Exhaustive Chemoselective Reduction of Nitriles by Catalytic Hydrosilylation Involving Cooperative Si-H Bond Activation

Article abstract of DOI:10.1055/s-0036-1588441

A chemoselective method for the catalytic hydrosilylation of nitriles to either the imine or amine oxidation level is reported. The chemoselectivity is controlled by the hydrosilane used. The usefulness of the nitrile-to-amine reduction is demonstrated for a diverse set of aromatic and aliphatic nitriles, and the amines are easily isolated after hydrolysis as their hydrochloride salts. This exhaustive nitrile reduction proceeds at room temperature.

Full text of DOI:10.1055/s-0036-1588441

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© Georg Thieme Verlag Stuttgart · New York
2017, 28, A–D
cluster
A
en
S. Wübbolt, M. Oestreich
Cluster
Synlett
Exhaustive Chemoselective Reduction of Nitriles by Catalytic Hy-
drosilylation Involving Cooperative Si–H Bond Activation
Simon Wübbolt
0
0
0
0
0-
0
0
2
0-
8
4
1
6-
0
2
2
[Ru]
[Ru]
SAr
SAr
Martin Oestreich*
0
0
0
0
0-
0
0
2
1-
4
8
7
9-
2
1
8
Et3P
Et3P
BArF
BArF
–
–
4
4
SiMe2Ph
Et3SiH
Me2PhSiH
N
R
N
SiEt3
Institut für Chemie, Technische Universität Berlin,
Straße des 17. Juni 115, 10623 Berlin, Germany
martin.oestreich@tu-berlin.de
R
N
r.t.
R
r.t.
SiMe2Ph
6 examples
(for R = aryl)
90–99% yield
19 examples
(for R = aryl and alkyl)
19–99% yield
chemoselective
even
w/excess
Et3SiH
chemoselective
even
w/substoichiometric
Me2PhSiH
Published as part of the Cluster Silicon in Synthesis and
Catalysis
Received: 09.03.2017
Accepted after revision: 09.05.2017
Published online: 31.05.2017
catalyst
Si–H
catalyst
Si–H
Si
N
Si
R
N
R
N
R
r.t.
r.t.
Si
III
DOI: 10.1055/s-0036-1588441; Art ID: st-2017-b0170-c
I
II
Abstract A chemoselective method for the catalytic hydrosilylation of
nitriles to either the imine or amine oxidation level is reported. The che-
moselectivity is controlled by the hydrosilane used. The usefulness of
the nitrile-to-amine reduction is demonstrated for a diverse set of aro-
matic and aliphatic nitriles, and the amines are easily isolated after hy-
drolysis as their hydrochloride salts. This exhaustive nitrile reduction
proceeds at room temperature.
this work
Nikonov (2010)
Me
Me
Me
Me
Ru
Ru
i-Pr3P
NCCH3
S
BArF
Me
–
Et3P
NCCH3
4
–
B(C6F5)4
Me
[3a]+[BArF
]
–
[1]+[B(C6F5)4]–
4
Key words chemoselectivity, cooperativity, hydrosilylation, reduc-
tion, silicon
I → II w/ Me2PhSiH (2a, 1.0 equiv) I → II w/ Et3SiH (2b, 2.0 equiv)
I → III w/ Me2PhSiH (2a, 2.0 equiv) I → III w/ Me2PhSiH (2a, 2.1 equiv)
Scheme 1 Chemoselective reduction of nitriles by hydrosilylation; ArF
Reduction of nitriles is an established way to prepare
primary amines.1 Routine approaches involve the stoichio-
metric use of main-group hydrides based on aluminum2 or
boron.3 Catalytic methods make use of dihydrogen4 and,
more recently, hydrosilanes5 and -boranes6 as reducing
agents. However, early examples of hydrosilylations do re-
quire either high reaction temperatures or reactive hydro-
silanes.5 A mild method displaying good chemoselectivity
was reported by Gutsulyak and Nikonov using [Cp(i-
Pr3P)Ru(NCCH3)2]+[B(C6F5)4]– ([1]+[B(C6F5)4]–) as the catalyst
(Scheme 1, left). With stoichiometric amounts of hydrosi-
lane 2a, full conversion into the corresponding N-silylated
