Full text of DOI:10.1021/acscatal.7b04013

Research Article
pubs.acs.org/acscatalysis
Cite This: ACS Catal. 2018, 8, 2473−2478
Ruthenium-Catalyzed α‑Olefination of Nitriles Using Secondary
Alcohols
Subramanian Thiyagarajan and Chidambaram Gunanathan*
School of Chemical Sciences, National Institute of Science Education and Research, HBNI, Bhubaneswar 752050, India
S
* Supporting Information
ABSTRACT: Ruthenium(II) pincer-catalyzed α-olefination of
nitriles is reported. This simple protocol provides a trans-
formation for the catalytic synthesis of β-disubstituted vinyl
nitriles using secondary alcohols. This catalytic method has an
extensive substrate scope, as arylmethyl nitriles, heteroaryl-
methyl nitriles, and aliphatic nitriles as well as cyclic, acyclic,
symmetrical, and unsymmetrical secondary alcohols are all
employed in the reaction to provide diverse α-vinyl nitriles.
CC bond formation proceeds through activation of the O−H
bond of secondary alcohols via an unsaturated 16-electron intermediate ruthenium pincer complex and further condensation of
in situ-formed ketones with nitriles. Remarkably, H2 and H2O are the only byproducts of this method.
KEYWORDS: α-olefination, ruthenium, nitriles, alcohols, acceptorless dehydrogenation, green synthesis
Acceptorless dehydrogenation of alcohols12 and concomitant
condensation of the resulting carbonyl compounds with
INTRODUCTION
■
Construction of the CC bond is central to chemical
nucleophilic molecules afforded atom economical and sustain-
synthesis. While there are several available methods for
able chemical transformations.13,14 In this direction, employing
introducing an unsaturation intramolecularly into a substrate,
the borrowing hydrogen concept, attractive methods for the
methods for intermolecular olefin synthesis remain scarce. As
construction of C−C and C−N bonds were developed.13−15
researchers work strategically toward this goal, the Wittig
Recently, we have reported the ruthenium-catalyzed α-
reaction with its variants,1 Peterson olefination,2 and carbonyl
alkylation of arylmethyl nitriles using primary alcohols as
coupling reactions3 are employed via conventional methods.
alkylating reagents (Scheme 1b).16 Water is the only byproduct
However, these transformations, in general, require extensive
in this green and efficient alkylation reaction, which was
prefunctionalization of reactants and involve a stoichiometric
enabled by metal−ligand cooperation operative in Ru−pincer
amount of toxic reagents. Catalytic methods for the
complex 1, and the reactions proceeded via the borrowing
intermolecular olefin synthesis are limited to ruthenium-
hydrogen pathway. As a continuation of this work, we explored
catalyzed alkene metathesis4 and rhodium-catalyzed diazo
the coupling of secondary alcohols and nitriles, which delivered
coupling.5
the β-disubstituted vinyl nitriles (Scheme 1c). Remarkably,
and prevalent among natural products and pharmaceuticals.6
Scheme 1. Catalytic α-Olefination of Nitriles Using Alcohols
They serve as key building blocks and intermediates in number
Vinyl nitriles are important intermediates in organic synthesis
of chemical transformations. Notably, vinyl nitriles have found
applications in optoelectronic materials and in the synthesis of
light-emitting diodes.7 Conventional synthesis of vinyl nitriles
requires a stoichiometric amount of base, which mediates the
reaction of carbonyl compounds and nitriles (Knoevenagel
condensation).8 However, base-promoted condensation reac-
tions involving side reactions such as the aldol reaction, the
Cannizzaro reaction, and self-condensation of nitriles are
limited to the substrates that are not sensitive to the basic
conditions.8b,9 Thus, attractive alternative methods have been
devised for the condensation of carbonyl compounds and
nitriles to provide the vinyl nitriles. However, such methods
often require the use of toxic reagents and elongated synthetic
processes that lead to the generation of copious amounts of
waste and poor yields.10,11
Received: November 24, 2017
Revised: February 2, 2018
© XXXX American Chemical Society
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liberated H2 and water are the only byproducts from this green
catalytic method. To the best of our knowledge, secondary
alcohols were never utilized in the transition metal-catalyzed
acceptorless dehydrogenative coupling with nitriles to provide
vinyl nitriles. However, while this work was being prepared,
Milstein and Wang reported the manganese- and rhodium-
catalyzed α-olefination of nitriles by employing primary
alcohols (Scheme 1a).17
hindrance in the proximity. However, m- and p-methoxyphe-
nylacetonitrile provided 94% and quantitative conversions,
respectively, and the corresponding products 2d and 2e were
isolated in very good yields. Similarly, reactions with di- and
trimethoxy-substituted arylmethyl nitriles afforded the desired
olefin products 2f−2h in good to excellent yields. Notably, 4-
vinyl-substituted arylmethyl nitriles provided complete con-
version under standard experimental conditions, and the
corresponding product 2i was obtained in 72% yield. The
presence of an electron-withdrawing substituent on the aryl
ring was also tolerated. Reaction of 4-bromophenylacetonitrile
with cyclohexanol provided the α-olefinated product 2j in 70%
yield; however, complete conversion of nitrile required 24 h.
