Pd-Senphos Catalyzed trans-Selective Cyanoboration of 1,3-Enynes

Article abstract of DOI:10.1002/anie.202005882

The first trans-selective cyanoboration reaction of an alkyne, specifically a 1,3-enyne, is described. The reported palladium-catalyzed cyanoboration of 1,3-enynes is site-, regio-, and diastereoselective, and is uniquely enabled by the 1,4-azaborine-based Senphos ligand structure. Tetra-substituted alkenyl nitriles are obtained providing useful boron-dienenitrile building blocks that can be further functionalized. The utility of our method has been demonstrated with the synthesis of Satigrel, an anti-platelet aggregating agent.

Full text of DOI:10.1002/anie.202005882

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Accepted Article
Title: Pd-Senphos Catalyzed trans-Selective Cyanoboration of 1,3-
Enynes
Authors: Yuanzhe Zhang, Bo Li, and Shih-Yuan Liu
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10.1002/anie.202005882
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COMMUNICATION
Pd-Senphos Catalyzed trans-Selective Cyanoboration of 1,3-
Enynes
Yuanzhe Zhang[a], Bo Li[a], and Shih-Yuan Liu*[a]
[a]
Y. Zhang, Dr. B. Li, Prof. Dr. S.-Y. Liu
Department of Chemistry, Boston College
Chestnut Hill, MA 02467-3860 (USA)
E-mail: shihyuan.liu@bc.edu
Supporting information for this article is given via a link at the end of the document.
Abstract: The first trans-selective cyanoboration reaction of an
alkyne, specifically a 1,3-enyne, is described. The reported palladium-
catalyzed cyanoboration of 1,3-enynes is site-, regio-, and
diastereoselective, and is uniquely enabled by the 1,4-azaborine-
based Senphos ligand structure. Tetra-substituted alkenyl nitriles are
obtained providing useful boron-dienenitrile building blocks that can
be further functionalized. The utility of our method has been
demonstrated with the synthesis of Satigrel, an anti-platelet
aggregating agent
difunctionalization of alkynes has significantly less precedent. 5b-d,
10b,12 For example, no trans-selective cyanoboration reaction of an
alkyne has been reported to date. Herein we describe the trans-
cyanoboration of 1,3-enynes catalyzed by
a Pd complex
supported by a 1,4-azaborine-based biaryl phosphine (Senphos)
ligand (Scheme 1, bottom). Highly substituted alkenyl nitriles,
including tetra-substituted derivatives are obtained in a site-,
regio- and diastereoselective fashion, providing boron-dienenitrile
building blocks that cannot be readily accessed by other synthetic
methods.
The alkenyl nitrile motif plays an important role in the field of
polymers,1 pharmaceutics,2 and agrochemistry.3 Thus, versatile
and stereoselective synthetic approaches to substituted alkenyl
nitriles has attracted significant attention. To date, a number of
methods have been reported that involve alkyne X-CN
difunctionalization (X = B,4 C,5 N,6 O,7 halogen,5d, 8 Ge,9 S,10 Se,10e
Si11 and Sn12). The difunctionalization approach is attractive
because the additionally installed functional group X provides a
handle for possible structural diversification. Among the
difunctionalization methods, the cyanoboration of alkynes4 is
particularly appealing due to the rich functionalization chemistry
of organoboron derivatives.13 Suginome reported the first intra-
and intermolecular cyanoboration of alkynes catalyzed by Pd and
Ni complexes (Scheme 1, top).4 The working mechanistic
hypothesis suggests initial oxidative addition of the B–CN bond to
the metal followed by cis-selective β-migratory insertion into the
alkyne and C–C reductive elimination, furnishing the cis-
cyanoboration product.14 The trans-selective X-CN
Our laboratory has been investigating BN/CC isosterism15
(substitution of a CC bond unit with a BN bond unit) as a strategy
to create structural, and as a consequence, functional diversity.
