Organic Letters
Letter
1
visible-light-induced approach. However, the direct insertion of
a free carbene into benzotriazole is not expected to improve
the site-selectivity of the N-alkylation. This is indirectly
evidenced by the recently reported visible-light-induced N−
chloranil, resulted in inferior N -selectivity and slight increase
of the dimer (Table 1, entries 2 and 3). It is worth noting that
in the absence of one or both of PBQ and TBN the N -
1
selectivity is decreased considerably (Table 1, entries 4−6).
These results indicate that it is the presence of both PBQ and
TBN that accounts for the high site-selectivity. The results of
replacing PBQ with other organic photosensitizers were
comparable to those without PBQ and TBN, which further
proves the unique effect of PBQ on site-selectivity in this
transformation (see the SI). Moreover, the yield of 3aa was
decreased under argon or oxygen atmosphere, indicating trace
amounts of oxygen are beneficial to this reaction (Table 1,
entries 7 and 8). Control experiments showed that no reaction
occurred at all in the dark, demonstrating that light is necessary
for this transformation (Table 1, entry 9). In addition, we also
examined a series of metal catalysts under ordinarily thermal
conditions, such as those based on Rh, Pd, Cu and Ag which
are commonly used in carbene transfer reactions. A mixture of
3aa and 4aa was obtained by silver trifluoromethanesulfonate,
showing poor site-selectivity, while almost no reaction
occurred in other cases. (For details, see the SI.) This further
shows the unique advantage of this protocol.
11a
H insertion of diazo compounds to 1,2,3-triazoles.
It is believed that the stability of N-centered radicals of
benzotriazole at different sites may be different. Upon
quantum-chemical calculations, we found that the energy of
1
2
N -benzotriazole radical is 9.0 kcal/mol lower than that of N -
benzotriazole radical (see the SI). In view of the significant
1
2
stability difference between the N - and N -centered
benzotriazole radicals, we speculated that the N -selective
1
N−H insertion of diazo compounds into benzotriazoles could
be achieved by a radical pathway under photocatalytic
1
6
1
conditions. There, a reaction of a stabilized N -centered
benzotriazole radical with a in situ generated carbene would
1
take place to afford N -selective alkylation, rather than the
nonselective carbene to N−H insertion reaction. Herein, we
report the successful implementation of this strategy, which
1
enables highly site-selective N -alkylation of benzotriazole with
diazo compounds under mild and metal-free conditions
(
Scheme 1b).
To investigate the feasibility of the proposed concept, the
To demonstrate the versatility of the developed protocol, we
investigated the substrate scope under the optimal reaction
conditions. Initially, a variety of α-diazoacetates (2a−2y) were
examined by the reaction with benzotriazole (1a), as illustrated
in Scheme 2. The methyl diazoacetates (2a−2l) with the α-
phenyl bearing either electron-donating or electron-with-
drawing groups reacted smoothly under the established
conditions, affording the alkylated products 3aa−3al in good
reaction of benzotriazole (1a) with methyl α-phenyldiazoace-
tate (2a) was chosen as the model reaction and performed at
room temperature (Table 1). After a great deal of experimental
a
Table 1. Optimization of Reaction Conditions
1
to excellent yields with exclusive N -selectivities. Expanding the
scope from methyl diazoacetates to other alkyl α-phenyl-
diazoacetates, including a broad range of linear, branched,
cyclic and functionalized alkyls, was also successful, leading to
the corresponding products 3am−3au without obvious effect
on the yield and selectivity. Gratifyingly, the diazoesters
derived from menthol, diacetone-D-glucose and nerol success-
b
entry
variation
yield (%) of 3aa/4aa
c
1
2
3
4
5
6
7
8
9
none
93 (88) /4
DDQ instead of PBQ
p-chloranil instead of PBQ
without PBQ and TBN
without PBQ
71/22
74/15
56/30
63/29
71/21
78/13
76/15
0/0
1
fully underwent the reaction to afford the N -alkylation
products 3av−3ax, indicating that this protocol could be
utilized for the late-stage diversification of natural products or
bioactive molecules. Additionally, ethyl diazoacetate was well
tolerated and gave the desired product 3ay in high yield.
Next, the scope with respect to substituted benzotriazoles
and other aromatic N-heterocycles was investigated by the
reactions with methyl α-phenyldiazoacetate (2a), as illustrated
in Scheme 3. We were pleased to observe that the
benzotriazoles bearing various substituents reacted smoothly
and led to the desired N-alkylated products 3ba−3ha in up to
91% yield. It should be noted that in the cases of 3ba, 3da and
without TBN
under O2
under N2
in the dark
a
Reaction conditions: 1a (0.3 mmol), 2a (0.51 mmol, 1.7 equiv) in
DCM (2 mL) with irradiation by 7 W blue LED at rt for 48 h. Yield
was determined by H NMR analysis of the crude mixture using
CH Br as an internal standard. Isolated yield in parentheses.
b
1
c
2
2
delightedly found that using the cheap, readily accessible 1,4-
benzoquinone (PBQ) as the catalyst and performing the
reaction in the presence of a catalytic amount of tert-butyl
nitrite (TBN) in dichloromethane under 7 W blue LED
irradiation led to the desired N -alkylated product 3aa in 93%
NMR yield and 88% isolated yield in 48 h (Table 1, entry 1).
Notably, only 4% of N -alkylated product 4aa was found, and
only trace amounts of the dimer of 2a were detected. The
UV−vis absorption spectra of PBQ, TBN, 1a, and 2a in
dichloromethane show that PBQ and 2a have significant
absorption in the blue light region, while 1a and TBN have no
or only a small part of absorption in the visible-light region
1
3
3fa, a mixtures of N - and N -alkylated products were
obtained. Notably, some other aromatic N-heterocycles, such
as indazole, indole and pyrazole derivates, also successfully
1
7
1
underwent the reaction, affording the corresponding N -
1
alkylated products 3ia−3ma in high yields. These results
further show the broad applicability and the high chemo- and
site-selectivity of the current approach.
2
10h
To illustrate the practical application of this blue light-
1
induced highly site-selective N -alkylation of benzotriazoles,
the reactions of 2a and 2y with 1a were performed in a gram-
scale under the standard conditions, affording 3aa and 3ay
with satisfactory yields (Scheme 4). Importantly, this method
has the potential to synthesize useful building blocks from
readily available starting materials, as the ester groups in the
(
see the SI). Replacing PBQ with other quinone catalysts, such
as 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) or p-
B
Org. Lett. XXXX, XXX, XXX−XXX