Highly Regio- and Stereoselective Ni-Catalyzed Hydrocyanation of 1,3-Enynes

Article abstract of DOI:10.1002/chem.202000651

A highly regio- and stereoselective hydrocyanation of 1,3-enynes was implemented by nickel/diphosphine catalysts. A wide range of highly regio- and stereoselective alkenyl nitriles were efficiently prepared. In this transformation, both the tethered alken

Full text of DOI:10.1002/chem.202000651

Accepted Article
Accepted Article
Title: Highly Regio- and Stereoselective Ni-Catalyzed Hydrocyanation
of 1,3-Enynes
Authors: Feilong Sun, Jie Ni, Gui-Juan Cheng, and Xianjie Fang
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10.1002/chem.202000651
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Highly Regio- and Stereoselective Ni-Catalyzed Hydrocyanation
of 1,3-Enynes
Feilong Sun,[a]+Jie Ni,[b]+ Gui-Juan Cheng,*[b] and Xianjie Fang*[a]
[a]
F. Sun, Prof. Dr. X. Fang
Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, School of Chemistry and Chemical Engineering, Frontiers Science Center for
Transformative Molecules, Shanghai Jiao Tong University
800 Dongchuan Road, Shanghai 200240, P. R. China
E-mail: fangxj@sjtu.edu.cn
[b]
[+]
J. Ni, Prof.Dr.G.-J. Cheng
Warshel Institute for Computational Biology, School of Life and Health Sciences,
The Chinese University of Hong Kong (Shenzhen)
Shenzhen, 518172, P. R. China
These authors contributed equally to this work.
Supporting information for this article is given via a link at the end of the document.
Abstract:A highly regio- and stereoselectivehydrocyanation of 1,3-
enynes was implemented by nickel/diphosphine catalysts. A wide
range of highly regio- and stereoselective alkenyl nitriles were
efficiently prepared. In this transformation, both the tethered alkene
and the ligand play key roles in the reactivity and selectivity. The
origin of regioselectivity was understood preliminarily by DFT studies.
Alkenyl nitriles motifs are widely distributed in a large number
of molecules, such as pharmaceuticals[1b], agrochemicals[1c] and
functional materials[1d], occurring naturally or synthetically.[1] The
versatility of the cyano group enables the further transformation
to important functional groups such as aminomethyl, aldehyde,
and carboxylic acid.[2] Given the importance of vinyl nitriles as
privileged scaffolds in chemical industry, the development of
benign protocols for the construction of alkenyl nitriles has been
pursued intensively in chemical research. In this context, various
methods have been developed for the synthesis of alkenyl
nitriles.[3] The transition-metal-catalyzed addition of hydrogen
cyanide (HCN) to alkynes represents one of the most
straightforward strategies for their preparation.[3d-e] Recently,
Ritter and coworkers reported on a Rh-catalyzed hydrocyanation
of terminal alkynes using acetone cyanohydrin, affording the
anti-Markovnikov product as major product (Scheme 1a).[4] Soon
afterwards, Liu and coworkers developed an elegant catalytic
method for Markovnikov hydrocyanation of terminal alkynes with
less toxic Zn(CN)2 in CH3CN/H2O under Ni/Mn catalysis
(Scheme 1b).[5] However, in contrast with terminal alkynes,
Scheme 1.Transition-Metal-Catalyzed Hydrocyanation Reactions of Alkynes
Like alcohol, carbonyl or imine functional groups, alkenes are
used to controlregiochemistry or reactivity over similar functional
groups. Numerous alkene-affected transformations were
reported in the last decades.[11]In 2004, an intriguing example
was reported by Jamison, where tethered olefins are directing
the Ni-catalyzed addition on aldehydes over alkynes.[11e] The
effect of alkene was most obvious upon comparison with the
analogous substrate lacking the olefin. We were curious to
observe if alkene effect can be applied to the hydrocyanation of
alkynes. In 1989, Jackson reported ahydrocyanation example of
1,3-enyne using HCN, with 9:1 regioselectivity(Scheme
1d).[12]However, the hydrocyanationof aryl substituted1,3-enynes
has not been reported so far.
highly
regio-
and
stereoselectivehydrocyanation
of
unsymmetrical alkynes still remains challenging (Scheme 1c).