To date, BN/CC isosterism has been successfully applied to
create new properties and functions in biomedical research,16
materials science,17 and organic synthesis.18 Somewhat
surprisingly, the application of BN/CC isosterism to the ligand
space has attracted less attention.19 To this end, we recently
reported a ligand family based on the biaryl 1,4-azaborine
scaffold.20 Electronic structure elucidation revealed a strong
borataalkene character (Scheme 2) which renders the C(3)
carbon significantly more nucleophilic/electron rich than the
corresponding carbonaceous arene. The access to the new
ligand space from BN/CC isosterism has resulted in new reaction
selectivity, specifically the trans-selective hydroboration of 1,3-
enynes.21 In our continued efforts to expand the utility of Senphos-
type ligands in metal-catalyzed transformations we are
addressing in this work the outstanding problem of trans-selective
cyanoboration reaction.
Prior work (Suginome):
B
CN
B
CN
M, ligand
classical
hydrocarbon
chemical space
new chemical space from BN/CC isosterism
R1
R2
R1
R2
M = Pd or Ni
Me
N
Me
Me
oxidative
addition
reductive
elimination
+
+
N
N
cis-selective
migatory insertion
–
(3)
B
R
CN
B
B
R
–
B
M
B
M
CN
R2
R
R1
R1
R2
borataalkene
This work:
Me
Scheme 2. Electronic structure of 1,4-azaborines.
N
Pd, ligand
CuCN, ClBcat
CN
R2
B
Me
PR2
R2
DFT calculations for the reported trans-hydroboration reaction
predict a reaction pathway that involves an outer-sphere oxidative
addition with catecholborane that is then followed by hydride
transfer and reductive elimination (Scheme 3).22 We envisioned
that chlorocatecholborane (Cl-BCat) could serve as a potential
boron source capable of facilitating the outersphere oxidative
R1
R1
trans-selective
addition
R3
B
R3
ligand
(Senphos)
Scheme 1. Cyanoboration of alkynes.
1
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10.1002/anie.202005882
Angewandte Chemie International Edition
COMMUNICATION
addition step and that a cyanide anion23 (instead of a hydride)
would attack the resulting Pd complex to furnish the
cyanoboration product.
substrate 1a (Table 1, entry 5 vs. 9). Lastly, we determined that
CC-L1, the carbonaceous analogue of the best performing
Senphos ligand, is inferior to L1 with regard to reaction efficiency
and selectivity (entry 10 vs. entry 5), highlighting the importance
of the unique electronic structure of the 1,4-azaborine motif in
promoting the reaction.26
Under optimized reaction conditions, various alkyl/terminal (E)-
1,3-enynes 1 were subjected to the trans-selective cyanoboration
followed by quench with 1,8-diaminonaphthalene (dan)27 or
pinacol (pin), and the results are summarized in Table 2. High
trans-selectivity was observed consistently with an array of
electronically (e.g., entries 4d-4j) and sterically different (e.g.,
entries 4c and 4k) substituents on the alkene. In addition to
arenes, the R1 position also tolerates heteroarenes (entries 4l and
4m) and alkyl groups (entries 4n-4r). Functional groups such as
aryl-halide (entries 4g-4i), alkyl chloride (entry 4o), esters (entries
4j and 4r), methoxy (entry 4d), and alcohol (with pre-treatment
Me
+
H
L
–
–
Pd(0)L
Me
Pd
BCat
CatB
•
H
H
“outer-sphere”
oxidative addition
Ph
Ph
Me
+
Pd
L
BCat
HBCat
via
•
Ph
HBCat
hydride
transfer
Me
N
H
H
L
B
Et
Pd
Me
BCat
PPh2
Ph
Me
BCat
reductive
elimination
Ph
L
Scheme 3. Mechanism of the trans-hydroboration of 1, 3-enynes predicted by
DFT calculations.
