Catalytic reduction of amides to amines by electrophilic phosphonium cations via FLP hydrosilylation

Article abstract of DOI:10.1039/c6cc06914b

A catalytic methodology for the conversion of amides to amines is reported. Of the 25 examples described, 14 examples involve the reduction of N-trifluoroacetamides to the corresponding trifluoroethylamines. These reductions are achieved by catalytic hydrosilylation of the amide mediated by an electrophilic phosphonium cation (EPC) catalyst.

Full text of DOI:10.1039/c6cc06914b

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Catalytic Reduction of Amides to Amines by Electrophilic
Phosphonium Cations via FLP Hydrosilylation
Alessandra Augurusa,a,b Meera Mehta,a,b Manuel Perez,a Jiangtao Zhu and Douglas W. Stephan*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
A catalytic methodology for the conversion of amides to acid catalysts for a variety of reactions. In particular the
amines is reported. Of the 25 examples described, 14 examples species [(C6F5)2PhPF][B(C6F5)4] 1
, [(C6F5)3PF][B(C6F5)4] 233 and
involve the reduction of N-trifluoroacetamides to the [(SIMes)PFPh2][B(C6F5)4]2 334 are potent catalysts for the
corresponding trifluoroethylamines. These reductions are hydrosilylation35-36 or the transfer hydrogenation of olefins,37
33-34
achieved by catalytic hydrosilylation of the amide mediated by an the
electrophilic phosphonium cation (EPC) catalyst.
hydrodefluorination
of
fluoroalkanes,
dehydrocoupling of silanes with amines, phenols, thiols or
carboxylic acids,37 the hydrodeoxygenation of ketones38 and
Amines are an important class of compounds in both the reduction of phosphine oxides.39 Most recently, we have
chemistry and biology.1-2 They are a vital functional group used exploited EPCs to effect alkyl C-F and CF3 bond arylations as
by the pharmaceutical industry for pesticides and drug well as sp3-sp3 C-C coupling.40-41 In this paper we demonstrate
development.3 As well, there is increasing use for the the ability of EPCs to catalyse the reductive hydrosilylation of
preparation of advanced materials.4-6 The reduction of amides amides. Moreover, this protocol is applied to reduce N-
to amines is an attractive strategy for amine synthesis given trifluoroacetamide derivatives to give trifluoroethylamines.
the large variety of commercially available amides.7-8 The most
common method for amide reduction is the use of
O
stoichiometric aluminium and boron hydrides.9-14 In spite of
their wide spread use, such methods suffer from the
production of stoichiometric by-products, over reduction, and
the challenge of purification. As a result there has been
increasing interest in catalytic transformations of amides to
amines. The direct hydrogenation of amides has been
described by Cole-Hamilton and coworkers15-16 using
ruthenium catalysts at temperatures above 160 ᵒC and 40 bar
of H2. Subsequent studies by the groups of Breit and
cat.
R
R
cat.
+ R3SiH
R
H2C CH2
RCO2H + R3SiH
O
SiR3
SiR3
R
R
cat.
R3P
+
(R3Si)2O
cat.
+ R SiH
3
CH2 + (R3Si)2O
O
+ R3SiH
O
R3P
R'
R'
R"
R
CH N
R
RCH2Ar
cat.
cat.
N
+ R3SiH
R"
+
RCH2F + R3SiH + ArH
R'
SiR3
R'
R3SiF
Catalysts:
C6F5
Mes
Thompson explored mixed metal heterogeneous catalysts for
17-18
F
F
F
N
such hydrogenations.
