Blue light-promoted cyclopropenizations of N-tosylhydrazones in water

Article abstract of DOI:10.1016/j.cclet.2021.05.031

Carbene transfer reactions play an important role in the field of organic synthesis because of their ability to construct a variety of molecules. Herein, we reported on blue light-induced cyclopropenizations of N-tosylhydrazones in water, which avoids the use of expensive metal-based catalysts and toxic organic solvents. This metal-free and operationally simple methodology enable highly efficient cyclopropenizations, X-H insertion reactions, and cyclopropanation under mild reaction conditions.

Full text of DOI:10.1016/j.cclet.2021.05.031

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Contents lists available at ScienceDirect
Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
Communication
Blue light-promoted cyclopropenizations of N-tosylhydrazones in
water
Kaichuan Yan, Hua He, Jianglian Li, Yi Luo, Ruizhi Lai, Li Guo∗, Yong Wu∗
Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Department of Medicinal Chemistry, Sichuan Engineering
Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan
University, Chengdu 610041, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Carbene transfer reactions play an important role in the field of organic synthesis because of their abil-
ity to construct a variety of molecules. Herein, we reported on blue light-induced cyclopropenizations of
N-tosylhydrazones in water, which avoids the use of expensive metal-based catalysts and toxic organic
solvents. This metal-free and operationally simple methodology enable highly efficient cyclopropeniza-
tions, X-H insertion reactions, and cyclopropanation under mild reaction conditions.
Received 10 March 2021
Revised 10 May 2021
Accepted 16 May 2021
Available online xxx
Keywords:
© 2021 Published by Elsevier B.V. on behalf of Chinese Chemical Society and Institute of Materia
Medica, Chinese Academy of Medical Sciences.
N-Tosylhydrazone
Carbene
Metal-free
Cyclopropenization
Cyclopropanation
Carbene transfer reactions are powerful synthetic tools in or-
ganic synthesis and open up a new window of reactivity patterns
ranging from cross-coupling reactions [1–3]; rearrangement reac-
tions [4–11], X-H insertion reactions [12–18], cycloadditions [19–
–
24] to C H activations [8,25–29] (Scheme 1a). In the past few
decades, although remarkable achievements have been made in
carbene transfer reactions, the presence of expensive metal-based
catalysts and toxic organic solvent limited their further develop-
ment [7,29–31]. In this context, the development of environmen-
tally benign transformations remains highly desirable.
Only recently, the visible light photolysis of diazoalkanes
has emerged as an important alternative to traditional metal-
catalyzed carbene-transfer reactions (Scheme 1a) [32–37]. Further-
more, identifying sustainable and safe carbene precursors has also
become one of the major tasks in the field of carbene transfer reac-
tions. In this regard, hydrazones have become especially important
carbene precursors through in situ generated diazo intermediates.
Compared with diazo compounds, hydrazones are more stable, less
explosive, and they can be easily prepared from aldehydes or ke-
tones [31]. Consequently, we reasoned the possibility that carbene
transfer reactions initiated by the visible light photolysis of hydra-
zones, which has recently been verified by the works of Koenigs
et al. and ourselves, respectively (Scheme 1b) [34,38–42].
Scheme 1. Carbene transfer reactions.
∗
On the other hand, cyclopropenes, as strained carbocyclic com-
pounds, are widely used synthons in organic synthesis due to their
Corresponding authors.
E-mail addresses: guoli@scu.edu.cn (L. Guo), wyong@scu.edu.cn (Y. Wu).
https://doi.org/10.1016/j.cclet.2021.05.031
1001-8417/© 2021 Published by Elsevier B.V. on behalf of Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.
Please cite this article as: K. Yan, H. He, J. Li et al., Blue light-promoted cyclopropenizations of N-tosylhydrazones in water, Chinese
Chemical Letters, https://doi.org/10.1016/j.cclet.2021.05.031

