Primary amides to amines or nitriles: A dual role by a single catalyst

Article abstract of DOI:10.1039/c9cc05856g

We report a manganese-catalyzed hydrosilylative reduction of various primary amides to amines (25 examples). On simple modification of the reaction conditions such as in the presence of a catalytic amount of secondary amide, the same catalyst can transform the primary amides into intermediate nitrile compounds (16 examples) in excellent yields. This is the first example where such a controlled catalytic transformation of primary amides to amines or nitriles with a single catalyst has been demonstrated.

Full text of DOI:10.1039/c9cc05856g

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DOI: 10.1039/C9CC05856G
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Primary Amides to Amines or Nitriles: Dual Role by a Single
Catalyst†
Hari S. Das,a‡ Shyamal Das,a‡ Kartick Dey,a Bhagat Singh,a Rahul K. Haridasan,a Arpan Dasa,
Received 00th January 20xx,
Accepted 00th January 20xx
Jasimuddin Ahmeda and Swadhin K. Mandal*a
DOI: 10.1039/x0xx00000x
amine. Till date, no single catalyst is known, which can control the
catalytic activity selectively transforming primary amides into nitriles
or into amines. As a part of our ongoing interest in developing
phenalenyl ligand based metal complexes for different reactions,29-30
herein we report a [MnIII(L)Cl] complex (1) bearing a phenalenyl
based ligand (H2L)29 that exhibited not only excellent catalytic activity
toward reduction of primary amides into primary amines via
hydrosilylation in presence of KOtBu and PhSiH3, but also the catalytic
transformation can be controlled to obtain selectively nitriles by
simple modification of reaction conditions (Scheme 1).
We report a manganese-catalyzed hydrosilylative reduction of
various primary amides into amines (25 examples). On simple
modification of reaction conditions such as in the presence of a
catalytic amount of secondary amide, the same catalyst can
transform the primary amides into intermediate nitrile compounds
(16 examples) in excellent yields. This is the first example where
such a controlled catalytic transformation of primary amides to
amines or nitriles with a single catalyst has been demonstrated.
Amines and nitriles are important intermediates for the industrial
synthesis of numerous products.1-4 In last decades, several catalytic
methods have been developed for the synthesis of amines such as
aryl halide amination, hydroamination, nitro reduction, imine
reduction, nitrile reduction, amide reduction and direct amination of
alcohols.5-10 Among all these methodologies, the reduction of amides
is considered to be the most difficult task due to the low
electrophilicity of the carbonyl group.11 Traditionally, primary amides
are reduced using a stoichiometric amount of reactive metal
hydrides which do not tolerate a wide variety of functional groups.
Alternatively, catalytic hydrogenation of amide into the
corresponding amine suffers from the use of expensive and rare
metal-based catalysts, elevated temperature, high pressure reactor
with low chemo- and regio-selectivity.12 On the other hand,
hydrosilylative reduction of primary amides has emerged as an
efficient alternative because it can proceed under mild conditions
with enhanced chemoselectivity.13-14 Although hydrosilylation of
tertiary or secondary amides was known,15-23 the same for more
challenging primary amides is very limited.23-24 Except a few reports
This work:
[Mn(L)Cl] (5 mol%)
KOtBu (15 mol%)
[Mn(L)Cl] (5 mol%)
KOtBu (15 mol%)
O
R
NH2
R
N
R
NH2
PhCONHMe
(20 mol%)
PhSiH3, 50 °C
16 examples
25 examples
Yield-up to 96%
Yield-up to 98%
PhSiH3, 50 °C
Single-metal-catalysed hydrosilylative reduction
Mild reaction condition Highly chemoselective
Scheme 1. Reduction of amides by manganese catalyst (this work),
showing dual activity in transforming primary amide into amine or
nitrile.
The complex 1 was synthesized using a tetra-coordinated
phenalenyl based ligand (H2L)29 on treatment with MnCl2.4H2O
in DMF-ethanol mixture (2:1 v/v) at 110 °C for 12 h as a black
micro-crystalline solid in 68% yield. Further treatment of 1 with
on dehydration of primary amides25-27, no base metal catalyzed AgClO4 in THF afforded [MnIII(L)(ClO4)] (2) and in DMF, it
afforded [MnIII(L)(DMF)](ClO4) (3) species (Figure 1, see later for
details on their relevance to understand mechanistic cycle).
