Manganese-Catalyzed α-Olefination of Nitriles with Secondary Alcohols

Article abstract of DOI:10.1021/acscatal.9b02811

An expedient catalytic approach for α-olefination of nitriles using secondary alcohols with the liberation of molecular hydrogen and water as the only byproducts is reported. This reaction is catalyzed by a molecularly defined manganese(I) pincer complex and operates in the absence of any hydrogen acceptors. A broad range of substrates including cyclic, acyclic, and benzylic alcohols, as well as various nitrile derivatives, such as arylmethyl and heteroarylmethyl nitriles, are employed in the reaction to provide a diverse range of α-vinyl nitriles in good to excellent yields. Mechanistic studies showed that the reaction proceeds via dehydrogenative pathway and the activation of α(C-H) bond of the alcohol is the rate-determining step.

Full text of DOI:10.1021/acscatal.9b02811

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Article
Manganese Catalyzed #-Olefination of Nitriles with Secondary Alcohols
vinita yadav, Vinod G. Landge, Murugan Subaramanian, and Ekambaram Balaraman
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.9b02811 • Publication Date (Web): 06 Dec 2019
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ACS Catalysis
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Manganese Catalyzed α-Olefination of Nitriles with Secondary Alcohols
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Vinita Yadav,†,‡ Vinod G. Landge,† Murugan Subaramanian,¶ and Ekambaram Balaraman*¶
¶Department of Chemistry, Indian Institute of Science Education and Research (IISER) Tirupati, Tirupati – 517507, India.
†Organic Chemistry Division, Dr. Homi Bhabha Road, CSIR-National Chemical Laboratory (CSIR-NCL), Pune – 411008,
India.
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‡Academy of Scientific and Innovative Research (AcSIR), Ghaziabad – 201002, India.
ABSTRACT: An expedient catalytic approach for α-olefination of nitriles using secondary alcohols with the liberation of
molecular hydrogen and water as the only by-products is reported. This reaction is catalyzed by a molecularly defined manganese(I)
pincer complex and operates in the absence of any hydrogen acceptors. A broad range of substrates including cyclic, acyclic, and
benzylic alcohols as well as various nitrile derivatives such as arylmethyl and heteroarylmethyl nitriles are employed in the reaction
to provide diverse range of α-vinyl nitriles in good to excellent yields. Mechanistic studies showed that the reaction proceeds via
dehydrogenative pathway and the activation of α(C-H) bond of the alcohol is the rate determining step.
KEYWORDS: manganese, -olefination, alcohol, hydrogen, acceptorless dehydrogenation
In recent years, the transition-metal catalysis has emerged as one
of the most promising tools for C-C and C-N bond forming
reactions in synthetic chemistry as a result of its efficiency,
selectivity and versatility. Considering the major concern towards
the depletion of fossil fuels, the use of abundantly available
renewable resources is highly demanding.1 In this regard, catalytic
acceptorless dehydrogenative coupling (ADC)2 is highly
enlightened as an atom-economical and environmental benign
process. ADC approach is very attractive due to its operational
simplicity, the use of renewable resources based starting
materials, and the generation of water as the only stoichiometric
byproduct.
efficient synthesis of -unsaturated nitriles under mild reaction
conditions using simple, easily available substrates are highly
demanding.
