Ligand-Controlled Regiodivergent Nickel-Catalyzed Hydrocyanation of Silyl-Substituted 1,3-Diynes

Article abstract of DOI:10.1021/acs.orglett.1c01262

A regiodivergent nickel-catalyzed hydrocyanation of 1-aryl-4-silyl-1,3-diynes is reported. When appropriate bisphosphine and phosphine-phosphite ligands are applied, the same starting materials can be converted into two different enynyl nitriles with good

Full text of DOI:10.1021/acs.orglett.1c01262

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Letter
Ligand-Controlled Regiodivergent Nickel-Catalyzed Hydrocyanation
of Silyl-Substituted 1,3-Diynes
Feilong Sun,§ Chengxi Yang,§ Jie Ni, Gui-Juan Cheng,* and Xianjie Fang*
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ABSTRACT: A regiodivergent nickel-catalyzed hydrocyanation of
1-aryl-4-silyl-1,3-diynes is reported. When appropriate bisphos-
phine and phosphine−phosphite ligands are applied, the same
starting materials can be converted into two different enynyl
nitriles with good yields and high regioselectivities. The DFT
calculations unveiled that the structural features of different ligands
bring divergent alkyne insertion modes, which in turn lead to
different regioselectivities. Moreover, the synthetic value of the
cyano-containing 1,3-enynes has been demonstrated with several downstream transformations.
1,3-Enynes are prominent structural motifs that are often
found in many bioactive molecules and organic materials.1 The
1,3-enyne scaffold is also a versatile building block in synthetic
organic chemistry.2 Of note, 1,3-enynes with electron-with-
drawing groups (i.e., esters, ketones) are particularly attractive
as they bear the potential to be employed in the construction
of thiophenes,3 isoxazoles,4 furans,5 pyrrolines,6 allenes,7 1,3-
dienes,8 and many others. Among these active 1,3-enynes, the
use of cyano-substituted ones was rarely reported, although
particularly useful in annulation reactions. Indeed, cyano-
substituted 1,3-enynes enable the preparation of pharmaceuti-
cally interesting cyano-containing heterocycles.9 Obviously, the
lack of efficient synthetic methods for cyano-containing 1,3-
enynes restricts their potential applications.10 It is therefore of
high interest to develop efficient, highly regio- and stereo-
selective synthesis of cyano-containing 1,3-enynes.
Recently, the transition-metal-catalyzed functionalization of
1,3-diynes has attracted increasing attention.11 In the view of
atom-efficient organic synthesis, the hydrofunctionalization of
1,3-diynes paved a new avenue for accessing functionalized 1,3-
enynes. Based on our continuous interest in catalytic
hydrocyanation of unsymmetrical internal alkynes,12 we
envisioned that the hydrocyanation of 1-aryl-4-silyl-1,3-diynes
(silyl activated 1,3-diynes) might be an efficient approach for
the synthesis of cyano-substituted conjugated enynes because
1-aryl-4-silyl-1,3-diynes were readily available via Glaser
coupling. The corresponding products could be easily derived
through desilylation. In sharp contrast to the hydrocyanation
of alkynes,13 the hydrocyanation of 1,3-diynes still remains
elusive in the literature due to the intractable challenges in
regio- and stereoselectivity control for unsymmetrical internal
alkynes. Until now, only a limited number of special
unsymmetrical internal alkynes have been hydrocyanated
with high regio- and stereoselectivity.14 Obviously, the
hydrofunctionalization of unsymmetrical 1-aryl-4-silyl-1,3-
diynes would pose extra difficulties in regard to monoalkynes:
(a) Regioselectivity between two alkyne motifs (Scheme 1a,
A);11a,b,e (b) regioselectivity in each migratory insertion
(Scheme 1a, B),11d (c) selectivity between mono- and
dihydrofunctionalization (Scheme 1a, C),11c and (d) stereo-
selectivity in each migratory insertion (Scheme 1a, D).