These complexes (1, 2 and 3) were characterized by an array of
analytical methods including elemental analysis (ESI), ESI-MS
(Figures S1-S3, ESI) and single crystal X-ray diffraction studies
(Figure 1, Tables S1-S3). In all the crystal structures, MnIII ion
adopts a distorted square pyramidal geometry by coordinating
with the doubly deprotonated form of tetra-dentate O,N,N,O-
phenalenyl based ligand (H2L) in a plane and the remaining
coordination site is occupied by the Cl- ion in 1, oxygen atom of
hydrosilylation of primary amides was reported until 2012. In 2012,
efforts were made by Beller and coworkers toward the reduction of
primary amides via two successive reaction steps using two different
iron catalysts.28 In such a design, one catalyst transforms primary
amide into nitrile while the other catalyst reduces nitrile into an
a. Department of Chemical Sciences, Indian Institute of Science Education and
Research−Kolkata, Mohanpur-741246, India.
E-mail: swadhin.mandal@iiserkol.ac.in
Hari S. Das and Shyamal Das contributed equally to this work.
‡
† Electronic supplementary information available: Experimental details including
NMR experiments and theoretical calculations. See DOI: 10.1039/x0xx00000x
-
ClO4 in 2 and oxygen atom of DMF in 3.
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Table 1. Reduction of primary amides into amines catalyzed by 1a.
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DOI: 10.1039/C9CC05856G
NH HN
1
1) (5 mol%)
KOtBu (15 mol%)
O
O
O
4
H2L
1 M HCl/MeOH
Et2O
PhSiH3
NH3+Cl-
5
NH2
R
R
MnCl2 .4H2O
DMF/EtOH (2:1)
110 °C, 12h.
NH2
THF, 50 °C, 12 h
2) 1 M NaOH
R
NH3+Cl-
NH3+Cl-
NH3+Cl-
NH3+Cl-
NH3+Cl-
O
N
N
III
p-5b, 87%
m-5d, 85%
o-5c, 84%
5a, 81%
5g, 83%
Mn
5f, 95%
Cl
5e, 90%
O
O
O
Cl
Cl
NH3+Cl-
NH3+Cl-
NH3+Cl-
NH3+Cl-
NH3+Cl-
1
AgClO4/ DMF
12h at RT.
AgClO4/THF
12h at RT.
F
O
Br
5i, 74%
p-5j, 75%
m-5k, 80%
o-5l, 67%
Cl
5n, 64%
5m, 78%
NH3+Cl-
5h, 87%
NH3+Cl-
NH3+Cl-
NH3+Cl-
F
NH3+Cl-
N
O
N
N
O
N
III
III
Mn
Mn
ClO4
S
Br
N
O
O
5o, 76%
NH3+Cl-
Cl
5r, 63%
5s, 61%
NH3+Cl-
5y, 82%
O
5q, 80%
NH3+Cl-
5v, 77%
5p, 81%
O
O
Cl
H
N
NH3+Cl-
5x, 62%
NH3+Cl-
5w, 65%
O
NH3+Cl-
O
3
2
5u, 89%
5t, 74%
[a] RCONH2 (0.5 mmol), PhSiH3(2.2 equiv.), complex 1 (5 mol%), KOtBu (15 mol%), THF (3
mL) for 12 h at 50 °C followed by base hydrolysis using 1 M NaOH. The Isolated yields are
based on HCl salt.
To understand the underlying mechanism of this catalytic
reduction, at first, we considered whether the present reaction
proceeds through dehydration of primary amide into a nitrile
intermediate. Earlier, it was reported that primary amides can
dehydrate into nitriles at high temperature in the presence of a
silane and a catalyst.31-33 Reeves et al. in 2012 have shown that
if nitrile is an intermediate in the amide to amine reduction then
the rate of the nitrile reduction should not be slower than the
rate of the amide to amine formation.34 To test this, we carried
out reduction of benzonitrile (6a) using our optimized condition
affording formation of benzylamine (5a) in 98% yield (Scheme
2a) which is more facile than that of benzamide reduction into
benzylamine (81%). This experiment indicates that nitrile may
be an intermediate during this transformation. Furthermore,
we were able to isolate such nitrile intermediate in 76% yield by
performing the reaction in the presence of a secondary amide
(N-methyl benzamide), when the secondary amide remained
unreactive (Scheme 2b). Later, it was established that 20 mol%
of N-methyl-benzamide (Table S6, ESI) can act as an inhibitor for
further reduction of nitrile intermediate. Under the optimized
reaction condition (5 mol% 1, 15 mol% KOtBu, 1.4 equivalent
PhSiH3, THF, 50 °C, 12 h and 20 mol% N-methyl-benzamide),
catalyst 1 displayed efficiency in selective conversion of various
aryl, hetero-aryl and aliphatic primary amides to the
corresponding nitriles in excellent yields (72-94%, Table 2).