Using an alternative approach a
P
C6F5
P
P
Ph
C6F5
C6F5
Ph
N
series of studies have explored the transition metal catalysts
incorporating Mo, Rh, Ru, Pt, Pd, and Ir for hydrosilylative
reduction of amides to amines.19-30
C6F5
Ph
Mes
[B(C6F5)4]
[B(C6F5)4]
2[B(C6F5)4]
2
1
3
Metal-free approaches to amide reduction have begun to
garner some recent attention. To this end, the Adronov
group31 have used B(C6F5)3 to effect catalytic hydrosilylation of
tertiary amides. The Huang group was able to expand this
scope to secondary amides with a protocol using a triflate
anhydride pre-treatment of the amides.32
Scheme 1 Examples of catalysis by Electrophilic Phosphonium Cations (EPCs)
Attempts to employ 3 mol% of the EPCs 1-3 as catalysts for
the hydrosilylative reduction of N,N-dimethylbenzamide were
screened in the presence of 2.1 equivalents of a series of
silanes at 100 °C (Table 1). In general the observed reactivity
trends for each silane parallels the increasing Lewis acidity of
In developing metal-free catalysts, we recently uncovered
the highly electrophilic fluorophosphonium cations (EPCs)
which derived their Lewis acidity from a σ*-orbital on the P
atom.33 These species have been shown to be active Lewis
the EPCs,
1
<
2
<
3
.
Similarly, conversion to the amine was
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enhanced with increasing hydricity of the silane employed. were again performed in order to ascertain the optimal
Thus, low conversions were generally observed with Et3SiH and selections (see SI). In these cases, catalyst was used in
Ph3SiH, while essentially quantitative conversion was seen for combination with tetramethyldisiloxane to effect the amide
3
each catalyst with the use of PhSiH3.
reductions at temperatures of either 50 or 100 ᵒC. In this
fashion 2,2,2-trifluoroethyl substituted amines were derived
from N-phenyl 2,2,2-trifluoroacetamide, and its p-bromo, p-
chloro, p-methyl and p-isopropyl substituted analogues as well
as from 2,2,2-trifluoro-N-3,5-dimethylphenylacetamide. In all
cases, the conversions exceeded 92% and in isolated yields
ranged from 80-92% (Table 3 Entries 1-5). The reductions of
N-benzyl-2,2,2-trifluoroacetamide (Entry 6), and the N-
isopropyl-, N,N-diphenyl, N,N-dibenzyl derivatives of 2,2,2-
trifluoroacetamide (Entries 11, 13, 14) to the corresponding
amines were achieved in moderate conversion of 59-74%
under similar conditions. 2,2,2-trifluoroacetamide as well as
the corresponding derivatives derived from N-p-methyl and p-
methoxybenzyl and N-benzhydryl amines and p-cyanoaniline
gave generally low yields of the targeting amide reduction
products (6-24%). These latter results are consistent with
previous observations suggesting that basic amide N-atoms or
donor substituents inhibit catalysis by binding to the
fluorophosphonium cation. In the case of N-benzhydyl
derivative (Entry 9) steric issues may also impede catalytic
reduction.
Table 1. N,N-dimethylbenzamide reductions using 1, 2 and 3 as catalyst.a
Catalyst
Silane
Conv.
(%)
0
0
9
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
1
1
1
1
1
1
2
2
2
2
2
2
3
3
3
3
3
3
Et3SiH
Ph3SiH
Ph2SiH2
HSiMe(OEt)2
(HSiMe2)2O
PhSiH3
Et3SiH
Ph3SiH
Ph2SiH2
HSiMe(OEt)2
(HSiMe2)2O
PhSiH3
Et3SiH
Ph3SiH
5
65
98
9
0
26
55
89
99
11
6
45
12
92
98
Ph2SiH2
HSiMe(OEt)2
(HSiMe2)2O
PhSiH3
a The mixture was heated to 100 °C for 24 h in C6D5Br. Conversions determined by
1H NMR spectroscopy.
