Synthesis of (Z)-nitroalkene derivatives through oxidative dehydrogenation coupling of α-aminocarbonyl compounds with nitromethane by copper catalysis

Article abstract of DOI:10.1016/j.tetlet.2018.07.032

A novel copper-catalyzed cross-dehydrogenative coupling reaction of α-amino carbonyl compounds with nitromethane to synthesis of (Z)-nitroalkene derivatives has been established. (Z)-Nitroalkene derivatives are achieved through the cleavage of sp³ CsbndH bonds and formation of CsbndC double bond, with mild reaction conditions and excellent stereoselectivity.

Full text of DOI:10.1016/j.tetlet.2018.07.032

Accepted Manuscript
Synthesis of (Z)-Nitroalkene Derivatives through Oxidative Dehydrogenation
Coupling of α-Aminocarbonyl Compounds with Nitromethane by Copper Cat-
alysis
Menghua Zhu, De Chen, Sheng Zeng, Chenhu Xing, Wei Deng, Jiannan Xiang,
Rui-Jia Wang
PII:
S0040-4039(18)30906-7
https://doi.org/10.1016/j.tetlet.2018.07.032
TETL 50141
DOI:
Reference:
Tetrahedron Letters
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Revised Date:
Accepted Date:
23 May 2018
27 June 2018
11 July 2018
Please cite this article as: Zhu, M., Chen, D., Zeng, S., Xing, C., Deng, W., Xiang, J., Wang, R-J., Synthesis of
(Z)-Nitroalkene Derivatives through Oxidative Dehydrogenation Coupling of α-Aminocarbonyl Compounds with
Nitromethane by Copper Catalysis, Tetrahedron Letters (2018), doi: https://doi.org/10.1016/j.tetlet.2018.07.032
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Tetrahedron Letters
Synthesis of (Z)-Nitroalkene Derivatives through Oxidative Dehydrogenation
Coupling of α-Aminocarbonyl Compounds with Nitromethane by Copper Catalysis
Menghua Zhu,†a De Chen,†a Sheng Zeng,a Chenhu Xing,a Wei Deng,a Jiannan Xiang,*a Rui-Jia Wang*a,b
a State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha, 410082, P. R.
China
b School of Pharmacy,Hunnan University of Chinese Medicine, ChangSha,410208, P. R. China
† These authors contributed equally to this work.
* Corresponding author, e-mail: jnxiang@hnu.edu.cn; wangruijia@hnu.edu.cn.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A novel copper-catalyzed cross-dehydrogenative coupling reaction of α-amino
carbonyl compounds with nitromethane to synthesis of (Z)-nitroalkene derivatives has
been established. (Z)-Nitroalkene derivatives are achieved through the cleavage of sp3
C-H bonds and formation of C-C double bond, with mild reaction conditions and
excellent stereoselectivity.
Available online
Keywords:
α-Amino carbonyl compounds
Nitromethane
2018 Elsevier Ltd. All rights reserved.
(Z)-Nitroalkene
Cross-dehydrogenative coupling
Introduction
The direct cross-dehydrogenative coupling (CDC) of C-H processes is the most efficient and straightforward method in building
complex molecules starting from easily available materials[1]. Among the various CDC reactions[2], the direct formations of C-C
bonds by the cleavage of C(sp3)-H bond has been a long standing challenges in organic and bioorganic synthesis, because of their
low reactivity and selectivity problems[3]. Under the circumstances, C(sp3)-H bond adjacent to heteroatoms or double bonds has
been used to construct C-C bonds due to their special activity, direction and site-specificity over the past decades [4]
.
α-Amino carbonyl compounds is one kind of important bioactive compounds[5], and the oxidative functionalization of their C-H
bond at the α-position by C-C single bond has been investigated for some times. For example, in 2008, Li and co-workers firstly
reported that copper-catalyzed oxidative cross-coupling of N-aryl glycine amides derivatives with malonates formed C-C bond at α-
position[6a]. Subsequently, the oxidative α-alkylation of N-aryl glycine esters/amino ketones with unmodified ketones/ethers have
been reported respectively by Huang and Li[6b, 6c]. After some investigations[7], the α-amino carbonyl compounds and nitromethane
may also react under certain conditions to form C-C single bond at the α-position. However, to the best of our knowledge, the
example of oxidation of functionalized α-aminocarbonyl compounds with nitromethane to form C-C double bonds by CDC
reactions has not been exploited.Because of the strong electron-deficient property in their alkene part and simple conversion of nitro
group to amino or other heterocycles, Synthesis of six-membered saturated heterocycles such as piperidines, tetrahydropyrans,
piperidinones, piperazines, tetrahydro-1,2-oxazines and thiopyrans are conveniently accessible using nitroalkenes.Therefore,
nitroalkenes are regarded as one of the most common and important intermediates in modern synthetic organic chemistry[8].