These methods suffer from the following drawbacks: (1) The
significant risks associated with the use of acetone cyanohydrin
as a source of highly toxic and volatile hydrogen cyanide.[6] (2)
The low regio- or stereoselectivity.[7] A neighboring functional
group such as silyl group is often used to control the selectivity
thanks to a large steric hindrance.[8] (3) The rather narrow
substrates scope.[7,8] The Perlmutter group reported a Ni-
catalyzed addition of HCN to internal alkynes.[9] Only three
substrates were reported, with tert-butyldimethylsilyl and
triphenylsilyl groups to control the selectivity. The recent
development of several HCN- or acetone cyanohydrin-free
strategies to realize hydrocyanationhightlights the importance of
such transformations.[10] However, these methods were rarely
extended to unsymmetrical internal alkynes except some limited
substrates containing silicon substituents.
Conversely to applications with HCN or acetone cyanohydrin,
applications with in situ-generated HCN from trimethylsilyl
cyanide (TMSCN) and protic additive such as water and acetic
acid has been well developed. For example, the recently
developed hydrocyanation of polar multiple bonds using a Lewis
1
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o
acid catalyst.[13]Similarly, commercially available TMSCN and
MeOH were alsousually used in the hydrocyanation of polar
multiple bonds, such as imine.[14] However, it was not
extensively studied in the hydrocyanation of carbon–
carbonunsaturatedbond.Schmalz and coworkers reported a Ni-
of Ni(cod)2 and Xantphos in MeOH at 80 C after 12 h (Table 1,
entry 1). The structure of 3a was confirmed by NOE analysis.
The use of 10 mol% Ni(cod)2 and 10 mol% Xantphos is essential
for the reaction to proceed (Table 1, entries 2 and 3). The ligand
effect was then investigated (Table 1, entries 4–12). We notably
observed an effect of the ligand on the reaction.[18e]The best
result was obtained with Xantphos as ligand (Table 1, entry
catalyzed hydrocyanation of vinylarene.[15] Nevertheless,
a
careful control of the MeOH and TMSCN concentration is
required. Moreover, alkynes easily undergo cyanosilylation with
TMSCN.[16] During the preparation of this manuscript, Arai and
1).This
phenomenon
was
similar with the alkene
hydrocyanationreaction, and the reason was stated that the
ligand could destabilize the Ni(II) species and stabilize the Ni(0)
complexes, thus the reductive eliminationand the overall
catalysis were enhanced.[18a-d]Alcohols were examined next, with
a decrease in yield observed when using either EtOH or t-BuOH
instead of MeOH (Table 1, entries 13–14). As low as 50
μLMeOH are required when toluene was employed as solvent
(Table 1, entry 15).
coworkers
reported
a
Ni-catalyzed,
tosyl-
affectedregioselectivehydrocyanation of terminal alkynes using
TMSCN and trifluoroethanol.[17]
Inspired by the elegant work on alkene-affected reactions, we
elaborated a strategy, whereby a transient interaction between a
conjugated alkene and a transition metal complex might achieve
highly regio- and stereoselectivehydrocyanation of internal
alkynes. Herein, we report the first nickel-catalyzed highly regio-
and stereoselectivehydrocyanation of 1,3-enynes using TMSCN
and MeOH.
a,b.c
Table 2.Alkenes Scope
Table 1. Reaction Optimization with Substrate 1a
entry
variation from standard conditonsa
none
yieldb(%)
88 (85)d
(3a:3a')c
1
> 20:1
2
3
without either Ni(cod)2 or Xantphos
with 5 mol% Ni(cod)2 and Xantphos
with 20 mol% PPh3
0
67
0
/
/
4
/
5
with 20 mol% P(OPh)3
with 20 mol% PCy3
0
/
6
0
/
7
with 20 mol% dppp
0
/
8
with 10 mol% dppb
0
/
9
with 10 mol% BINAP
with 10 mol%DPEphos
with 10 mol% dppf
0
/
7:1
[a] Reaction conditions: 1 (0.2 mmol, 1.0 equiv.), 2 (1.0 mmol, 5.0 equiv.), Ni(cod)2
(10 mol%), and Xantphos (10 mol%) in MeOH (1.0 mL) at 80 oC under N2 for 12 h.
[b] Isolated yields and the yields are reported as a mixture of isomers. [c] r.r. =
regioselectivities were determined by 1H NMRanalysis.
