Nickel-Catalyzed Asymmetric Hydrocyanation of Allenes

Article abstract of DOI:10.1021/acs.orglett.9b03938

The first catalytic enantioselective hydrocyanation of allenes catalyzed by a (R,R)-Ph-BPE-Ni(0) complex catalyst has been accomplished. Numerous optically active allylic nitriles were obtained in good yield with excellent enantioselectivities (up to 98%

Full text of DOI:10.1021/acs.orglett.9b03938

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Nickel-Catalyzed Asymmetric Hydrocyanation of Allenes
Jinguo Long, Jihui Gao, and Xianjie Fang*
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ABSTRACT: The first catalytic enantioselective hydrocyanation of allenes catalyzed by a (R,R)-Ph-BPE−Ni(0) complex catalyst
has been accomplished. Numerous optically active allylic nitriles were obtained in good yield with excellent enantioselectivities (up
to 98% ee).
nantioenriched organonitriles are crucial building blocks
in organic synthesis and represent important moieties in
vinylarenes and 1,3-dienes. The development of new prochiral
substrates for the asymmetric hydrocyanation remains
desirable.
E
2
diverse natural products and in molecules of medicinal and
1
agrochemical interest. The enantioselective transition-metal-
Allenes are versatile intermediates in organic synthesis owing
to the fact that numerous products could be formed through a
single transformation from the functionalization of two
catalyzed hydrocyanation of C−C double bonds is probably
2
−7
the most effective approach for their construction.
The
10
hydrocyanation of multiple C−C bonds to prepare racemic
different C−C double bonds. It should be mentioned that
8
,9
organonitriles has been well studied. The so-called DuPont
adiponitrile process, hydrocyanation of 1,3-butadiene to
adiponitrile, is a representative example of a successful
the Arai group made outstanding contributions to the allene
10f,11
hydrocyanation reactions.
In 2015, Arai and coworkers
described a Ni-catalyzed regio- and stereoselective hydro-
11d
9
cyanation of allenes (Scheme 1a). The key functionalities to
commercial application in this area. Nonetheless, the access
routes to enantiomerically enriched organonitriles by the
corresponding asymmetric catalysis have usually been
restricted to norbornene, vinylarenes, and 1,3-dienes as
Scheme 1. Ni-Catalyzed Hydrocyanation of Allenes
2
prochiral substrates so far.
The transition-metal-mediated asymmetric hydrocyanation
of C−C double bonds has occasionally appeared in the
3
−7
3a
literature
since the pioneering report from Elmes and
Jackson in 1979. Since then, a wide range of novel chiral
ligands have emerged and advanced the asymmetric hydro-
2
cyanation for the construction of various chiral nitriles. Most
notably, a Ni-catalyzed asymmetric hydrocyanation of 2-
methoxy-6-vinyl-naphthalene in the presence of carbohy-
drate-derived diphosphonite ligands was developed by
RajanBabu and Casalnuovo in 1992, affording the correspond-
4a
ing nitriles with excellent levels of enantiocontrol. This
catalyst system was also examined in the hydrocyanation of 1-
phenyl-1,3-butadiene, providing the desired product with 83%
4d
ee. The Vogt group reported the Ni-catalyzed asymmetric
hydrocyanation of 1,3-cyclohexadiene in the presence of
binaphthol-derived diphosphite ligand, which gives the
5b
corresponding product in 45% yield with 86% ee. Recently,
Schmalz and coworkers succeeded in identifying a TADDOL-
based phosphine−phosphite ligand for the Ni-catalyzed
asymmetric hydrocyanation of styrenes with high enantiose-
Received: November 4, 2019
6a
lectivities (up to 97% ee). Despite these contributions, good
enantioselectivities of hydrocyanation have been limited to
©
XXXX American Chemical Society
https://dx.doi.org/10.1021/acs.orglett.9b03938
A
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gain high regio- and stereocontrol rely on introducing aryl and
cyclopropyl groups in the substrates. Recently, the Arai group
managed to transfer the axial chirality of allenes through Ni-
catalyzed hydrocyanation, which gives the corresponding chiral
carbonitriles with up to 97% ee (Scheme 1b). However, for
most substrates, a drastic loss of enantiomeric purity was
detected in this transformation. Despite these contributions,
the catalytic asymmetric hydrocyanation of allenes toward
chiral carbonitrile preparation has not been documented.