Interestingly, the reduction of 4-cyanobenzamide or N-(4-
carbamoylphenyl)benzamide led to only selective conversion of
primary amide group into nitrile, sparing the existing nitrile or
secondary amide group in the substrate (Table 2, 6m or 6n). The
heteroaryl amide was converted into corresponding nitrile with
72% yield (Table 2, 6o). Aliphatic amide such as cyclohexyl-
caroboxamide was also transformed into the nitrile product
(Table 2, 6p) in 84% yield. Considering these results, it appears
that nitrile is a key intermediate for the present hydrosilylative
primary amide to amine reduction.
Figure 1. Syntheses and X-ray structures of 1, 2 and 3.
Next, we checked the catalytic activity of 1 (5 mol%) for reduction of
the primary amide to primary amine using phenyl silane (2.2 equiv.)
as a hydride source and benzamide (4a) as a model substrate at 50
°C in THF (Table S4, ESI). Delightfully, on addition of 15 mol% of
KOtBu, complex 1 (5 mol%) catalyzed the hydrosilylative reduction of
4a successfully. The product (benzyl amine) was isolated as its
hydrochlorinated salt (5a) in 81% yield (Table S4, entry 2). Without 1,
KOtBu (15 mol%) alone could not reduce the primary amide (Table
S4, entry 3).[22] Furthermore, we tested several combinations of the
catalyst loading, amount of KOtBu, temperature, time, silanes,
additives, and solvents (Table S4, ESI) resulting no further
improvement in yield. Kinetic studies at different time intervals (2, 4,
6, 8, 10, and 12 h) show evolution of the reaction indicating that
within 10 h, the reaction reaches near completion (Figure S4, ESI).
Under the optimized conditions (Table S4, entry 2), we further
explored the reduction of various aryl, hetero-aryl and aliphatic
primary amides into their corresponding amine salts in good to
excellent yields (61-95%, Table 1). The substituted benzyl amides
were reduced into amines with 64-95% isolated yield as their
hydrochloride salts (Table 1, 5b-q). The hetero-aryl amides e.g. 3-
pyridine-carboxamide
and
2-thiophenecarboxamide
were
successfully reduced with moderate yields 61–63% (Table 1, 5r-s).
The bicyclic aromatic compound 1-naphthamide was also reduced
into amine salt 5t in 74% yield (Table 1). To our delight, several
aliphatic amides were also reduced successfully into the
corresponding amine salts with good yield (62-89%, Table 1, 5u-y).
Additionally, we can scale up the synthesis of amine in gram scale
resulting in 74% yield for 5a (Scheme S2, ESI). Furthermore, we
tested the functional group tolerance of ketone, aldehyde, ester and
imine in presence of benzamide. Not surprisingly, these groups were
not tolerated as the KOtBu-PhSiH3 combination itself is known to
reduce these functional groups.22
2 | J. Name., 2012, 00, 1-3
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N
1) 1 (5 mol%)
KOtBu (15 mol%)
(a)
a tertiary amide (DMF), the Mn(III) center howevVeierwpArreticfleerOanblinlye
binds with DMF in its primary coordination sphere forming
NH3+Cl-
5a (98% yield)
NH2
1 M HCl/MeOH
Et2O
DOI: 10.1039/C9CC05856G
PhSiH3 (2.2 equiv.)
THF, 50 °C, 12 h
2) 1 M NaOH
complex 3 which was characterized by single crystal X-ray study
revealing coordination between Mn(III) center and oxygen of
DMF (Figure 1). Formation of complex 3 directly points out the
interaction between an amide group and Mn(III) center. Based
on this result, and preliminary DFT calculations, we propose a
plausible mechanistic path as depicted in Scheme 3. In the first
O
O
O
N
+
1) 1 (5 mol%)
KOtBu (15 mol%)
NH2
+
(b)
N
N
H
H
PhSiH3 (2.2 equiv.)
THF, 50 °C, 12 h
2) 1 M NaOH
4a
6a (76% yield)
(unreacted)
Scheme 2. Tests for the intermediacy of nitrile in the primary amide
reduction: (a) direct nitrile reduction displaying 98% yield of amine step, 1 reacts with KOtBu and produces a labile alkoxide
and (b) arresting the nitrile intermediate in presence of a secondary
amide.
complex (1a). Formation of such alkoxide complex was reported
earlier on reaction with Fe-halide in presence of KOtBu.36
Following this, PhSiH3 can abstract the alkoxide group from 1a
resulting in the formation of a coordinatively labile complex 1b
and an active silane (Scheme 3a) as also reported earlier35. The
formation of an active silane is evident from our stoichiometric
reaction between the suspension of 1 in THF-d8 with KOtBu
resulting in a clear reddish pink color solution followed by a
sharp color change to blue on addition of one equiv. of PhSiH3.