The acceptorless dehydrogenation of renewable resource based
alcohols10 followed by condensation of the resultant carbonyl
compounds with nitriles can offer a sustainable and atom-
economical approach for the synthesis of vinyl nitriles with the
formation of dihydrogen and water.11 Employing this hydrogen
auto transfer (HA)2 concept, the α-olefination and α(C)-alkylation
of nitriles using primary alcohols were reported under noble
catalysis (Scheme 1).8e, f, 12-15
Previous works
The tri-, and tetra-substituted olefins are of great significance in
organic synthesis as well as in natural products and
pharmaceutical industries. The -substituted acrylonitriles are
the key building blocks and intermediates in numerous synthetic
transformations.3 Remarkably, they have found manifold
applications in the synthesis of high electron affinity polymers for
light emitting diodes (LED) and in optoelectronic materials.4
Various natural products and pharmaceuticals can be synthesized
based on the unsaturated nitrile functionality.5 For example,
entacapone (for Parkinson’s disease), CC-5079 (a potent
antitumor agent), lanoconazole, and luliconazole (antifungal
drugs) etc.5b The conventional synthesis of vinyl nitriles involving
condensation of aldehydes and arylacetonitriles using
stoichiometric or catalytic bases and is challenged by the side
reactions such as self-condensation of the nitriles, the aldol
reaction or the Cannizzaro reaction, and poor functional group
tolerance towards base.6, 7 With the progression of time, several
other methods for the condensation of carbonyl compounds and
nitriles have been devised. However, still the issues like the use of
toxic reagent, tedious synthetic procedure, poor yields and
generation of waste; limited the applicability of the classical
methods.8, 9 Hence, an alternative approach for the selective and
for primary alcohols
CN
CN
Ru, Rh, Os, Mn, Fe
base
R1
CN
R2
OH
R2
R2
or
R1
R1
for secondary alcohols
OH
CN
[Ru]
R1
CN
R1
base
-H2O, -H2
This work
Br
H
for secondary alcohols
N
PR2
CO
OH
CN
Mn
[Mn]
R1
CN
P
R1
base
-H2O, -H2
R2
CO
[Mn]
Scheme 1. Catalytic dehydrogenative coupling of nitriles with
alcohols.
Although noble metals has made tremendous advances in the field
of homogeneous catalysis, the earth-abundant first-row transition
metals are economical, globally available to obtain, essential to
life and thus often have less health and environmental impact as
compared to the precious metals.16,
17
Therefore, it is highly
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o
desired to surpass the reactivity and selectivity of the noble metal
based catalyst systems by finding the base metal based
alternatives.17 Being the third most abundant metal in the earth
crust, manganese can be a suitable substitute to the noble metal
catalysts.18 In 2017, research group of Milstein19 and Maji20
independently reported the manganese catalyzed α-olefination and
α-alkylation of nitriles using primary alcohols, respectively. Of
late, the research group of Xiao and Wang reported an iron(II)-
catalyzed α-alkylation of nitriles using primary alcohols as
alkylating agent.21a In 2019, El-Sepelgy and Rueping reported the
first manganese catalyzed α-alkylation of nitriles with primary
alcohols.21b Recently, base promoted α-alkylation was also
described by Kundu and co-workers.22 Further in 2019, the
research group of Poater and Wang independently performed the
computational studies on the α-olefination reaction of nitriles and
alcohols and gave the mechanistic insights into this important
reaction.23 Despite of the several available methods for the α-
olefination and α-alkylation of nitriles with primary alcohols,
methods based on secondary alcohols remain scarce. Recently,
Gunanathan et al. reported the pioneer work on ruthenium
catalyzed α-olefination of nitriles using secondary alcohols.24
Since, there are many potential benefits for studying catalysts
based on the earth abundant metals (Fe, Co, Mn, Ni) over the
noble metals (Ru, Rh, Ir, Os) in homogeneous catalysis and
chemical synthesis, the use of earth-abundant metals is highly
appreciated in catalytic transformations. To the best of our
knowledge, the base-metal catalyzed α-olefination of nitriles
using secondary alcohols is yet to be explored. Herein we report
an elegant method for the acceptorless dehydrogenative coupling
of nitriles and secondary alcohols to form vinyl nitriles with the
liberation of molecular hydrogen and water as the by-products.
product yield while decreasing the temperature (80 C) further
resulted in low yield of the product 3a.
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3
4
5
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7
8
Table 1. Optimization of the reaction conditions.a,b
CN
OH
[Mn]-1
(3 mol%)
CN
H2
KOtBu (30 mol%)
H2O
9
toluene,120 °C, 12 h
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60
1a
2a
3a
b
3a
(%)
Entry
deviation from above
alcohol (2.5 eq.),
Yield of
65 (99)c
1
2
[Mn]-1
(5 mol%), 16 h
alcohol (2.0 eq.),
85 (>99)c
Br
[Mn]-1
(3 mol%), 10 h
none
H
85 (>99)c
65 (90)c
50 (75)c
trace
N
PR2
3
Mn
[Mn]-2
4
5
6
CO
P
R2
CO
[Mn]-3
[Mn]-1,
R = phenyl
R = cyclohexyl
R = isopropyl
no catalyst
[Mn]-2,
[Mn]-3,
no KOtBu
trace
58
7
8
9
15 mol% KOtBu
NaOtBu, Cs2CO3, KOH as base
<50
<60
m-xylene, n-octane, 1,4-dioxane,
10
CH3CN as solvent
aReaction Conditions: phenyl acetonitrile 1a (0.5 mmol),
cyclohexanol 2a (1.0 mmol), catalyst [Mn]-1 (3 mol %), KOtBu
(30 mol %) and toluene solvent (1.5 mL) were heated at 120 °C
(oil-bath temperature) for 12 h under Ar atm. bYield of the
isolated product. cGC conversion of nitriles using mesitylene as an
internal standard.