imine was observed (I → II).7,8 With double the amount of
2a, exhaustive reduction to the N,N-bissilylated amine was
seen (I → III). Chang and co-workers recently developed a
broadly applicable method where tris(pentafluorophe-
nyl)borane (B(C6F5)3) is employed for hydrosilane activa-
tion.9,10 The chemoselectivity was dependent on the hydro-
silane used: With bulky Et3SiH (2b), the reduction stops at
the imine oxidation level (I → II)11 whereas full reduction is
= 3,5-bis(trifluoromethyl)phenyl
achieved with Et2SiH2 (2c) as reductant (I → III). Another
transition-metal-free strategy introduced by Beller and co-
workers utilizes TBAF as the catalyst.12
Our laboratory demonstrated a few years ago that the
Ru–S bond in Ohki–Tatsumi complexes13 [3a–c]+[BArF ]–
4
readily engages in the heterolytic splitting of Si–H bonds to
generate a sulfur-stabilized silicon electrophile and a ruthe-
nium hydride.14,15 This activation mode emerged as syn-
thetically useful, and several unique dehydrogenative cou-
pling reactions have been realized with these catalysts.16
Conversely, reductive transformations, that is, hydrosilyla-
tions, promoted by this system are relatively rare.17–19 We
report herein the room-temperature hydrosilylation of ni-
triles to amines catalyzed by these cationic tethered ruthe-
nium complexes and compare our results with the prior art
(Scheme 1, right).7,8
We began with probing the reactivity of various hydro-
silanes by reacting them with benzonitrile (4a) in the pres-
ence of 1.0 mol% of catalysts [3a–c]+[BArF ]– (Table 1). Un-
4
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D

B
S. Wübbolt, M. Oestreich
Cluster
Synlett
like Nikonov’s catalyst [1]+[B(C6F5)4]– with equimolar
tuted 4e furnished the corresponding hydrochloride salt
6e·HCl in 99% yield (Table 2, entry 5). The electron-with-
drawing CF3 substituent was tolerated (4f–h → 6f–h∙HCl,
Table 2, entries 6–8) but the yield was low for the ortho-
substituted isomer. Electron-donating groups such as pro-
tected amines (NMe2 as in 4i) or alcohols (OMe as in 4j–l
and OTBDPS as in 4m,n) were not compatible with this pro-
cedure (Table 2, entries 9–14). Compound 4o with an OTB-
DPS group in the para position stood out and was converted
into 6o·HCl in 98% yield at an elevated reaction temperature
of 60 °C (Table 2, entry 15). Chloro- and bromo-substituted
substrates afforded excellent yields, regardless of the regio-
isomer (4p–u → 6p–u·HCl, Table 2, entries 16–21).
Me2PhSiH (2a),7 our ruthenium complex [3a]+[BArF ]– con-
4
verted 4a directly into the N,N-bissilylated amine 6aa, not
stopping at the N-silylated imine 5aa (Table 1, entry 1). In
turn, catalyst [3b]+[BArF ]– with a less electron-donating
4
phosphine ligand led to a mixture of amine 6aa and imine
5aa (Table 1, entry 2). Catalyst [3c]+[BArF ]– with a bulky
4
phosphine ligand did not promote the hydrosilylation (Ta-
ble 1, entry 3). We therefore continued with [3a]+[BArF ]– as
4
catalyst. Full conversion into amine 6aa was achieved with
a slight excess of hydrosilane 2a (Table 1, entry 4). In con-
trast, imine 5ab was formed exclusively when employing
more bulky Et3SiH (2b), regardless of the equivalents used
(Table 1, entries 5 and 6). These findings are in agreement
with those of Chang9 and Stephan.11 No conversion was
seen with even bulkier MePh2SiH (2d, Table 1, entry 7).