When we examined 1-naphthylacetonitrile under standard
experimental conditions, only 34% olefin product was isolated.
Thus, the catalyst load was increased to 2 mol %, which
provided the product 2k in 80% yield. A similar reactivity was
also observed with 2-naphthylacetonitrile (entry 12, Table 2).
In addition, a dinitrile such as 1,4-phenylenediacetonitrile was
tested for the olefination reaction using cyclohexanol, which
provided divinyl nitrile 2m in 48% yield. Despite the 99%
conversion of dinitrile, the observed low yield of the product
may be due to deleterious side reactions. Notably, hetero-
arylmethyl nitriles are also well tolerated in the olefination
reaction. When (pyridin-2-yl)acetonitrile was used, the α-
olefinated product 2n was isolated in 62% yield. Remarkably,
aliphatic nitriles were amenable to catalytic synthesis of vinyl
nitriles upon reaction with secondary alcohols. Reaction of 3-
phenylpropionitrile and nonanenitrile was evaluated, which
resulted in the corresponding vinyl nitrile products 2o and 2p
in 62% and 48% yields, respectively.
RESULTS AND DISCUSSION
■
At the outset, phenylacetonitrile, a slight excess of cyclohexanol
and ruthenium pincer catalyst 1 (1 mol %, Ru-MACHO) were
reacted in toluene. Although complete conversion of nitrile was
observed in 16 h, the desired olefin product 2a was isolated in
only moderate yields (entries 1 and 2, Table 1). Analysis of the
Table 1. Optimization of the Reaction Conditions for the α-
a
Olefination of Nitriles Catalyzed by 1
b
c
entry
alcohol (equiv)
time (h)
conv. (%)
yield (%)
1
2
3
1.05
1.2
2
16
16
10
24
24
24
24
>99
>99
>99
57
70
78
84
40
60
−
d
4
2
e
5
2
78
f
6
2
−
−
g
7
2
−
a
Reaction conditions: phenylacetonitrile (1 mmol), cyclohexanol (2
The scope of the secondary alcohols with respect to the
catalytic olefination using different nitriles was further
investigated. In general, a variety of secondary alcohols can
be employed under the reaction conditions to deliver α-
olefinated products in good to excellent yields (Table 3). When
4-methyl cyclohexanol was reacted with phenylacetonitrile and
2-(3,4,5-trimethoxyphenyl)acetonitrile, the corresponding ole-
fin products were obtained in 75% and 93% yields, respectively
(3a and 3b, respectively, Table 3). Similarly, 4-tert-butyl
cyclohexanol also exhibited very good reactivity. Remarkably,
the nitrogen-containing cyclic secondary alcohol, 1-phenethyl-
piperidin-4-ol, underwent olefination with 2-(3,4,5-
trimethoxyphenyl)acetonitrile to provide the product in 60%
isolated yield (3d). Cycloheptanol reacted with phenyl-
acetonitrile and 2-(4-methoxyphenyl)acetonitrile to provide
the corresponding products in 86% (3e) and 70% (3f) isolated
yields, respectively. A bulky cyclic alcohol such as cyclooctanol
provided the corresponding olefin product 3g in 46% yield with
a 2 mol % catalyst load; in addition, increasing the catalyst load
to 5 mol % enhanced the yield of 3g to 66%. A sterically
demanding substrate, 2-adamantanol delivered the α-olefinated
product 3h in 69% yield. Ultimately, an aliphatic secondary
alcohol such as 3-pentanol and 4-heptanol was subjected to
catalytic olefin synthesis, which provided the corresponding
vinyl nitriles 3i and 3j in 58% and 48% isolated yields,
