Nickel-catalyzed hydrogen-borrowing strategy: Chemo-selective alkylation of nitriles with alcohols

Article abstract of DOI:10.1039/d0cc02261f

The first nickel-catalyzed hydrogen-borrowing alkylation of a series of aryl acetonitriles with a variety of aryl, heteroaryl, allylic and alkyl alcohols releasing water as the by-product (>33 examples, up to 90% yield) is reported.

Full text of DOI:10.1039/d0cc02261f

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DOI: 10.1039/D0CC02261F
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Received 00th January 20xx,
Accepted 00th January 20xxDOI:
10.1039/x0xx00000x
Nickel-Catalyzed Hydrogen-Borrowing Strategy: Chemo-selective
Alkylation of Nitriles with Alcohols
Sourajit Bera, Atanu Bera and Debasis Banerjee*
The first nickel-catalyzed hydrogen-borrowing alkylation of a utilized PNP or NNN-ligand core for successful transformations.8
Nevertheless, these organometallic ligands are expensive, required
multi-step synthesis and are often major concern in comparison to
the base-metal catalysts (Scheme 1a).8
series of aryl acetonitriles with a variety of aryl, heteroaryl,
allylic and alkyl alcohols is reported releasing water as by-
product (>33 examples, up to 90% yield). Mechanistic studies
involving defined Ni-H species, deuterium-labeling, kinetic
studies and determination of rate and order of the process
indicate the participation of benzylic C−H/D bond of alcohols
(PH/PD = 1.6). Synthesis of intermediate of antiarrhythmic
agent verapamil broadens the scope of the present protocol.
a) Previous report
Pincer-based-catalysts
Air-sensetive ligands
Multi-step ligand synthesis
Expensive organometalic catalysts
R
M
+
CN
R
OH
Ar
Ar
CN
M = Ir, Ru, Os, Rh, Pd, Fe and Mn
b) This work: Synthesis of functionalized secondary nitriles
ipr
CN
MeO
N
R1
Ni
R1
OH
+
CN
R
MeO
MeO
gram scale synthesis
H2O
R
CN
> 33 examples, up to 90% yield
Nitriles are omnipresent in various bioactive natural products,
pharmaceuticals, drugs and extensively used as versatile building
blocks in laboratory as well as in fine chemical industries.1 For
instance, anastrazole, widely used for treatment in breast cancer
and marketed by Astra-Zeneca, verapamil and gallopamil
(antiarrhythmic agent) are widely used pharmaceuticals having
benzonitrile functionality (Scheme 1). In this context, alkylation and
functionalization of arylmethyl nitriles attracts potential attention.
Nevertheless, conventional catalytic transformations often
limited with expensive and rare noble-metal catalysts.2 However,
metal-catalyzed hydrogen borrowing (HB) strategy using biomass
derived alcohols as the key alkylating agent would be a potential
alternative, releasing only water as by-product and rendering the
process sustainable.3 Such practise avoids the use of pre-
functionalized alkyl halides and the generation of stoichiometric
waste. Therefore, recently, there has been a potential drive in
catalytic research to replace these expensive and toxic noble-metals
using an earth-abundant base-metal catalyst. In this direction, HB
processes for the alkylation of ketones, esters, amides, amines etc.
using base-metal catalysts are noteworthy.4
Another major issue is sensitive nature of cyano group towards
water and hydrogen; therefore, alkylation of arylmethyl nitrile
following HB process associated with poor selectivity and prone to
undesired side reaction to amide,5a and primary amine.5b
Additionally, controlling the selectivity to alkyl nitrile over the
olefinic nitrile intermediate is the key issue (Table 1).6 Thus, Ru, Ir,
Rh, Os, and Pd-based metals were used for the alkylation of nitriles
using alcohols.7 Recently, a few applications of base-metal catalysts
for such transformations are known.8 Notably, such processes
MeO
Verapamil
(antiarrhythmic agent)
Non-precious metal-catalyst
Scope with aryl, heteroaryl, aliphatic and allylic alcohols
phosphine free catalysis
Mechanistic studies
Scheme 1: a) Metal-catalyzed alkylation of arylmethyl nitriles. b) Nickel- catalyzed
chemo-selective functionalization of nitriles with alcohols.