The 1H NMR spectrum of such reaction mixture reveals a
resonance at δ 5.08 ppm (Figure S7, ESI) which is comparable to
previously reported value (δ 5.05 ppm)22 for the same active
silane. Next, complex 1b can bind with the primary amide
through its vacant coordination site resulting in formation of 7
(Scheme 3b). The formation of amide coordinated complex 7
can be supported by the structural characterization of complex
3 displaying interaction between an amide functionality and
Mn(III) center. Furthermore, the DFT optimized structure of
such complex considering a primary amide (7, Figure 2)
supports that the carbonyl oxygen of primary amide binds with
Mn(III) center along with the amide N-H hydrogen interacting
with the oxygen of phenalenyl ligand backbone through a
hydrogen bond. Such hydrogen bonded interaction enhances
the acidity of N-H proton of primary amide. Next, this activated
amide can be converted into nitrile via N-silylation by tert-
butoxide activated silane with evolution of hydrogen gas28
which was detected by a peak appearing at δ 4.61 ppm in
DMSO-d6 in 1H NMR spectroscopy (see Figure S8 and details in
Scheme S9, ESI). Once nitrile is formed, catalytically active 1b is
regenerated which in turn can react with nitrile to form 9
(supported by DFT, see Figure 2) finally converting into amine
(Scheme 3c) through hydrosilylative reduction process in
presence of the activated silane via an imine intermediate (see
details in Scheme S8, ESI). Formation of the imine intermediate
was proposed by Beller and coworkers earlier during nitrile to
amine conversion in presence of a silane and an Fe-based
catalyst.28 In the present study, we observed the imine
Table 2. Transformation of primary amides into nitriles catalyzed by
1 a.
1) 1 (5 mol%)
KOtBu (15 mol%), PhSiH3
N-methylbenzamide (20 mol%)
THF, 50 °C, 12 h
O
4
R
N
NH2
R
6
2) 1 M NaOH
N
N
N
N
O
o- 6b, 96%
m- 6c, 83%
p- 6d, 90%
6e, 89%
6f, 81%
6a, 75 %
N
N
N
Br
N
N
Br
Cl
o- 6h, 77%
m- 6i, 80%
p- 6j, 76%
Cl
6g, 74%
O
6l, 87%
6k, 85%
N
N
NC
N
HN
N
6p, 84%
6o, 72%
6n, 82%
6m, 94%[b]
[a] RCONH2 (0.5 mmol), phenylsilane (1.4 equiv.), complex 1 (5 mol%), KOtBu (15 mol%),
20 mol% N-methylbenzamide, THF (3 mL) for 12 h at 50 °C followed by base hydrolysis
[b]
using
1
M
NaOH. Isolated yields were calculated based on 4.
Without N-
methylbenzamide in 3 mL DMSO/THF (1:1 v/v).
Next, to understand the mechanism of the reduction process,
at first, the possibility of radical pathway was excluded by
observing
that
a
radical
scavenger,
2,2,6,6-
tetramethylpiperidinoxyl (TEMPO) could not arrest the reaction
(Scheme S5, ESI). The reported non-radical pathway involves
the reaction of metal-halide with KtOBu forming a metal-
alkoxide which can easily be transformed into a metal-hydride
complex by σ-bond metathesis with silane.35 Control reaction of
primary amide into nitrile in the presence of a secondary amide
or chemoselectivity towards only primary amide conversion
into nitrile sparing secondary amide (Scheme 2b and 6m, Table
2) indicates that the reaction does not proceed through a Mn-
hydride complex since such complex is expected to be more
reactive for reduction of nitrile or secondary amide as
compared to primary amide. On the other hand, we have
observed that electronically rich amides were reduced easily
(5b, 87%, Table 1) compared to electron deficient amides (5i,
74%, 5n, 64%, Table 1) as expected for a catalyst which acts as
a Lewis acid. To test this hypothesis, we have used the
perchlorate complex 2 where the fifth coordination site is more
labile as compared to 1. Interestingly, 2 showed higher catalytic
activity, delivering excellent yield of benzylamine salt (97%,
Scheme S6, ESI) when compared with yield (81%, 5a, Table 1)
obtained using catalyst 1. Such a result signifies that a vacant
coordination site on Mn(III) ion improves catalytic performance
significantly. In presence of an electronically rich amide such as
1
resonance at δ 10.04 ppm in H NMR spectroscopy upon base
hydrolysis of the reaction mixture when the reaction was
stopped prematurely (after 1 h, Figure S9, ESI). Considering the
proposed mechanistic cycle (Scheme S9, ESI), the DFT
calculations explain the difference in reactivity observed
between primary amides, secondary amides and nitrile based
on their binding strength with Mn(III) center (Figure S100, ESI).
The DFT calculations revealed that the binding energy of
primary amide with Mn(III) center in 7 is higher (-8.5 Kcal/mol)
than that of the secondary amide (-3.8 Kcal/mol) in 8. As a
result, the primary amides get activated over the secondary
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