respectively. Finally, unactivated unsymmetrical secondary
alcohols such as 2-butanol, 2-hexanol, and 2-heptanol were
investigated with different arylmethyl nitriles using catalyst 1 (5
mol %, 24 h), which provided vinyl nitrile products 3k−m as an
E/Z mixture in moderate yields. Overall, this protocol allows
rapid access to highly branched β-disubstituted vinyl nitriles
mmol), catalyst 1, base and toluene (1.5 mL) heated at 135 °C under
open conditions with an argon flow. Conversion of nitrile was
b
determined by gas chromatography (GC) using benzene as an internal
c
d
standard. Isolated yields after column chromatography. Using 0.5
e
f
mol % catalyst and 1 mol % base. Heated at 120 °C. Only 2 mol %
base was used. Reaction performed without catalyst and base.
g
1
reaction mixture using H nuclear magnetic resonance (NMR)
indicated the possible formation of aldol condensation products
resulting from the in situ-formed cyclohexanone intermediate.
However, contrary to the primary alcohol, no alkylation
product was observed.16 Thus, the catalytic olefination was
performed using 2 equiv of cyclohexanol, which resulted in
quantitative conversion of nitrile in 10 h, and the olefin product
was isolated in 84% yield (entry 3, Table 1). In addition,
decreasing the catalyst load from 1 to 0.5 mol % and the
temperature from 135 to 120 °C turned out to be detrimental
to the progress of the reaction as incomplete conversions were
observed even after 24 h (entries 4 and 5, respectively, Table
1). A control experiment using only a base and an experiment
without catalyst and base proved that the olefination requires a
catalyst (entries 6 and 7, respectively, Table 1).
Having established the optimum reaction conditions, we
examined the scope of the different nitriles with respect to the
catalytic olefination reaction using cyclohexanol (Table 2).
Reaction of cyclohexanol with 4-methyl phenylacetonitrile
afforded the corresponding olefin product 2b in 78% yield.
When 2-methoxy phenylacetonitrile was subjected to the
reaction under standard condition, a diminished conversion
(77%) and yield (2c, 72%) of the product were obtained,
indicating that the catalytic olefination is sensitive to steric
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a
Table 2. Ruthenium-Catalyzed α-Olefination of Nitriles Using Cyclohexanol
a
Reaction conditions: nitrile (1 mmol), cyclohexanol (2 mmol), toluene (1.5 mL), catalyst 1 (1 mol %), and KOtBu (2 mol %) heated at 135 °C
b
c
under open condition with an argon flow. Conversion of nitriles determined by GC using benzene as an internal standard. Isolated yields after
column chromatography. Using 2 mol % catalyst and 4 mol % base. Reaction time of 24 h. Reaction performed with 0.25 mmol of nitrile and 0.5
d
e
f
mmol of cyclohexanol using 3 mol % catalyst 1 and 6 mol % base.
from very simple and readily available starting materials with
liberated dihydrogen and water as the only byproducts.
increasing concentrations of product 2a (red line). While nearly
1.5 equiv of cyclohexanol (green line) was consumed in the
reaction, the intermediate cyclohexanone (magenta line) was
only short-lived as it undergoes rapid condensation with
phenylacetonitrile.