Therefore, we report herein the first Ni-catalyzed asymmetric
hydrocyanation of allenes under mild reaction conditions,
affording allyl nitriles with high optical purity (Scheme 1c).
Initially, we investigated the asymmetric hydrocyanation of
bis((2R,5R)-phospholano)ethane ligands L6−L8 with differ-
ent steric properties were tested. To our delight, (R,R)-Ph-BPE
(L6) was identified as the most effective ligand, and the
reaction led to the desired product 3a in 79% yield with 87%
ee.
To further improve the enantioselectivity, the influence of
critical reaction parameters has been evaluated (e.g., temper-
ature, solvent, catalyst loading) for the model reaction using L6
as the ligand. As shown in Table 1, when the reaction
11f
Table 1. Investigation of Reaction Conditions for the Ni-
a
Catalyzed Asymmetric Hydrocyanation of 1a
(
±)-1a with acetone cyanohydrin (2) as a model reaction in
the presence of Ni(cod) and different chiral phosphorus
2
ligands L1−L8 (Scheme 2). It is worth mentioning that no
b
c
entry
solvent
temp (°C)
yield (%)
ee (%)
Scheme 2. Influence of the Ligand on the Ni-Catalyzed
Asymmetric Hydrocyanation of 1a
1
2
3
4
5
6
7
8
toluene
toluene
1,4-dioxane
THF
MTBE
60
30
30
30
30
30
30
30
30
30
79
87
51
31
89
37
87
88
46
42
83
94
82
96
86
95
a
MeCN
d
d
d
d
MeCN/toluene (1/1)
MeCN/toluene (3/2)
MeCN/toluene (2/1)
MeCN/toluene (3/2)
82
e
83 (78)
9
1
87
26
f
0
a
Reaction conditions: (±)-1a (0.1 mmol), 2 (0.3 mmol, 3.0 equiv),
and solvent (0.3 mL) in the presence of Ni(cod) (10 mol %) and L6
2
b
(
10 mol %). Yields were determined by GC analysis using n-
dodecane as the internal standard. ee values were determined by
chiral HPLC analysis. Solvent (v/v, 0.3 mL). Isolated yield.
c
d
e
f
Ni(cod) (5.0 mol %), L6 (5.0 mol %).
2
temperature was lowered to 30 °C, the enantioselectivity of
product 3a remained at the same level, and the yield increased
to 87% (Table 1, entry 2). Several other solvents were tested
next (Table 1, entries 3−6), and 1,4-dioxane and tetrahy-
drofuran (THF) led to much lower yields and enantioselectiv-
ities than toluene and methyl tert-butyl ether (MTBE) (Table
1
, entries 3−5). Acetonitrile (MeCN) was an effective solvent
for high enantioselectivity, albeit in low yield (Table 1, entry
). A solvent mixture of MeCN/toluene (3/2) was found to
6
give both the highest reactivity and the highest enantiose-
lectivity (Table 1, entry 8). Lowering the catalyst loading
further caused a significant decrease in yield (Table 1, entry
1
0). As a result, the optimal reaction conditions were
established as 30 °C Ni(cod) /L6/MeCN/toluene (3/2). It
2
a
is worth mentioning that the regioisomer 3a′ was isolated in
Reactions were carried out at 60 °C for 12 h with (±)-1a (0.1
1
3% yield under standard conditions. (For details, see the
Supporting Information (SI).)
mmol), 2 (0.3 mmol, 3.0 equiv), and toluene (0.3 mL) in the
presence of Ni(cod) (10 mol %) and ligand (10 mol %). The yields
2
were determined by gas chromatography (GC) analysis using n-
dodecane as the internal standard. The ee values were determined by
chiral high-performance liquid chromatography (HPLC) analysis.
After the preliminary optimization (Table 1, entry 8), we
examined the scope and generality of this asymmetric
transformation (Scheme 3). Besides propyl substitution at
the R position, a variety of alkyl-substituted allenes were all
suitable for the reaction, and the corresponding allyl nitrile
products (3b−f) were obtained in 46−75% yield with 83−96%
ee. A 1 mmol scale reaction with (±)-1b was achieved,
affording the desired chiral nitrile 3b in good yield and with
high enantioselectivity (60% yield and 92% ee). Notably, −Cl
and −OH functional groups were well tolerated (3e, 3f).