Table 2. Pd-catalyzed trans-cyanoboration of alkyl/terminal 1,3-enynes (R2
alkyl/H)a
=
1.8 equiv. BCatCl
1.6 equiv. CuCN
5 mol% Pd(COD)(CH2TMS)2 (3)
Thus, with Cl-BCat as the boron source,24 copper(I) cyanide as
the cyanide source,25 Pd complex 3 as the precatalyst, and enyne
1a as the initial substrate, we evaluated the effects of the ligand
structure on the cyanoboration reactivity and selectivity. As can
be seen from Table 1, the absence of a supporting ligand does
not lead to an efficient productive reaction (entry 1). The presence
of monodentate phosphine ligands promotes the product
formation, albeit in low yield (entries 2 and 3). On the other hand,
the bidentate phosphine ligand dppe is completely ineffective
(entry 4). Gratifyingly, the use of Senphos-type ligands results in
a substantial increase in the product yield while also achieving
greater than 95:5 trans addition selectivity (entries 5-9). The
substituent R at the C(3) position of the ligand has a profound
influence on the product yield but not on the diastereoselectivity.
For example, when L1, which bears the methyl group at the C(3)
position, is used as the ligand, the reaction gives the product in
superior yield (Table 1, entry 5) compared to those with bigger R
substituents (entries 6-8). Switching the boron substituent from
the o-dicyclohexyl-phosphinophenyl to o-diphenyl-phosphino-
phenyl group results in diminished reactivity for the model
R2
CN
5-7 mol% L1
alkyl/H
R1
R1
o-DCB, 105-135 oC, 2.5 h
then
1,8-diaminonaphthalene or pinacol
CH2Cl2, RT, 12 h
R3
B(dan) or B(pin)
R3
R2 = alkyl/H
1
4
CN
CN
Me
Me
B(dan)
B(dan)
86% (96:4)
4a
77% (98:2)
X-ray structure of 4b
4b
CN
4d
X = OMe 64% (96:4)
4e
4f
4g
4h
4i
X = Me
X = CF3
X = F
X = Cl
X = Br
87% (97:3)
80% (>98:2)
66% (96:4)
84% (>98:2)
55 % (95:5)
CN
Me
Me B(dan)
63% (>98 : 2)b
Me
B(dan)
X
4j
X = CO2Et 69% (>98:2)
4c
Me
CN
CN
Me
Me
B(dan)
EtO
B(pin)
O
4j-B(pin)
4k
56% (>98:2)
CN
X-ray structure of 4j-B(pin)
58% (94:6)
CN
Table 1. Pd-catalyzed trans-cyanoboration as a function of the ligand structure
CN
Me
Me
Me
nC6H13
O
B(dan)
B(pin)
60% (96:4)
4n
B(dan)
S
1.8 equiv. BCatCl
1.6 equiv. CuCN
5 mol% Pd(COD)(CH2TMS)2 (3)
71% (98:2)c
4l
72% (97:3)
Me
CN
4m
5 mol% L
Me
Ph
CN
Me
Ph
CN
CN
o-DCB, 115 oC, 2.5 h
then
1,8-diaminonaphthalene
Me
1a
4a B(dan)
Me
HO
ClnC6H12
B(dan)
B(dan)
Me
N
B(pin)
L
4a yield (trans:cis)a
entry
60% (93:7)
35% (98:2)d
55% (96:4)
L1, R = Me
4q
L2, R = Et
L3, R = iPr
L4, R = tBu
4p
4o
1
2
3
4
5
6
7
8
none
PhPCy2
XPhos
dppe
L1
L2
L3
L4
L5
3% (89:11)
13% (95:5)
10% (90:10)
<1% (N/A)
92% (96:4)
69% (95:5)
48% (95:5)
24% (95:5)
46% (96:4)
6% (89:11)
B
R
O
O
CN
CN
CN
PCy2
Me
H
Et
p-tol
nC6H13
B(dan)
B(dan)
45% (96:4)e
4t
B(dan)
73% (96:4)
66% (93:7)
Me
N
Me
4r
4s
a Yields of isolated isomerically pure trans product (average of 2 runs), based on 1. The
diastereomeric ratio in parenthesis (trans:cis) was determined by 1H NMR of the crude
material after addition of 1,8-diaminonaphthalene or pinacol. b Isomerization occured at
the highlighted position. E/Z ratio of the crude material is 5:1. Yield is of isolated pure E
isomer. c L5 was used instead of L1. d The substrate was first pre-treated with HBCat
before subjecting it to the reaction conditions. e 10 mol% catalyst loading, 90 °C, 40 min
reaction time.
