Base-Catalyzed Hydrosilylation of Nitriles to Amines and Esters to Alcohols

Article abstract of DOI:10.1002/ejoc.202100834

Base-catalyzed hydrosilylation of nitriles to amines and esters to silylated alcohols is reported. This protocol tolerates electron-rich and electron-neutral olefins and works in the presence of basic functional groups (e. g. tertiary amines) but fails for acidic substrates, such as phenols and NH anilines. This catalytic system does not tolerate carbonyl groups, such as aldehydes, ketones, esters and carbamides, which are reduced to corresponding alcohols and amines. With the exact amount of silane, esters can be selectively reduced in the presence of nitriles, but the selectivity drops for the pairs ester/carboxamide and carboxamide/nitrile. Through competition experiments, the following preference in functional group reactivity was determined: ester > carboxamide > nitrile.

Full text of DOI:10.1002/ejoc.202100834

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: Base-catalyzed Hydrosilylation of Nitriles to Amines
Authors: Joshua A. Clarke, Art van der Est, and Georgii Nikonov
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202100834
Link to VoR: https://doi.org/10.1002/ejoc.202100834
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10.1002/ejoc.202100834
European Journal of Organic Chemistry
FULL PAPER
Base-catalyzed Hydrosilylation of Nitriles to Amines and Esters to
Alcohols
Joshua A. Clarke,[a] Art van der Est[a] and Georgii I. Nikonov*[a]
Dedication ((optional))
Abstract: Base-catalyzed hydrosilylation of nitriles to amines is and
esters to silylated alcohols is reported. This protocol tolerates
electron-rich and electron-neutral olefins and works in the presence
of basic functional groups (e.g. tertiary amines) but fails for acidic
substrates, such as phenols and NH anilines. This catalytic system
does not tolerate carbonyl groups, such as aldehydes, ketones, esters
and carbamides, which are reduced to corresponding alcohols and
amines. With the exact amount of silane, esters can be selectively
reduced in the presence of nitriles, but the selectivity drops for the
and Hosomi et al. reported that fuoride can be replaced by
alkoxide in the hydrosilylation of ketones, esters and imines.[13,14]
In the past 10 years the application of base catalysts received
renewed attention for the reduction of ketones,[15] imines[15b] and
esters via hydrosilylation.[15b, 16 ] In addition, the Nolan group
showed deoxygenative hydrosilylation of tertiary amides to
amines catalyzed by KOH under solvent-free conditions (Scheme
1),[16] and Cui and co-workers reported that this reaction can be
17
]
also catalyzed by cesium carbonate.[
In contrast, the
pairs
ester/carboxamide and
carboxamide/nitrile.
Through
hydrosilylation of tertiary phenylacetamides with trialkoxysilanes
in the presence of KOtBu led to enamines.[18]
competition experiments, the following preference in functional group
reactivity was determined: ester > carboxamide > nitrile.
Introduction
Reduction reactions are among the most important
transformations in organic chemistry.[1] The traditional reduction
methods are based on the application of active metals,[ 2 ]
3
]
stoichiometric amounts of aluminium alkoxides,[
alkali
alkoxides[4] and soluble aluminum and boron hydrides,[5] which
often pose safety concerns, selectivity problems and may lead to
a substantial amount of unwanted waste. Recently, there has
been significant progress in developing alternative reduction
methods, of which the use of silanes offers significant advantages
in that they are air-stable, easy to handle, and some of them are
quite inexpensive.[6] While earlier efforts were primarily focused
on the development of transition metal-catalyzed reactions,[ 7 ]
there is a significant recent shift to the use of main-group[ 8 ]
element- and organo-catalysts.[ 9 ] At the border of these two
techniques lies the application of simple alkali metal bases. This
approach goes back to the pioneering work of Volpin and Corriu
on the application of stoichiometric amounts of alkali metal
fluorides in the hydrosilylation of aldehydes, ketones, and esters
to the corresponding alcohols.[ 10 , 11 ] Fujita and Hiyama then
showed that the fluoride ion (in the form of TBAF,
tetrabutylammonium fluoride) can be used in catalytic amounts,[12]
Scheme 1. Reported base-catalyzed reductions of amides and nitriles.
