Copper-catalyzed one-pot oxidation-aldol/henry reaction of benzylic amines to α,β-unsaturated methyl ketone/nitro compounds

Article abstract of DOI:10.1055/s-0033-1338986

A novel one-pot synthesis of α,β-unsaturated methyl ketone/nitro compounds from benzylic amines through an oxidation-aldol/Henry reaction is reported. The reaction proceeded well by using MCPBA as oxidant and CuCl ₂·2H₂O as catalyst. A variety of functionalized α,β-unsaturated methyl ketone/nitro compounds were assembled in moderate yields by application of this catalytic one-pot reaction. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0033-1338986

2740▌
LETTER
lCettoerpper-Catalyzed One-Pot Oxidation–Aldol/Henry Reaction of Benzylic
Amines to α,β-Unsaturated Methyl Ketone/Nitro Compounds
Oxidation–Aldol/Henry Reaction of Benzylic Amines
Jia Liu,a,b Xiao-Rui Zhu,a Jiangmeng Ren,a,b Wei-Dong Chen,*b Bu-Bing Zeng*a,b,c
a
Shanghai Key Laboratory of New Drug Design, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237,
P. R. of China
b
Shanghai Key Laboratory of Chemical Biology, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237,
P. R. of China
Fax +86(21)64253689; E-mail: renjm@ecust.edu.cn; E-mail: zengbb@ecust.edu.cn
c
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, P. R. of China
Received: 01.08.2013; Accepted after revision: 09.09.2013
but-3-en-2-one (2a; Table 1, entry 2). By increasing the
Abstract: A novel one-pot synthesis of α,β-unsaturated methyl ke-
temperature to reflux (60 °C), only 2a could be isolated
tone/nitro compounds from benzylic amines through an oxidation–
(49% yield; Table 1, entry 3). When the amount of
MCPBA was increased to 1.5 equiv, benzaldehydeoxime
aldol/Henry reaction is reported. The reaction proceeded well by us-
ing MCPBA as oxidant and CuCl2·2H2O as catalyst. A variety of
functionalized α,β-unsaturated methyl ketone/nitro compounds C was the main product instead of the desired product 2a
were assembled in moderate yields by application of this catalytic
one-pot reaction.
(Table 1, entry 4).
Key words: aldol reaction, amines, copper, condensation, oxida-
tion
ref. 5
O
MCPBA, Na2CO3
0 °C, CH2Cl2
NH2
N
+
O
α,β-Unsaturated methyl ketone/nitro compounds, which
are not only present in many bioactive natural products1
but also serve as useful electrophilic species in a broad
range of chemical transformations such as Michael addi-
tion, cycloaddition and cross-coupling reactions,2 have
been drawing significant interest in the development of
new methods in organic synthesis. Such compounds are
generally obtained through aldol/Henry condensation of
acetone/nitromethane with aldehydes.3 A literature survey
revealed that oxidation of amines to aldehydes had al-
ready been reported.4 The wide availability of amines
prompted us to consider such compounds as viable sub-
strates for the oxidative preparation of the desired alde-
A
1a
O
O
+
+
NH3
B
this work:
O
MCPBA, CuCl2⋅2H2O
acetone, reflux
2a
3a
NH2
NO2
MCPBA, CuCl2⋅2H2O
1a
hydes. Moreover,
a one-pot oxidation-aldol/Henry
MeNO2, 60 °C
approach could eliminate the difficulties associated with
aldehyde separation and purification. In 1971, Blackman5
reported the oxidation of benzylamine (1a) to benzalde-
hyde by MCPBA through the acidic hydrolysis of an in-
termediate oxaziridine (Scheme 1). In this paper, the
oxidation of benzylic amines and its condensation with
acetone/nitromethane to form α,β-unsaturated methyl
ketone/nitro compounds is reported (Scheme 1).