9
10
CC-L1
B
Me
Me
PCy2
PPh2
a Determined by 1H NMR of the crude mixture
vs. a calibrated internal standard after quenching
with dan. dan: 1,8-diaminonaphthalene,
COD: cyclooctadiene, o-DCB: orthodichlobenzene.
L5
CC-L1
2
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10.1002/anie.202005882
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COMMUNICATION
with H-BCat; entry 4q) are also tolerated. When the steric demand
of the R2 substituent is increased from Me to Et, a slight decrease
in diastereoselectivity was observed (4s vs. 4a). For the furyl
substrate 1l, L5 was a superior ligand compared to L1 with regard
to reaction selectivity.28 The terminal enyne substrate 1t required
higher catalyst loading at a lower reaction temperature and
reaction time (entry 4t). The bond connectivity and
stereochemistry of two trans-cyanoboration products, 4b and 4j-
B(pin) was confirmed by single crystal X-ray diffraction analysis
(Table 2).
fluorination of 6a with Selectfluor30 produces a novel (E)-2-nitrile-
fluorodiene motif 6d. We also determined that our borylated
dienylnitriles can be hydrogenated regioselectively. For example,
when diene 5g is subjected to Pd/C catalyzed hydrogenation,
tetra-substituted borylated alkenylnitrile 6e is obtained after
transesterification with pinacol (eq 1).
CN
CN
aq. HCl (3M)
Me
Me
6a
B(dan)
B(OH)2
4a
For aryl (E)-1,3-enynes (R2 = Ar) 2, we determined that L5 was a
superior ligand compared to L1.29 The diastereoselectivity of the
reaction for diaryl 1,3-enynes (R1 = Ar, R2 = Ar) substrates 2a-d
is dependent on the electronic nature of the R2 substituent, with
electron-deficient R2 groups resulting in higher trans-
cyanoboration selectivity (entry 5c and 5d vs. 5b and 5a). On the
other hand, for monoaryl 1,3-enynes (R2 = Ar, R1 ¹ Ar) the
observed trans-cyanoboration selectivity remains excellent
(>94:6) regardless of the electronic nature of the R2 substituent
(entries 5e-i). Good diastereoselectivity was also observed for the
alkenyl silane and alkenyl chloride substrates 2h and 2i, albeit
with diminished yields. We have obtained the X-ray crystal
structure of product 5g, thus unambiguously establishing
connectivity and diastereoselectivity.
5 mol% XPhos-Pd-G2
K3PO4, bromobenzene or
4-B(dan)-bromobenzene
RT
NaOH, AgOTf, MeOH,
Selectfluor, acetone
RT
CN
Me
CN
CN
Me
Me
Ph
F
6b
6c
6d
86%
85%
67%
B(dan)
F
F
(1)
NC
NC
1) 20 mol% Pd/C, EtOAc, 40 °C
2) THF/HCl, pinacol, RT
Me
Me
B(dan)
B(pin)
5g
6e
54%
Scheme 4. Functionalization of cyanoboration products.
Table 3. Pd-catalyzed trans-cyanoboration of aryl 1,3-enynes (R2 = Ar)a
Finally, we applied our trans-selective cyanoboration reaction to
the synthesis of Satigrel 7, an anti-platelet aggregating agent that
1.8 equiv. BCatCl
1.8 equiv. CuCN
10 mol% Pd(COD)(CH2TMS)2 (3)
contains
a
tetra-substituted acrylonitrile core.31 With
a
R2
CN
10 mol% L5
stereoselective method for the construction of tetra-substituted
acrylonitrile now at our disposal, we reasoned that Satigrel could
be synthesized from 5e in a straight forward fashion (Scheme 5).