Scheme 1. Cross-Dehydrogenative Coupling using α-Amino carbonyl
compounds as the raw materials
Herein, we wish to report our preliminary results on the synthesis of (Z)-nitroalkene derivatives through CDC reaction by
copper catalyst and tert-butyl hydrogen peroxide (TBHP).
Results and discussion
To begin our study, we examined various copper salts, oxidants, the amount of catalysts and oxidants, the reaction temperature,
and the atmosphere for the desired CDC reaction between 2-(phenylamino)-1-(p-tolyl)ethanone (1a) and nitromethane (2a, CH3NO2
) (Table 1). Among the copper salts tested, they all showed catalytic activity, and results indicated that the Cu(OAc)2 has the best
catalytic activity, which gave 58% yield of the desired product (Z)-3-nitro-2-(phenylamino)-1-(p-tolyl)prop-2-en-1-one (3a), using
CH3NO2 as solvent and TBHP as oxidant at 60°C under air (entries 1-8). It was also found that no reaction was observed in the
absence of the copper salt or oxidant (entries 9-10). The reactions using other oxidants are less effective (entries11-13). Then, a
screening of the amount of both Cu(OAc)2 and TBHP revealed that a combination of Cu(OAc)2 (5 mol%) with TBHP (2 equiv) is
the best choice (entries 14-17). It is worth noting that the highest yield could be achieved under oxygen atmosphere (entry 19),
however, the reaction almost stopped under the nitrogen atmosphere(entry 18). Finally, decreasing or increasing the reaction
temperature all lowered the product yield (entries 20-21). The structure of 3a was unambiguously identified by single-crystal X-ray
diffraction analysis (Figure1).
Figure 1. X-ray crystal structure of 3a.
Table 1. Optimization of the reaction conditions a
Entry
Catalyst ( mol %)
Oxidant (equiv)
T(oC)
Yield(%) b

Tetrahedron
4
1a
2a
CuI (10)
TBHPc (1)
TBHP (1)
TBHP (1)
TBHP (1)
TBHP (1)
TBHP (1)
TBHP (1)
TBHP (1)
TBHP (1)
--
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
25
80
42
30
CuBr (10)
3a
CuCl (10)
28
4a
CuCl2 (10)
25
5a
CuBr2 (10)
38
6a
Cu(acac)2 (10)
35
7a
Cu(OTf)2 (10)
Cu(OAc)2·H2O (10)
--
15
8a
58
9
trace
trace
21
10
11
12
13
14
15
16
17
18d
19e
20
21
Cu(OAc)2·H2O (10)
Cu(OAc)2·H2O(10)
Cu(OAc)2·H2O(10)
Cu(OAc)2·H2O(10)
Cu(OAc)2·H2O(10)
Cu(OAc)2·H2O(10)
Cu(OAc)2·H2O (5)
Cu(OAc)2·H2O (20)
Cu(OAc)2·H2O (5)
Cu(OAc)2·H2O (5)
Cu(OAc)2·H2O (5)
Cu(OAc)2·H2O (5)
DTBP(1)
H2O2 (1)
28
K2S2O8 (1)
TBHP (2)
TBHP (3)
TBHP (2)
TBHP (2)
TBHP (2)
TBHP (2)
TBHP (2)
TBHP (2)
7
63
44
65
52
trace
75
47
59
d
a Reaction conditions: 1a (0.3 mmol), [cat.], [O] and 2a (2 mL) at 60oC under air atmosphere for 4 h . b Isolated yields. c TBHP (70% aqueous solution).
under N2 atmosphere. e under O2 atmosphere.
Table 2. Reaction scope for the formation of (Z)-3-nitro-prop-2-en-1-one a,b
a Reaction conditions: 1a (0.3 mmol), Cu(OAc)2, H2O (5 mol%), TBHP(2 equiv,70% aqueous solution) and 2a (2 mL) under O2 atmosphere at 60 oC for
4 h. b Isolate yield. c N.D.= not detected.
With the optimal reaction conditions in hand (Table 1, entry 19), different sets of experiments were carried out to investigate the
scope and limitations of this reaction. Initially, the electronic and steric factors of the aryl group of 1-aryl-ethanone moiety did not
affect the reaction significantly under the standard reaction conditions (Table 2, 3b–3l). They could smoothly furnish the desired
products in 40%-73% yields. In addition, when the naphthyl replaced aryl group of 1-aryl-ethanone moiety, the reaction could still
be done to give the desired product 3m in 66% yield. Unfortunately, the 1-alkyl-ethanone (3n) and N-aryl-glycine ester (3o) were
unsuitable substrate for this reaction. Then, steric and electronic variations in the N-aryl moiety were tested. The results showed that
the steric factors of the aryl group of N-aryl moiety also have no obvious effect on the reaction (3p-3s). However, the electron-
withdrawing substituent could obviously prevent this reaction (3t). Finally, we attempted to use the less active nitroethane to
synthesize desired product 3u, but failed.
To understand the reaction mechanism, the following control experiments were designed. Firstly, the process of optimization
reaction conditions disclosed that the Cu(OAc)2, TBHP and oxygen were all necessary for the conversion of 1a into 3a (Table 1,
entry 9, 10, 18, 19). Furthermore, when a radical inhibitor TEMPO (2,2,6,6-tetramethylpiperidyloxy) was added to the reaction
system, the yield of the coupling product 3a decreased dramatically from 75% to less than 5%. Nitromethane radical, the key
intermediate in this transformation, was captured by TEMPO which was identified through GC-MS. This means that the reaction
may proceed by a radical mechanism (Scheme 2 Eq. (1)). Then, when the nitrogen was substituted, the desired product was not
detected (Scheme 2 Eq. (2)). Finally, the result in Eq.(3)(4) demonstrate that no imine intermediates were formed during the