To the best of our knowledge, there has been no report on an
alkoxide-catalyzed hydrosilylation of nitriles. In fact, the groups of
Beller,[15a] Cui,[15c] and Guo[15d] reported that cyano groups are
tolerated by the KOtBu/PhSiH3, Cs2CO3/Ph2SiH2 and
[a]
Joshua Clarke, Dr. Art van der Est and Dr. Georgii I. Nikonov
Chemistry Department
Brock University
1812 Sir Isaac Brock Way, St. Catharines, Niagara Region, L2S
3A1, Ontario, Canada
E-mail: gnikonov@brocku.ca
K2CO3/PMHS
reducing
systems
(PMHS
=
polymethylhydrosiloxane). On the other hand, Beller and co-
workers showed that fluoride (in the form of TBAF) can catalyze
the reduction of aromatic nitriles by PhSiH3 (Scheme 1).[19]
Herein we report a simple base-catalyzed hydrosilylation of
nitriles and provide an insight into the chemoselectivity of this
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.202100834
European Journal of Organic Chemistry
FULL PAPER
process in comparison to the related reductions of amides and
esters.
With the optimized reaction conditions in hand, the scope of the
hydrosilylation of aromatic nitriles was explored. In general,
aromatic substrates performed well (Table 2, entries 1-3),
including a heterocyclic nitrile, such as nicotinonitrile (entry 3).
The presence of donor substituents had little or no effect on the
course of reduction (entries 4-6). In contrast to the usual Lewis
acid-catalyzed hydrosilylations, a substrate with a basic amino
function could also be reduced in very high yield (entry 6).
However, for nitriles containing electron-withdrawing groups, the
reduction works equally well (entries 7-9), except that for the para-
formyl-substituted benzonitrile the reaction was compromised by
the reduction of these functionalities (entry 9). Substrates with
labile protons presented another drawback as the easy
deprotonation and quenching of the base catalyst halted reactivity
(Table 2, entries 10-12). This catalytic method did not work for a
nitro-substituted substrate either (entry 13), which is a known
complication for hydrosilylation catalysis. Gratifyingly, bulky
aliphatic nitriles also can be reduced by this catalytic system, so
that pivalonitrile was converted to the corresponding ammonium
salt in very good yield (entry 14). Typically, the hydrosilylation of
aliphatic nitriles is restricted to the domain of transition metal
catalysts.[20] However, application of this methodology to short
chain aliphatics (Table 2, entries 15 and 16) resulted in a mixture
of carbon-carbon coupling products, suggesting a radical process.
This was elucidated by an EPR experiment in which the reduction
of butyronitrile, via the standard conditions (3 equiv. (EtO)3SiH
and 10% KOtBu), was treated with the spin-trapping reagent
M4PO (3,3,5,5-tetramethyl-1-pyrroline-N-oxide). The EPR
spectrum of the adduct (Figure 1) shows hyperfine coupling to
nitrogen and two equivalent b protons, indicating the formation of
the spin-adduct M4PO/·H and confirming the involvement of the
H· radical. The hyperfine splitting: AN = 16.49 G and AH = 21.53 G
obtained from the simulation of the spectrum matched previously
reported values.[21]
Results and Discussion
Hydrosilylation of Nitriles. Initially, we screened a series of silanes
in their ability to reduce benzonitrile (1a). THF, aromatic solvents
and neat conditions were tried. THF was found to be the best
media due to the formation of highly colored precipitates in less
polar solvents, which terminated catalysis. The choice of silane
was key to this transformation. PhSiH3, a very active silane that is
used in many hydrosilylation reactions, led to the formation of
intractable mixtures (Table 1, entry 1). The tertiary silanes
PhMe2SiH and Et3SiH did not produce the reduced product even
with elevated temperatures (entries 2 and 3). In contrast, the
inexpensive silane (EtO)3SiH worked well with 5 mol% catalyst
(entry 5). Given the known hazards of using trialkoxysilanes at
large loads, due to the production of highly flammable SiH4, we
also
tested
the
less
hazardous
siloxanes
TMDS
(tetramethyldisiloxane) and PMHS, but these reagents led only to
the production of uncharacterizable gels (Table 1, entries 8 and
9). It should also be noted that while higher temperatures did
improve overall rates, reductions were adequately facile at room
temperature (Table 1, entries 5 and 6). When comparing the
amount of silane to catalyst load, similar results could be obtained
with either an increase in silane equivs or mol% base, thus a
higher catalyst load was chosen in favor of a larger excess of
silane (entry 7), no further reactivity was observed with longer
reaction times. A hydrolytic work-up using HCl in a diethyl ether
solution allowed for the isolation of the corresponding
hydrochloride salt.