Initially, we have started to optimize the reaction conditions using
phenylacetonitrile (1a) and cyclohexanol (2a) as the benchmark
substrates. Reaction of phenylacetonitrile (0.5 mmol) with
cyclohexanol (1.25 mmol, 2.5 eq.) using [Mn]-1 (5 mol %)
catalyst and KOtBu (30 mol %) in toluene solvent in a closed
system at 120 °C for 16 h resulted in the almost complete
conversion of nitrile with olefinic product in 65% isolated yield
(Table 1, entry 1). Inspite of the complete conversion, the desired
product yield was low. The 1H NMR analyses indicated the
formation of decent amount of -alkylated product (not
quantified) along with the aldol condensation product of the in
situ generated cyclohexanone. The gas phase GC analysis of the
reaction mixture indicated the liberation of H2 gas during the
reaction. Gratifyingly, with 2 eq. of alcohol and decrease in the
reaction time to 10 h resulted in complete conversion of nitrile
with 85% of the isolated olefinic product (Table 1, entry 2) and
only a trace amount of alkylated product was observed. A similar
outcome was obtained when 3 mol% of the catalyst was used after
12 h (Table 1, entry 3). Further varying the catalyst systems
[Mn]-2 and [Mn]-3 didn’t improve the yield of 3a (Table 1,
entries 4-5). Thus, the complex 1 found to be the efficient catalyst
for the catalytic olefination of nitriles with secondary alcohols. In
the absence of either of the catalyst system or the base, only trace
amount of the product was observed (Table 1, entries 6-7). Also,
the attempts to decrease the mol % of base ended up with the low
yield of the desired product (Table 1, entry 8). Changing the base
from KOtBu to either of NaOtBu, Cs2CO3, Na2CO3, KOH resulted
in lower yield of the desired product (Table 1, entry 9). Also the
solvent variation to m-xylene, n-octane or acetonitrile either ended
with low to moderate yield or with no desired product (Table 1,
entry 10). With increase in temperature, there was no effect in the
With the optimized reaction conditions, next we have examined
the structural diversity of nitriles using cyclohexanol as the model
substrate. As shown in table 2, the position as well as the nature of
the substituents on aromatic ring has remarkable effect on
the olefination reaction. The electron-donating substituents like
methyl, methoxy (Table 2, 1b to 1e) as well as the mild electron
withdrawing groups like halogens (Table 2, 1h to 1j) on either of
the meta or para position of phenylacetonitrile afforded good
yield of the olefinated product. Notably, the strong electron
withdrawing groups like trifluoromethyl, nitro (Table 2, 1l and
1n) on para position failed to give the desired product. This may
be the consequence of strong electron withdrawing
resonance/reverse hyperconjugation effect operating on para
position. Additionally, reaction with 3,5-di-methoxy (1f), 3,4-
methylene (1g) and 3,5-bis-trifluoromethyl (1m) substituted aryl
methyl nitriles provided the desired olefins in good to excellent
yields. The compatibility of the catalytic olefination reaction was
also examined with respect to the heteroaromatic nitriles. To our
delight, moderate yield of the corresponding olefinated product
was obtained with 2-thiophene nitrile and 3-pyridine nitrile (Table
2, products 3o in 47% and 3p in 64% yields). Indeed, 3-
phenylpropionitrile marks a sufficient decrease in the yield of the
corresponding 2-cyclohexylidene-3-phenylpropanenitrile product
(3q). The gas chromatographic analysis indicated 60% conversion
of starting material; however, 45% of the desired product was
observed. Aliphatic nitriles such as hexanenitrile and octanenitrile
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require 6 mol% of [Mn]-1 catalyst and 0.5 equivalent of a base to
provide the olefinated product in lower yields (Table 2,
products 3r in 35%, and 3s in 40% yields, respectively).
analyzed using GC and GC-MS. It was found that only 10% of the
1
2
3
4
5
6
7
8
desired product was formed. Later, under modified reaction
conditions, 20% yield of product 4p was obtained. The reaction
worked well with 1-phenyl-2-propanol and the desired -
olefinated product was obtained as E/Z mixture in 60% yield (4q).