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Table 1
Optimization of the reaction conditions.a
Entry
Base
Solvent
1a:2a (molar)
Yield (%)b
1
–
DCM
DCM
DCM
DCM
DCM
DCM
DCE
Tol
1:4
1:4
1:4
1:4
1:4
1:4
1:4
1:4
1:4
1:4
1:4
1:7
1:10
1:12
trace
33
32
30
38
55
54
54
43
0
2
KOH
t-BuOK
K2CO3
DBU
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
3
4
5
6
7
8
9
PhCl
HFIP
H2O
H2O
H2O
H2O
10
11
12
13
14
66
73
88
82
a
Reaction conditions: 1a (0.1 mmol), 2a (1.0 mmol), and Et3N (2.0 equiv.)
were dissolved in 1 mL of solvent indicated and were irradiated at room
temperature with blue LEDs (10 W, 470 nm) for 24 h.
b
Isolated yield.
high reactivity [43,44]. A particularly practical reaction to access
cyclopropylenes is the cyclopropenization reaction of alkynes, for
which a variety of expensive, precious metal catalysts, based on
AuII, RhII, IrI, and AgI have been reported [45–48]. Also, a metal-
free cyclopropenization reaction using tosylhydrazones has been
reported, despite the shortcomings of low yields and elevated tem-
perature [34,40,49–51]. In the context of the development of en-
vironmentally benign methods for the synthesis of cyclopropy-
lenes and our previous work, herein we developed a blue light-
induced cyclopropenization reaction of N-tosylhydrazones with
alkynes (Scheme 1c). Notably, this is the first report on light-
induced metal-free cyclopropenizations of N-tosylhydrazones in
water.
Scheme 2. Substrate scope of N-tosylhydrazones and alkynes. Reaction conditions:
1 (0.1 mmol), 2 (1.0 mmol) and Et3N (2.0 equiv.) were dissolved in 1.0 mL of H2O
and were irradiated at room temperature with blue LEDs (10 W, 470 nm) for 24 h.
Isolated yield by chromatography on silica gel.
3aa). Among them, the electronic effect of substituted functional
groups had a strong influence on the yields of target compounds,
which mainly manifested that the transformation efficiency of the
electron-withdrawing substituents was generally lower than that
of electron-donating substituents. Surprisingly, styrenes possessing
fluorine at the benzene ring were exceptions and afforded the cor-
responding cyclopropenes in 83% and 91% yields (3k, 3l), respec-
tively. It is worth mentioning that N-tosylhydrazone and alkyne
substituted by naphthalene had poor compatibility with optimal
conditions, and their corresponding cyclopropylenes were achieved
in yields of 52% and 52% (3r, 3ad). Besides, we explored other
substrates such as heterocyclic terminal alkynes, alkynes bearing
electron-withdrawing groups, and non-aromatic terminal alkynes.
Unfortunately, they were not suitable for this reaction condition,
and no expected cyclopropenes were obtained (2ae-2aj).
Furthermore, other carbene transfer reactions involving the
visible light photolysis of N-tosylhydrazones, such as X-H inser-
tions and cyclopropanations were proved to compatible with these
water-mediated conditions.
Initially, the blue-light-mediated cyclopropenization of N-
tosylhydrazone 1a (0.1 mmol) and phenylacetylene 2a (10 equiv.)
was examined in dichloromethane (DCM) at 25 °C without the
base. Unfortunately, no desired product was detected (Table 1, en-
try 1). Surprisingly, required methyl 1,2-diphenylcycloprop-2-ene-
1-carboxylate (3a) was obtained in yields ranging from 30% to 55%
when using KOH, t-BuOK, K2CO3, Et3N, and DBU as bases, and Et3N
gave the best result (entries 2–6). After that, we further screened
the solvent (entries 6–11), and the results showed that the reaction
proceeded smoothly in water delivering the desired product in 66%
isolated yield (entry 11). Besides, we investigated the equivalents
of phenylacetylene and found that adding 10 equiv. of phenylacety-
lene significantly increased the yield of the target product (entry
13). Finally, through a detailed investigation of the amount of base
and the reaction concentration, we have obtained the optimal re-
action conditions.
Based on the success of the light-mediated cyclopropeniza-
tions of N-tosylhydrazones in water, we further studied the ap-
plicability of this optimal condition to other carbene transfer re-
actions. First, we investigated the insertion reactions between N-
tosylhydrazones and X-H bonds (Scheme 3). Primarily, we focused
on testing N-tosylhydrazones and a variety of aromatic amines. The
results showed that under the optimal conditions, both monosub-
stituted and disubstituted aromatic amines reacted smoothly with
N-tosylhydrazones, and all the expected amino acid ester products
were obtained in good to excellent yields (5a-5n). However, naph-
thalamine reacted with N-tosylhydrazons and afforded the desired
product in 66% yield under these conditions (5o). Unfortunately,
other aliphatic thiols, alcohols, phenols and amines did not pro-
vide the expected products. (4r-4v). Besides, we investigated the
With the optimized conditions in hand (Table 1, entry 13),
we next explored the functional group tolerance of both the N-
tosylhydrazones 1 and alkynes 2 (Scheme 2). In general, sub-
strates with different substituents were compatible with the op-
timized reaction conditions, and the corresponding cyclopropy-
lenes were obtained with moderate to excellent yields (3a-
2