Scheme 1 The oxidation of benzylamine by MCPBA
Lewis acids are well-known catalysts for the aldol reac-
tion and they are often used because of their simple oper-
ation and low cost. Several enolate derivatives have been
studied such as magnesium,6 aluminum,7 iron,8 and zinc
enolates.9 On the basis of the previously developed reac-
tion conditions, the influence of different Lewis acids was
investigated. When CuSO4·5H2O, ZnCl2, ZnI2, LiCl·H2O
and LiBr·H2O were used, the reactions tended to stop at
the benzaldehyde stage (Table 2, entries 1–5). However,
the reaction could be conducted with 10 mol% FeCl3,
CuCl2·2H2O, or CuCl2 (Table 2, entries 6, 7 and 10), and
CuCl2·2H2O afforded the desired product 2a with the
highest yield (Table 2, entry 7). By adjusting the amount
of CuCl2·2H2O, it was found that 25 mol% CuCl2·2H2O
was optimal (Table 2, entries 7–9 and 11).
Initially, optimization of the reaction conditions was ex-
amined. The oxidation of 1a in acetone with MCPBA (1.1
equiv) at 0 °C afforded oxaziridine as the major product
(Table 1, entry 1). Reaction at room temperature provided
a mixture of oxaziridine, benzaldehyde and (E)-4-phenyl-
SYNLETT 2013, 24, 2740–2742
Advanced online publication: 05.11.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1338986; Art ID: ST-2013-W0735-L
© Georg Thieme Verlag Stuttgart · New York

LETTER
Oxidation–Aldol/Henry Reaction of Benzylic Amines
2741
Table 1 Optimization of Reaction Conditionsa
formation, generating the desired products 2 in moderate
yields. It can be seen that all the substituted benzylamines
gave lower yields than benzylamine (1a). The reaction of
secondary amine 1b with MCPBA (2.1 equiv) and
CuCl2·2H2O (50 mol%) proceeded to give 2a in 44%
yield (Table 3, entry 2). The lower yield in the case of 2-
chloro-3,6-difluorobenzylamine as substrate may be due
to steric hindrance (Table 3, entry 12).
MCPBA
acetone
N
NH2
O
+
+
O
A
B
1a
O
NOH
+
2a
C
Table 3 Substrate Scope
Entry MCPBA Temp
(equiv)
A
B
2a
C
R3
NHR2
MCPBA, CuCl2⋅2H2O
R1
R1
solvent, 60 °C
solvent = acetone, R3 = COMe 2a–n
b
c
c
1
2
3
4
1.1
1.1
1.1
1.5
0 °C
r.t.
*
*
–
–
*
*
*
*
*
–
1a–n
solvent = MeNO2, R3 = NO2
3a–n.
3 (%)b,c
61
b
c
c
c
c
*
–
Entry
1
R1
R2
H
Bn
H
H
H
H
H
H
H
H
H
H
H
H
2 (%)a,c
65
reflux
reflux
49%d
–
–
60%d
H
a Reaction conditions: benzylamine 1a (5 mmol), acetone (25 mL),
2
H
44d
50
50e
45
10 h.
3
4-OMe
4-F
b The structure of this compound was determined by NMR spectro-
scopic analysis.
4
61
48
c This compound was detected by TLC analysis against a standard.
d Isolated yield.
5
3-F
44
41
6
3-CF3
2-CF3
3-Cl-4-Me
3,4-Cl2
2,5-F2
3-Me-4-F
2-Cl-3,6-F2
3-CN
4-Cl
52
76
Table 2 Lewis Acids in the Oxidation–Aldol Reactiona
7
47
60
O
8
51
36
MCPBA, Lewis acid
NH2
9
63
55
acetone, reflux, Ar, 10 h
10
11
12
13
14
53
51
1a
2a
Yield (%)b
45
31
Entry
Lewis acid
Mol%
37
trace
1
2
CuSO4·5H2O
ZnCl2
10
10
10
10
10
10
10
5
trace
trace
trace
trace
trace
32
f
34
–
f
–
62
3
ZnI2
a Reaction conditions (unless otherwise noted): 1 (5 mmol), MCPBA
(5.5 mmol), 25 mol% CuCl2·2H2O, acetone (12 mL), reflux, 10 h.
b Reaction conditions (unless otherwise noted): 1 (5 mmol), MCPBA
(5.5 mmol), 5 mol% CuCl2·2H2O, MeNO2 (12 mL), 60 °C, 10 h.
c Isolated yield.
4
LiCl·H2O
LiBr·H2O
FeCl3
5
6
d Reaction conditions: 1a (5 mmol), MCPBA (11 mmol), 50 mol%
CuCl2·2H2O, acetone (20 mL), reflux, 10 h.
