Manganese-Mediated Reductive Transamidation of Tertiary Amides with Nitroarenes

Article abstract of DOI:10.1021/jacs.8b03739

Amides are an important class of organic compounds, which have widespread industrial applications. Transamidation of amides is a convenient method to generate new amides from existing ones. Tertiary amides, however, are challenging substrates for transamidation. Here we describe an unconventional approach to the transamidation of tertiary amides using nitroarenes as the nitrogen source under reductive conditions. Manganese metal alone mediates the reactions and no additional catalyst is required. The method exhibits broad scope and high functional group tolerance.

Full text of DOI:10.1021/jacs.8b03739

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Communication
Manganese-Mediated Reductive Transamidation
of Tertiary Amides with Nitroarenes
Chi Wai Cheung, Jun-An Ma, and Xile Hu
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b03739 • Publication Date (Web): 18 May 2018
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Manganese-Mediated Reductive Transamidation of Tertiary Amides
with Nitroarenes
Chi Wai Cheung,†,‡ JunꢀAn Ma,‡ and Xile Hu*,†
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†
Laboratory of Inorganic Synthesis and Catalysis, Institute of Chemical Sciences and Engineering, Ecole Polytechnique
Fédérale de Lausanne (EPFL), ISICꢀLSCI, BCH 3305, Lausanne 1015 (Switzerland).
‡
Department of Chemistry, Tianjin Key Laboratory of Molecular Optoelectronic Sciences, and Tianjin Collaborative Innovaꢀ
tion Center of Chemical Science & Engineering, Tianjin University, Tianjin 300072, P. R. China
Supporting Information Placeholder
ABSTRACT: Amides are an important class of organic comꢀ
pounds, which have widespread industrial applications. Transꢀ
amidation of amides is a convenient method to generate new
amides from existing ones. Tertiary amides, however, are
challenging substrates for transamidation. Here we describe an
unconventional approach to the transamidation of tertiary
amides using nitroarenes as the nitrogen source under reducꢀ
tive conditions. Manganese metal alone mediates the reactions
and no additional catalyst is required. The method exhibits
broad scope and high functional group tolerance.
Amides are ubiquitous in nature and are among the most essential
molecules in the chemical and pharmaceutical industries1,2 Due to
their prevalence and stability, amides are attractive reagents for
chemical transformations. Transamidation is a useful method for
Figure 1. Methods of transamidation of tertiary amides.
the diversification of amides.3 However, the amide CꢀN linkage is
unreactive due to resonance stabilization.1 Various catalytic transꢀ
To overcome the difficulties in the transamidation of tertiary
amidation methods have been developed, but most of them use
primary amides as substrates.3,4 A twoꢀstep strategy, first conꢀ
amides, we decided to employ nitroarenes instead of anilines as
ceived by Garg,5 is recently employed to transamidate secondary
the incoming amine reagents. We showed earlier that under reducꢀ
tive conditions the intermediates formed by partial reduction of
nitroarene, e.g., nitrosoarene, azoxyarene, and azoarene, could
engage in efficient CꢀN bond forming reactions,7,11aꢀ11c including
the transamidation of Bocꢀactivated secondary amides.7 We reaꢀ
soned that since anilines were not involved, the problem of yieldꢀ
ing an equilibrium mixture of reactant and product amides, as
observed in the Lewis acidꢀcatalyzed transamidation of tertiary
amides,10 could in principle be avoided. Moreover, compared to
anilines, nitroarenes are generally more accessible, more stable,
and less costly.7,11 Here we report the development of a Mnꢀ
mediated method that fulfills these promises and is efficient and
general for the transamidation of tertiary amides (Figure 1b).
amides by preꢀactivation with a tertꢀbutyloxycarbonyl (Boc)
group.5ꢀ7 On the other hand, the transamidation of tertiary amides
remains challenging due to the steric hinderance around their CꢀN
linkage and no possibility for preꢀactivation of the nitrogen groups.
Only several reports of Lewis acidꢀmediated or ꢀcatalyzed transꢀ
amidation of tertiary amides are known, however, the scope is
narrow.8ꢀ10 For example, Stahl, Gellman, and coꢀworkers develꢀ
oped Alꢀ and Zrꢀcatalyzed transamidation of tertiary amides, but
only N,Nꢀdialkyl amides were suitable substrates, and the reacꢀ
tions yielded an equilibrium mixture of reactant and product
amides (Figure 1a).10 An efficient and general method for transꢀ
amidation of tertiary amides remains hitherto elusive.
The transamidation of N,Nꢀdiphenyl benzamide (1j) with nitroꢀ
benzene (2j, 1.5 equiv.) was used as the test reaction (Table 1).
