Facile Ruthenium(II)-Catalyzed α-Alkylation of Arylmethyl Nitriles Using Alcohols Enabled by Metal-Ligand Cooperation

Article abstract of DOI:10.1021/acscatal.7b01427

A facile ruthenium(II)-catalyzed α-alkylation of arylmethyl nitriles using alcohols is reported. The ruthenium pincer catalyst serves as an efficient catalyst for this atom-economical transformation that undergoes alkylation via borrowing hydrogen pathways, producing water as the only byproduct. Arylmethyl nitriles containing different substituents can be effectively alkylated using diverse primary alcohols. Notably, using ethanol and methanol as alkylating reagents, challenging ethylation and methylation of arylmethyl nitriles were performed. Secondary alcohols do not undergo alkylation reactions. Thus, phenylacetonitrile was chemoselectively alkylated using primary alcohols in the presence of secondary alcohols. Diols provided a mixture of products. When deuterium-labeled alcohol was used, the expected deuterium transposition occurred, providing both α-alkylation and α-deuteration of arylmethyl nitriles. Consumption of nitrile was monitored by GC, which indicated the involvement of first-order kinetics. Plausible mechanistic pathways are suggested on the basis of experimental evidence. The ruthenium catalyst reacts with base and generates an unsaturated intermediate, which further reacts with both nitriles and alcohols. While nitrile is transformed to enamine via [2 + 2] cycloaddition, alcohol is oxidized to aldehyde. The metal bound enamine adduct reacts with aldehyde via Michael addition, resulting in an ene-imine adduct, which perhaps undergoes direct hydrogenation by a Ru dihydride intermediate, produced from alcohol oxidation. However, in situ monitoring of the reaction mixture confirmed the presence of unsaturated vinyl nitrile in the reaction mixture in minor amounts (10%), indicating the possible dissociation of ene-imine adduct during the catalysis, which may further be hydrogenated to provide the α-alkylated nitriles. Overall, the efficient α-alkylation of nitriles using alcohols can be attributed to the amine-amide metal-ligand cooperation that is operative in the ruthenium pincer catalyst, which enables all of the catalytic intermediates to remain in the +2 oxidation state throughout the catalytic cycle.

Full text of DOI:10.1021/acscatal.7b01427

Research Article
pubs.acs.org/acscatalysis
Facile Ruthenium(II)-Catalyzed α‑Alkylation of Arylmethyl Nitriles
Using Alcohols Enabled by Metal−Ligand Cooperation
Subramanian Thiyagarajan and Chidambaram Gunanathan*
School of Chemical Sciences, National Institute of Science Education and Research, HBNI, Bhubaneswar 752050, India
S
* Supporting Information
ABSTRACT: A facile ruthenium(II)-catalyzed α-alkylation of
arylmethyl nitriles using alcohols is reported. The ruthenium
pincer catalyst serves as an efficient catalyst for this atom-
economical transformation that undergoes alkylation via
borrowing hydrogen pathways, producing water as the only
byproduct. Arylmethyl nitriles containing different substituents
can be effectively alkylated using diverse primary alcohols. Notably, using ethanol and methanol as alkylating reagents,
challenging ethylation and methylation of arylmethyl nitriles were performed. Secondary alcohols do not undergo alkylation
reactions. Thus, phenylacetonitrile was chemoselectively alkylated using primary alcohols in the presence of secondary alcohols.
Diols provided a mixture of products. When deuterium-labeled alcohol was used, the expected deuterium transposition occurred,
providing both α-alkylation and α-deuteration of arylmethyl nitriles. Consumption of nitrile was monitored by GC, which
indicated the involvement of first-order kinetics. Plausible mechanistic pathways are suggested on the basis of experimental
evidence. The ruthenium catalyst reacts with base and generates an unsaturated intermediate, which further reacts with both
nitriles and alcohols. While nitrile is transformed to enamine via [2 + 2] cycloaddition, alcohol is oxidized to aldehyde. The metal
bound enamine adduct reacts with aldehyde via Michael addition, resulting in an ene-imine adduct, which perhaps undergoes
direct hydrogenation by a Ru dihydride intermediate, produced from alcohol oxidation. However, in situ monitoring of the
reaction mixture confirmed the presence of unsaturated vinyl nitrile in the reaction mixture in minor amounts (10%), indicating
the possible dissociation of ene-imine adduct during the catalysis, which may further be hydrogenated to provide the α-alkylated
nitriles. Overall, the efficient α-alkylation of nitriles using alcohols can be attributed to the amine-amide metal−ligand
cooperation that is operative in the ruthenium pincer catalyst, which enables all of the catalytic intermediates to remain in the +2
oxidation state throughout the catalytic cycle.