7
CuCl2·2H2O
CuCl2·2H2O
CuCl2·2H2O
CuCl2
60
e Reaction conditions: 1a (5 mmol), MCPBA (11 mmol), 10 mol%
CuCl2·2H2O, MeNO2 (20 mL), 60 °C, 10 h.
8
55
f Not attempted.
9
25
25
50
65
10
11
58
When nitromethane was used as solvent instead of ace-
tone, we were pleased to find that the desired product (E)-
2-nitro-1-phenylethene (3a) was generated in 58% yield.
Further screening of the amount of CuCl2·2H2O required
for this reaction showed that 5 mol% CuCl2·2H2O was
sufficient.
CuCl2·2H2O
33
a Reaction conditions: 1a (5 mmol), MCPBA (5.5 mmol), acetone (12
mL), reflux, 10 h.
b Isolated yield.
To further establish the scope of the reaction, the opti-
mized conditions were applied to various substituted ben-
zylamines and the results are summarized in Table 3.
Transformations of benzylamine derivatives containing
either electron-donating or electron-withdrawing substit-
We then examined the scope of the oxidation–aldol reac-
tion. Various substituted benzylamines 1 were investigat-
ed under the optimized reaction conditions (Table 3).
Substrates with both electron-donating groups and elec-
tron-withdrawing groups smoothly underwent the trans-
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 2740–2742

2742
J. Liu et al.
LETTER
(2) In Advanced Organic Chemistry, Part B: Reactions and
uents at different positions, proceeded efficiently to give
the corresponding nitroalkene derivatives in moderate
yields. It was confirmed that the steric hindrance of sub-
strates had a limited effect on the yields of the reactions
(Table 3, entries 4–7 and 12).
Synthesis; Carey, F. A.; Sundberg, R. J., Eds.; Springer: New
York, 2007, 5th ed. Chap. 2,: 63.
(3) For reviews, see: (a) Heathcock, C. H. In Comprehensive
Organic Synthesis; Vol. 2; Trost, B. M.; Fleming, I.;
Heathcock, C. H., Eds.; Pergamon Elsevier: Oxford, 1991,
133. (b) Ballini, R.; Castagnani, R.; Petrini, M. J. Org.
Chem. 1992, 2160. (c) Bauer, H. H.; Urbas, L. In The
Chemistry of the Nitro and Nitroso Group; Feuer, H., Ed.;
Interscience: New York, 1970, Chap. 2, 75. (d) In The Nitro
Group in Organic Synthesis; Ono, N., Ed.; Wiley-VCH:
New York, 2001, Chap. 3, 30. (e) Rosini, G. In
With the reaction conditions described above, the scope of
this oxidation system was studied further with α-substitut-
ed benzylamines. Unfortunately, under neither conditions
did 4-chloro-α-methylbenzylamine (1o) produce the cor-
responding α,β-unsaturated methyl ketone/nitro com-
pound. Instead, when 1o was treated with MCPBA (1.1
equiv) and CuCl2·2H2O (5 mol%) in nitromethane at
60 °C, it was found that 1-(4-chlorophenyl)ethanone (4o)
was generated in 52% yield (Table 4, entry 1). Thus, by
using this approach, the resultant carbonyl compounds
could be obtained from α-substituted benzylamines in
moderate yields (Table 4, entries 1 and 2).
Comprehensive Organic Synthesis; Vol. 2; Trost, B. M., Ed.;
Pergamon: Oxford, 1996, 321. (f) Luzzio, F. A. Tetrahedron
2001, 915.
(4) (a) George, M. V.; Balachandran, K. S. Chem. Rev. 1975,
491. For metal-catalyzed oxidations of amines leading to
various synthetic targets, see: (b) Murahashi, S.-I.; Okano,
Y.; Sato, H.; Nakae, T.; Komiya, N. Synlett 2007, 1675.
(c) Suzuki, K.; Watanabe, T.; Murahashi, S.-I. Angew.
Chem. Int. Ed. 2008, 2079. (d) Murahashi, S.-I.; Zhang, D.
Chem. Soc. Rev. 2008, 1490. (e) Srogl, J.; Voltrova, S. Org.
Lett. 2009, 843. (f) Lechner, R.; König, B. Synthesis 2010,
1712. (g) Samuel, D.; Guillaume, J.; Sylvain, C. Synlett
2012, 23, 1497.