In this context, we wondered, whether Ni-based catalysts would be
useful for chemo-selective alkylation of nitriles with alcohols.
Particularly, nickel is well recognized as a hydrogenation catalyst,
therefore, controlling selectivity for alkylation over the reduction of
nitriles to primary amines by in situ formed Ni-H species is a
challenging task. Additionally, Ni-salts have strong binding affinity
towards the free hydroxyl-group of alcohols and make it inferior
substrate class for organic transformations.9
Pleasingly, recently we demonstrated a couple of novel protocols
for amination of alcohols, α-alkylation of ketones as well as
synthesis of N-heterocycles using suitable Ni-catalysts and bench-
stable nitrogen ligands.10 Encouraged by these findings, herein we
reported the first Ni-catalyzed chemo-selective alkylation of aryl
and alkyl nitriles with primary alcohols. Remarkably, the present
Ni-catalyzed transformations allows a series of functionalized
branched-nitriles with excellent chemo-selectivity and in up to 90%
yield (Scheme 1b). Only a catalytic amount of mild base in
combination with inexpensive nickel-catalyst is required to activate
a number of bonds and allows selective formation of secondary
nitriles derivatives in one-pot operation releasing water as sole by-
product. Preliminary catalytic and mechanistic studies involving
deuterium labeling experiments, determination of rate and order of
the reactions including the generation of water during HB process
were determined (Scheme 1b).
To identify the suitable catalytic system, initial optimization studies
were carried out using phenyl acetonitrile 1a with benzyl alcohol 2a
as model substrates. Primarily, Ni(acac)2 (5 mol%) was employed
using 1,10-phenanthroline L1 as a ligand (10 mol%) and catalytic
amount of t-BuOK (15 mol%) as a base in toluene at 130 oC for 36 h.
The desired alkylated product 3a was obtained in 42% conversion
along with 5% of 3a’ (Table 1, entry 1). Thereafter, application of
Department of Chemistry, Laboratory of Catalysis and Organic Synthesis,
Indian Institute of Technology Roorkee, Roorkee-247667, Uttarakhand, India.
E-mail: debasis.banerjee@cy.iitr.ac.in
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here].
See DOI: 10.1039/x0xx00000x
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other different nickel pre-catalysts found less efficient for the p-trifluoromethyl benzylalcohol 2j and hetero-aryl alcohols, such as,
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2-furfurylmethanol 2k as well as 2-pyridinemethanol 2l were
DOI: 10.1039/D0CC02261F
-alkylation (Table 1, entries 2-4, SI Table S1). Next, influence of
sluggish under the standard conditions. However, when NiCl2.dme
was used as a catalyst in combination with NaOH as a base, 3j-3l
were obtained in up to 80% yields (Scheme 2).
different inorganic bases (t-BuONa, t-BuOK, Na2CO3, K3PO4, K2CO3
and Cs2CO3) as well as organic bases (Et3N, pyridine, and N,N-di-
isopropylethylamine) were examined for the model reaction. To our
delight, K2CO3 resulted with 68% conversion to the alkylated
product 3a (Table 1, entry 5 and SI Table S3).