Despite the lack of examples involving the hydrocyanation of
1-aryl-4-silyl-1,3-diynes, significant advancements in the hydro-
functionalization of 1-aryl-4-silyl-1,3-diynes have been made
over the past few decades. These hydrofunctionalizations
usually occurred at one alkyne of the unsymmetrical 1,3-diynes
with high regioselectivity (Scheme 1b). For example, hydro-
amidation,11a hydroesterification,11b hydroboration,11f and
hydrosilylation,11e of 1-aryl-4-silyl-1,3-diynes preferentially
took place at the 1,2-CC (Scheme 1b, left). Furthermore,
the Ge group reported a regiodivergent hydroboration of 1-
aryl-4-silyl-1,3-diynes in which the 1,2-CC bond inserted
into either a cobalt−hydride or cobalt−boryl intermediate
(Scheme 1b, left).11d To the best of our knowledge, the only
example concerning the selective hydrofunctionalization of the
3,4-CC bond of 1-aryl-4-silyl-1,3-diynes was reported by
Krische and co-workers wherein α-hydroxy esters were
constructed, and the reaction occurred exclusively at the
silyl-substituted CC bond (Scheme 1b, right).11g However,
the regiodivergent hydrofunctionalization of aryl-/silyl-sub-
stituted 1,3-diynes is an alluring but rather demanding task,
which may offer new tools for the construction of more
Received: April 14, 2021
Published: May 12, 2021
https://doi.org/10.1021/acs.orglett.1c01262
© 2021 American Chemical Society
Org. Lett. 2021, 23, 4045−4050
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a b
,
Scheme 1. Hydrofunctionalization of 1,3-Diynes
Table 1. Reaction Optimization with Substrate 1a
c
d
e
entry
ligand
/
conv. 1a/%
3a/4a
major product/%
1
2
3
4
5
6
trace
19
100
75
/
/
h
L1
L2
N.D.
N.D.
N.D.
N.D.
36
h
L3
L4
L5
L5
L6
L7
L8
72/12
78/22
88/12
94/6
92/8
91/9
/
N.D.
46/40
27/73
15/85
/
50
21
100
100
100
100
trace
35
100
100
85
43
93(91)
g
f
7
g
8
g
81
76
/
9
g
10
h
11
L9
N.D.
42
36
42
/
complex molecules with high skeletal diversities.15 We herein
describe a complementary strategy for the hydrofunctionaliza-
tion of 1,3-diynes by showing that an appropriate ligand could
help to control the regiodivergent hydrocyanation of 1-aryl-4-
silyl-1,3-diynes (Scheme 1c).
12
13
14
15
16
L10
L11
L12
L13
L14
trace
95
f
3/97
63(61)
With the aforementioned in mind, we commenced our study
by investigating 1-phenyl-4-trimethylsilyl-butadiyne (1a), with
acetone cyanohydrin 2 to identify reliable conditions for 1,3-
diyne hydrocyanation. We first performed the reaction using
Ni(cod)2 and monophosphine ligands in toluene at 100 °C.
The application of L1 proved to be futile, with only 19%
conversion of 1a (Table 1, entry 2). L2 could also not afford
the hydrocyanation product, albeit with 100% conversion of 1a
(Table 1, entry 3). In the cases of L1 and L2, fluorescent
products were formed which might be attributed to the
oligomerization/polymerization of 1a.11a Next, various bi-
sphosphine ligands were evaluated (Table 1, entries 4−6).
After extensive screening, we found that 1a could be fully
converted to the monohydrocyanation product 3a using L5
(Table 1, entry 6). In order to further improve the reaction, we
evaluated the influence of critical reaction parameters. We
found that 1a could react with 2 to afford the monohydrocya-
nation product 3a in 93% GC yield with excellent selectivity in
the presence of L5 at 50 °C (Table 1, entry 7). A slight tuning
in the ligand environment would decrease the reaction
efficiency (Table 1, entries 8−10). We also examined the
effects of the phosphite ligands on the reaction efficiency. For
monodentate phosphite ligand L9, 35% of 1a was consumed
without any formation of the hydrocyanation product.
Although using bisphosphite ligands led to unsatisfactory 3a/
4a (Table 1, entries 12 and 13), an obvious enhancement in
the selectivity toward 4a was observed. These promising results
a
Reaction conditions (entries: 1−13): 1a (0.1 mmol), Ni(cod)2 (7.5
mol %), ligand (7.5 mol %), 2 (0.3 mmol), toluene (0.5 mL), 100 °C,
b
18 h. Reaction conditions (entries: 14−16): 1a (0.1 mmol),
Ni(cod)2 (12.5 mol %), ligand (25 mol %), 2 (0.3 mmol), toluene
c
(0.5 mL), 100 °C, 14 h. Conversion of 1a was determined by GC
analysis using n-dodecane as the internal standard. The ratio of 3a to
4a was determined by GC and GC-MS analysis (for more details, see
Supporting Information). Yield refers to the major product and is
d
e
determined by GC analysis using n-dodecane as the internal standard.
f
g
h
Isolated yield. The reaction was carried out at 50 °C. Ligand (15
mol %). N.D. = no detected. L1 = PPh3, L2 = PCy3, L3 = Xantphos,
L4 = dppp, L9 = P(OPh)3.
encouraged us to divert to the regioselectivity. Next, we turned
our attention to the phosphine−phosphite ligand. To our
delight, 4a could be obtained as a major product in 85:15
selectivity with L12 (Table 1, entry 14). Further ligand
screening revealed that (Sax,S,S)-Bobphos L1416 could afford
4a with good yield and excellent selectivity at 100 °C (Table 1,
entry 16). It is noteworthy that synthetic methods for
constructing enynyl silanes like 4a were continuously refined.17
Eventually, a regiodivergent condition on nickel-catalyzed
hydrocyanation of 1-aryl-4-silyl-1,3-diynes was identified.