Ultimately, a simple protocol for the synthesis of highly branched
vinyl nitriles from readily available starting materials with the
liberation of molecular hydrogen and water as the sole by
products is reported.
Table 2. Scope of manganese catalyzed -olefination of nitriles
with cyclohexanol.a,b
Br
Table 3. Scope of manganese catalyzed -olefination of nitriles
OH
CN
H
with secondary alcohols.a,b
9
[Mn]-1
(3 mol%)
N
PPh2
CO
R
R
CN
H2
KOtBu (30 mol%)
H2O
Mn
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Br
P
toluene,120 °C, 12 h
H
CN
Ph2
1
CO
2a
3
OH
R2
[Mn]-1
N
(3 mol %)
PPh2
CO
R2
CN
Mn
H2
KOtBu (30 mol%)
H2O
R
CN
CN
CN
CN
R1
R1
P
MeO
toluene,120 °C, 12 h
Me
Ph2
CO
1
2
4
Me
3c,
3d,
75%
81%
3b,
72%
3a,
85%
CN
CN
CN
CN
CN
CN
CN
CN
MeO
O
O
MeO
Cl
O
O
MeO
OMe
4a,
60%
4b,
4f,
4d,
85%
70%
CN
4c,
75%
CN
3g,
70%
3e,
3f,
84%
88%
3h,
65%
OMe
CN
CN
CN
CN
CN
CN
MeO
O
O
F3C
Cl
Br
F3C
OMe
3l,
0%
3k, 52%
4e,
4i,
88%
CN
3i,
3j,
68%
CN
60%
CN
70%
CN
4g,
80%
4h,
70%
CN
CN
CN
CN
MeO
F3C
O
S
N
O
O2N
3pc,
64%
3n,
3o,
47%
0%
3m,
OMe
50%
CF3
4j,
4k,
4l,
65%
70%
55%
50%
CN
CN
CN
CN
CN
CH3
CN
CN
3qd,
3rd,
3sd,
40%
45%
35%
4m,
4n,
62%
58%
4o,
50%
4pc,d
,
20%
CN
aReaction Conditions: nitrile 1 (0.5 mmol), cyclohexanol 2a (1.0
mmol), [Mn]-1 (3 mol %), KOtBu (30 mol %) and toluene solvent
CH3
b
(1.5 mL) were heated at 120 °C for 12 h under Ar atm. Yield of
c
4q,
60%
the isolated products after purification. The reaction was carried
d
aReaction Conditions: nitrile 1 (0.5 mmol), alcohol (1.0 mmol),
[Mn]-1 (3 mol %), KOtBu (30 mol%) and toluene solvent (1.5
out for 8 h. The reaction performed with [Mn]-1 (6 mol %) and
50 mol% of KOtBu.
b
mL) were heated at 120 °C for 12 h under Ar atm. Yield of the
Lately, the scope with respect to a wide variety of secondary
alcohols was investigated. Various cyclic as well as acyclic
secondary alcohols showed good to excellent reactivity under the
standard reaction conditions to deliver the desired α-olefinated
products (Table 3). When cyclopentanol was reacted with
phenylacetonitrile the corresponding α-olefinated product was
obtained in 60% yield (4a). Similarly, 4-trans-methyl
cyclohexanol also showed good reactivity with phenylacetonitrile,
c
isolated products after purification. The reaction performed with
[Mn]-1 (6 mol %) and 50 mol% of KOtBu. d20% of C(α)-
alkylated product was observed.
With the almost complete conversion in short period of time, the
Mn-catalyst has been proven to be an excellent catalyst for the
olefination reaction. In view of the activity of the catalyst, we
have performed kinetic experiments to gain detailed information
about the catalytic process. Monitoring the progress of the
reaction indicated that around 1.2 equivalent of cyclohexanol was
used for the reaction and the consumption of phenylacetonitrile
follows an exponential decay. The rate of product formation is
faster as 0.37 mmol of the -olefinated product was observed just
after the completion of 1 h. The intermediate cyclohexanone was
also detected in GC which was consumed in due course of the
reaction (Figure 1).