Table 2 Substrate Scope I: Aryl-Substituted Nitrilesa
[Ru]
SAr
Table 1 Development of the Catalytic Hydrosilylation Catalyzed by
Et3P
[3a]+[BArF
–
BArF
4
[3a–c]+[BArF ]–a
– (1.0 mol%)
4
]
4
N
Me2PhSiH (2a, 2.1 or 5.0 equiv)
neat, r.t., 18 h
NH2⋅HCl
R
R
[Ru]
SAr
R3P
then 2M HCl, Et2O, r.t., 1 h
–
BArF
4
4a−u
6a−u⋅HCl
–
[3a−c]+[BArF
]
4
N
(1.0 mol%)
Si–H 2a,b,d
Si
Si
Entry
Substrate
R
Product
Yield (%)b
N
N
+
Si
1
2
4ac
4bc
4cc
H
6a·HCl
6b·HCl
6c·HCl
6d·HCl
6e·HCl
6f·HCl
6g·HCl
6h·HCl
6i·HCl
6j·HCl
6k·HCl
6l·HCl
6m·HCl
6n·HCl
6o·HCl
6p·HCl
6q·HCl
6r·HCl
6s·HCl
6t·HCl
6u·HCl
99
neat, r.t., 18 h
4a
5aa,ab,ad
6aa,ab,ad
2-Me
73
3
3-Me
85
Entry Catalyst
Hydrosilane (equiv) Ratio 5a/6ab
Yield (%)c
4
4dd
4ed
4fc
4-Me
99
1
2
3
4
5
6
7
[3a]+ R = Et
Me2PhSiH (2a, 1.0) 0:>99 (5aa/6aa)
Me2PhSiH (2a, 1.0) 18:82 (5aa/6aa)
42
5
4-Ph
99
[3b]+ R = Ard
[3c]+ R = i-Pr
[3a]+ R = Et
[3a]+ R = Et
[3a]+ R = Et
[3a]+ R = Et
39
6
2-CF3
3-CF3
4-CF3
4-NMe2
2-OMe
3-OMe
4-OMe
2-OTBDPS
3-OTBDPS
4-OTBDPS
2-Cl
19
Me2PhSiH (2a, 1.0)
–
n.r.e
99
7
4gd
4hd
4id
99
Me2PhSiH (2a, 2.1) 0:>99 (5aa/6aa)
8
99
Et3SiH (2b, 1.0)
Et3SiH (2b, 2.0)
MePh2SiH (2d, 2.1)
>99:0 (5ab/6ab)
>99:0 (5ab/6ab)
–
60
9
n.r.f
n.r.f
n.r.f
n.r.f
n.r.f
n.r.f
98
91
10
11
12
13
14
15
16
17
18
19
20
21
4jd
n.r.e
4kd
4ld
a Reactions were performed on a 0.2 mmol scale.
b Determined by 1H NMR spectroscopy.
c Determined by 1H NMR spectroscopy using mesitylene as internal stan-
4md,e
4nd,e
4od,e
4pd
4qd
4rd
dard.
d Ar = 4-FC6H4.
e No reaction.
We then investigated the scope of the full reduction un-
der the optimized setup (Table 1, entry 4). Solid substrates
were dissolved in 5.0 equivalents of the hydrosilane. After
completion of the reaction and subsequent hydrolysis of
the N,N-bissilylated amine with 2 M HCl in Et2O, the corre-
sponding amines could be easily isolated as their hydro-
chloride salts by filtration (Table 2).20 The parent compound
was converted in quantitative yield (4a → 6a·HCl, Table 2,
entry 1). The tolyl derivatives 4b–d reacted irrespective of
the position of the methyl substituent but yields increased
with the methyl further away from the cyano group (4b–d
→ 6b–d·HCl, Table 2, entries 2–4). 1,1′-Biphen-4-yl-substi-
98
3-Cl
99
4-Cl
99
4sd
4td
2-Br
99
3-Br
99
4ud
4-Br
99
a Reactions were performed on a 0.2 mmol scale.
b Isolated yield of hydrochloride salt after filtration.
c 2.1 equiv of hydrosilane was used.
d 5.0 equiv of hydrosilane was used.
e Reaction was performed at 60 °C.
f No reaction.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D

C
S. Wübbolt, M. Oestreich
Cluster
Synlett
We also subjected alkyl- and heteroaryl-substituted ni-
triles to the general procedure20 (Scheme 2). Acetonitrile re-
acted in moderate yield (4v → 6v·HCl). A terminal alkene re-
mained untouched, affording the corresponding hydrochlo-
ride salt quantitatively (4w → 6w·HCl). The yield for benzyl
substitution was good (4x → 6x·HCl). Among the het-
eroarenes, it was only the fur-2-yl-substituted nitrile that
reacted smoothly (4y → 6y·HCl); thien-2-yl- and pyridin-3-
yl-substituted16e,17a cyanides led to intractable mixtures (4z
and 4a′).
