802
Ruan et al. Sci China Chem May (2021) Vol.64 No.5
a)
Table 1 Optimization of reaction conditions
reliably and selectively perform the late-stage functionali-
zation of specific benzylic C‒H bonds in more complicated
compounds. The reaction also exhibited acceptable tolerance
of alkylbenzenes carrying a longer side chain (6–8). Grati-
fyingly, the azolation of different electronic diphe-
nylmethanes gave corresponding products in excellent yields
(9–11). The structure of product 9, benzylated on N2-site of
tetrazole, was unambiguously confirmed by single-crystal X-
ray diffraction studies. Thereafter, we investigated the effect
of substituents on alkylbenzene. Thus, the robust nature of
the electrooxidative azolation was reflected by fully toler-
ating a wealth of valuable functionalities, including sensitive
alcohols (15), esters (12–14), aliphatic nitriles (16), ketones
b)
Entry
Deviation from standard conditions
none
Yield (%)
1
2
3
4
5
6
7
8
9
83
61
75
56
nBu NBF instead of nBu NHSO
4
4
4
4
Et NClO instead of nBu NHSO
4
4
4
4
MeCN/H O (9:1) instead of MeCN
2
c)
MeOH instead of MeCN
23 °C instead of 80 °C
0
60
39
0
(17 and 18), amides (19 and 20), and acetals (24), which
10 mol% of Cp Fe was added
2
could serve as a handle for future late-stage modifications. It
is noteworthy that the reaction displayed a highly site se-
lectivity on p-alkoxy-activated benzylic positions (21–24).
To our delight, the strategy for the direct electrochemical
benzylic C‒H amination of azoles proved to be suitable for
the substrates with various alkoxyl (23–25), ortho-methoxyl
(26), phenoxyl (27) and morpholine- (28 and 29) substituted
benzenes as well as xanthenes (30). However, the electron
poor aromatics were not suitable substrates for the trans-
formation. Notably, the desired product was obtained by
directly employing a radical scavenger BHT (2,4-di-tert-
butyl-4-methylphenol) as a benzylic reactant (31).
10 mol% of 1,4-benzoquinone was added
Pt as anode
70
0
10
no electricity
a) Reaction conditions: undivided cell, graphite anode (1.0 cm×1.0 cm×
.2 cm), Pt cathode (1.0 cm×1.0 cm×0.01 cm), 1a (1.5 mmol), 2a
0.5 mmol), nBu NHSO (0.5 mmol), MeCN (5.0 mL), constant current=
mA, 12 h (7.2 F mol ), 80 °C. b) Yields of isolated products. c) 4′-
0
(
8
4
4
−
1
methoxyacetophenone was isolated.
constant current of 8 mA in an electrolyte solution of nBu4-
NHSO in MeCN, at 80 °C, under atmospheric conditions for
4
1
2 h without additional catalysts or bases (Table 1, entry 1).
Furthermore, encouraged by these exciting results, the
scope of the reaction with respect to azole nucleophiles in the
electrochemical amination approach was also investigated
(Scheme 3). Various substitutents on the 5-phenyl-tetrazoles,
including methyl (32), fluoro (33), chloro (34), carboxyl (35
and 36) at the para- or meta-position of the phenyl ring, were
found to be fully tolerated by the optimized electrooxidation.
The practical utility of our approach was further illustrated
by successfully performing the desired azolation with N-
heterocycle and benzyl substituted tetrazoles in good yields
(37–39). Remarkably, the biphenyl substituted tetrazoles
resulted in a mixture product of benzylation on N2 and N4
positions, which could be isolated by column chromato-
graphy, probably due to the steric hinderance or electronic
properties (40). In addition, it is particularly noteworthy that
other nucleophiles such as simple tetrazoles (41), imidazoles
(42), indazoles (43) and triazoles (44–51), were well suited
to the robust metal- and oxidant-free electrooxidation pro-
tocol to generate a series of products of benzylic C‒H ami-
nation. These observations mirror the unique potential for
applications in the late-stage azolation in the building of
diversity decorated bioactive compounds.
The use of an alternative electrolyte, such as nBu NPF and
Et NClO , showed a moderate to good efficacy (entries 2‒3).
The choice of solvent was found to be essential for the re-
action to achieve the optimal yield. The use of a mixed
solvent of MeCN/H O (9:1) resulted in a decreased yield of
4
6
4
4
2
5
6% (entry 4), as well as the solvent system of DCE/HFIP
developed by Xu (Table S1) [18]. Moreover, the replacement
of MeCN with MeOH completely shut down the azolation
reaction, occurring with the side-product formation of 4′-
methoxyacetophenone (entry 5). Reducing the temperature
to 23 °C exhibited less effective (entry 6). In addition, per-
forming the transformation via indirect electrolysis manner
by the addition of redox mediators, such as Cp Fe or 1,4-
benzoquinone, resulted in an extremely low conversion
2
(entries 7‒8). Notably, a 70% yield of 3 was still obtained
when using a Pt anode (entry 9). Further control experiments
verified the essential role of the external electricity (entry
1
0).
After establishing the optimal reaction conditions for the
electrooxidative azolation, we next explored its versatility of
a set of representive benzylic substrate 1 with tetrazole 2a
(
Scheme 2). The electrolysis reaction exhibited good com-
The practical utility of our benzylic C‒H azolation ap-
proach was further demonstrated by the gram-scale synthesis
of 3, in which larger electrodes and higher constant current
(160 mA) were employed to ensure the conversion in 12 h
(Scheme 4).
patibility with secondary benzylic positions, primary C‒H
bonds as well as tertiary sites to afford desired products (3–
5
), overcoming competitive overoxidation problems in the
photoredox catalytic system. This result allows chemists to