Organic Letters
Letter
5
′ neolignan analogs in good to excellent yields. The
Scheme 3. Scope for Synthesis of 8−O−4′ Neolignan
a
unsubstituted precursor was also oxidized in good yield to its
corresponding cyclized product (3f). para-Coumaryl alcohol,
one of the phenylpropenoid monolignol units of lignin, was
suitable for producing 3g in 81% yield. The alkenyl phenol
bearing an ethyl group in the β position exhibited high
reactivity (3h). Pterostilbene, a dimethyl ether derivative of
resveratrol, could afford adduct 3i in 36% yield. A terminal
alkene worked well to generate the expected 3j in good yield.
Interestingly, N,N-dimethyl-4-(prop-1-en-1-yl)aniline was also
a useful substrate to give product 3k in moderate yield due to
its formation of a resonance-stabilized free radical intermedi-
ate. ortho-Alkenyl phenols substrate was also found to be
suitable for the reaction to afford the expected product 3l albeit
with less efficiency. The nonreactivity of 1n may attribute to its
Analogs
ox
Encouraged by the above results, we next switched our
attention to investigate the scope of electron-rich phenols.
Various N-substituted 4-aminophenols (3m−3o, 3q−3t) were
well accommodated. Unfortunately, 4-methoxyphenol 2k
ox
(
Ep/2 = 1.06 V vs Ag/AgCl) failed to participate in this
reaction most likely due to the inferior efficiency for the single-
electron oxidation to generate the phenol radical intermediate.
Remarkably, the presence of an additional tert-butyl group at 4-
methoxyphenol afforded product 3p in 47% yield. 3-
a
ox
Reaction conditions: 1 (0.22 mmol), 2, phenoxazine or phenothia-
(
Dimethylamino)phenol 2l (Ep/2 = 0.58 V vs Ag/AgCl) has
zine (0.2 mmol), anilines (0.2 mmol), Cu(OAc) (8 mol %) were
added in 2 mL EA under air at rt, 12−24 h. MeOH as solvent.
2
a low oxidant potential but failed to give the product, probably
due to its non-formation of a resonance-stabilized phenol
radical compared with 2a (Ep/2 = 0.38 V vs Ag/AgCl).
b
ox
Interestingly, without 2a present, dimerization product Licarin
A was isolated in 60% yield. This suggests that the cross-
coupling between 1a and 2a proceeds much faster than the
homocoupling of 1a under the standard reaction conditions.
It was found that 8−O−4′ neolignan analog 5a could be
produced dominantly instead of 8−5′ coupling 3a when
15
nucleophile aniline was introduced into our copper(II)/air
catalyst system (Table S1). An increased yield was observed
(
92%, dr = 16:1) when ethyl acetate (EA) was used as the
solvent. With the optimized conditions in hand, we directed
our studies toward exploring the scope of this three-
component radical cross-coupling reaction. This effective
method exhibits good tolerance of a broad range of functional
groups. When using various anilines as nucleophiles, diverse
functionalized products could be achieved via the copper-
catalyzed aerobic coupling (5a−5g) (Scheme 3). The late-
stage modification of DL-α-Tocopherol was also feasible to give
the 8−O−4′ neolignan analog 5h in 90% yield. Moreover, we
found that phenoxazine as well as phenothiazine could also
take part in the three-component cross-coupling (5e−5g and
5
i). Other nucleophiles such as MeOH were also efficient in
this process, which afforded the corresponding adduct 5i in
supported by the radical trapping experiment with TEMPO to
give adduct 5j (Scheme 4c). Moreover, the desired products
were still obtained in satisfactory yields with 2 equiv of
5
0% yield.
To gain some insight into the reaction process, we carried
out a series of mechanistic studies. Methyl isoeugenol 1m
Cu(OAc) under Ar, suggesting that the oxygen might mainly
2
ox
(
Ep/2 = 0.97 V vs Ag/AgCl) failed to give product, although
function as the oxidant of the Cu(I) species (Scheme 4d).
Based on these results, a plausible mechanism is proposed in
Scheme 5. The proposed pathway of these reactions features
formation of Cu(II)-phenolates and subsequent single-electron
transfer to afford phenoxyl radicals and cuprous species which
could be oxidized to copper(II) by molecular oxygen. The key
step of the reaction is the selective radical cross-coupling of 1a-
II with 2a-I or 2a-II. The formation of 3a can be rationalized
the oxidant potential of 1m is comparable to isoeugenol 1a
ox
(
Ep/2 = 0.95 V vs Ag/AgCl), indicating that the phenolic OH
group is crucial to substrate activation (Scheme 4a). The
product 6 from 4g and 2a was achieved in our Cu/air catalyst
system (Scheme 4b), probably via a radical cross-coupling
16
process based on previous studies. Thus, the radical cross-
coupling pathway was likely involved, which was further
2
818
Org. Lett. 2021, 23, 2816−2820
Dong, Kui