reaction..
Scheme 2. Control Experiments
Based on our experimental results and previous reports[1-4, 6-7,10], we speculate that the reaction may be nitromethane radical
direct attack 1a through the intermediates A and Bto get the final product. the mechanism of the reaction is proposed, as shown in
Scheme 3. Single-electron transfer from copper (II) species to CH3NO2 in the presence of molecular oxygen forms nitromethane
cation radical. Water deprotonates this cation radical to produce nitromethane radical, which attacks 1a to result intermediate A,
followed by hydrogen atom abstraction from intermediate A with Cu2+(OH) which takes place to afford the intermediate
B.Subsequently, the formed intermediate B is split by copper (II) into an alkyl radical intermediate C, Finally, tert-butoxy radical
acts on radical intermediate C synthesize the desired product 3a.
Scheme 3. Plausible Mechanism
Conclusion
In summary, a simple and mild approach to the formation of the
new compound (Z)-3-nitro-prop-2-en-1-one by the α-aminocarbonyl
compound with nitromethane has been reported. The reaction is
characterized by forming a carbon-carbon double bonds through
oxidative cross coupling between the C(sp3)-H bond of nitromethane
and the α-C-H bond of the α-aminocarbonyl compound to generate a
new α-amino group carbonyl nucleus. Most importantly, the
synthesis of this novel nitroalkene compound broadens the use value
of α-aminocarbonyl compounds, making it more research
significance.
Acknowledgment
We are grateful for financial support from the National Natural Science Foundation of China (Nos. 21502049 and 51573040), the
Planned Science and Technology Project of Hunan Province, China (No. 2015WK3003).
Supplementary data
Supplementary data associated with this article can be found, in
the online version
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Highlights:
Synthesis of new bioactive compound (Z)-Nitroalkene Derivatives.
A novel method for constructing double C-C bonds through cross coupling of C(sp3)-H bond.
The direct cross-dehydrogenative coupling between Nitromethane and α-Aminocarbonyl Compounds.
The reaction conditions are mild and have excellent stereoselectivity.

Tetrahedron
8
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Synthesis of (Z)-Nitroalkene Derivatives through
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Oxidative Dehydrogenation Coupling of
α-Aminocarbonyl Compounds with Nitromethane by Copper Catalysis
Menghua Zhu,†a De Chen,†a Sheng Zeng,a Chenhu Xing,a Wei Deng,a Jiannan Xiang,*a Rui-Jia Wang*a,b