Scheme 2: Synthesis of functionalized branched nitrilesa
CN
L1
Ni(acac)2/
Ar
R1
CN
+ H2O
Ar
OH
R1
K2CO3
toluene, 140 °C, 36 h
2a-m
1a-1m
3-4 (Isolated yield)
CN
Table 1. Catalytic screening for alkylation of 1a with 2aa,b
A. Scope of phenylacetonitrile with aryl alcohols
F
Ni(acac)2 (5 mol%)
CN
CN
3a
R = p-H, , 90%
CN
L1 (10 mol%)
Ph
CN
Ph
Ph
72%, (gram scale)
Ph
OH
R
Ph
Ph
t-BuOK (15 mol%)
toluene, 130 °C, 36 h
3b
R = p-Me, , 83%
2a
1a
3a
3a'
3g
, 70%
3c
R = p-Et, , 61%
Entry Deviation from the above
Conv. (%)b
3d
R = p-iPr, , 62%
CF3
CN
3e
R = p-OMe, , 58%
3a
42
17
21
30
68
10
20
93(90)
76
41
2
3a’
5
b
3f
R = o-Me, , 67%
1
2
none
NiBr2
CN
Cl
c
3j
, 80%
CN
12
22
10
2
28
30
-
-
3
-
-
Br
3i
, 45%
3
4
NiCl2
NiCl2.dme
3h
, 61%
CN
CN
CN
O
5
6
7
8
K2CO3 (15 mol%) as base
L4, K2CO3 (15 mol%)
L5, K2CO3 (15 mol%)
K2CO3 (50 mol%), 140 °C
130 °C
N
d
3m
, 87%
3l
, 80%
d
3k
, 56%
B. Scope of aryl/alkyl acetonitriles with alcohols
OMe
CN
CN
CN
MeO
9
e
4c
CN
, 53%
e
e
10
11
12
no base
only catalyst
only base
4a
, 63%
4b
, 52%
OMe CN
CN
MeO
MeO
5
g
4d, 56%f
e
Reaction conditions: 1a (0.50 mmol), 2a (0.75 mmol), Ni(acac)2 (0.025 mmol), L (0.05
mmol), base (0.015-0.25 mmol), toluene (2.0 mL), Schlenk tube under N2 atmosphere,
140 °C oil bath, 36 h reaction time. bConversion was determined by GC-MS (isolated
yield in parentheses, average yield of two runs). L1 = 1,10-phenanthroline. L2 = 2,9-
dimethyl-1,10-phenanthroline. L3 = bipyridine. L4 = 4,4’- dimethylbipyridine. L5 = 2,2'-
biquinoline. L6 = tri-cyclohexylphosphine.
4f
, 47%
4e
, 65%
F
CN
CN
CN
O
O
g
h
g
4g
, 53%
4i
, 80%
N
4h
, 30%
Cl
Br
from 3-phenyl propionitrilei
CN
R2
Ph
Further, applications of different nitrogen-based ligands L2-L6 proof
less efficient (Table 1, entries 6-7, SI Table S2). Again, applications
of different solvents, such as, p-xylene, 1,4-dioxane, N,N-dimethyl
formamide (DMF), N,N-dimethyl acetamide (DMA) were less
effective for the alkylation of nitriles (SI, Table S4). Notably, under
identical conditions, an increment of catalytic amount of K2CO3 (50
mol%) at 140 °C resulted 3a in 90% isolated yield with excellent
chemo-selectivity (Table 1, entry 8, SI Table S5). Alkylation reaction
at a lower temperature resulted 76% conversion to 3a (Table 1,
entry 9). Control experiments, in absence of Ni-catalyst or ligand as
well as in absence of base resulted albeit with moderate or poor
yield of 3a (Table 1, entries 10-12, SI Table S1-S8). Gratifyingly, best
results were obtained using Ni(acac)2 (5 mol%), L1 (10 mol%), K2CO3
(50 mol%) in toluene at 140 oC for 36 h and we did not observe any
3a’ under this optimized conditions (Table 1, entry 8).
CN
4m
, trace
Ph
4j
R = p-H, , 50%
CN
4n
CN
4k
R = p-OMe, , 10%
4l
R = p-Cl, , <5%
Ph
4o
, trace
, trace
CN
Reaction Conditions: a1 (0.50 mmol), aryl alcohols 2 (0.75 mmol), Ni(acac)2 (0.025
mmol), L1 (0.05 mmol), K2CO3 (0.25 mmol), toluene (2.0 mL), Schlenk tube under N2
atmosphere at 140 ⁰C in an oil bath for 36 h. See ESI for more details (Scheme S12).