KEYWORDS: alkylation, ruthenium, nitriles, alcohols, metal−ligand cooperation, borrowing hydrogen
Scheme 1. Selective Catalytic α-Alkylation of Arylmethyl
Nitriles Enabled by Borrowing Hydrogen Concept
INTRODUCTION
■
Alkylation reactions that can result in formation of C−C bonds
are important transformations in organic synthesis. Conven-
tional alkylation reactions involve toxic alkyl halides and the use
of a stoichiometric excess amount of base, which also produces
salt waste. Advancement in homogeneous catalysis and catalyst
design has led to the development of an alternative protocol for
alkylation reactions in which alcohols are used as alkylating
partners.1 These transformations are highly atom economical
and environmentally benign, as they release water as the only
byproduct. They are often referred to as “borrowing hydrogen”
and also as “hydrogen autotransfer” methods, as the catalytically
liberated hydrogen from the oxidation of alcohols is later
reinstalled in the unsaturated intermediates that form via
condensation reactions, resulting in redox neutral alkylation
reactions (Scheme 1).1,2
From this perspective, catalytic alkylation of nitriles using
alcohols has gained prominence, as nitriles serve as important
compounds from which a number of carboxylic derivatives can
be easily derived and widely used in the fine chemical industry
and also in the synthesis of biologically active compounds.3
Grigg and co-workers reported the pioneering ruthenium-
mediated α-alkylation of acetonitriles in 1981.4 Later,
iridium-5−7 and rhodium-based8,9 catalytic protocols were
developed for this transformation. Despite the well-known
Received: May 2, 2017
Revised: July 6, 2017
© XXXX American Chemical Society
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catalytic activity of ruthenium in borrowing hydrogen
strategies,1 its application in the α-alkylation of nitriles is
poorly documented. Kaneda and co-workers developed hydro-
talcite-supported ruthenium heterogeneous catalysts, which
required prolonged heating at high temperature (180 °C, 20−
30 h) in addition to the use of alkylating alcohols as solvents (2
mL alcohols for 1 mmol of nitriles).10 Ruthenium(II) half-
sandwich complexes developed for this transformation
exhibited poor catalytic activity and provided partial hydro-
genation, resulting in the presence of unsaturated vinyl nitrile
predominantly in the mixture of products.11 The Fukuyama and
Ryu group also reported the ruthenium-catalyzed alkylation of
acetonitrile using primary alcohols.12 Recently, the groups of
Esteruelas and Yus reported an osmium(II) half-sandwich
complex catalyzed alkylation of benzyl nitriles by benzyl
alcohols, which required removal of in situ formed water
using the Dean−Stark method.13 Invariably, in all of these
homogeneous catalytic reactions substoichiometric to stoichio-
metric excess amounts of various bases (20−110%) were also
used.