Table 2. Amide reductions using 2 and 3 as catalyst.a
Substrate
Cat
Conv
(Yld %)
99
99(72)
99
98(96)
99
99(74)
99
99
78
74
88
Product
With the optimal silane established, the substrate scope of
the reduction of tertiary amides to amines was probed using
1
2
3
4
5
6
7
8
p-ClC6H4C(O)NMe2
p-ClC6H4C(O)NMe2
p-BrC6H4C(O)NMe2
p-BrC6H4C(O)NMe2
m-MeOC6H4C(O)NMe2
m-MeOC6H4C(O)NMe2
p-MeC6H4C(O)N(CH2)4
p-MeC6H4C(O)N(CH2)4
p-NO2C6H4C(O)NMe2
p-NO2C6H4C(O)NMe2
p-MeOC6H4C(O)NEt(Bn)
p-MeOC6H4C(O)NEt(Bn)
EtC(O)NEt2
EtC(O)NEt2
PhC(O)NH(Ph)
PhC(O)NH(Ph)
PhC(O)NH(p-BrC6H)
PhC(O)NH(p-BrC6H)
PhC(O)NH(C6H4-p-NO2)
PhC(O)NH(C6H4-p-NO2)
p-H2NC6H4C(O)NMe2
p-H2NC6H4C(O)NMe2
PhC(O)NH2
2
3
2
3
2
3
2
3
2
3
2
3
2
3
2
3
p-ClC6H4CH2NMe2
p-ClC6H4CH2NMe2
p-BrC6H4CH2NMe2
p-BrC6H4CH2NMe2
m-MeOC6H4CH2NMe2
m-MeOC6H4CH2NMe2
p-MeC6H4CH2N(CH2)4
p-MeC6H4CH2N(CH2)4
p-NO2C6H4CH2NMe2
p-NO2C6H4CH2NMe2
p-MeOC6H4CH2NEt(Bn)
p-MeOC6H4CH2NEt(Bn)
PrNEt2
the catalyst 2 and 3 (Table 2). High conversions of the amide to
the amine were observed for the N,N-dimethyl p-Cl, p-Br, and
o-methoxy-benzamides and pyrrole-p-methyl-benzamide with
no significant difference in activity between catalyst
while the N,N-dimethyl-p-nitro- benzamide was reduced to the
corresponding amine in 78 and 74% conversions using and
2 and 3,
2
3
9
as the catalyst, respectively. Similarly, N-benzyl-N-ethyl-4-
methoxybenzamide was reduced in 88 and 87% to the
10
11
12
13
14
15
16
17
corresponding amine using
2 and 3 as the catalyst,
87
99
87
99
respectively. In a similar fashion, the aliphatic amide N,N-
diethylpropionamide as well as N-phenyl-benzamide, N-p-
bromophenylbenzamide and N-p-nitrophenyl-benzamide,
PrNEt2
PhCH2NHPh
PhCH2NHPh
PhCH2NH(p-BrC6H4)
PhCH2NH(p-BrC6H4)
PhCH2NH(C6H4-p-NO2)
94
were reduced by both catalyst
2 and 3 in high conversions. No
2
3
2
99
99
99
99
0
conversion was observed for N,N dimethyl-p-aminobenzamide,
benzamide, N-methylbenzamide or N-benzylbenzamide.
These latter cases suggest that more basic amides may inhibit
the reduction. This view is consistent with stoichiometric
18
19
20
21
22
23
24
25
26
27
28
3
2
3
2
3
2
3
2
3
PhCH2NH(C6H4-p-NO2)
0
0
reactions of
the 31P NMR to 68.7 ppm, from 78.1 ppm. Similarly, addition of
N-benzylbenzamide to
showed a 31P resonance at 36.0 ppm.
3 with N-phenylbenzamide which show a shift in
PhC(O)NH2
0
0
0
0
PhC(O)NH(Me)
PhC(O)NH(Me)
PhC(O)NH(Bn)
3
In both cases the P-F coupling constant is decreased,
consistent coordination of the amide to the Lewis acid P centre
PhC(O)NH(Bn)
0
in
3
. Presumably binding to
3 precludes the catalytic cycle.
a The mixture was heated to 100 °C for 24 h in C6D5Br. Conversions determined by
1H NMR spectroscopy.
In extending the scope of these amide reductions, a series
of 2,2,2-trifluoro substituted acetamides were prepared from
reactions of an amine and trifluoroacetic anhydride at room
temperature. For these amides, catalyst and silane screening
2 | J. Name., 2012, 00, 1-3
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analogous FLP mechanism has been suggested for
hydrosilylations mediated by EPCs.35-36 Moreover, this
proposed mechanism is directly analogous to that proposed
and supported by computational studies for the phosphonium
mediated reduction of phosphine oxides. Moreover the
present proposal is consistent with the 31P and 19F NMR data
showing that the EPC catalyst is intact after catalysis.