With the optimized conditions for efficient switch between
two alkyne sites in hand, we set out to explore the generalities
of substrates of this divergent transformation. As shown in
Scheme 2, aryl-substituted 1,3-diynes, including electron-rich,
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a
Scheme 2. Substrate Scope
a
Condition A as Table 1, entry 7. Reactions performed on a 0.2 mmol scale. Condition B as Table 1, entry 16. Reactions performed on a 0.15
mmol scale. Unless with footnote, r.r. = the ratios of 3 to 4, and it was determined by GC and GC-MS analysis. Yield refers to the isolated major
b
c
d
product. Ni(cod)2 (10 mol %), L5 (10 mol %), 24 h. Ni(cod)2 (15 mol %), L14 (30 mol %). The ratios of 3 to 4 were determined by NMR
e
f
g
analysis. The ratio of total monohydrocyanation products to 4 was determined by NMR analysis. Ni(cod)2 (15 mol %) and L12 (30 mol %). 70
°C.
-neutral, and -deficient functional groups, were well tolerated
under condition A (3a−3m). Compared with 3, the yield and
selectivity of 4 were slightly affected by the substituents (4a−
4m). Electron-rich substrates could be smoothly converted to
the corresponding product. For electron-deficient substrates,
slight fine-tuning of the condition B was required to enhance
the reactivity and selectivity. Moreover, using an electron-
withdrawing group such as a carbonyl or ester group, the
corresponding product 4 was obtained with poor selectivity
because at least three monohydrocyanation products were
generated (4k and 4l). The vinyl (1n) and internal alkynyl
(1o) groups, which would otherwise react under Ni-catalyzed
hydrocyanations,13,18 remained untouched under both con-
dition A and B. The naphthyl-substituted 1,3-diyne was also
tolerated (1p). 1,3-Enynes bearing oxygen- (1q and 1r),
nitrogen- (1s−1u), and sulfur-containing (1x) heteroaryl
substituents also produced the corresponding products in
high yield and selectivity. It is worth mentioning that electron-
deficient pyridyl-substituted 1,3-diyne 1v was exclusively
tolerated under condition A. Due to the strong electron-
donating and electron-withdrawing effects of the substrate, the
products 3b and 4h were indicated as traces amounts. To
further demonstrate the synthetic applications of this reaction,
the estrone-derived diyne (1y) was subjected to our protocol,
leading to 3y and 4y in 80% and 51% yield, respectively.
Instead of a trimethylsilyl group, a dimethylphenylsilyl group
was also well tolerated under both conditions. When alkyl- or
TMS-substituted 1,3-diynes were employed, almost no
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reaction was observed. This phenomenon might be attributable
to the lack of p-π hyperconjugative effect. Remarkably, 1b, 1s,
and 1u could all be converted to the corresponding product 4
with good yield and excellent selectivity when L12 was used
instead of L14.
To highlight the utility of this Ni-catalyzed hydrocyanation
reaction, we conducted a gram-scale reaction of 1c and acetone
cyanohydrin 2, and this reaction yielded enynyl nitrile 3c in
85% isolated yield with excellent selectivity (Scheme 3). We
cyanohydrin 2, and this reaction yielded enynyl nitrile 4a in
54% isolated yield with excellent selectivity. Treatment of the
divergent product 4a with 2-acetamidomalonate and DBU
provided the 2,3-dihydro-1H-pyrroles 11 in 86% yield.
This divergent transformation displayed a remarkable
selectivity that encouraged us to elucidate the reaction
mechanism. First, we checked whether the Bobphos ligand
was a monodentate or bidentate ligand with nickel, although it
has been proved to coordinate as a bidentate ligand with either
rhodium or palladium.16b The reaction between Ni(cod)2 and
Bobphos (2.0 equiv) in toluene-d8 was monitored by 31P NMR
at room temperature. Compared with the 31P peaks of
Bobphos (8.6 and 125.8 ppm), two new peaks were observed
at 177.5 ppm (d, J = 124 Hz) and 66.0 ppm (d, J = 128 Hz)
with two doublets (for more details, see the Supporting
Information). These signals suggested that the Bobphos ligand
may be a bidentate ligand with nickel in the reaction. To
further understand the induced selectivity, we conducted
density functional theory (DFT) calculations for this
regiodivergent hydrocyanation reaction.20 DFT calculations
(for more details, see the Supporting Information) suggested
that the anti-geometry of the [H−Ni(Dppf)−CN] complex
preferentially inserted at 1,2-CC, while the syn-geometry of
the [H−Ni(Bobphos)−CN] complex (to reduce the cost of
DFT calculations, L12 was used) inserted at 3,4-CC, thus
tuning the regioselectivity (Figure 1). The proposed
mechanism was also shown in the Supporting Information.