Table 3 Selected Examples of the Chemoselective Nitrile-to-Imine Re-
ductiona
[Ru]
SAr
Et3P
BArF
–
4
[3a]+[BArF
]
4
– (1.0 mol%)
N
SiEt3
Et3SiH (2b, 2.0 equiv)
N
neat, r.t., 18 h
R
R
4a,d,h,o,r, and u
5ab,db,hb,ob,rb, and ub
Entry
Substrate
R
Product
Yield (%)b
1
2
3
4
5
6
4a
4d
4h
4o
4r
H
5ab
5db
5hb
5ob
5rb
5ub
91
n.r.c
92
90
99
99
[Ru]
SAr
Et3P
–
BArF
Me
4
[3a]+[BArF
]
4
– (1.0 mol%)
CF3
Me2PhSiH (2a, 2.1 equiv)
neat, r.t., 18 h
N
OTBDPS
Cl
R
NH2⋅HCl
6v−a'⋅HCl
R
then 2M HCl, Et2O, r.t., 1 h
4v−a'
4u
Br
NH2⋅ HCl
NH2⋅HCl
a Reactions were performed on a 0.2 mmol scale.
NH2⋅HCl
3
b Determined by 1H NMR spectroscopy using mesitylene as internal stan-
6v⋅HCl
(from 4v): 34%
6w⋅HCl
(from 4w): 98%
6x⋅HCl
(from 4x): 68%
dard.
c No reaction.
NH2⋅HCl
NH2⋅ HCl
NH2⋅HCl
O
S
Funding Information
N
6y⋅HCl
(from 4y): 78%
6z⋅HCl
(from 4z):
complex mixture
6a'⋅HCl
(from 4a'):
This research was supported by the Deutsche Forschungsgemein-
schaft (Oe 249/10-1). M.O. is indebted to the Einstein Foundation
complex mixture
Scheme 2 Substrate scope II: alkyl- and heteroaryl-substituted nitriles
(Berlin) for an endowed professorship
D
e
ustch
e
F
orsc
h
u
n
gsg
e
m
en
i
sc
h
atf
O(e
2
4
9
1/0-1)
Supporting Information
For the sake of completeness, we tested several of those
4-substituted benzonitriles, which had participated in the
nitrile-to-amine reduction (Table 2), in the chemoselective
nitrile-to-imine reduction (Table 3).21 All of these aryl-sub-
stituted nitriles furnished the corresponding N-silylated
imines in high yields (Table 3, entries 1 and 3–6) except the
4-tolyl derivative (Table 3, entry 2). As in previous cases, we
cannot explain this odd reactivity pattern. Moreover, appli-
cation of this hydrosilylation to any alkyl-substituted nitrile
did mainly result in complex mixtures (e.g., as for 4x) or no
reaction occurred (e.g., as for 4v).
To summarize, we disclosed here a room-temperature
reduction of aryl- and alkyl-substituted nitriles with hydro-
silanes catalyzed by an Ohki–Tatsumi complex,13 only re-
quiring 1.0 mol% catalyst loading. The hydrosilylation is
chemoselective depending on the hydrosilane used: With
Et3SiH, the reaction stops at the imine even with excess of
the reducant while full reduction is obtained with
Me2PhSiH even in substoichiometric amounts. The scope
was demonstrated for both the nitrile-to-amine as well as
the nitrile-to-imine reduction, and isolation of the amines
was accomplished after hydrolysis by facile precipitation of
the corresponding hydrochloride salts.
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1588441.
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p
p
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p
p
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References and Notes
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(2) Wünsch, B.; Geiger, C. In Science of Synthesis;
4
V0ao.
l
Schaumann, E.,
Ed.; Thieme: Stuttgart, 2009, 34.