Table 1. Optimization of conditions for the reduction of benzonitrile with
silanes
Table 2. KOtBu catalyzed reduction of aromatic nitriles [a]
Entry
silane (equiv.)
x
T (°C)
Conv. 2ab [%]
1
2
3
4
5
6
7
8
9
PhSiH3 (5.0)
10
10
10
3
5
5
10
10
10
r.t.
r.t.
60
r.t.
r.t.
40
r.t.
r.t.
r.t.
0c
0
0
0
Conv. [%][a]
Entry
1
Nitrile
PhMe2SiH (5.0)
(Et)3SiH (3.0)
(EtO)3SiH (5.0)
(EtO)3SiH (5.0)
(EtO)3SiH (5.0)
(EtO)3SiH (3.0)
PMHS (5.0)b
(Yield [%][b]
)
96
>98
>98
0c
(1a)
(1b)
>98 (96)
TMDS (3.0)
0c
2
4
>98 (88)
>98 (76)
a Reaction conditions: KOtBu (x mol%), nitrile 1a (2 mmol), THF (1 mL)
and silane (6.0-10.0 mmol) under N2 atm. Hydrolysis was performed using
HCl (2 mL, 1M) in Et2O. b Conversion determined by 1H-NMR
spectroscopy. c Full conversion to a non-target product or formation of an
uncharacterizable gel.
(1d)
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10.1002/ejoc.202100834
European Journal of Organic Chemistry
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3
(1c)
(1e)
34[c]
5
6
>98 (86)
(1f)
>98 (96)
7
8
(1g)
(1h)
>98 (95)
>80 (79)
Figure 1. EPR spin-trap experiment. Black line: in situ detection of M4PO/·H,
1.0 mM H2O solution in flat cell, red line: simulated spectrum, M4PO/·H model.
Hydrosilyation of amides and esters. Given the sensitivity of
carbonyl functionalities to these reduction conditions (Table 1,
entry 7), we set out to further probe the applicability of this method
to a broader range of reducible functionalities. To this end, the
hydrosilylation of N,N-dimethyl benzamide was attempted and
produced a deoxygenation product, dimethylbenzyl amine which
9
(1i)
(1j)
>98 (72)[d]
10
0
1
was characterized by H NMR (Scheme 2). Additional reaction
time, 16h, was required for the complete conversion of the amide.
This result is in line with the reports by Nolan and Cui on the base-
[16,17]
catalyzed deoxygenation of carboxamides,
so further
11
12
(1k)
(1l)
0
0
substrate screening was not pursued. The standard conditions did
not work for secondary and primary amides, likely because of
deactivation of the catalyst by deprotonation of NH.
13
(1m)
0
Scheme 2. KOtBu-catalyzed reduction of N,N-dimethyl benzamide.