3,4-(methylenedioxy)phenylacetonitrile
and
(3,5-
dimethoxyphenyl)acetonitrile and afforded the corresponding α-
olefinated products in 70% (4b), 75% (4c) and 85% (4d) yields,
respectively. Interestingly, other cyclic secondary alcohols such as
cycloheptanol and cyclooctanol also provided good yield of the
desired products with differently substituted phenylacetonitriles
under the standard reaction conditions (Table 3, products 4e to
4j). A number of asymmetric aliphatic alcohols such as 2-butanol,
2-hexanol, and 3-hexanol were investigated under the given set of
conditions and it was observed that the corresponding olefinic
products were obtained in moderate yield as E/Z mixture (Table 3,
products 4k to 4m). Delightfully, symmetric acyclic alcohols such
as 3-pentanol and 4-heptanol afforded the desired olefinic
products in 62% (4n), and 50% (4o) yields, respectively. To check
whether this protocol works for aromatic secondary alcohols, we
have tried the reaction with 1-phenylethyl alcohol under the
optimal reaction conditions for 16 h and the reaction mixture was
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The rate of the reaction also increases with the initial
1
2
3
4
concentration of cyclohexanol (Figures 3 (A) and (B)). The
catalyst showed fractional order dependence for the -olefination
reaction (Figure 4 (A) and (B)). Considering the role of catalyst in
multiple steps during the reaction showed that the fractional order
with respect to catalyst might be rational.
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50
51
52
53
54
55
56
57
58
59
60
Figure 1. Kinetic profile of the Mn(I)-catalyzed α-olefination
reaction of phenyl acetonitrile (1a) with cyclohexanol (2a).
Further to understand the effect of each of the reaction
components on the -olefination reaction, the rate order was
determined using initial rate method. The order of reaction with
respect to phenylacetonitrile comes out to be around 0.97 which
indicated that the reaction is first order with respect to
phenylacetonitrile and it plays a crucial role in the -olefination
reaction as the rate of product formation increases with increase in
initial concentration of phenylacetonitrile (Figures 2 (A) and (B)).
Figure 3. (A) Concentration versus time plot at various
concentrations of (2a). (B) log(rate) versus log(conc.) graph of
(2a).
Figure 2. (A) Concentration versus time plot at various
concentrations of (1a). (B) log(rate) versus log(conc.) graph of
(1a).
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procedure25 which was later used for the -olefination reaction
(Scheme 2d).
1
a) Dehydrogenation
2
3
O
OH
[Mn]-1
(3 mol%)
H2
(99% GC conversion)
KOtBu (30 mol%)
4
5
toluene,120 °C, 12 h
2a'
2a
6
7
8
9
% conversion
Conditions
without cat
n.d
trace
without base
b) C-C bond formation
CN
O
[Mn]-1
(3 mol%)
KOtBu (30 mol%)
toluene,120 °C, 10 min
CN
10
11
12
13
14
15
16
17
18
19
20
21
22
23
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3a
, 54%
1a
2a
3a
Yield of
Conditions
[Mn]-1
without
58%
trace
without base
c) H2 detection
OH
[Mn]-1
(3 mol%)
CN
H2
KOtBu (30 mol%)
toluene,120 °C, 10 min
(identified by GC)
1a
2a
d) Deutrieum labelling
D (50%)
CN
OH
D (87%)
D (92%)
[Mn]-1
(3 mol%)
CN
KOtBu (30 mol%)
toluene,120 °C
2a-[D]
1a
kH / kD = 2.53
Scheme 2. Mechanistic studies.
The kinetic deuterium labeled experiment (Figure 5) indicated
that the dissociation of C-H bond of cyclohexanol might be the
moderately slow step in the reaction as the kH/kD ratio is 2.53.20
Figure 4. (A) Concentration versus time plot at various
concentrations of catalyst. (B) log(rate) versus log(conc.) graph of
catalyst.