According to Arai’s report, substrates having aryl group are
conversion was observed in the absence of a ligand. Ligands
L1−L3, which were previously proven to be effective in the
asymmetric hydrocyanation reactions, were examined. Very
low and even no enantioselectivities were observed, although
the desired product 3a was obtained in high yield. Moreover,
commercially available bidentate ligands SEGPhos (L4) and
DIOP (L5) exhibited moderate activity and nearly no
enantioselectivities in the formation of 3a. Next, 1,2-
11d
conducive to achieving high regio- and stereocontrol. Thus
B
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a
Scheme 3. Reaction Scope
but gave products with lower ee when compared with the result
obtained with allenes with electron-neutral and electron-rich
substituents. Substrates bearing versatile flexible functional
groups including halogens (1m, 1n, 1o, 1r, 1s), ethers (1j, 1p,
1
t), trifluoromethyl (1k), and methanesulfonyl (1l) were also
well accommodated. In addition, substrates with heterocyclic
substituents (such as quinolyl, pyridyl, and thiophenyl groups)
were established to be efficient coupling partners to generate
the corresponding products in acceptable yield with high
enantioselectivities (3v−x). Moreover, the substrate employing
the structurally complex estrone was also successfully
converted into the desired product 3y in moderate yield
with excellent enantioselectivity. The absolute configuration of
product 3y was confirmed to be S by X-ray diffraction analysis,
and the stereochemical assignments of the other products were
tentatively made on this basis.
To illustrate the preparative utility of the current
enantioselective hydrocyanation reaction, several transforma-
tions were conducted, as shown in Scheme 4. Because the
Scheme 4. Synthetic Transformations of Product 3i
product 3i contains a cyano and an alkene, two unsaturated
functional groups, the selective reductions can be readily
performed. For example, with NiCl /NaBH in MeOH, 3i can
2
4
be fully reduced and converted into the aliphatic chiral amine
i-A in good yield. Additionally, the alkene can be selectively
3
reduced in the presence of the cyano group to give aliphatic
chiral nitrile 3i-B in excellent yield. Furthermore, epoxide 3i-C
can be efficiently synthesized following alkene epoxidation.
Importantly, almost no loss of enantiomeric purity was
observed in these manipulations.
Then, fully deuterium-labeled acetone cyanohydrin (D-2,
97% D) was subjected to the model reaction under standard
conditions (eq 1). In this experiment, we observed deuterium
incorporation (60% D) only at the C2 position of D-3a. This
observation is consistent with a previously reported result from
a
Reaction conditions: (±)-1 (0.1 mmol), 2 (0.3 mmol, 3.0 equiv),
and MeCN/toluene (3/2, 0.3 mL) in the presence of Ni(cod) (10
mol %) and L6 (10 mol %) at 30 °C for 12 h. Yields of isolated
products after flash column chromatography. The ee values were
2
11f
Arai.
The erosion of deuterium content is due to the
b
determined by chiral HPLC. 1 mmol scale reaction.
deuterocyanation of 1,5-cyclooctadiene, and the corresponding
deuterated adducts were detected by GC−MS analysis. Finally,
(
S)-1b and (R)-1b were successively prepared and subjected to
various aryl-substituted allenes with electron-neutral/deficient/
rich substituents underwent efficient and regioselective hydro-
cyanation to form the corresponding allyl nitriles in moderate
to good yield with good to excellent enantioselectivities (3g−
y). It should be pointed out that the reaction of allenes with
electron-deficient substituents (1k, 1l, 1t) proceeded smoothly
the hydrocyanation reaction under standard conditions (eq 2).
The same configuration of product (S)-3b was isolated in
similar yield with the same ee value when compared with the
racemic 1b. These results indicate that the reaction rate does
not depend on any of the enantiomers of the substrate.
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Corresponding Author
̈
Xianjie Fang − Shanghai Jiao Tong University, Shanghai,
People’s Republic of China; orcid.org/0000-0002-
̈
(
2
̈
3471-8171; Email: fangxj@sjtu.edu.cn
Other Authors
(
2
Jinguo Long − Shanghai Jiao Tong University, Shanghai,
People’s Republic of China
Jihui Gao − Shanghai Jiao Tong University, Shanghai,
People’s Republic of China
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ACKNOWLEDGMENTS
■
This work was financially supported by the Recruitment
Program of Global Experts and the startup funding from
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