Organic Letters
Letter
cyanohydrin (2) as the HCN source. The effect of different
chiral ligands on the model reaction was investigated. (For
more details, see Table S1.) The use of L1, which has
previously been employed in the enantioselective hydro-
cyanation of conjugated olefins,4a,6b furnished 3a in moderate
yield with a moderate ee value (Table 1, entry 1). The chiral
asymmetric reaction (Scheme 2a). Aryl-substituted 1,3-dienes
with electron-deficient groups, including trifluoromethyl (1j),
cyano (1e), and ester (1g) groups, or electron-donating
groups, including hydroxyl (1f), methyl (1h), and methoxyl
(1c) groups, at the para and meta positions on benzene ring
undergo efficient asymmetric hydrocyanation to produce the
desired products 3 in moderate to decent yields (67−98%)
with moderate to high ee values (71−95% ee). Various
functional groups including halogens and heterocycles were
well tolerated. The reaction seems to be insensitive to steric
effects. Hence, when 1,1-disubstituted 1,3-dienes were applied
and L3c was used as the ligand, the desired allylic nitriles
were afforded in good yields with excellent enantioselectiv-
ities (Scheme 2b, 3q−3t). The substituent at the four-
position of the substrates produced nitriles with a variety of
alkyl groups at the stereogenic carbon. When L2 was
employed as the ligand, the corresponding nitriles were
obtained in good yields with good ee values (Scheme 2e,
3w−3z), and alcohol (1y), ester (1z), and cyanide (1x)
functionalities were tolerated. It is worth mentioning that
(E,Z)-1w is much more reactive than the corresponding
(E,E)-isomer, delivering the corresponding nitrile 3w in 88%
yield with 52% ee. Importantly, the chiral nitrile with a
quaternary center, which is a pivotal synthetic building
block,8 was also readily obtained in 92% yield with 85% ee
(Scheme 2d, 3v). Additionally, two-substituted 1,3-dienes
(1aa, 1an) and cyclic 1,3-diene (1u) could generate the
corresponding allylic nitriles with good enantioselectivities
(Scheme 2c,f). Interestingly, 1,3,5-triene (1ab) delivered a
single product 3ab in moderate yield with a moderate ee
value, and no further dihydrocyanated product was detected
(Scheme 2g). Unfortunately, low reactivity in the formation
of hydrocyanated product was observed when tetrasubstituted
diene (1am) was used as a substrate (Scheme 2i). Finally, the
stereochemical assignment of the products as R was
determined though the correlation of 3t according to a
known compound.4d
After the initial success of this catalytic system in the
highly efficient and selective hydrocyanation of aryl-
substituted 1,3-dienes, we further explored the scope with
the less reactive aliphatic 1,3-dienes. (For more details, see
Table S2.) Owing to the lower stability of the alkyl-
substituted π-allyl−Ni species, there is a competitive reaction
between 1,4-hydrocyanation and 1,2-hydrocyanation. After
carefully screening the reaction conditions, we were delighted
to realize that an array of aliphatic 1,3-dienes successfully
transformed into the corresponding allylic nitriles with good
enantiocontrol when subjected to the previous general
reaction conditions under a higher reaction temperature
(Scheme 2h). Various functional groups, such as cyano
(1ad), ester (1ac and 1ae), amide (1ah), amine (1af), and
thioether (1ai), all were well tolerated. Conjugated dienes
with two flexible substituents with less steric distinction (1aj
and 1ak) could also be applied to this reaction, and the
acyclic nitriles were produced with good enantioselectivities.
Finally, the substrate derived from estrone was also efficiently
transformed into the corresponding product 3al in 78% yield
with perfect diastereoselectivity when L2 used as the ligand.
Notably, the diastereoselective reactions indicated that the
reactivity and selectivity of this reaction were controlled not
only by the catalyst but also by the substrate (3ac′, 3ad′,
3al). The stereochemical assignment of the aliphatic products
Table 1. Influence of Chiral Phosphorus Ligand on the
a
Enantioselective Hydrocyanation of 1a
b
c
entry
ligand
3a yield (%)
3a ee (%)
1
2
3
4
5
6
7
8
9
L1
L2
75
99
99
61
78
77
94
89
71
72
76
34
L3a
L3b
L3c
L3d
L3e
L3f
L3g
L3h
d
99 (96)
91
99
87
78
65
85
99
10
11
78
−94
e
L3b′
a
b
0.2 mmol scale. Yield was determined by GC analysis using n-
dodecane as the internal standard. ee value was determined by chiral
HPLC. Isolated yield. L3b′ is the opposite enantiomer of L3b.
c
d
e
atropisomeric bisphosphite ligand L2 was tested, and the
reaction led to the desired product 3a in quantitative yield
with a good ee value (Table 1, entry 2). To our delight, the
bisphosphite ligands bearing a TADDOL scaffold were
effective in this asymmetric hydrocyanation. For these
ligands, the substituents on the aromatic ring have a
remarkable impact on both the ee value and the yield of
this asymmetric transformation. Notably, the para-trifluor-
omethyl-substituted L3b delivered 3a in quantitative yield
and with an excellent ee value (Table 1, entry 4). The
enantiomer of 3a was obtained in quantitative yield with
−94% ee when L3b′ was applied (Table 1, entry 11).
After identifying a suitable catalytic system (Table 1, entry
4), we first set out to investigate the influence of 1,3-diene
stereochemistry on the reaction. When (Z)-1a was applied in
lieu of (E)-1a, only (E)-3a was observed in almost equal
yield (94%) with slightly lower enantioselectivity (83% ee)
compared with (E)-1a (96% yield, 94% ee). Next, we turned
our attention to test various 1-aryl-1,3-dienes for this
931
Org. Lett. 2021, 23, 930−935
Yu, Rongrong
