Blue Light-promoted Carbene Transfer Reactions of Tosylhydrazones

Article abstract of DOI:10.1002/asia.202000378

Metal-free photochemical carbene-transfer reactions of tosylhydrazones were developed under blue light irradiation at room temperature. This reaction constructs C?X (X=C, N, O, S) bonds and cyclopropanes from readily available and stable starting material

Full text of DOI:10.1002/asia.202000378

CHEMISTRY
AN ASIAN JOURNAL
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Accepted Article
Title: Blue light-promoted carbene transfer reactions of
tosylhydrazones
Authors: Yingying Xu, Guanghui Lv, Kaichuan Yan, Hua He, Jianglian
Li, Yi Luo, Ruizhi Lai, Li Hai, and Yong Wu
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To be cited as: Chem. Asian J. 10.1002/asia.202000378
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10.1002/asia.202000378
Chemistry - An Asian Journal
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Blue light-promoted carbene transfer reactions of
tosylhydrazones
Yingying Xu,[a] Guanghui Lv,[b] Kaichuan Yan,[a] Hua He,[a] Jianglian Li,[a] Yi Luo,[a] Ruizhi Lai,[a] Li Hai*[a]
and Yong Wu*[a]
[a]
[b]
Y. Xu, K. Yan, H. He, Dr. J. Li, Y. Luo, R. Lai, Dr. L. Hai, Prof. Dr. Y. Wu
Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, 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.
E-mail: wyong@scu.edu.cn
G. Lv
Department of Pharmacy, Taihe Hospital, Hubei University of Medicine, No. 32 South Renmin Road, Huibei, Shiyan 442000, P. R. China
Supporting information for this article is given via a link at the end of the document.
Abstract: Metal-free photochemical carbene-transfer reactions of
tosylhydrazones were developed under blue light irradiation at room
temperature. This reaction constructs C-X (X= C, N, O, S) bonds and
cyclopropanes from readily available and stable starting materials.
etc.) catalysts have also been shown to promote the carbene-
transfer reactions.8 Furthermore, light-promoted photolysis of
aryldiazoacetates opens up a new window of chemical reactivity
that leads to the metal-free functionalization of carbene
precursors (Scheme 1b).9 Identifying sustainable and safe
surrogates for the generation of metal carbenes promotes the
further development of carbene transfer reactions. Hydrazones,
triazoles, cyclopropenes, sulfonium ylides, enynes, allenes and
other starting materials have been successfully exploited as
carbene precursors under various conditions.7a Among them,
hydrazones, especially N-tosylhydrazones are particularly valued
by chemists. N-tosylhydrazones can generate diazo compounds
in situ under basic conditions (Scheme 1c). Tosylhydrazones,
which are readily available from aldehydes or ketones, are more
stable than diazo compounds. Since the early applications,
enormous progress has been achieved in the realm of N-
tosylhydrazone chemistry.10
In the past few decades, carbene-transfer reactions of diazo
compounds have received widespread attention in academia and
chemical industry fields for allowing the straightforward
preparation of a variety of molecules.1 Metal carbenes typically
generated in situ from diazo compounds possess versatile
reactivities,
such
as
cycloadditions,2
insertions,3
5
rearrangements,4 cross-coupling reactions and C-H activations
6
(Scheme 1a). However, expensive metal-based catalysts and
explosive starting materials have somewhat limited their further
Herein, we describe the blue-light-induced carbene-transfer
reactions of N-tosylhydrazones under basic conditions (Scheme
1d). This procedure does not require metal-based catalysts and
avoids the use of explosive diazo compounds. Although
photochemical studies with hydrazones have been performed
before,11 light-induced carbene-transfer reactions of N-
tosylhydrazone remains undeveloped.12
This study was started with the model reaction of N-
tosylhydrazone 1a with 4-methoxyaniline 2a under blue-light
irradiation. Unfortunately, no desired product was detected (Table
1, entry 1). Subsequently, we tried to add different kinds of bases
to activate the reaction (entries 2-7). To our delight, using Cs2CO3,
Et3N, K2CO3 as the bases, the required α-amino acid ester 3a was
obtained in yields ranging from 64% to 83%, and Et3N gave the
best result. The screening of solvents showed that DCM appeared
to be the best solvent for this reaction, whereas other solvents like
DCE, THF and PhCl were found to be less effective (entries 8-10).
Through detailed investigation of the amount of base, the
equivalent of 2a and the reaction concentration, we have obtained
Table 1. Optimization of Reaction Conditions. a
development.7
Scheme 1. Carbene-transfer reactions.
In contrast to the numerous protocols reported on noble
transition metals, some nonprecious metal-based (Cu, Co, Ag,