Thereafter, scopes of the α-alkylation of various electronically
different aryl acetonitrile with primary alcohols were studied
(Scheme 2). To our delight, (p-methylphenyl)acetonitrile 1b,
(m-methoxyphenyl)acetonitrile 1c, (o-methoxyphenyl)acetonitrile
1d, and 2-(3,4-dimethoxyphenyl)acetonitrile 1e were employed
with benzylalcohol 2a and the desired functionalized secondary
nitrile derivatives 4a-4e were obtained in 52-65% isolated yield
respectively (Scheme 2). It is important to note that, (p-
flourophenyl)acetonitrile 1f, and (p-chlorophenyl)acetonitrile 1g,
efficiently participated with 2a under the nickel-catalysis and
transformed into the desired branched products in up to 53% yield
(Scheme 2, 4f-4g). However, α-alkylation of (p-bromophenyl)
acetonitrile 1h was quite slow and afforded 4h in 30% yield
(Scheme 2). Interestingly, when heterocyclic core, 1,3-
benzodioxole-5-acetonitrile 1i was used with 2a, the desired
product 4i was obtained in 80% yield (Scheme 2). Notably, more
challenging 3-phenylpropionitrile 1j, could be used under Ni-
catalysis and chemo-selectively transformed into the desired
branched nitrile derivative 4j in 50% yield; whereas, only a small
amount of 4k-4l were detected using GC-MS (Scheme 2). However,
under similar reaction conditions acetonitrile 1k, malononitrile 1l
and 1-pyrrolidineacetonitrile 1m, did not result any desired product
(Scheme 2, 4m-4o).
Notably, an in situ 1H-NMR and GC-MS analysis studies of the crude
reaction mixture using model reaction confirm the participation of
olefin intermediate 3a’ and formation of benzaldehyde 2a’
(Scheme 5e).
Next, we studied the scope of phenyl acetonitrile 1a with a series of
electronically different primary alcohols (Scheme 2). For instance,
benzylalcohols, 2b-2e, bearing p-methyl, p-ethyl, p-iso-propyl and
p-methoxy substituents resulted in up to 83% isolated yield of 3b-
3e (Scheme 2). Pleasingly, sterically hindered o-methyl benzyl
alcohol 2f and 1-naphthylmethanol 2m reacted efficiently with 1a,
3f and 3m were obtained in 67-87% yields respectively (Scheme 2).
Notably, halides substituted benzyl alcohols (F, Cl, and Br) 2g-2i,
efficiently participated for the alkylation process and transformed
into the functionalized secondary nitriles in 45-70% isolated yield
respectively without much effecting the sensitive halide groups
(Scheme 2, 3g-3i). Nevertheless, reactions with electron poor
Next, it was observed that, under the optimized reaction conditions
of Table 1, participations of alkyl alcohols are quite slow and
2 | J. Name., 2012, 00, 1-3
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therefore; we realized the potential role of the base for alkylation (Schemes 2-4). Importantly, the model reaction couldVbieewpAertricfloerOmnleinde
of alkyl alcohols. Therefore, when using NiCl2.dme (0.025 mmol) in in higher scale and resulted in up to 72% yield (SI Scheme 8).
DOI: 10.1039/D0CC02261F
combination with NaOH (0.25 mmol) as a base, the desired alkyl Notably, the catalytic protocol is highly chemo-selective and
substituted acetonitriles were obtained in up to 83% yield (Scheme tolerant to electronically different aryl, alkyl, methoxy, halides (F, Cl
3).
and Br), trifluoromethyl, di-oxolone including the pyridine and furan
moiety. Interestingly, allylic, cyclic and acyclic alkyl alcohols
including cyclopropyl methanol could be used for the alkylation
process. Remarkable chemo-selective transformations in the
presence of sensitive nitrile and reducible internal alkene as well as
intermediate synthesis of important pharmaceuticals highlight the
practical utility of the established protocol.