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Scheme 4. Substrate scope of N-tosylhydrazones and aryl olefins. Reaction condi-
tions: 1 (0.1 mmol), 6 (1.0 mmol), and Et3N (2.0 equiv.) were dissolved in 1.0 mL of
H2O and were irradiated at room temperature with blue LEDs (10 W, 470 nm) for
24 h. Isolated yield by chromatography on silica gel.
Scheme 3. Substrate scope of N-tosylhydrazones and X-H bonds.
reaction of N-tosylhydrazons with monosubstituted aryl thiophe-
nols, and the corresponding products were obtained with moder-
ate yields (5p, 5q).
Reaction conditions:1 (0.1 mmol), 4 (0.4 mmol), and Et3N (2.0
equiv.) were dissolved in 1.0 mL of H2O and were irradiated at
room temperature with blue LEDs (10 W, 470 nm) for 24 h. Iso-
lated yield by chromatography on silica gel.
Scheme 5. 10-Fold scale-up reaction.
Besides, we tested the cyclopropane reactions between N-
tosylhydrazones and aryl olefins in water (Scheme 4). The results
show that the reaction of N-tosylhydrazones and aryl olefins can
be successfully achieved under optimal conditions. Target products
can be obtained more efficiently than we previously reported in
DCM (7a-7n). Unfortunately, alkenes bearing following functional
groups, such as methyl acrylate, acrolein, acrylonitrile, did not pro-
vide the expected products (6o-6q).
To further study the efficiency and practicality of this trans-
formation, a 10-fold scale-up of the reaction was conducted in
50 mL of H2O. The desired product 3a was isolated with 74% yield
(Scheme 5).
According to the existing literatures [30,39,52,53], The mech-
anism proposed for this reaction comprises the following steps
(Scheme 6): 1) decomposition of the hydrazone in the presence
of the base to form the diazo compound, 2) and then formation of
Scheme 6. Proposed mechanism.
would contribute to broadening the applications of free carbene in
organic synthesis.
–
a carbene intermediate under blue light irradiation, 3) C C bond
formation by carbene migration insertion of the alkyne, alkene or
other X-H bonds with loss of nitrogen to give the final product.
In summary, we reported on metal-free carbene transfer reac-
tions of N-tosylhydrazones in water, which were induced by low
energy blue light. Notably, this methodology allowed efficient cy-
clopropenizations, X-H insertion reactions (X = N, S), and cyclo-
propanations in the context of environmental harmony. We firmly
believe that this water-mediated photolysis of N-tosylhydrazones
Declaration of Competing Interest
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared to
influence the work reported in this paper.
3

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