14
15
16
17
(1n)
(1o)
(1p)
(1q)
98 (88)
55 [e][f]
>98 [e]
>96 [g]
The compatibility with esters was then tested. The application of
our catalytic system to ethyl benzoate resulted in silylated
alcohols derived from the former benzoic and alcoholic parts of
ester, in agreement with the results reported by the Nolan
group.[16] We were curious as to why two closely related classes
of compounds, amides and esters, afforded such different
outcomes, i.e. deoxygenation for amides (C-N is retained) but
cleavage of the C-OR bond for esters.
Catalytic deoxygenation of esters to ethers is known but is usually
observed in transition-metal catalyzed hydrogenation[ 22 ] or
hydrosilylation.[23] Main-group catalyzed deoxygenation of esters
is usually performed by Lewis acid catalysts, such as InBr3,[24] and
in one recent case by a fluorinated borate [B(C6F5)4]− where the
noncovalent interactions between the borate, hydrosilane and
ester direct the course of reduction.[25] To find out whether the
a Reaction conditions: KOtBu (10 mol%), nitrile (2 mmol), THF (1 mL) and
silane (6.0 mmol) under N2 atm. Hydrolysis was performed using HCl (2
mL, 1M) in Et2O.
b Isolated yield. c Conversion determined by 1H-NMR spectroscopy;
isolation procedure resulted in a complex mixture of products. d Aldehyde
was reduced to alcohol. e Conversion to a mixture of C-C coupled products.
f No further conversion observed with increased time. g Attempting isolation
of product resulted in the formation of an uncharacterizable gel.
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10.1002/ejoc.202100834
European Journal of Organic Chemistry
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nature of the ester substrate can have any impact on the
chemoselectivity of reduction, we screened the hydrosilylation of
several aromatic and aliphatic esters by 3 equivalents of
(EtO)3SiH in the presence of potassium tert-butoxide catalyst
(Table 3). While the reduction of aromatic, mixed aromatic-
aliphatic (in the carbonyl and alkoxy parts) and aliphatic
substrates generally proceeds well (Table 3, entries 1-4 and 6), in
all cases the silylated alcohols were formed. This catalytic
reduction did not work for a nitro-substituted substrate (entry 4)
that likely poisons the catalyst (vide supra). Neither did it work for
an ester of a dibasic acid, diethyl oxalate, but the reason is
unknown (Table 3, entry 7).
slowest of the three. In fact, with this reduced silane load, esters
can be selectively reduced in the presence of nitriles (Scheme 3,
b). In the competition between amides and nitriles, the amide
reduction product was observed in a ratio of approximately 1.5:1
to the bis(silyl)amine product of the nitrile reduction, indicating that
the amide reduction is favored (Scheme 3, a). A similar ratio of
products was observed for the amide and ester competition
results (1.8:1 for silyl ether to amine), again confirming that ester
reduction is the favored process among the three substrates.
Table 3. KOtBu-catalyzed reduction of esters[a]
Entry
1
Ester
Conv.[%][a]
>98
5a
5b
5c
5d
Scheme 3. Competition experiments between benzonitrile (1a), ethyl
benzoate (3a) and N,N-dimethylbenzamide (5a). a
2
mL THF, (0.2 mmol)
2
3
4
>98
>98
>98
each substrate, 2.5eq (0.5 mmol) (EtO)3SiH, 10 mol % (0.02 mmol) KOtBu,
25°C, 16h. b Conversion determined by 1H-NMR spectroscopy.
To probe further the chemoselectivity of this catalytic system,
reductions of benzonitrile, ethyl benzoate, and dimethyl
benzamide in the presence of electron-neutral and electron-rich
olefins were attempted (Table 4). In all cases the carbonyl
substrates were converted into the respective products without
the compromising reduction of the C=C bond.