10
11
12
13
14
15
25
8
/
with 20 mol% CyJohnphos
EtOH instead of MeOH
t-BuOH instead of MeOH
Toluene instead of MeOHe
0
/
75
69
85
> 20:1
> 20:1
> 20:1
Upon the identification of viable reaction conditions, we
examined the effect of aryl groups. As depicted in Table 2, para-
substituents on the aryl ring are greatly influencing the
regioselectivity of internal alkynes. Methoxy, methyl and
hydrogen delivered the product with excellent selectivity and
yield (3a-c). Electron-withdrawing groups (3d-h) furnished the
product with moderate yield but with moderate to excellent
selectivity. 4-Cy, 4-OBn and 4-SMe groups could afford 3i-3k
with good yield and selectivity. Notably, 3-OMe and piperonyl
groups also gave product in >20:1 selectivity (3land 3o). 3,5-
Dimethoxy groups afford the product with better selectivity than
the 3,4,5-trimethoxy groups (3m and 3n). Sterically hindered 2-
naphthyl-substituted alkyne smoothly afforded nitrile 3p in 60%
yield albeit with low selectivity. The vinyl or internal alkynyl
groups remained intact in the cases of 3q and 3r, indicating that
[a]Reaction conditions: 1a (0.1 mmol), 2 (0.5 mmol, 5.0 equiv.) and MeOH
(0.5 mL) in the presence of Ni(cod)2 (10 mol%), Xantphos (10 mol%) at 80 oC
for 12 h. Xantphos: 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene, PPh3:
triphenylphosphine,
P(OPh)3:
triphenylphosphite,
PCy3:
tricyclohexylphosphine, dppp: 1,3-bis(diphenylphosphino)propane, dppb: 1,4-
bis(diphenylphosphino)butane, BINAP: (±)-2,2'-Bis(diphenylphosphino)-1,1'-
binaphthalene, DPEphos: bis(2-diphenylphosphinophenyl)ether, dppf: 1,1'-
bis(diphenylphosphino)ferrocene,
CyJohnphos:
(2-
biphenyl)dicyclohexylphosphine. [b] The yields were determined by GC
analysis using n-dodecane as the internal standard.[c] The ratios were
determined by 1H NMRanalysis. [d] Isolated yield. [e] 50 μl MeOH was added.
Initially, we explored the feasibility of our strategy by using a
series of internal alkynes directly linked to an alkene, namely
1,3-enyne, such as 1a (Table 1) and 3ah (Table 3) and their
reaction with TMSCN and MeOH under Ni catalysis. We
observed that the hydrocyanation of 1a proceeded smoothly to
afford 3a with high regioselectivity in 88% yield in the presence
the
reaction
is
highly
chemoselective.
Interestingly,
hydrocyanation of 1r gave 3r with chemo- and stereoselective
manner without any transformation of a TMSC≡C functionality.
This is in high contrast with the usually good reactivity and
2
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selectivity observed when a silyl group is directly connected to
the alkyne.Heterocyclic substituents such as furanyl and thienyl
groups found to be effective coupling partners to produce
thecorresponding products in good yield and regioselectivity (3s
and 3t).When the substrate has a methyl group instead of an
aryl group, a desired reaction occurred, giving product in 68%
yield with 3/1 regioselectivity (3w, the corresponding DFT
calculations are in agreement with the low regioselectivity
observed, see SI).The aromatic ring in this substrate is therefore
a key functionality allowing high regioselectivity.Conversely to
terminal alkene, internal alkene or carbonyl directing groups
exhibited no activity in theformation of the desired product (3u
and 3v).After extensive alkene groups examination, 4-OMe
substituted and non-substituted styrene exhibited the highest
selectivity and yield.
TMSCN and MeOH (Scheme 2a). To gain insight into the
reaction mechanism, deuterium labelling experiments were
carried out. As shown in Scheme 2, subjection of 1a and 2 to the
reaction conditions using CD3OH as solvent in lieu of CH3OH
resulted in 3a with no deuterium incorporation (Scheme 2b).
However, nearly 100% deuterium incorporation was observed
when using CH3OD as solvent instead, indicating that the proton
derives from the methanol O−H group and not from the C−H
bond of the alcohol (Scheme 2c).[19]
a,b.c
Table 3.Alkynes Scope
Scheme 2.Gram-scale and Deuterium-labelling Experiments
[a] Reaction conditions: 1 (0.2 mmol, 1.0 equiv.), 2 (1.0 mmol, 5.0 equiv.), Ni(cod)2
(10 mol%), and Xantphos (10 mol%) in MeOH (1.0 mL) at 80 oC under N2 for 12
h.[b] Isolated yields and the yields are reported as a mixture of isomers. [c] r.r. =
regioselectivities were determined by 1H NMRanalysis.