Table 3. 2,2,2-trifluoroacetamide reductions using 3 as catalyst.
Substrate
CF3C(O)NH(Ph)
CF3C(O)NH(p-C6H4Br)
CF3C(O)NH(p-C6H4Cl)
CF3C(O)NH(p-C6H4i-Pr)
CF3C(O)NH(3.5-C6H3Me2)
CF3C(O)NH(CH2Ph)
T
Conv
Product
(ᵒC) (Yld %)
The above amide reductions of trifluoroacetamide
1
2
3
4
5
6
7
8
9
50 92(80) CF3CH2NH(Ph)
derivatives provide
a new avenue to 2,2,2-trifluoroethyl
50 97(92) CF3CH2NH(p-C6H4Br)
50 99(89) CF3CH2NH(p-C6H4Cl)
50 99(82) CF3CH2NH(p-C6H4i-Pr)
50 99(88) CF3CH2NH(3.5-C6H3Me2)
substituted amines, an important moiety in drug candidates.44-
48 Previous efforts have focused on nucleophilic substitution by
amines,49 use of hypervalent-iodine-CH2CF3 reagents,50 Pd
catalysed Buchwald-Hartwig couplings51 and a protocol based
on diazomethane in combination with silver salts.52 The
present work provides a metal-free and catalytic approach to
such trifluoroethylamine derivatives.
100
59 CF3CH2NH(CH2Ph)
CF3C(O)NH(CH2 p-C6H4Me) 100
CF3C(O)NH(CH2 p-C6H4OMe) 100
CF3C(O)NH(CH(Ph)2)
24 CF3CH2NH(CH2 p-C6H4Me)
11 CF3CH2NH(CH2 p-C6H4OMe)
19 CF3CH2NH(CH(Ph)2)
11 CF3CH2NH(p-C6H4CN)
64 CF3CH2NH(i-Pr)
100
100
100
100
10 CF3C(O)NH(p-C6H4CN)
11 CF3C(O)NH(i-Pr)
12 CF3C(O)NH2
6
CF3CH2NH2
13 CF3C(O)NPh2
14 CF3C(O)N(CH2Ph)2
100 66(64) CF3CH2NPh2
50 74(69) CF3CH2N(CH2Ph)2
Conclusion
In
summary,
EPCs
act
of
as
catalysts
for
the
the
Conditions: (HSiMe2)2O (2.1 eq.), 3 (3 mol%), substrate (0.15 mmol, 1.0 eq) in
CD2Cl2, heated. Conversions determined by 1H NMR spectroscopy.
hydrosilylation/reduction
amides
affording
corresponding amines. Notably, high chemoselectivity for
reductions of 2,2,2-subsituted acetamides was observed,
providing a facile route to N-trifluoroethyl substituted amines.
This reactivity further affirms that EPCs are effective metal-
free, Lewis acid catalysts. We are continuing to explore the
utility of this amide reductions in synthetic chemistry as well as
exploring the versatility of EPCs in catalytic reactions of
interest. The results of these studies will be reported in due
course.
Acknowledgements
D.W.S. is grateful for the financial support of the NSERC of
Canada and the award of a Canada Research Chair.
Notes and references
a Department of Chemistry, University of Toronto, 80 St. George St.,
Scheme 2 Proposed Mechanism of Amide reduction by EPCs.
Toronto,
Ontario
M5S
3H6,
Canada,
Email:
dstephan@chem.utoronto.ca
This reduction is thought to proceed via an FLP-type
mechanism involving the action of the Lewis acid and the
amide on the SiH fragment. This Initial interaction of silane by
the Lewis acidic P centre is thought to weakening the Si-H
bond and facilitate nucleophilic attack of the Si centre by the
amide. The transient R2NCH(OSiR’3)R” is thought react further
with silane to liberate silylether and the amine, freeing the
phosphonium cation for further catalysis (Scheme 2). This
proposed mechanism of the amide reduction is directly
b
These authors contributed equally to this work.
†Electronic
Spectroscopy
DOI: 10.1039/x0xx00000x.
Supplementary
Information
been
(ESI)
deposited
available:
details have
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