Journal of the American Chemical Society
Article
Table 1. Effects of Variations in the Reaction Parameters
and Conditions
cross-coupling. Desired products 3ab−ah were obtained in
generally good yields (62−78%) with excellent enantioselec-
tivity (91−93% ee). Notably, the halogen atoms (Cl, Br, I)
may be subjected to further synthetic manipulations (in
particular, transition-metal-catalyzed cross-coupling reactions)
at the halogenated positions (products 3ae−ag). Moreover,
oxime esters 1i−k with functional groups at the meta- or ortho-
position also reacted well, affording 3ai−ak in 73−80% yields
with 91−94% ee and indicating that steric hindrance did not
affect the transformation. Reactions with substrates possessing
a fused aromatic ring (2l) or heteroaromatic ring (2m−p)
were also amenable to this process, giving the corresponding
coupled products 3al−ap in good yields with consistently
excellent enantioselectivity (89−93% ee). Then, we proceeded
to examine the generality of this asymmetric cross-coupling by
using a range of aliphatic carboxylic-acid-derived oxime esters.
For instance, oxime esters 2q−w derived from cyclobutanone
and primary, secondary (cyclohexyl), tertiary (e.g., t-butyl and
adamantyl acids), and α,β-unsaturated acids were all well
accommodated under the current catalytic system. Thus, the
expected allylic ester products 3aq−aw were isolated in good
yields ranging from 54% to 94% with 90−94% ee.
Markedly, as shown in Table 2b, oxime esters 2x−z and 2aa
derived from drugs diclofenac, febuxostat, gemfibrozil, and
ciprofibrate were converted into their corresponding 1,2-
cyanoalkylacyloxylation products 3ax, 3ay, 3az, and 3aaa,
respectively, with good yields and satisfactory enantioselectiv-
ity. Naturally occurring acid-derived oxime esters 2ab−ac were
also suitable for coupling, providing the expected products
with good yields and stereoselectivity. These results showed
the robustness and utility of the developed reaction.
a
b
c
entry
variation
yield (%)
ee
d
1
none
88 (79)
21 (33)
0 (99)
0 (99)
81
15 (16)
61
69
5 (63)
0 (99)
0 (22)
0 (99)
84
94
86
-
-
94
9
88
−82
91
-
e
2
use of THF, 16 h
use of DMF, 16 h
use of CuI
use of Cu(OTf)2
ligand (R,R)-L2
ligand (R,R)-L3
ligand (S,S)-L4
blue LEDs
e
3
e
4
5
6
e
7
8
9
e
e
10
11
12
13
no light
e
e
no ligand (R,R)-L1
no Cu(CH CN) PF
6
-
-
94
3
4
added water (0.1 equiv)
a
Reaction conditions: 1a (0.3 mmol), 2a (0.2 mmol), Cu-
CH CN) PF (1.0 mol %), ligand L1 (1.2 mol %), 1,2-dichloro-
(
3
4
6
ethane (DCE) (4.0 mL), 2 × 20 W purple LEDs (λ = 390 nm), at
max
b
1
room temperature. Yields were determined by H NMR analysis
c
with 1,3,5-trimethoxybenzene as the internal standard. Determined
d
by HPLC analysis on a chiral stationary phase. Isolated yield.
e
Finally, we investigated the effect of varying the oxime
moiety on the efficiency and enantioselectivity of the reaction
with 1a (Table 2c). The reaction of 3,3-disubstituted oxime
esters 5a and 5b proceeded smoothly to afford the expected
products 6aa and 6ab in high yields with 92% and 94% ee,
respectively. Sterically more demanding 5c was also well
tolerated to give 6ac with modest reaction statistics. 2-Methyl-
substituted oxime ester 5d also efficiently participated in the
reaction to produce a good yield of 6ad with high ee values,
but the d.r. was 1:1 because of the initial nonenantioselective
addition of cyanoalkyl radicals. Notably, benzocyclobutenone-
derived oxime ester 5e also proved to be suitable for the
reaction, leading to product 6ae in 75% yield with 92% ee.
Substrate Scope of 1,3-Dienes. Next, a representative set
of 1,3-dienes was evaluated to further investigate the generality
of this cross-coupling (Table 3). First, it was found that the 1-
aryl- and heteroaryl-substituted 1,3-dienes were all competent
reaction partners. For example, substrates 1b−g bearing either
Recovery of 2a.
efficiency and enantioselectivity (entries 6−8). Interestingly,
the reaction that was performed under irradiation by blue
LEDs (λmax = 460 nm) proceeded sluggishly, with 3aa being
obtained in only 5% yield with 91% ee (entry 9).
Control experiments established that each component is
critical to the desired cross-coupling reaction (entries 10−12).
Remarkably, without ligand L1, the majority of oxime ester 2a
was consumed but led to a messy mixture. Our concern that
allylic radicals initially formed upon radical addition might
isomerize to oxidize labile benzylic radicals to lead to the 1,4-
adduct appeared to be unfounded, as evidenced by the
exclusive formation of the 1,2-adduct. In terms of the method
practicality, Cu(CH CN) PF and chiral bisoxazoline ligands
3
4
6
are commercially available, and the protocol is not moisture-
sensitive (entry 13). Until now, oxime esters have been mainly
used as cyanoalkyl radical sources, with the generation of a
stoichiometric carboxylic anion as a byproduct. In contrast, this
protocol allows waste carboxylic anions to be used as O-
nucleophiles, leading to atom-economic incorporation of
oxime esters.
Substrate Scope of Cyclobutanone Oxime Esters.
With the optimized conditions in hand, we examined the
substrate scope with respect to the two coupling partners on a
alkyl or electron-withdrawing groups (e.g., F, Cl, Br, CF ) at
3
the para-position of the phenyl ring were well tolerated,
furnishing the corresponding allylic esters 7ba−ga in 60−73%
yields with 87−92% ee. Again, as shown in the reactions of
1h−m, variations in the substitution pattern and steric
hindrance of the aromatic ring had little effect on both the
reaction efficiency and enantioselectivity. As such, the expected
products 7ha−ma were isolated in 70−80% yields with 87−
95% ee, regardless of the electronic properties of the
substituent. The reaction of 1-(2-naphthyl)-substituted 1,3-
diene 1n also proceeded smoothly to produce 7na in 53% yield
with 88% ee. Additionally, 1,3-dienes 1o and 1p with 3-furanyl
or 3-thiophenyl groups were well tolerated, furnishing the
relative products 7oa and 7pa in good yields with 88% and
0.2 mmol scale. First, the scope of oxime esters was tested by
varying the O-acyl moiety (Table 2a). Aside from 2a, aryl-
carboxylic-acid-derived oxime esters 2b−h bearing various
neutral (H), electron-donating (e.g., t-Bu, OMe), or electron-
withdrawing (e.g., Cl, Br, I, CO Me) groups at the para-
2
position of the aromatic ring were all suitable partners for the
1
3384
J. Am. Chem. Soc. 2021, 143, 13382−13392