With the optimal reaction conditions and suitable directing
group in hand, we determined the alkynes scope and limitations
(Table 3). Alkyl substituents showed good selectivity and yield
(3x-y). Functional groups including aryl (3z-3aa), hydroxyl (3ab),
nitrile (3ac), amide (3ad), esters (3ae and 3ag), chloride (3af),
and ether (3ah) were well tolerated. With an aryl substituent, the
substrate 3ai was not tolerated under the reaction conditions. To
highlight the synthetic utility of this mild catalytic manifold, a
number of derivatives of naturally occurring and biologically
active molecules have been tested, including those derived from
L-menthol (3aj) and deoxylcholic acid (3ak). The desired
transformation occurred smoothly, furnishing the corresponding
nitriles with high selectivity and moderate to good yields.
Scheme 3. Proposed Catalytic Cycle for the Hydrocyanation of 1,3-Enynes
Based on the above observations and related literature, we
propose a plausible reaction mechanism (Scheme 3). The initial
step would be the oxidative addition of in situ generated HCN to
Ni(0). The resulting HNi(II)CN species would promote
hydronickelation to insert on the internal alkyne via syn-addition.
Then generated organometallic complex undergoes reductive
elimination to produce 3a and regenerates the Ni(0) catalyst. In
this step, the ligand Xantphos could destabilize the Ni(II) species
and stabilize the Ni(0) complexes, thus the reductive elimination
could be accelerated.[18a-d] We further conducted density
To demonstrate the practicality of the process, the reaction of
1a on 5 mmol scale was performed. Gratifyingly, 3a was
obtained in good yield(77%) by slightly modifying the loading of
3
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functional theory (DFT) calculation of this hydrocyanation
reaction to understand the origin of regioselectivity (Figure 1 and
SI). Computational results suggest that the irreversible insertion
step determines the regioselectivity (Figure S1 in SI) and TS1-a
is more stable than TS1-b by 4.4 kcal/mol (Figure 1), which is
consistent with the experimentally observed regioselectivity. The
electrostatic potential map (ESP) and NPA charges (Figure 2)
indicate that carbon b is more electron rich than carbon a and
thus suggest a favorable electrostatic interaction between
carbon b and Ni. However, the addition of carbon b to Ni brings
the alkene group to the close proximity of nitrile group (dN-H = 2.5
Å, dC-H = 2.4 Å) which leads to sever steric repulsion and
destabilizes TS1-b. By comparison, the alkyl group is farther
away from the nitrile group (dN-H = 3.0 Å, dC-H = 2.8 Å) in TS1-a
which avoids the repulsion and makes TS1-a more favorable.
FeilongSun and Xianjie Fang thank the Recruitment Program of
Global Experts and the startup funding from Shanghai Jiao Tong
University for financial support. Jie Ni and Gui-Juan Cheng
thank the National Natural Science Foundation of China
(21803047) for financial support.We thank Dr. BastienCacherat
(SIOC, Shanghai) for critical proofreading of this manuscript.We
also acknowledge Dr. LinlinWu(HKUST, Hong Kong)for the NBO
calculation.
Keywords:hydrocyanation • 1,3-enynes • alkene effect • nickel •
alkenyl nitriles
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In conclusion, the first nickel-catalyzed highly regio- and
stereoselective hydrocyanation of 1,3-enynes using TMSCN as
the cyanide source and MeOH as a hydrogen source was
reported. We found that both the tethered alkene andthe ligand
play key roles in the reactivity and selectivity in this reaction. A
wide range of highly regio- and stereoselective alkenyl nitriles
were efficiently prepared. Notably, the origin of regioselectivity
was understood preliminarily by DFT studies. This finding
provides new insight into metal-catalyzed hydrocyanation and
could lead to further applications including the synthesis of
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5
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Entry for the Table of Contents
A nickel-catalyzed highly regio- and stereoselectivehydrocyanation of 1,3-enynes has been developed.A wide range of alkenyl nitriles
were synthesized conveniently.
6
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