A plausible mechanism for the α-olefination of nitriles using
secondary alcohols catalyzed by 1 is depicted in Scheme 2. Our
previous work with catalyst 1 established facile O−H, N−H,
Mechanistic Investigations. GC monitoring of the
progress of the catalytic α-olefination reaction of phenyl-
acetonitrile using cyclohexanol catalyzed by 1 indicated that the
reaction follows first-order kinetics with respect to phenyl-
acetonitrile (Figure 1). Over time, decreasing the concentration
of phenylacetonitrile (black line) can be corroborated with
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a
Table 3. Ruthenium-Catalyzed α-Olefination of Nitriles Using Secondary Alcohols
a
Reaction conditions: nitrile (1 mmol), alcohol (2 mmol), toluene (1.5 mL) catalyst 1 (1 mol %), and KOtBu (2 mol %) heated at 135 °C under
open conditions with an argon flow. Reported yields correspond to isolated pure compounds. Conversion of nitriles is given within parentheses and
b
c
determined by GC analysis using benzene as an internal standard. Using 2 mol % catalyst 1 and 4 mol % base. Reaction performed with 0.25 mmol
d
e
of nitrile and 0.5 mmol of secondary alcohol using 5 mol % catalyst 1 and 10 mol % base. Reaction time of 24 h. Isolated as an E/Z mixture.
Scheme 2. Proposed Mechanism for the Ruthenium-
Catalyzed α-Olefination of Nitriles Using Secondary
Alcohols
Figure 1. Monitoring the progress of the reaction by GC.
Concentrations of phenylacetonitrile (black line), cyclohexanol
(green line), product 2a (red line), and the intermediate cyclo-
hexanone (magenta line) in the catalytic α-olefination of nitriles.
and spC−H bond activation reactions.16,18 Catalyst 1 reacts
with a base to generate a coordinatively unsaturated reactive
intermediate I (under similar conditions, the formation of I
from catalyst 1 in the reaction mixture was previously
established by us),18a which further reacts with secondary
alcohols to provide an alkoxy ligand-coordinated intermediate
II (such an alkoxy complex coordinated with benzyloxy ligand
was characterized in situ by us)18c upon O−H activation of
secondary alcohol.18c The amide donor present in unsaturated
intermediate I accepts the proton upon activation of the O−H
bond and becomes the amine donor in II. In concert with the
metal center, the ligand motif participates in bond formation
and bond breaking and hence displays metal−ligand cooper-
ation. At this point, a dehydrogenation reaction takes place by a
β-hydride elimination reaction (perhaps via decoordination of
one of the donor atoms), which releases the ketone and
generates a ruthenium dihydride complex III. However,
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CONCLUSION
■
In conclusion, we have presented an unprecedented transition
metal-catalyzed α-olefination of nitriles using secondary
alcohols, which resulted in β-disubstituted vinyl nitriles.
Notably, arylmethyl nitriles, heteroarylmethyl nitriles, and
aliphatic nitriles were amenable to this catalytic transformation.
Similarly, cyclic and acyclic secondary alcohols as well as
symmetrical and unsymmetrical secondary alcohols were also
employed in this reaction, which resulted in an assortment of α-
vinyl nitrile products. The acceptorless dehydrogenative
coupling of nitriles and alcohols proceeds via amine−amide
metal−ligand cooperation that occurs in the activated complex
of 1. Remarkably, dihydrogen and water are the only
byproducts in this catalytic olefination reaction, which make
this method highly attractive for the synthesis of different kinds
of fine and bulk chemicals.
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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.7b04013.
■
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K.; Mori, K.; Mizugaki, T.; Kaneda, K. Reconstructed Hydrotalcite as a
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Experimental procedures, spectral data, and copies of 1H
and 13C NMR spectra of the products (PDF)
AUTHOR INFORMATION
Corresponding Author
*E-mail: gunanathan@niser.ac.in.
ORCID
■
Chidambaram Gunanathan: 0000-0002-9458-5198
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank SERB New Delhi (EMR/2016/002517),
DAE, and NISER for financial support. S.T. thanks UGC for a
research fellowship.
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DOI: 10.1021/acscatal.7b04013
ACS Catal. 2018, 8, 2473−2478