Scheme 3: Functionalization of nitriles using alkyl alcoholsa (see SI)
CN
NiCl2.dme/Phen
CN Alkyl
Ar
OH
Alkyl
Ar
NaOH
toluene, 140 °C, 36 h
2n-u
(1a,e,i,n)
5a-j, Isolated yield
CN
C4
CN
C6
CN
C4
MeO
O
5a
, 38%
5b
, 47%
C10
5e
5c
, 53%
O
Next, to interrogate the initial mechanistic studies for the process,
olefin intermediate 3a’ was independently prepared and employed
using standard conditions. 3a was obtained in 65% yield (Scheme
5a). Similarly, when 3a’ was employed with deuterated benzyl
alcohol 2a-d2 (92% D), we exhibited 43% yield to 3a-d2 along with
43-61% deuterium incorporation in both α and  position (Scheme
5a, SI Scheme S2). Additionally, to establish the participation of the
Ni-H species, we made an attempt to prepare the Ni-H species of
L1, unfortunately, it was not successful. Therefore, we choose
electron rich tricyclohexylphosphine and the Ni-H Species Cat.B-H
was radially prepared and employed using stoichiometric
equivalent with intermediate 3a’.10a Interestingly, 3a was obtained
in 51% yield when one equivalent of Cat.B-H was used. However,
application of two equivalent of Cat.B-H resulted almost
quantitative yield to 3a. These experiments strongly support the
participation of the Ni-H species and the Ni-catalyzed HB process
(Scheme 5b, SI Scheme S6). Next, alkylation of 1a with 2a-d1 did not
result any deuterium incorporation in 3a (Scheme 5ci).
MeO
CN
CN
CN
C7
5d
, 80%
, 65%
CN
5f
, 80%
MeO
CN
5h
, 52%
5g
, 83%
, 34%
MeO
from cinnamyl alcohol
CN
from citronellol
5j
, 47%
CN
5i
Importantly, more challenging C4–alkylation using n-butanol 2n
with 2-(3,4-dimethoxyphenyl)acetonitrile 1e, and 1,3-benzodioxole-
5-acetonitrile 1i, gave the desired products 5a-5b in up to 47% yield
respectively (Scheme 3). Similarly, long chain acyclic alkyl alcohols,
such as, C6, C7 and C10-alcohols, participated with 1a and resulted
5c-5e in up to 80% yield (Scheme 3). Pleasingly, cyclopropyl
methanol 2r and cyclohexyl methanol 2s, efficiently transformed in
to the branched nitriles 5f-5h in excellent yields (up to 83%, Scheme
3). Interestingly, more challenging alkyl alcohols having reducible
olefinic double bond, such as, cinnamyl alcohol 2t and renewable
terpenoid intermediate, citronellol 2u resulted the branched alkyl
nitriles 5i-5j in 34% and 47% yield respectively without much
affecting the internal double bond (Scheme 3). This remarkable
chemo-selective transformation of cinnamyl alcohol and citronellol
highlights the synthetic potential of the present protocol,
However, catalytic alkylation of 1a with 2a-d2 resulted 81% yield to
3a-d2 along with deuterium incorporated in both α and  position
(Scheme 5cii, SI Scheme S4). Further, alkylation of 1a with 2b and
2b-d2 were compared independently and found a value of PH/PD
=
1.6 (SI, Scheme S4). This KIE value shows that the rate of the
reaction depends on the breaking of the C−H bond of alcohol and
hence the oxidation of alcohol to aldehyde is the rate limiting step.
More specifically, breaking of C−D bond of alcohol is slower as
compared to the C−H bond. Further, a competition experiment
using 1a with 1:1 mixture of 2a and 2a-d2 gave 3a-d2 in moderate
yield with variable amount of deuterium incorporation (Scheme
5ciii, SI Scheme S3). Additionally, when 1a-d2 (97% D) was treated
with benzyl alcohol 2a, 3a-d2 was obtained in quantitative yield
following Ni-catalyzed micro-reversible H/D exchange process
(Scheme 5civ, SI Scheme S1). These experimental observations were
strongly support our hypotheses for the participation of benzylic
C-H/D bond of 1a and 2a for the alkylation process following
hydrogen borrowing strategy (Scheme 5a-c). In addition, a series of
control experiments using benzyl cyanide 1a with 4-methoxy
benzylalcohol 2e and 4-methoxy benzaldehyde 2e’ in the presence
and absence of Ni(acac)2/L1 were performed (Scheme 5d). Under
standard reaction conditions, condensation of 2e’ with 1a yielded
95% to 3e’. However, in absence of Ni(acac)2/L1 as well as K2CO3,
we did not observe any product. Notably, it also supports for the
key role of the Ni-catalyst for α-alkylation (Scheme 5d).