(5) Black, D. St. C.; Blackman, N. A. Aust. J. Chem. 1975, 2547.
(6) Heathcock, C. H. In Comprehensive Organic Synthesis; Vol.
1; Trost, B. M.; Fleming, I., Eds.; Pergamon Press: Oxford,
1991, 181.
(7) Moon Kim, B.; Williams, S. F.; Masamune, S. In
Comprehensive Organic Synthesis; Vol. 1; Trost, B. M.;
Fleming, I., Eds.; Pergamon Press: Oxford, 1991, 239.
(8) Paterson, I. In Comprehensive Organic Synthesis; Vol. 1;
Trost, B. M.; Fleming, I., Eds.; Pergamon Press: Oxford,
1991, 301.
Table 4 Substrate Scope and Limitationsa
O
NH2
R2
R2
MCPBA, CuCl2⋅2H2O
R1
R1
MeNO2, 60 °C
1o,p
4o,p
Entry
R1
R2
Product
Yield (%)b
1
2
4-Cl
2-Cl
Me
4o
4p
52
64
CO2Me
a Reaction conditions: α-methylbenzylamine 1 (5 mmol), MCPBA
(5.5 mmol), 5 mol% CuCl2·2H2O, MeNO2 (12 mL), 60 °C, 10 h.
b Isolated yield.
(9) Rathke, M. W.; Weipert, P. In Comprehensive Organic
Synthesis; Vol. 1; Trost, B. M.; Fleming, I., Eds.; Pergamon
Press: Oxford, 1991, 277.
(10) Oxidation–Aldol Reaction (Table 2); General
Procedure: Under an argon atmosphere, to a solution of
benzylamine (5 mmol) and CuCl2·2H2O (0.21 g, 1.25 mmol)
in acetone (12 mL), MCPBA (1.12 g, 5.5 mmol) was added
portionwise at 0 °C. The reaction mixture was heated at
reflux in an oil bath with thorough stirring for 10 h (reaction
monitored by TLC analysis). Upon cooling, saturated
aqueous Na2S2O3 (10 mL) was added to quench the reaction.
The solvent was removed under reduced pressure and the
residue was treated with 10% aq NaOH (15 mL) followed by
extraction with EtOAc (3 × 10 mL). The combined extracts
were washed with H2O (5 mL) and brine (5 mL), and dried
over anhydrous Na2SO4. Removal of the solvent under
vacuum afforded the crude product, which was purified by
column chromatography (hexane–EtOAc).
In summary, a one-pot protocol that provides α,β-unsatu-
rated methyl ketone/nitro compounds from benzylic
amines under mild conditions, requiring catalytic
CuCl2·H2O and MCPBA as oxidant, has been estab-
lished.10 The advantages and limitations of this catalytic
system were demonstrated. The ready availability
of MCPBA and comparatively mild aldol/Henry con-
densation conditions of this protocol should provide an
alternative choice for the preparation of functionalized
α,β-unsaturated methyl ketone/nitro compounds.
Acknowledgment
Oxidation–Henry Reaction (Table 3); General
Procedure: Under an argon atmosphere, to a solution of
benzylamine (5 mmol) and CuCl2·2H2O (0.04 g, 0.25 mmol)
in MeNO2 (12 mL), MCPBA (1.12 g, 5.5 mmol) was added
portionwise at 0 °C. The reaction mixture was stirred at
60 °C in an oil bath for 10 h (reaction monitored by TLC
analysis). Upon cooling, saturated aqueous Na2S2O3 (10 mL)
was added to quench the reaction. The solvent was removed
under reduced pressure and the residue was treated with 10%
aq NaOH (15 mL) followed by extraction with EtOAc
(3 × 10 mL). The combined extracts were washed with H2O
(5 mL) and brine (5 mL), and dried over anhydrous Na2SO4.
Removal of the solvent under vacuum afforded the crude
product, which was purified by column chromatography
(hexane–EtOAc).
We are grateful for financial support from The Fundamental
Research Funds for the Central Universities (WY1113007).
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnoIufproig
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References and Notes
(1) Jeffrey, B.; Harborne, J. B. In Comprehensive Natural
Products Chemistry; Vol. 8; Barton, D.; Nakanishi, K., Eds.;
Elsevier: New York, 1999, 137.
Synlett 2013, 24, 2740–2742
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