Table 1. Optimization of Reaction Conditions for the α-
Alkylation of Arylmethyl Nitriles
a
alcohol
(equiv)
conv
b
c
entry 1 (mol %) base (mol %)
(%)
yield (%)
1
2
3
4
5
6
7
8
9
1
2
5
>99
>99
80
98
98
78
72
78
98
90
76
1
2
2
d
1
2
2
1
2
1.2
1.5
2
80
1
2
83
0.5
0.3
0.1
1
>99
>99
88
e
e
f
0.6
0.2
1
2
2
2
f
10
2
a
Conditions unless specified otherwise: phenylacetonitrile (1 mmol),
The general problem in this method is the water, which is
formed in situ, that can effectively hydrolyze the unstable
intermediates to regenerate aldehydes. In addition, the
homogeneous catalyst should be compatible with water. The
chemoselectivity of the overall reaction also depends on the
efficient hydrogenation of vinyl nitriles. Due to these
challenges, in general, α-alkylated nitriles are still being
synthesized using alkyl halides with a stoichiometric excess
amount of base.14 Thus, an efficient catalyst for the α-alkylation
of arylmethyl nitriles is highly desirable. N−H activation of
amines and formyl C−H activation of DMF by ruthenium(II)
pincer complex 1 (Ru-MACHO) were established recently,
which were utilized in the catalytic synthesis of urea derivatives
using DMF as a CO surrogate.15 We have also disclosed the
highly efficient and selective deuteration of terminal alkynes,16
α- and α,β-deuteration of primary and secondary alcohols,17
upon using deuterium oxide, catalyzed by complex 1. In these
studies, we have established the sp-C−H activation of terminal
alkynes and O−H activation of alcohols and water by complex
1 upon deprotonation by a base. As our work confirmed that
complex 1 is very compatible with water, we envisage
employing complex 1 for the catalytic alkylation of nitriles
using alcohols. Herein we report the ruthenium pincer complex
[(PNPPh)RuHCl(CO)] (1; PNP = bis(2-(diphenylphosphino)-
ethyl)amine)18 catalyzed highly efficient α-alkylation of
arylmethyl nitriles using alcohols.
butanol (2 mmol), catalyst, base, and toluene (1.5 mL) were heated at
135 °C for 4 h under open conditions with a nitrogen flow.
b
Conversion of nitriles; determined by GC using mesitylene as an
c
internal standard. Isolated yields after column chromatography.
d
e
Heated at 110 °C. A minor amount of alkene formation was also
f
observed. Reaction performed up to 24 h.
(entry 2, Table 1). When the reaction temperature was reduced
to 110 °C, both the conversion and yield of this alkylation
reaction were decreased (80% and 78%, respectively, entry 3,
Table 1). Further, decreasing the amount of 1-butanol also
resulted in diminished conversion and yield of the product
(entries 4 and 5). When the catalyst load was lowered to 0.5
mol % with 2 equiv of 1-butanol, alkylation of phenyl-
acetonitrile provided quantitative conversion and a 98% yield of
the product after 4 h (entry 6). From the above conditions
(entry 6), further lowering of the catalyst loads (0.3 and 0.1
mol %) resulted in decreased yields (entries 7 and 8, Table 1).
Finally, when control experiments were carried out without
catalyst 1 in the presence of base (entry 9, Table 1) and in the
absence of both catalyst and base (entry 10, Table 1), no
product was found, implying that a catalyst is essential for
alkylation of nitriles using alcohols.
With the optimized conditions in hand, we examined the
reaction of an assortment of alcohols using phenylacetonitrile
(Table 2). In general, quantitative conversions occurred with a
low loading of catalyst 1 (0.5 mol %), leading to the efficient
oxidation of alcohols and subsequent C−C bond formation.
Use of the low-boiling alcohol 1-propanol (bp 97 °C) provided
2-phenylpentanenitrile in 91% yield (95% conversion, entry 1,
Table 2). Further, a series of nonactivated alcohols such as 1-
butanol, 1-pentanol, 1-hexanol, 1-heptanol, and 3-methyl-1-
butanol were reacted with 2-phenylacetonitrile. These alcohols
resulted in quantitative conversions and provided the
corresponding 2-phenylalkylnitriles in good isolated yields of
95−98% (entries 2−6, Table 2). Next we investigated the
reaction of electron-rich piperonyl alcohol, which also provided
quantitative conversion and a 95% yield of the alkylated
product (entry 7, Table 2). Linear alcohols appended with aryl
and heteroaryl ring systems provided excellent yields in general
with quantitative conversions (entries 8−11, Table 2);
however, (pyridin-2-yl)methanol provided only 66% conver-
sion and the alkylation product was obtained in 61% yield
RESULTS AND DISCUSSION
■
In a continuation of our efforts in the development of atom-
economical catalytic transformations using environmentally
benign ruthenium pincer complex catalyzed processes, we
envisaged developing a facile catalytic method for the alkylation
of arylmethyl nitriles using alcohols as alkylating partners. At
the outset of our work, phenylacetonitrile and 1-butanol were
selected as benchmark substrates to find the optimal reaction
conditions for the ruthenium pincer complex 1 catalyzed
alkylation reactions and the results are summarized in Table 1.