Scheme 3. Gram-Scale Synthesis of 3c and Diverse
a
Transformations of Enynyl Nitrile Proucts
a
(i) DIBAL-H, toluene, −78°C, 3 h; (ii) cyclohexanone, pyrrolidine,
InCl3, 4 Å molecular sieves, DCE, 80 °C, 20 h; (iii) NH2NH2·H2O,
K2CO3, DMA, 40 °C, 12 h; (iv) acetylacetone, DBU, DMF, 100 °C,
14 h; (v) 2-acetamidomalonate, DBU, DMF, r.t., 0.5 h.
Figure 1. Optimized geometries and quadrant diagrams of lowest-
energy transition states for the alkyne insertion step with L5 or L12 as
ligand. Refer to the SI for TSs leading to other isomers and for the
origins of regioselectivity.
also demonstrated that cyano-functionalized 1,3-enyne 3c
underwent desilylation and afforded 1,3-enyne 5 containing a
terminal alkyne unit. Moreover, enynyl nitrile 3a could be
easily converted to enynals 6, which are important synthons in
organic chemistry.19 As mentioned in the introduction,
conjugated enynes with an electron-withdrawing group have
been widely employed in the construction of cyclic or
heterocyclic compounds. With this hydrocyanation of 1,3-
diynes protocol in hand, we are able to provide a diverse range
of cyano-containing cyclic or heterocyclic products. For
example, bicyclo[3.3.1]alkenone 7 was obtained in 92% yield
by In-catalyzed intermolecular annulation of enamine with 1,3-
enyne 1c. Pyrazole (8) and pyrans (9 and 10) were also
obtained under mild conditions. Interestingly, the trimethyl-
silyl group could be easily removed in these transformations.
We also conducted a large-scale reaction of 1a and acetone
In summary, the Ni-catalyzed regiodivergent hydrocyanation
of 1-aryl-4-silyl-1,3-diynes was successfully developed. The
efficient switch between two alkyne sites depends on suitable
steering ligands between diphosphine and the phosphine−
phosphite ligand. Two kinds of enynyl nitriles can be
synthesized in good yields with high regioselectivity from the
same reactants. The obtained cyano-containing 1,3-enynes
could easily undergo simple transformations to various cyano-
substituted heterocycles.
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ASSOCIATED CONTENT
* Supporting Information
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The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c01262.
Experimental procedures, characterization data, and
copies of NMR spectra for all new products (PDF)
Accession Codes
CCDC 1983075 and 2017792 contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Authors
■
Xianjie Fang − Shanghai Key Laboratory for Molecular
Engineering of Chiral Drugs, Frontiers Science Center for
Transformative Molecules, School of Chemistry and Chemical
Engineering, Shanghai Jiao Tong University, Shanghai
200240, China; orcid.org/0000-0002-3471-8171;
Email: fangxj@sjtu.edu.cn
Gui-Juan Cheng − Warshel Institute for Computational
Biology, Shenzhen Key Laboratory of Steroid Drug Discovery
and Development, School of Life and Health Sciences, The
Chinese University of Hong Kong (Shenzhen), Shenzhen
518172, China; Email: chengguijuan@cuhk.edu.cn
Authors
Feilong Sun − Shanghai Key Laboratory for Molecular
Engineering of Chiral Drugs, Frontiers Science Center for
Transformative Molecules, School of Chemistry and Chemical
Engineering, Shanghai Jiao Tong University, Shanghai
200240, China
Chengxi Yang − Warshel Institute for Computational Biology,
Shenzhen Key Laboratory of Steroid Drug Discovery and
Development, School of Life and Health Sciences, The
Chinese University of Hong Kong (Shenzhen), Shenzhen
518172, China
Jie Ni − Warshel Institute for Computational Biology,
Shenzhen Key Laboratory of Steroid Drug Discovery and
Development, School of Life and Health Sciences, The
Chinese University of Hong Kong (Shenzhen), Shenzhen
518172, China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c01262
Author Contributions
§F.S. and C.Y. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
X.F. thanks the Recruitment Program of Global Experts and
the startup funding from Shanghai Jiao Tong University for
their financial support. G.-J.C. thanks the National Natural
Science Foundation of China (21803047) and the research
grant from Shenzhen Key Laboratory Project (no.
ZDSYS20190902093417963).
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(20) Details of the computational method, energies, and geometry
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