Journal of the American Chemical Society
Article
yield, 82:18 er, entry 2), whereas diphosphine BINAP L4 gave
little 3. The use of oxidant O2 gave a slightly higher yield of 3
(entry 3). The installation of an iodine at C8 of the quinoline
auxiliary improved the er of 3 to 92:8 (IQ, entries 4−7).17 The
use of peroxycarbonate oxidant O4, recently introduced by
Liu,18 allowed the reaction to take place efficiently at room
temperature, forming 3 in higher yield and with a 95:5 er
(entries 9−11). Finally, the use of SEGPHOS-based oxide
ligand L7 in dichloromethane (DCM) gave the highest er
(entry 19). Product 3 was obtained in 72% isolated yield with
97:3 er using 30 mol % SEGPHOSO (entry 20). As shown in
entry 24, reaction with O4 in the absence of ligand gave a
considerable amount of N-benzylation side product 4 (∼16%)
and double-alkylation side product 5 (32%). The use of
diphosphine ligands such as L6 gave results comparable to
those of L7 when the O4 oxidant was used because they can be
quickly oxidized (>95% conversion within 3 h) in situ to
generate the corresponding oxide ligands. In comparison, only
a small amount of oxidation product L4 or L6 (∼20% in 12 h)
was observed when oxidants O1 and O2 were used. (See the SI
for details.) Monophosphine oxide ligand L8 gave a racemic
product. CuI catalysts bearing strong coordinating anionic
ligands such as halide or acetate provided little reactivity
(entries 12 and 13). CuII catalysts were significantly less
effective (entry 17). Notably, the use of the CuOTf catalyst
gave the highest yield of 3 but with a slightly decreased er
(95:5, entry 21). The addition of 3 equiv of radical trapping
reagent butylated hydroxytoluene (BHT) suppressed the
formation of 3, giving benzyl-BHT adduct 6 in 42% yield
(entry 25; see the SI for details).
Scheme 1. Directed CAF of Unactivated Alkenes
Substrate Scope. With the optimized conditions in hand,
we next examined the scope of 4-benzyl Hantzsch esters using
the reaction of IQ-coupled cis-3-hexenamide 1 (Scheme 2A).19
Overall, benzyl-DHPs bearing various substituents on the
phenyl ring worked well, giving the desired β-lactam products
(8−13) in good to excellent yields, exclusive anti diaster-
eoselectivity, and high enantioselectivity (up to 98:2 er). The
absolute stereochemistry of 3 was determined by X-ray
crystallography. In comparison with 3, compound 3′ equipped
with an AQ group was obtained in slightly diminished yield
and er under the same conditions. In comparison with cis-3-
hexenamide 1, the reaction of its trans alkene isomer, trans-1,
gave lactam product 7 in much lower yield (∼12%), with
excellent diastereoselectivity and slightly diminished enantio-
selectivity (91:9 er; absolute stereochemistry was not
determined) under the same conditions. As shown in Scheme
2B, a variety of cis-3-alkenamides bearing different terminal R
groups reacted with benzyl-DHPs to give the corresponding β-
lactams in good yields and with high er values under the
standard conditions. Terminal alkene (15), primary alkyl
chloride (16), and cyclopropyl (17) groups were tolerated.
The reaction of cis-3-phenyl-3-butenamide gave 19. This
chemoselectivity is different from that of many reported Cu-
catalyzed reactions in which the alkyl radical tends to attack
the outer position of aryl alkenes to form a more stable
benzylic radical intermediate. The structure of 19 was
confirmed by X-ray crystallography. (See the SI.) The reaction
of terminal alkene 3-butenamide with benzyl-DHP gave simple
β-lactam product 20 in good yield and with excellent
enantioselectivity. The reaction of 3-butenamide with 1-
phenylethyl-DHP gave 22 as a 1.1:1 diastereomeric mixture
at the benzylic position.
metric carbofunctionalization is mainly limited to the addition
of π nucleophiles such as indoles or enolates. This AQ-directed
reaction strategy has also been extended to other trans-
formations under the catalysis of different metals.12,13 Notably,
the Zhao group recently reported an interesting carboamina-
tion of alkenes with benzyl radicals under Cu catalysis.14 It was
proposed that benzyl radicals, generated from the in situ
hydrogen atom abstraction of methylarene (e.g., toluene), add
to alkene to form an AQ-chelated CuIII-metallacycle, which
undergoes intramolecular C−N reductive elimination to give a
β-lactam product. The reaction required relatively forced
conditions using the di-tert-butyl peroxide (DTBP, O1)
oxidant and methylarene as a solvent at 130 °C. Encouraged
by the study, we questioned whether we can develop a more
generally applicable and even enantioselective version of this
reaction under mild operating conditions.
We commenced our study with the model reaction of N-
quinolyl-cis-3-hexenamide (1) with 4-alkyl-1,4-dihydropyri-
dines (alkyl-DHP, Hantzsch esters), which recently have
emerged as excellent radical donors in various redox catalytic
systems (Table 1).15,16 The reaction of 1 and 2 equiv of Bn-
DHP (2) in the presence of 10 mol % Cu(MeCN)4PF6
catalyst, 2 equiv of O1 oxidant, and 20 mol % MOX in chiral
ligand L1 at 50 °C in 1,2-dichloroethane (DCE) gave the
desired product 3 in 12% yield, exclusive anti-diastereoselec-
tivity, and promising enantioselectivity (71:29 er) (entry 1).
Other oxazoline ligands such as MOXca L2 and BOX-type
ligands gave lower er values and yields. (See the SI for more
details.) Interestingly, diphosphine oxide BINAPO L5 gave
significant reactivity and enantio-induction enhancement (52%
1196
J. Am. Chem. Soc. 2021, 143, 1195−1202
Bai, Zibo