Thus, the reaction of 1 mol % of ruthenium pincer catalyst 1,
base (2 mol %), phenylacetonitrile (1 mmol), and 1-butanol (5
mmol) in toluene solvent at 135 °C (entry 1, Table 1) was
performed. The desired product of 2-phenylhexanenitrile was
isolated in 98% yield. A similar outcome was obtained when
only 2 equiv of alcohol (2 mmol) was used in the reaction
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Table 2. Ruthenium-Catalyzed α-Alkylation of
Phenylacetonitrile with Primary Alcohols
Table 3. Ruthenium-Catalyzed α-Alkylation of Arylmethyl
Nitriles with Primary Alcohols
a
a
a
Reaction conditions: phenylacetonitrile (1 mmol), alcohol (2 mmol),
toluene (1.5 mL), catalyst 1 (0.5 mol %), and KOtBu (1 mol %) were
b
heated at 135 °C under a flow of nitrogen for 4 h. Conversion of
nitrile; determined by GC using mesitylene as an internal standard.
c
Isolated yield after column chromatography.
(entry 10, Table 2). This low conversion and yield with
(pyridin-2-yl)methanol may be due to its chelation properties,
which perhaps diminish the catalyst reactivity.
Then, we explored the scope of different arylmethyl nitriles
in the catalytic α-alkylation reactions using different alcohols
(Table 3). Substrates bearing various electron-donating
substituents on the aryl ring of nitriles were well tolerated to
afford the α-alkylated nitriles in excellent yields. When (4-
methylphenyl)acetonitrile was reacted with 1-heptanol and 3-
(pyridin-2-yl)propanol in the presence of catalyst 1 (0.5 mol
%), quantitative conversion of nitrile was observed and the
corresponding α-alkylated products were obtained in excellent
yield and selectivity (entries 1 and 2, Table 3). Interestingly,
with use of only 2 equiv of 1-hexanol, 2-(4-aminophenyl)-
acetonitrile exhibited both α-alkylation and N-alkylation to
provide the dialkylated product in 97% yield with complete
selectivity (entry 3, Table 3), indicating facile catalytic N-
alkylation under these conditions. Benzylnitriles containing
mono-, di-, and trimethoxy substituents were reacted with
various alcohols (entries 4−12, Table 3). Apart from the
reaction of 3-methylbutanol with piperonyl nitrile (92%
conversion, 90% yield, entry 9, Table 3), quantitative
a
Reaction conditions: nitrile (1 mmol), alcohol (2 mmol), toluene
(1.5 mL), catalyst 1 (0.5 mol %), and KOtBu (1 mol %) were heated at
135 °C under a flow of nitrogen for 4 h. Conversion of nitriles;
determined by GC using mesitylene as an internal standard. Isolated
yield of products after column chromatography.
b
c
conversion of nitriles was observed with all of the substrates
and the corresponding α-alkylated benzylnitriles were isolated
in 96−98% yields. Notably, electron-withdrawing groups on the
benzene ring of arylmethyl nitriles slightly diminished the
reactivity. Thus, when 2-(4-bromophenyl)acetonitrile and 2-
(2,4-dichlorophenyl)acetonitrile were reacted with 1-butanol
and 1-hexanol, 92% and 85% conversions of nitriles were
observed and the corresponding α-alkylated products were
isolated in 90% and 82% yields, respectively (entries 13 and 14,
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Table 4. Ruthenium-Catalyzed α-Ethylation of Arylmethyl
Nitriles Using Ethanol
Table 5. Ruthenium-Catalyzed α-Methylation of Arylmethyl
Nitriles Using Methanol
a
a
a
Reaction conditions: nitrile (1 mmol), ethanol (5 mmol), toluene
(1.5 mL), catalyst 1 (2 mol %), and KOtBu (4 mol %) were heated at
135 °C under a flow of nitrogen for 4 h. Conversion of nitriles;
determined by GC using mesitylene as an internal standard. Isolated
b
c
yield of products after column chromatography.