b) Applications to intermediates
of nitrile based drugs
a) Derivatization of 3a
NH2
Ph
ipr
CN
MeO
N
(i)
6, 40% Ph
MeO
MeO
O
NH2
Ph
5a
Verapamil
(antiarrhythmic
agent)
CN
3a
(ii)
7, 70%
MeO
Ph
Ph
Ph
O
Cl
CN
OH
O
(iii)
8, 61%
Ph
HN
N
N
Cl
F
Ph
Letrazuril, anti-HIV agent
O
Scheme 4. Synthetic applications and synthesis of intermediates of nitrile based drugs:
(i) LAH/THF, 0 oC, 15 h. (ii) H2O2/NaH/EtOH, reflux, 15 h. (iii) H2SO4/AcOH, H2O, reflux,
15 h.
After witnessing the key importance of these alkyl nitriles and its
derivatives in the fine chemical industries, we focused on the
synthetic modulation of the synthesized branched nitriles (Scheme
4, SI Scheme S7). Effective post product derivatization to primary
amine 6, secondary amide 7 and di-substituted acid 8 were
obtained from 3a following reduction using LiAlH4, oxidation using
inexpensive H2O2 and by acid hydrolysis. Remarkably, the
functionalized nitriles 5a and 1f could be useful for the
intermediate synthesis of the important pharmaceuticals verapamil,
used for antiarrhythmic agent, and anti-HIV agent letrazuril
Thereafter, a time conversion plot for α-alkylation of 1a with 2a was
monitored using GC and after
a certain periods of time,
intermediate 3a’ gradually hydrogenated to the 3a, whereas, 70%
product were obtained after 25 h. Notably, complete conversion
was obtained after 36 h. Again, kinetics studies were performed to
determine the rate and order of the alkylation of nitrile and we
observed first order kinetics. Finally, in situ 1H-NMR studies were
performed to detect the generation of water in the alkylation
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J. Name., 2013, 00, 1-3 | 3
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process (SI Schemes S9-S11). On the basis of these control The authors thank DAE-BRNS, India (Young Scientist Research
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experiments and mechanistic studies, a probable catalytic pathway Award to D. B., 37(2)/20/33/2016-BRNS). IIT Roorkee (SMILE-32)
DOI: 10.1039/D0CC02261F
for the Ni-catalyzed α-alkylation of nitrile with alcohols is presented and FIST-DST are gratefully acknowledging for instrument facilities.
in Scheme 5e. Primarily, a Ni-catalyzed dehydrogenation of alcohol S. B. thank INSPIRE (DST) and A. B. thank IIT-R for financial support.
gave aldehyde 2a’ via Ni-alkoxy species B following -hydride
elimination. Thereafter, condensation of aldehyde 2a’ with 1a
resulted the intermediate species 3a’, which subsequently
Conflicts of interest
There are no conflicts to declare.
Notes and references
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D. Xue, C. Li, J. Xiao and C. Wang, Chem. −Eur. J., 2017, 23, 14445; (l) M.
L. Buil, M. A. Esteruelas, J. Herrero, S. Izquierdo, I. M. Pastor and M. Yus,
ACS Catal., 2013, 3, 2072. (m) Z.-H. Zhu, Y. Li, Y.-B. Wang, Z.-G. Lan, X.
Zhu, X.-Q. Hao and M.-P. Song, Organometallics, 2019, 38, 2156.
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Wang, Chem.−Eur. J., 2018, 24, 13118; (b) A. Jana, B. C. Reddy and B.
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Roy, I. A. Ansari, S. A. Samim, and S. Kundu, Chem. Asian J. 2019, 14,
2215.
