Efficient metal-free hydrosilylation of tertiary, secondary and primary amides to amines

Article abstract of DOI:10.1039/c4cc02894e

Hydrosilylation of secondary and tertiary amides to amines is described using catalytic amounts of B(C₆F₅)₃. The organic catalyst enables the reduction of amides with cost-efficient, non-toxic and air stable PMHS and TMDS hydrosilanes. The methodology was successfully extended to the more challenging reduction of primary amides.

Full text of DOI:10.1039/c4cc02894e

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Efficient metal-free hydrosilylation of tertiary,
secondary and primary amides to amines†
Cite this:DOI: 10.1039/c4cc02894e
Enguerrand Blondiaux and Thibault Cantat*
Received 18th April 2014,
Accepted 24th June 2014
DOI: 10.1039/c4cc02894e
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Hydrosilylation of secondary and tertiary amides to amines is orbital and the vicinal nitrogen lone pair in amides significantly
described using catalytic amounts of B(C6F5)3. The organic catalyst lower the electrophilicity of the CQO group and the efficient
enables the reduction of amides with cost-efficient, non-toxic and air catalytic hydrosilylation of amides remains an issue in synthetic
stable PMHS and TMDS hydrosilanes. The methodology was success- organic chemistry.7 Tertiary and/or secondary amines can be
fully extended to the more challenging reduction of primary amides. obtained by hydrosilylation of amides and catalysts based on
earth abundant metals (Fe, Zn, Cu and Co) that have been
The late 1990s witnessed the birth of a novel field in homo- developed over the last few years for this transformation.8
geneous catalysis, when compelling successes were obtained in Interestingly, simple bases, such as Cs2CO3, KOH, KOtBu or
enantioselective synthesis using small organic molecules as LiHBEt3, have emerged as hydrosilylation catalysts, lately.9 Over-
asymmetric catalysts.1 Organocatalysis has since then witnessed all, these systems offer only a partial solution to the reduction of
a growth spurt, resulting from a better rationalization of the amides as they either operate at elevated temperatures
catalyst families and motivated by the advantages provided by (4120 1C), require the use of air sensitive hydrosilanes (such
metal-free catalysts.2 Indeed, organocatalysts usually combine as PhSiH3) and/or are limited to a narrow scope of amide
low cost and low toxicity with an enhanced stability to moisture derivatives. These limitations have encouraged us to explore
and air, which can circumvent classical drawbacks of many the use of metal-free catalysts in the reduction of amides to
metallic catalysts. So far, organocatalysts have been applied amines using hydrosilylanes. Herein, we show that the B(C6F5)3
efficiently in condensation and cycloaddition reactions, phase- catalyst, combined with cost-efficient, non-toxic and air stable
transfer catalysis and oxidation chemistry, while their use in PMHS (polymethylhydrosiloxane) and TMDS (tetramethyldisilox-
reduction chemistry has been only scarcely explored.3 In fact, the ane) hydrosilanes, is a potent system for the hydrosilylation of
finding that molecular hydrogen could be activated using tertiary, secondary and primary amides.
organic frustrated Lewis pairs (FLPs) enabled the metal-free
Very recently, Beller and coworkers showed that boronic
catalytic hydrogenation of imines and alkenes.4 In parallel, acids could act as organocatalysts in the hydrosilylation of
organic Lewis acids and bases were shown to promote the tertiary and secondary amides.10 Yet, the transformation pro-
hydrosilylation and hydroboration of a variety of carbonyl sub- ceeds at 110–130 1C with an excess of PhSiH3, and the turnover
strates, including CO2.5 These recent results are an encourage- numbers (TONs) are very limited (o2) in the reduction of
ment, and future efforts in the field should focus on challenging primary amides. From another standpoint, Piers and coworkers
metal catalysts for the reduction of reluctant substrates, under demonstrated, in the late 1990s, the potential of B(C6F5)3 as a
mild reaction conditions. In this context, the hydrosilylation of catalyst in the hydrosilylation of aromatic aldehydes, ketones,
amides is an attractive alternative to classical methods utilizing and esters.11 This seminal contribution has since then been
reactive aluminium and boron hydrides for the synthesis of successfully applied in the hydrosilylation of alcohols, ethers,
amines, as it usually proceeds with enhanced chemoselectivity.6 carboxylic acids, imines and olefins and reduction of N-phenyl-
Nonetheless, strong resonance effects between the vacant pꢀC¼O acetamide with Ph2SiH2 suggests that B(C6F5)3 could be an
efficient catalyst for the hydrosilylation of amides.12
The ability of B(C6F5)3 to catalyze the hydrosilylation of amides
was first tested in the reduction of N-benzylbenzamide (1a).