Table 3). Unlike the reaction of (pyridin-2-yl)methanol (entry
10, Table 2), (pyridin-2-yl)acetonitrile was quantitatively
converted to provide the α-alkylated product in 96% yield
(entry 15, Table 3).
To extend the scope of alcohols employed in the ruthenium-
catalyzed α-alkylation of nitriles, ethanol and methanol were
investigated as potential primary alcohols. First, on the basis of
the optimized conditions, we performed the α-alkylation
reactions of different nitriles using 2 equiv of ethanol, which
provided the products in poor yields. Then we used 5 equiv of
ethanol, which provided efficient α-ethylation of all arylacetoni-
triles (entries 1−5, Table 4) and the corresponding ethylated
products were isolated in good yields.
Next, we investigated the challenging methylation of nitrile
compounds using methanol and the ruthenium catalyst 1. Due
to the lower boiling point and difficulty associated with the
oxidation of methanol, methylation reactions using methanol
have been rarely documented.19 In general, methylation is an
important transformation in chemical synthesis, which is
invariably achieved by using methyl iodide or toxic dimethyl
sulfate reagents.14 Reactions of various arylmethyl nitriles with
methanol (2 mL) and catalyst 1 (2.5 mol %) under the closed
conditions for a prolonged time (40 h) resulted in good
conversion and provided the corresponding methylated
products in moderate to good yields of 40−83% (Table 5).
Unlike the α-alkylation of long-chain alcohols, selectivity for
both α-ethylation and α-methylation of nitriles decreased to
some extent, perhaps due to the longer reaction time, resulting
in other side reactions.
a
Reaction conditions: nitrile (1 mmol), methanol (2 mL), catalyst 1
(2.5 mol %), and KOtBu (5 mol %) were heated for 40 h at 135 °C in
a sealed pressure tube. Conversion of nitrile; determined by GC using
toluene as an internal standard. Isolated yield of products after
column chromatography.
b
c
Such α-alkylation of arylmethyl nitriles occurs only with
primary alcohols. When secondary alcohols such as 1-
phenylethanol and cyclohexanol were employed as alkylating
partners under the optimized conditions, no alkylation products
were observed. Thus, chemoselective alkylation by primary
alcohols in the presence of secondary alcohols was explored.
Phenylacetonitrile (1 equiv) was reacted with 1-butanol and
cyclohexanol (each 2 equiv) in the presence of catalyst 1 (0.5
mol %) and KOtBu (1 mol %), and quantitative conversion of
nitrile was observed to provide the exclusive formation of 2-
phenylhexanenitrile (97% isolated yield, Scheme 2a). Cyclo-
hexanol remained unreacted and was recovered quantitatively
from column chromatographic purification of the reaction
mixture. Similar experiments using 3-pentanol also provided
almost identical results (Scheme 2b). When diols such as 1,3-
propanediol and 1,6-hexanediol were subjected to the alkylation
of phenylacetonitrile, a mixture of products was formed
(Scheme 2c). Diols having both primary and secondary alcohol
functionalities were also employed in the catalytic α-alkylation
of phenylacetonitrile. While no reaction was observed with 1,2-
propanediol, 1,3-butanediol provided a mixture of products.
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Scheme 2. Ruthenium-Catalyzed Chemoselective α-Alkylation of Phenylacetonitrile
Scheme 3. Ruthenium-Catalyzed Selective α-Alkylation of
Phenylacetonitrile Using a Labeled Alcohol
followed first-order kinetics with respect to consumption of
nitriles (Figure 1a). The formation of α-alkylated product and
1
an unsaturated intermediate were also observed in GC and H
NMR of the reaction mixture. 1H NMR analysis of the reaction
mixture showed a triplet signal at δ 6.75 ppm (J = 7.8 Hz),
indicating the formation of an olefin intermediate, whereas the
alkylated product displayed the characteristic doublet of
doublets at δ 3.69 ppm (J1 = 6.48 Hz, J2 = 1.8 Hz; see the
Supporting Information). The progress of the catalytic α-
alkylation reaction was rapid; almost 90% of the product
formation was observed in just 20 min by GC (Figure 1b),
while 10% of the unsaturated intermediate was present in
solution. Further completion of the α-alkylation reaction
occurred at a slow rate over a 4 h period.