Using the conditions previously employed for transamidation of
Bocꢀactivated secondary amides with nitroarenes,7 that is,
Ni(glyme)Cl2 (10 mol%; glyme = ethylene glycol dimethyl ether)
as catalyst, terpyridine (10 mol %; terpy, L1) as ligand, Mn as
reductant (5 equiv.), iodotrimethylsilane (1 equiv.; TMSI) as
additive, and Nꢀmethyꢀ2ꢀpyrrolidone (NMP) as solvent, the transꢀ
amidation was actually successful, giving the desired amide prodꢀ
uct, Nꢀphenyl benzamide (3j), in 81% yield (Figure 2). A control
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experiment then showed that a yield of 64% was obtained in the
amide products in good to excellent yields. Electronꢀrich (3i,
3l, 3w, 3x) ꢀneutral (3j, 3n), ꢀdeficient (3m, 3r, 3v, 3y), and
sterically congested aryl groups (3ak), heteroaryl groups (3o,
3p, 3z), secondary cyclic alkyl groups (3f, 3g, 3aj, 3al), as
well as primary (3aa, 3ab) and tertiary alkyl groups (3ao)
could be transferred from the starting to the final amides.
Amides substituted by electronꢀrich (3e, 3f, 3h, 3o, 3p, 3v, 3x,
3ah, 3al), ꢀneutral (3j), ꢀdeficient (3b-3d, 3n, 3ab), and steriꢀ
cally bulky (3l) aryl groups, as well as heteroaryl groups such
as pyrrole (3a), benzodioxole (3g), pyridine (3k), carbazaole
(3w), benzothiophene (3ae), benzoxazole (3af), pyrazole (3ag),
and quinoline groups (3an) could be accessed from the correꢀ
sponding nitro(hetero)arenes. The transamidation method
tolerated a wide range of functional groups from both amide
and nitroarene partners, such as sulfonamide (3b), chloro (3c,
3y, 3ac, 3ai), nitrile (3d), amino (3e, 3o, 3v, 3x), thio (3ah,
3al), fluoro (3v, 3ab), bromo (3ad), olefin (3h, 3aa), keto
(3am) moieties. The protocol allowed gramꢀscale transamiꢀ
dation without significant diminishment of yield (3z).
absence of Ni(glyme)Cl2 catalyst (Figure 2). We then optimized
the Mnꢀmediated transamidation of 1j with 2j. By changing ligꢀ
and L1 to 1,10ꢀphenanthroline (phen, L2), and increasing the
reaction time to 24 h, the yield of 3j was increased to 80% (Table
1, entry 1). The use of chlorotrimethylsilane (TMSCl) instead of
TMSI, L1 or 2,2’ꢀdipyridyl (L3) instead of L2, lower loading of
Mn (4 equiv.) or TMSI (0.5 equiv.) all led to a modest reduction
of yields (Table 1, entries 2ꢀ6). Other metal reductants such as
zinc, copper, and iron were not effective (Table 1, entries 7ꢀ9).
Without L2, the yield was slightly lower (Table 1, entry 10). As
shown below for a few other substrates (Figure 3, 3h, 3k, 3m, 3p;
Figure 5, 3m), the use of L2 led to 8ꢀ25% higher transamidation
yields compared to ligandꢀless conditions. Thus, L2 was used for
the general protocol to favor the yields. A ligandꢀless protocol
might be more advantageous for specific substrates or applicaꢀ
tions, but it was not further explored here.
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Table 1. Optimization of Mnꢀmediated transamidation with nitroꢀ
benzenea
Entry Variations from 'standard conditions'
Yield of 3j
%
b
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6
No variation
80
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72
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TMSCl (1 equiv.) instead of TMSI
L1 instead of L2
L3 instead of L2
Mn (4 equiv.) instead of (5 equiv.)
TMSI (0.5 equiv.) instead of (1 69
equiv.)
7
Zn (5 equiv.) instead of Mn
Cu (5 equiv.) instead of Mn
Fe (5 equiv.) instead of Mn
No L2
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0
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(a) 0.25 mmol of 1j was used for screening of conditions. (b) GC
yield of 3j using nꢀdodecane as an internal standard.
Figure 3. Transamidation of N,Nꢀdiaryl and NꢀalkylꢀNꢀaryl amꢀ
ides with nitroarenes. Isolated yields were shown. (a) Reaction
without the addition of phen ligand.
Figure 2. Discovery of Mnꢀmediated transamidation of tertiary
amide with nitrobenzene.
