 1 and 2,
displayed in Figure 3) or Al-catalyzed8a,b (eq 3, displayed in
Figure 3) transamidation methods with anilines in many
examples.
To probe the nature of the nitrogen-containing intermediates
in the reductive transamidation, reactions with viable
intermediates from reduction of nitrobenzene were studied.
Nitrobenzene could be reduced to nitrosobenzene, N-phenyl
hydroxylamine, and azobenzene under the reductive con-
ditions.14,16 In the test reaction with Boc-activated alkyl amide
(1a) using nitrobenzene, the desired amide product was formed
in 80% yield (Figure 4a). Azobenzene reacted to give the amide
in 63% and 40% in the presence of 2 equiv and 1 equiv of Zn,
respectively (Figure 4b(i)), which were comparable to the
parent reaction, given the inevitable differences in the exact
reaction conditions, compared to the model reaction (Figure
4a). In contrast, reactions with nitrosobenzene or N-phenyl
hydroxylamine did not give the product at all (Figure 4b(ii) and
4b(iii)). In the test reaction with Boc-activated aryl amide (2a)
using nitrobenzene, the desired amide product was formed in
88% yield (Figure 4c). Azobenzene reacted with 2a to give the
amide product in much higher yields (56% and 40%, Figure
4d(i)) than the reactions with nitrosobenzene or N-phenyl
hydroxylamine (0−35%; see Figures 4d(ii) and 4d(iii)). The
results suggested that azobenzene is a likely intermediate in the
reductive transamidation reactions with both alkyl and aryl
amides, which is consistent with our mechanistic proposal, as
shown in Figure 2.
In conclusion, a new methodology has been developed to
enable the transamidation of Boc-activated secondary alkyl and
aryl amides with nitroarenes via a two-step process. Broad
scope and functional group compatibility have been demon-
strated. The direct use of nitroarenes in place of anilines would
provide potential advantages in cost and step economy.
■ ASSOCIATED CONTENT
* Supporting Information
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acscatal.7b02859.
Experimental and spectral data (PDF)
■
AUTHOR INFORMATION
Corresponding Author
*E-mail: xile.hu@epfl.ch.
ORCID
Xile Hu: 0000-0001-8335-1196
Author Contributions
The manuscript was written through contributions of all
authors, and they have given their approval to the final version
of the manuscript.
Notes
The authors declare no competing financial interest.
DOI: 10.1021/acscatal.7b02859
ACS Catal. 2017, 7, 7092−7096
ACS Catalysis Letter

■ ACKNOWLEDGMENTS
This work is supported by the EPFL and the NoNoMeCat
Marie Skłodowska-Curie training network funded by the
European Union under the Horizon 2020 Program (No.
675020-MSCA-ITN-2015-ETN).

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ACS Catal. 2017, 7, 7092−7096