In the presence of a large catalyst loading of 20 mol%
E. Blondiaux, Dr. T. Cantat CEA, IRAMIS, NIMBE, CNRS UMR 3299,
91191 Gif–sur–Yvette, France. E-mail: thibault.cantat@cea.fr; Web: http://iramis.
cea.fr/Pisp/thibault.cantat/index.htm; Fax: +33 1 6908 6640
B(C6F5)3 and 1.3 equiv. of PhSiH3, dibenzylamine 2a is formed
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
c4cc02894e
in a low 16% yield after 18 h at room temperature in toluene
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Table 1 Reduction of N-benzylbenzamide with B(C6F5)3
Table 2 Reduction of secondary amides using B(C6F5)3 and TMDS
Yielda
[%]
Yielda
[%]
Cat. loading
[mol%]
Temp.
[1C]
Yielda
[%]
Entry Amide
1
Entry Amide
6
Entry
X3SiH (n)
1
2
3
4
5
6
7
8
9
10
PhSiH3 (1.3)
PhSiH3 (1.3)
PhSiH3 (1.3)
PhSiH3 (1.3)
PhSiH3 (1.3)
PhSiH3 (1.3)
PhSiH3 (1.3)
PhSiH3 (1.3)
PMHS (4)
—
20
20
5
2
1
5
5
5
5
100
20
0
16
99
92
87
53
62b
14
76
91
85b
24
100
100
100
100
100
80
2
3
4
94b
92b
3
7
8
9
95
96b
92
100
100
TMDS (2)
Reaction conditions: N-benzylbenzamide 1a (0.10 mmol), hydrosilane
a
(n equiv.), 18 h under an inert atmosphere. GC/MS yield using
b
mesitylene as an internal standard. 5 h reaction.
(Table 1, entry 2). Nonetheless, increasing the temperature to
100 1C leads to a quantitative conversion of 1a to 2a (Table 1,
entry 3) and, at 100 1C, 2 mol% B(C6F5)3 is sufficient to afford 2a
in 87% yield (Table 1, entry 5). The reaction temperature plays a
significant role in the catalytic activity and, at 80 1C, the conver-
sion yield to 2a drops to 14% (Table 1, entry 8). This effect likely
results from the formation of an adduct between the coordinat-
ing amide substrate and the catalyst B(C6F5)3, that must be
thermally cleaved to release the active Lewis acid. To our delight,
PMHS and TMDS are active reductants in the hydrosilylation of 1a,
despite their lower reactivity. Using 5 mol% B(C6F5)3, 2a is
obtained in 76 and 91% yields in the presence of 4 equiv. of
5
40
10
11
20
41
Reaction conditions: amide (0.10 mmol), TMDS (0.20 mmol), B(C6F5)3
(0.0050 mmol), toluene (0.30 mL), 100 1C, 18 h. a GC/MS and/or 1H NMR
b
yield using mesitylene as an internal standard. Isolated yields.
PMHS and 2 equiv. of TMDS, respectively (Table 1, entries 9 and 10). 2i is obtained in 92% yield from 1i. In contrast, the p-OMe sub-
In comparison, Beller et al. have shown that benzothiophene- stituent somewhat deactivates the reactivity of N-benzylbenzamide
derived boronic acids were active catalysts in the hydrosilylation and 1j is converted to 2j in 20% yield after 18 h at 100 1C. Overall,
of amides.10 However, boronic acids display a low activity in the these results are consistent with the original mechanism unveiled
reduction of secondary (and primary) amides and 1a was reduced to by Piers et al. for the B(C6F5)3-catalyzed hydrosilylation of carbonyl
2a in 67% yield, in the presence of 20 mol% boronic acid catalyst groups.12f Its transposition to the reduction of amides likely
and 2.4 equiv. of PhSiH3, after 24 h at 130 1C.
involves the formation of an ion pair, in which the carbonyl
The B(C6F5)3 (cat.)–TMDS system therefore appears to be a functionality is activated by coordinatioꢁn to a silylium cation while
convenient reducing medium, which combines the advantages of the active reductant is the HB(C6F5)3 anion (Scheme 1). This
an organocatalyst with low cost (o4 h kgꢁ1), low toxicity and the pathway is therefore favoured in the presence of EWGs on the
stability of the TMDS hydrosilane. The scope of reactive secondary amide reactant because they weaken the amide–B(C6F5ꢁ)3 inter-
amides was thus explored using this system (Table 2). Reduction of action and facilitate the hydride transfer from HB(C6F5)3 to the
N-phenylbenzamide (1b) was quantitative, after 18 h at 100 1C, and carbonyl group.
amine 2b was obtained in 94% isolated yield after hydrolysis of the
The B(C6F5)3 (cat.)–TMDS system is also competitive or superior
reaction mixture (see the ESI† and entry 2 in Table 2). Replacing to known metal catalysts in the hydrosilylation of secondary amides.