(3) (a) Wünsch, B.; Geiger, C. In Science of Synthesis;4V0o.al Schaumann, E.,
Ed.; Thieme: Stuttgart, 2009, 38. (b) Wünsch, B.; Geiger, C. In
Science of Synthesis;
4
0Vao.
l
Schaumann, E., Ed.; Thieme: Stuttgart,
2009, 41.
(4) Wünsch, B.; Geiger, C. In Science of Synthesis;
4
V0ao.
l
Schaumann, E.,
Ed.; Thieme: Stuttgart, 2009, 29.
(5) (a) Murai, T.; Sakane, T.; Kato, S. Tetrahedron Lett. 1985, 26,
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D

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S. Wübbolt, M. Oestreich
Cluster
Synlett
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(18) Enolizable ketones16b and imines16d are initially converted into
silyl enol ethers and N-silyl enamines, respectively, but undergo
at prolonged reaction times subsequent hydrogenation with the
dihydrogen released in the preceding dehydrogenative coupling
step.17c,d
(19) For a synthetic and mechanistic study of hydrogenation cata-
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Oestreich, M. Chem. Eur. J. 2016, 22, 10009.
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Organometallics 2001, 20, 937. (b) Hashimoto, H.; Aratani, I.;
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Chem. 2015, 80, 7281.
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Park, J.; Jeong, J.; Park, S.-W.; Park, S.; Chang, S. Angew. Chem.
Int. Ed. 2015, 54, 6832.
(11) A similar observation where the chemoselectivity is controlled
by the reaction temperature (25 °C vs. 100 °C) was made by
Stephan and co-workers before: Perez, M.; Qu, Z.-W.; Caputo, C.
B.; Podgorny, V.; Hounjet, L. J.; Hansen, A.; Dobrovetsky, R.;
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Chem. 2013, 37, 2061.
(20) General Procedure for Nitrile-to-Amine Reduction
In a glove box, a flame-dried GLC vial equipped with a magnetic
–
stir bar is charged with [3a]+[BArF
]
(1.0 mol%) and Me2PhSiH
4
(2a, 2.1 or 5.0 equiv). The indicated nitrile is added either in the
glove box (for solid starting materials) or by microsyringe
outside the glove box, and the resulting reaction mixture is
maintained at r.t. for the indicated time. The reaction is
quenched by the addition of a mixture of cyclohexane and tert-
butyl methyl ether (90:10) containing 4% Et3N (0.5 mL), and the
resulting solution is filtered through a pad of Celite® coated by a
small layer of silica gel with a solution of cyclohexane and tert-
butyl methyl ether (90:10) containing 4% Et3N (3–4 mL) as
eluent. Solvents are removed under reduced pressure, and the
residue is dissolved in Et2O (1 mL) followed by addition of HCl (2
M in Et2O, 1.0 mL, 2.0 mmol, 10 equiv). The resulting suspen-
sion is stirred for 1 h and filtered, affording the amines as
hydrochloride salts as white to yellow solids.
(13) Ohki, Y.; Takikawa, Y.; Sadohara, H.; Kesenheimer, C.;
Engendahl, B.; Kapatina, E.; Tatsumi, K. Chem. Asian J. 2008, 3,
1625.
(14) For a recent summary, see: Omann, L.; Königs, C. D. F.; Klare, H.
F. T.; Oestreich, M. Acc. Chem. Res. 2017, 50, 1258.
(15) Stahl, T.; Hrobárik, P.; Königs, C. D. F.; Ohki, Y.; Tatsumi, K.;
Kemper, S.; Kaupp, M.; Klare, H. F. T.; Oestreich, M. Chem. Sci.
2015, 6, 4324.
(21) General Procedure for Nitrile-to-Imine Reduction
In a glove box, a flame-dried GLC vial equipped with a magnetic
stir bar is charged with [3a]+[BArF4]– (1.0 mol%), Et3SiH (2b, 2.0
equiv), and mesitylene (10 μL, 8.7 mg, 0.20 mmol, internal stan-
dard). The indicated nitrile is added either in the glove box (for
solid starting materials) or by microsyringe outside the glove
box, and the resulting reaction mixture is maintained at r.t. for
18 h. The mixture is then dissolved in CD2Cl2 (0.6 mL) and trans-
1
ferred into a NMR tube. H NMR spectroscopy is used to deter-
mine the yield with reference to mesitylene.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D