The deuterium labeling experiment confirmed the expected
deuterium incorporation at the α-position of the alkylation
product. Upon reaction of phenylacetonitrile with piperonyl
alcohol-d3 catalyzed by 1 under the standard optimized
conditions, α-alkylated isotopomers C and D were obtained
in a 1:1 ratio, indicating that the dideuterium liberated upon
catalytic oxidation of piperonyl alcohol-d3 was predominantly
reinstalled in the unsaturated intermediate, which resulted from
the aldol condensation reaction. The incorporation of protons
in the labeling experiment indicated H/D exchange between
the pincer backbone ND/H2O and Ru-D/H2O (Scheme 3).17
On the basis of these observations and the experimental
studies involving catalyst 1 in our earlier work17 on selective
deuteration reactions, we propose the reaction mechanism for
the selective α-alkylation of arylmethyl nitriles depicted in
Scheme 4. The catalyst 1 displayed robust amine-amide metal
ligand cooperation, which made this green transformation
possible. Catalyst 1 underwent dechlorination and deprotona-
tion upon reaction with base to provide the 16-electron
unsaturated intermediate I. Intermediate I reacts with both
Figure 1. GC monitoring of the reaction progress of α-alkylation of
phenylacetonitrile catalyzed by 1 using 1-butanol: (a) conversion of 2-
phenylacetonitrile; (b) formation of α-alkylation product A and
unsaturated intermediate B in the reaction mixture.
Mechanistic Investigations. To understand the reaction
mechanism of the selective α-alkylation of arylmethyl nitriles
using alcohols catalyzed by complex 1, we have carried out in
situ monitoring of the reactions progress and labeling studies.
GC monitoring of the reactions progress for phenylacetonitrile
with 1-butanol catalyzed by 1 (0.5 mol %) confirmed the
complete conversion of nitrile substrate in 20 min. The reaction
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Scheme 4. Proposed Reaction Mechanism: (a) Selective α-Alkylation of Arylmethyl Nitriles Catalyzed by Ruthenium Pincer
Complex 1; (b) Coupling of in Situ Generated Enamine and Aldehyde Intermediates by Michael Addition; (c) Catalytic
Hydrogenation of Olefin Intermediates
alcohol and nitrile reactants. Reaction of I with nitrile leads to
the formation of 1,2-cycloadduct II involving the ruthenium
center and deprotonated amide backbone. Such a four-
membered metallacyclic intermediate containing ruthenium
has precedence in the alkene metathesis process by the Grubbs
catalyst.20,21 The imine intermediate II tautomerizes to become
enamine form III, and these are in equilibrium (Scheme 4a).
The unsaturated intermediate I also reacts with alcohol to
provide alkoxy-ligated complex IV, which resulted from the O−
H activation of alcohols.17 Further, β-hydride elimination of
ruthenium-ligated alkoxy ligand on intermediate IV provides
the corresponding aldehydes and Ru dihydride complex V. A
Michael addition of ruthenium enamine adduct III over the in
situ formed aldehyde generates the intermediate VI. The
detailed mechanism of this Michael addition and subsequent
water elimination, perhaps assisted by base, is delineated in
Scheme 4b. Intermediate VI, resulting from the condensation
of enamine and aldehydes, reacts directly with ruthenium
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dihydride V to deliver the selective α-alkylated products with
regeneration of the catalytically active unsaturated intermediate
I. Rapid formation of the α-alkylated product as shown in
Figure 1b suggests that this pathway is predominantly
operative. However, formation of a minor amount of vinyl
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CONCLUSION
■
In summary, we have demonstrated facile ruthenium-catalyzed
α-alkylation of arylmethyl nitriles using alcohols as alkylating
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acscatal.7b01427.
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AUTHOR INFORMATION
Corresponding Author
*E-mail for C.G.: gunanathan@niser.ac.in.
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ORCID
Chidambaram Gunanathan: 0000-0002-9458-5198
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
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thank Prof. S. Muthusamy for his kind help in recording IR
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