5a. Evidence for olefin intermediate and catalytic deuteration studies
CN
CN
standard conditions
Ph
Ph
Ph
Ph
OH
Ph
t-BuOK (50 mol%), 20 h
3a
CN
Ph
Ph
65% yield
2a
3a'
CN
(61%)
H/D
D
D
standard conditions
Ph
(43%)
Ph
t-BuOK (50 mol%), 20 h
Ph
OH
43% yield
3a'
3a-d2
D/H
2a-d2 (92% D)
5b. Evidence for participation of Ni-H species
CN
H
Cy3
P
H
CN
Ph
K2CO3 (0.029 mmol)
Ni
Ph
Ph
Br
PCy3
toluene d8, 140 °C, 36 h
3a
Ph
H
Cat B-H (0.058 mmol)
Cat B-H (0.116 mmol)
51% yield
3a' (0.058 mmol)
94 % yield
CN
5c. Parallel and competetive studies
standard conditions
t-BuOK (50 mol%), 20 h
84% yield
(i)
Ph
Ph
Ph
OD
Ph
CN
Ph
3a
2a-d1 (98% D)
1a
1a
CN
standard conditions
D
D
(18%)
H/D
Ph
Ph
CN
t-BuOK (50 mol%), 20 h
(ii)
Ph
OH
PH/PD = 1.6
81% yield
2a-d2 (92% D)
3a-d2
(40%)
Ph
D/H
CN
D
D
standard conditions
H/D (30%)
Ph
Ph
CN
2a
Ph
OH
t-BuOK (50 mol%), 20 h
(iii)
1a
44% yield
2a-d2 (92% D)
3a-d2
CN
D/H (85%)
Ph
D
D
standard conditions
Ph
OH
H/D (75%)
Ph
t-BuOK (50 mol%), 20 h
Ph
CN
2a
(iv)
1a-d2 (97% D)
5d. Control experiments
Ph CN
91% yield
D/H
3a-d2
1a
75%
1a
5% 0%
(66%)
3e
20% 5%
standard conditions
10 h
3e'
Base
Catalyst
Catalyst
Ar
OH
1a
2e
Ar
O
standard conditions
Ph
CN
3e
3e'
Base
2e'
OMe
1a
CN
18 h
95%
Ar= 4-OMePh
97% <2% 1%
80% 0% 17%
3e'
Ph
5e. Proposed catalytic cycle
Ph
CN
overall reaction
CN
1a
3a
R
[LnNi]
Ph
Ph
OH
2a
A
[LnNi-OBn]
hydrogenation
B
dehydrogenation
via -hydride elimination
(9) P. V. Ananikov, ACS Catal., 2015, 5, 1964.
CN
3a'
isolated
C
(10) (a) M. Vellakkaran, K. Singh and D. Banerjee, ACS Catal., 2017, 7,
8152; (b) K. Singh, M. Vellakkaran and D. Banerjee, Green Chem., 2018,
20, 2250; (c) J. Das, K. Singh, M. Vellakkaran, and D. Banerjee, Org. Lett.,
2018, 20, 5587; For recent selected examples using different metals,
see: (d) Z. Tan, H. Jiang and M. Zhang, Chem. Commun., 2016, 52, 9359;
(e) C.-S. Wang, T. Roisnel, P. H. Dixneuf and J.-F. Soule, Org. Lett., 2017,
19, 6720.
R
[LnNi-H]
Ph
isolated
detected by
GC-MS/1H-NMR
R
O
2a'
base
trapped using 2a-d2
H2
O
condensation
1a
detected using 1H-NMR
Scheme 5. Preliminary mechanistic studies and control experiments (See. SI).
In conclusion, herein we demonstrated the first Ni-catalyzed
chemo-selective alkylation of nitriles to a series of branched
products using primary alcohols. A simple and inexpensive Ni-
catalyst and 1,10-phenanthroline ligand enables to a vareity of
functionalized secondary nitriles in up to 90% yield. Alkyl, alkoxy,
halides (F, Cl, Br), trifluoromethyl, pyridine, furfural, dioxolone,
cyclopropyl group including allylic and unsaturated alcohols could
be used. Mechanistic studies using defined Ni-H species; deuterium
labelling, kinetics experiments and determination of the generation
of water were performed to establish the hydrogen borrowing
process and involvement of the benzylic C−H/D bond of alcohols.
4 | J. Name., 2012, 00, 1-3
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