We commenced first with the transesterification of 5e followed by
Ar
R1
R1
o-DCB, 105 oC, 1 h
then, 1,8-diaminonaphthalene
CH2Cl2, RT, 12 h
R2 = Ar
B(dan)
2
5
CF3
Suzuki-Miyaura coupling to produce
a variety of bis-aryl
X
OMe
CN
CN
CN
substituted dienenitriles 8a-c in a stereospecific manner. The bis-
4-methoxy-phenyl derivative 8a was then subjected to oxidation32
to yield the carboxylic acid 9a. Finally, catalytic hydrogenation33
CF3 Me
B(dan)
B(dan)
B(dan)
5a X = H 60% (86:14)
5b X = Me 48% (75:25)
5c X = CF3 84% (93:7)
86% (>98:2)
71% (94:6)
5d
5e
OMe
F
F
Satigrel
CO2H
CN
NC
B(dan)
Me
Me
Me
B(dan)
B(dan)
CN
CN
MeO
MeO
7
5e
70% (95:5)
63% (98:2)
5g
5f
R
F
B(dan)
CN
CN
CN
1) THF/HCl, pinacol, 84%
Me
Me
X-ray structure of 5g
TMS
Cl
2) 5 mol% XPhos-Pd-G2
ArBr
CN
B(dan)
B(dan)
28% (96:4)b
5i
MeO
MeO
5e
K3PO4, THF/H2O
88%
80%
90%
8a R = 4-MeO
8b R = 4-F
8c R = 3-MeO
38% (94:6)
5h
a Yields of isolated isomerically pure trans product (average of 2 runs), based on 2. The
diastereomeric ratio in parenthesis (trans:cis) was determined by 1H NMR of the crude
material after addition of 1,8-diaminonaphthalene. b 15 mol% catalyst loading, 1.2 equiv.
CuCN, 1.6 equiv. BCatCl, 90 °C, 25 min.
OMe
OMe
1) SeO2, AcOH, H2O
1,4-dioxane, 77%
COOH
Me
2) NaClO2, NaH2PO4, H2O2
MeCN, H2O, 69%
Vicinal boron-substituted alkenylnitrile derivatives are versatile
synthetic building blocks. For example, Scheme 4 illustrates that
cyanoboration product 4a undergoes hydrolysis (to form boronic
acid derivative 6a) and subsequent Pd-catalyzed Suzuki-Miyaura
coupling with bromobenzene or 4-B(dan)-bromobenzene to
furnish 6b and 6c in 86% and 85% yield, respectively, with
complete retention of olefin stereochemistry. Furthermore,
CN
CN
MeO
MeO
8a
9a
10 mol% Pd/C, H2
EtOAc, 91%
Satigrel 7
Scheme 5. Synthesis of Satigrel.
3
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10.1002/anie.202005882
Angewandte Chemie International Edition
COMMUNICATION
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The synthesis described in Scheme 5 offers a modular and
stereoselective synthetic approach toward bis-aryl substituted
dienenitriles, taking advantage of the versatile boron functional
handle.
In summary, we have developed the first trans-selective
cyanoboration reaction of an alkyne. The described palladium-
catalyzed cyanoboration of 1,3-enynes is site-, regio-, and
diastereoselective, and we have determined that our 1,4-
azaborine-based Senphos ligand structure is uniquely suited to
support the Pd catalysis. The described method provides access
to the important tetra-substituted alkenyl nitrile motif in a
straightforward fashion, and we demonstrated the utility of our
method with the synthesis of Satigrel. Future efforts will be
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Acknowledgements
Research reported in this publication was supported by the
National Institute of General Medical Sciences of the National
Institutes of Health under Award Number R01GM094541 and by
Boston College start-up funds.
Keywords: trans-cyanoboration • azaborine • enyne
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4
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5
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Entry for the Table of Contents
A trans-selective alkyne cyanoboration reaction debuts! A Pd complex supported by an 1,4-azaborine-derived phosphine ligand
is uniquely capable in transforming 1,3-enynes into tetra-substituted borylated dienenitriles with high site-, regio- and trans-
diastereoselectivity.
6
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