This transamidation method proved to be general (Figures
3ꢀ5). A wide range of N,Nꢀdiaryl and NꢀalkylꢀNꢀaryl amides
(Figure 3, AA-1 to AA-8), amides bearing heterocycles (Figꢀ
ure 4, H1-H5), and N,Nꢀdialkyl amides (Figure 5, DA-1 to
DA-6) all reacted smoothly with nitroarenes to give the Nꢀaryl
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crobial agent 4b13 in 80% yield from a tertiary amide (Figure
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6b). These examples highlight the potential utility of this
method in medicinal chemistry.
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Figure 6. Applications of the present transamidation method in
medicinal chemistry.
Although an ultrapure Mn powder (99.9%) was used in this
method, a trace amount of Ni (11.6 ppm) and Pd (5.6 ppm)
was detected by atomic absorption spectroscopy. To probe the
possible catalytic role of these trace metals in the transamiꢀ
dation, a catalytic amount of NiCl2 or PdCl2 (2 mol %) was
added intentionally to the reaction system. Slightly lower
yields of 3m were obtained (Figure 7, (ii) and (iii)) compared
to the parent reaction (87%, Figure, 7, (i)). When a lower
grade of Mn (97%) was used, 3m was obtained in a similar
yield (82%, Figure 7, (iv)) to the parent reaction. These results
suggest that trace amounts of Ni or Pd were unlikely the cataꢀ
lysts for the transamidation.
Figure 4. Transamidation of tertiary amides bearing heterocycles
with nitroarenes. Isolated yields were shown. (a) 2 days. (b) 16 h.
Figure 7. Effect of trace metals and purity of Mn on transamiꢀ
dation.
During the transamidation, nitrobenzene could be reduced
to nitrosobenzene, Nꢀphenyl hydroxylamine, azobenzene, and
anilines under the reductive conditions.7,11aꢀ11c To probe their
potential roles as intermediates in transamidation, the reactions
of these species with tertiary amide under conditions relevant
to the transamidation were monitored. When nitrobenzene 2j
was used as the substrate, the transamidation had a yield of
80% (Table 1, entry 1). When Nꢀphenyl hydroxylamine or
aniline was used as the substrate, no transamidation occurred
(Figure 8, (i) and (ii)). Thus, Nꢀphenyl hydroxylamine and
aniline are unlikely intermediates. When nitrosobenzene was
used as the substrate and in the presence of 2 equiv. of Mn, the
yield of transamidation was 30%, while azobenzene was
Figure 5. Transamidation of N,Nꢀdialkyl amides with nitroarenes.
(a) ArNO2 (3 equiv.), phen (20 mol %), Mn (10 equiv.), TMSI (2
equiv.). (b) Reaction without the addition of phen ligand. (c) 2
days.
The transamidation method was successfully applied to the
modification of a bioactive amide S12, which was an inhibitor
of leukemia cell line,12 to give a new amide 4a in 42% yield
(Figure 6a). The method was also applied to make an antimiꢀ
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ASSOCIATED CONTENT
formed as a byproduct in 50% yield (Figure 8, (iii)). When 4
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7
8
equiv. of Mn was used as reductant for the reaction with nitroꢀ
sobenzene, the yield of transamidation was improved to 74%
(Figure 8, (iii)). These results suggested that nitrosoarene was
a possible intermediate, but likely through a further reduction
to azobenzene. Indeed, in the absence of an amide substrate, 3
equiv. of Mn was sufficient to reduce nitrobenzene to azobenꢀ
zene in 61% isolated yield. This reduction required TMSI,
which might serve to deoxygenate nitrobenzene. Azobenzene
was then tested as the substrate. In the presence of only 2
equiv. of Mn and 10 mol% TMSI, a high yield of 86% for
transamidation was achieved (Figure 8, (iv)). If TMSI was
omitted, the transamidation had an even higher isolated yield
of 91%. Thus, TMSI is not necessary for the Mnꢀmediated
reaction of azobenzene with an amide to form a new amide.
Taking together, these results all support azobenzene as an
active intermediate in the transamidation. The mechanism of
the reaction is subjected to a further, dedicated study.
Supporting Information.
The Supporting Information is available free of charge on the
ACS Publications website. Experimental and spectral data (PDF).
AUTHOR INFORMATION
Corresponding Author
*xile.hu@epfl.ch
9
Notes
The authors declare no competing financial interests.
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ACKNOWLEDGMENT
This work is supported by the EPFL, the National Natural Science
Foundation of China (No. 21225208, 21472137, and 21532008),
and the National Basic Research Program of China (973 Program,
2014CB745100). We thank Marten L. Ploeger (EPFL) for conꢀ
ducting some early mechanistic investigations and performing 19
F
NMR spectroscopic analysis, ShaoꢀPeng Wang (TJU), Ni Shen
(TJU), and Asim Ullah (TJU) for assistance in synthesizing startꢀ
ing materials, and Baili Li (TJU) for assistance in performing IR
spectroscopic analysis.
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