To probe a plausible mechanism several control experiments were
carried out under the standard reaction conditions. Firstly, the
reaction of cyclohexanol under the standard conditions in the
absence of nitrile was carried out. The GC-MS analysis of the
crude mixture indicated the quantitative conversion of
cyclohexanol to cyclohexanone (Scheme 2a). Recent
computational studies by the research groups of Poater,23a and
Wang23b showed that dehydrogenation of alcohols to give
carbonyl compounds is energetically feasible. Indeed, the reaction
failed with base alone. Further, the condensation of 1a with 2a
under the standard reaction conditions was found to be fast and a
similar rate was observed for the KOtBu catalyzed reaction
(Scheme 2b). The observation is convincing in view of the free
base available in the system, because activation of the precatalyst
only consumes half the amount of base. Notably, the cubic
tetramer (KOtBu)4 based Knoevenagel condensation mechanism
suggested by Lu et al. might be operative.23b Thus, in addition to
the role as a catalyst activator, KOtBu can also play crucial role in
the coupling step. These results strongly indicate that the
manganese catalyst might not be involved in the C−C bond
formation step while it is playing a major role in the activation of
alcohols to give the corresponding ketones. Notably, the evolution
of molecular hydrogen was quantitatively analyzed by gas
chromatography (Scheme 2c). Further, the deuterium labeled
cyclohexanol was prepared using the literature reported
Figure 5. Time dependent formation of product 3a using
deuterium and normal cyclohexanol.
Next, we have performed competitive KIE to verify the kH/kD.
Thus, two parallel reactions using nitrile (0.256 mmol),
cyclohexanol (0.512 mmol) or cyclohexanol-D (0.512 mmol),
[Mn]-1 (3 mol%) and KOtBu (30 mol%) were performed under
standard conditions (see ESI). It was found that with cyclohexanol
and cyclohexanol-D the isolated yield of the product is 6.1 % and
14.3 %, respectively which indicates kH/kD = 2.34. Further, the
competition reaction was carried out using both cyclohexanol (2a)
and cyclohexanol-D (2a-[D]) together in a single screw cap
pressure tube and kept the reaction under standard conditions for
2 h. After isolating the product using column chromatography, the
KIE value was determined by NMR. It was found that 69% of the
non-deuterated product and 31% of the deuterated product formed
(see ESI). The KIE value is around 2.23. These results are in close
5
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Page 6 of 9
agreement with the already mentioned kH/kD value, and provide a
very strong support for the C–H cleavage being the RDS.20
ASSOCIATED CONTENT
Supporting Information
1
2
3
4
5
6
7
8
9
Based on experimental results and the previous literature reports,
a plausible catalytic cycle is depicted in Scheme 3. Initially, upon
treatment with base, the precatalyst generates the coordinatively
unsaturated reactive intermediate I. Further the O-H activation of
the alcohol via proton transfer to the amido nitrogen of
intermediate I, results in the formation of an alkoxy type
intermediate II. At this point, the dehydrogenation takes place via
the more likely base promoted -hydrogen abstraction instead of
the less probable -hydride elimination (as shown by Beller and
co-workers for -alkylation of ketones with primary alcohols).26
Thus, the intramolecular metal-ligand cooperation leads to ketone
and the manganese hydride complex III that further liberates
hydrogen gas to regenerate the catalytically active intermediate I.
Eventually, the Knoevenagel condensation between in situ
generated ketones and nitriles provides vinyl nitriles by
elimination of water molecule.
The Supporting Information is available free of charge on the
ACS Publications website.
Experimental procedures and spectral data for new compounds
(PDF).
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ACKNOWLEDGMENT
This work is supported by the SERB, India
(CRG/2018/002480). EB acknowledges CSIR-NCL, Pune
and IISER-Tirupati for analytical and infrastructure facilities.
VY and MS acknowledge UGC, India for fellowship.
Br
H
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In conclusion, we have reported an elegant example of base metal
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access diverse tri- or tetra-substituted vinyl nitriles. This
straightforward protocol applies to a wide range of alcohols and
nitriles. The use of earth-abundant manganese catalyst
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AUTHOR INFORMATION
Corresponding Author
* E-mail: eb.raman@iisertirupati.ac.in
Notes The authors declare no competing financial interest
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ACS Catalysis
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Table of content (TOC):
1
OH
CN
2
3
4
5
6
7
8
R
Br
cat. [Mn]
H
CN
cat. KOtBu
N
PPh2
CO
R
Mn
-H2, -H2O
OH
R2
CN
P
Ph2
CO
R1
R2
 Base-metal catalysis
 Efficient and Selective
 Mild conditions
R
R1
(36 examples)
 Wide substrate scope
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