1
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a Reaction conditions:1 (0.1mmol), 2 (0.4mmol) and additives (1.5 equiv) were
dissolved in 1.5 mL of DCM and were irradiated at room temperature with blue
LEDs (10 W) for 24 h. Isolated yield by chromatography on silica gel
Entry
Additives
Solvent
1a: 2a ratio
Yield b
1
-
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCE
THF
1: 1.5
1: 1.5
1: 1.5
1: 1.5
1: 1.5
1: 1.5
1: 1.5
1: 1.5
1: 1.5
1: 1.5
1: 2
0
the optimal reaction conditions (entry 12). In addition, a blank
experiment in the absence of light proved that light was necessary
for the reaction (entry 14).
2
KOH
LiOt-Bu
n-Bu4NI
Cs2CO3
Et3N
0
3
0
With the optimized conditions in hand, we next investigated the
functional group tolerance of both the N-tosylhydrazone 1 and
anilines 2 (Scheme 2). Primarily, we focused on testing a wide
variety of monosubstituted aryl anilines with N- tosylhydrazone.
Most of monosubstituted aryl anilines bearing both electron-
donating and electron-withdrawing groups on the benzene ring
reacted smoothly, and the corresponding α-amino acid esters
products were obtained in good to excellent yields (3a-3j).
Compared with chlorine-substituted anilines, the yields of bromine
and fluorine-substituted anilines were lower (3k-3i). Surprisingly,
nitro-substituted aniline was not suitable for this reaction condition,
and no corresponding amino acid ester was obtained (3m).
Considering the variety of poly-substituted anilines, we also
tested some disubstituted anilines. The results showed that the
yields of disubstituted aromatic amines were generally lower than
monosubstituted aromatic amines (3n-3s). Furthermore, we have
investigated N-tosylhydrazones possessing different substituents
4
0
5
72
83
64
41
49
67
75
90
88
0
6
7
K2CO3
Et3N
8
9
Et3N
10
11
12
13
14c
Et3N
PhCl
DCM
DCM
DCM
DCM
Et3N
Et3N
1: 4
Et3N
1: 5
Et3N
1: 4
Scheme 3. Scope of N-tosylhydrazones and X−H bonds. a
a. Reaction conditions: 1a (0.1mmol), 2a and additives (1.5 equiv) were
dissolved in 1.5 mL of solvent indicated and were irradiated at room temperature
with blue LEDs (10 W) for 24h. b Isolated yield. c in the absence of light.
Scheme 2. Scope of N-tosylhydrazones and amines. a
a Reaction conditions:1 (0.1mmol), 4 (0.4mmol) and additives (1.5 equiv) were
dissolved in 1.5 mL of DCM and were irradiated at room temperature with blue
LEDs (10 W) for 24 h. Isolated yield by chromatography on silica gel.
2
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10.1002/asia.202000378
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and found that they all gave corresponding products with
moderate to good yields (3t-3v).
Keywords: Tosylhydrazones • Carbene • Photochemistry • X-H
insertions • Cyclopropanation
Due to the successful N-H insertion reaction between N-
tosylhydrazone and aromatic amines, we also investigated the
insertion reactions between N-tosylhydrazone and X−H bonds
(Scheme 3). The results showed that the reaction of aromatic
thiophenols and aromatic acids could also be amenable to the
reaction and the corresponding products were obtained with low
to moderate yields (5a-5h). In addition, N-tosylhydrazone can
also react with N-heterocyclic compounds such as N-methyl
indole and pyrrole for C-H insertion(5i-5j).
In addition, we also investigated the cyclopropanation between
N-tosylhydrazones and aryl olefins (Scheme 4). The results
showed that the reaction of N-tosylhydrazones with aryl olefins
could be successfully implemented under the optimal conditions,
the corresponding products could only be obtained at relatively
low yields but high diastereoselectivities (7a-7e).
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In conclusion, we have successfully developed the blue-light-
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carbene trapping agents. In the presence of a variety of partners,
a variety of products of X-H (X = N, O, S and C) insertions and
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under visible light irradiation conditions. Compared with previous
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reaction conditions. Based on this strategy, it is expected that
more applications for the photochemical carbene transfer
reactions of tosylhydrazones will be applied.
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Acknowledgements
We are grateful for the support from the National Natural Science
Foundation of China (Grant No: 81373259; 81573286).
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Entry for the Table of Contents
Metal-free photochemical X-H insertions and cyclopropanelation of tosylhydrazones were developed
under blue light irradiation at room temperature.
5
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