Table 4. Chemoselectivity experiments[a]
5
5e
0
Entry
1
Substrate
Additive
Product
Conv. [%][a]
>98
6
7
5f
>98
0
1a
5g
2
3a
>98
3
4
5a
1a
>98
>98
a Conversion determined by 1H-NMR spectroscopy with Me6Si2 as an
internal standard
Based on these findings, we then studied whether this catalytic
system could differentiate between different types of carbonyl
substrates. Aldehydes and ketones were excluded based on
previous experiments and the data from Table 2 (entry 7), which
showed that these functionalities are effectively reduced.[15]
Competition experiments were carried out under the standard
conditions but with a reduced silane load (Scheme 4). These
experiments revealed that the rate of ester reduction is faster than
that of amides and nitriles. Comparison of a nitrile, ester, and
carboxamide showed that benzonitrile (1a) is consumed the
5
6
7
3a
5a
1a
>98
>98
>98
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10.1002/ejoc.202100834
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8
3a
>98
>98
(25°C), unless specified otherwise. EPR spectra were collected
using a Bruker Elexsys E580 X-band spectrometer equipped
with nitrogen gas temperature control system. Mass
spectrometry analysis was measured on a Bruker HCT-plus Ion-
Trap, with an ESI ion source for positive (+) and negative (-)
polarity in MeOH.
9
5a
a Conversion determined by 1H-NMR spectroscopy
Typical procedure for the hydrosilylation of nitriles. A 50 mL
Schlenk ampoule affixed with a Chem-Vac™ valve was charged
with the nitrile (2.0 mmol) dissolved in 5 mL of THF. (EtO)3SiH (3
equiv. to nitrile) was added to the ampoule followed by 10 mol%
of KOtBu dissolved in THF (2 mL) and the ampoule was
immediately sealed and taken out of the glovebox to be left at
room temperature overnight. After 12 h, the reaction mixture was
hydrolyzed with aqueous NaOH (2 mL, 1M) solution for 1 h.
After that the aqueous phase was extracted with Et2O (3 x 20
mL), the organic layer was washed with brine and dried over
Na2SO4 for 15 min. After gravity filtration, HCl/Et2O (10 mL, 1M)
was added to the organic phase, resulting in immediate
precipitation of the ammonium salt. The mixture was aged
overnight to allow for complete precipitation. The salt was then
washed twice with 15 mL of DCM and twice with 10 mL of
EtOAc to obtain the pure product.
Conclusions
We showed that base-catalyzed hydrosilylation can be applied to
the reduction of nitriles to amines. This protocol tolerates basic
functions but fails for OH and NH acidic substrates, such as
phenols and anilines. This system does not tolerate carbonyl
substrates, such as aldehydes, ketones, esters and carbamides,
which are reduced to corresponding alcohols and amines, but
tolerates electron-rich and electron-neutral olefins. We also
established the following preference for reduction: ester >
carboxamide > nitrile. With an exact amount of silane, esters can
be selectively reduced in the presence of nitriles, but the
selectivity drops for the pairings of ester/carboxamide and
carboxamide/nitrile.
Experimental Section.
Acknowledgements
All reactions were run under a nitrogen atmosphere by using an
MBraun glovebox or a standard Schlenk line. All glassware was
oven dried before use. All isolated compounds were
characterized by 1H NMR and 13C NMR spectroscopy by using
Bruker AV 400 or AV 600 instrument at room temperature
G.I.N. thanks NSERC for the generous support (DG 2017-05231).
Keywords: Esters • Base catalysis • Hydrosilylation • Nitriles •
Reduction
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10.1002/ejoc.202100834
European Journal of Organic Chemistry
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Base-catalyzed hydrosilylation allows
for easy reduction of nitriles to amines
that tolerates olefins and basic
functionalities but does not tolerate
carbonyls (aldehydes, ketones, esters
and carboxamides).
Joshua A. Clarke, Art van der Est and
Georgii I. Nikonov*
Page No. – Page No.
Base-catalyzed Hydrosilylation of
Nitriles to Amines and Esters to
Alcohols
.
.
This article is protected by copyright. All rights reserved.