the phenyl ring on the carbonyl group with a methyl group did not Among the few catalysts able to promote the hydrosilylation of
impact the reactivity of the amide and 2c was isolated in 92% yield, secondary amides with PMHS or TMDS, Zn(OTf)2 displays a low
under the same conditions (Table 2, entry 3). Yet, introduction of reactivity and it reacts at 100 1C,8a with high loadings (20 mol%),
an aliphatic group on the nitrogen atom significantly hampers the while Cu(OTf)2 complexes are reactive at 65 1C.8f
conversion yields and 1d, 1e and 1f are converted to their corre-
Tertiary amides are classically more reactive than secondary
sponding amines in lower yields (o40%) (Table 2, entries 4–6). amides in hydrosilylation reactions. Indeed, reduction of
The allyl derivative 1k is reduced to 2k in 41% yield, without N,N-dimethylbenzamide (3a) to 4a is quantitative after 18 h at
reduction of the CQC bond. The presence of electron withdrawing 100 1C with 1 mol% B(C6F5)3 and 1.3 equiv. of PhSiH3. Using
groups on the benzamide ring of 1a favours the reaction and the TMDS and PMHS as reductants and catalyst loadings of 2 mol%
p-Cl- and p-Br-substituted N-benzylbenzamides are converted to 2g and 5 mol%, respectively, 4a is also formed in a quantitative yield.
and 2h in quantitative yields (Table 2, entries 7 and 8). Similarly, As expected, a wide range of tertiary amides was successfully
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Table 3 Reduction of tertiary amides using B(C6F5)3 and PMHS
Scheme 1
Reaction conditions: amide (0.10 mmol), PMHS (0.40 mmol, 4 equiv.
‘‘Si–H’’), B(C6F5)3 (0.0050 mmol), toluene (0.30 mL), 100 1C, 18 h; yield
determined by GC/MS using mesitylene as an internal standard. a With
PhSiH3 (0.13 mmol, 4 equiv. of ‘‘Si–H’’).
reduced using the B(C6F5)3 (cat.)–PMHS system and both aliphatic
and aromatic amides 3a–3j were converted in good to excellent
yields (472%, Table 3 and ESI†). Amide 3k exhibits a somewhat
lower reactivity, presumably because of the presence of three
aliphatic groups on the nitrogen and carbonyl groups and 4k is
formed in 42% yield. Similarly, 3l and 3m afford amines 4l and 4m
in 60 and 49% yields, respectively. It is noteworthy that the
methodology is compatible with the presence of nitro groups
and 4n is obtained in 82% yield when 3n is reduced in the presence
of PhSiH3 (14% yield when PMHS is utilized as a reductant). In
contrast, the cyano group in 3o hampers the catalytic activity of
B(C6F5)3, presumably because of the strong coordination of the CN
functionality to the Lewis acid catalyst. B(C6F5)3 (cat.)/PMHS is also
able to reduce enones and esters and the reduction of the amide
functionality in 5 and 7 is also accompanied with the reduction of
the CQC and –CO2Me groups (eqn (4)–(6)).
amide 9a to the benzonitrile intermediate. In order to prevent
the coexistence of 9a and benzonitrile in the reaction mixture,
the rapid silylation of one N–H bond in 9a was undertaken,
using TMSCl, prior to the hydrosilylation step. Using this
simple procedure, primary amines 11a and 11b were obtained
in excellent 91 and 83% yields from primary amides 9a and 9b,
respectively (eqn (8)).
(7)
(4)
(8)
In conclusion, B(C6F5)3 is an efficient organocatalyst for the
hydrosilylation of tertiary, secondary and primary amides, with
cost-efficient, non-toxic and air stable PMHS and TMDS hydro-
silanes. The methodology enables the formation of tertiary,
secondary and primary amines from the corresponding amides.
We acknowledge CEA, CNRS, ADEME, and the European
Research Council (ERC Starting Grant Agreement no. 336467)
for financial support of this work. T.C. thanks the Fondation
Louis D. – Institut de France for its support.
It is well recognized that primary amides are singular
substrates in catalytic hydrosilylation.8g,13 Indeed, they display
a low reactivity and can be converted to secondary amines by
coupling, after subsequent hydrolysis.8g,h In fact, reduction of
benzamide 9a with 10 mol% B(C6F5)3 and 2 equiv. of TMDS
affords the secondary amine 2a in 65% yield, after 18 h at
100 1C (eqn (7)). As proposed by Darcel et al. and Beller et al.,
benzonitrile PhCN can form by slow dehydrogenative silylation
of the N–H bonds of 9a and subsequent elimination of a
siloxane by-product.8g,h A plausible mechanism for the cou-
pling reaction can thus involve the addition of nucleophilic
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