Nanocrystalline copper(II) oxide catalyzed aza-Michael reaction and insertion of α-diazo compounds into N-H bonds of amines

Article abstract of DOI:10.1016/j.tetlet.2009.05.059

Nanocrystalline copper(II) oxide efficiently catalyzed the conjugate addition of aliphatic amines to α,β-unsaturated compounds to produce β-amino compounds with excellent yields under mild reaction conditions. Similarly, Glycine esters are obtained in good yields by the insertion of α-diazoacetate into N-H bonds of amines. The catalyst is used for three cycles with minimal loss of activity.

Full text of DOI:10.1016/j.tetlet.2009.05.059

Tetrahedron Letters 50 (2009) 4467–4469
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Tetrahedron Letters
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Nanocrystalline copper(II) oxide catalyzed aza-Michael reaction and insertion
of a-diazo compounds into N–H bonds of amines
a
a
b
M. Lakshmi Kantam a, , Soumi Laha , Jagjit Yadav , Shailendra Jha
*
a Inorganic and Physical Chemistry Division, Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500 007, India
b Department of Chemistry, Jadavpur University, Kolkata, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Nanocrystalline copper(II) oxide efficiently catalyzed the conjugate addition of aliphatic amines to
a,b-
Received 24 April 2009
Revised 14 May 2009
Accepted 16 May 2009
Available online 23 May 2009
unsaturated compounds to produce b-amino compounds with excellent yields under mild reaction con-
ditions. Similarly, Glycine esters are obtained in good yields by the insertion of -diazoacetate into N–H
bonds of amines. The catalyst is used for three cycles with minimal loss of activity.
Ó 2009 Elsevier Ltd. All rights reserved.
a
Keywords:
Nanocrystalline copper(II) oxide
Heterogeneous catalyst
Aza-Michael addition
a,b-Unsaturated compounds
Insertion
Diazoacetate
b-Amino carbonyl compounds are important intermediates in
dling, simple work-up, and regenerability. Nanocrystalline metal
oxides have attracted attention due to their unusual magnetic,
physical, and surface chemical and catalytic properties.24 These
high reactivities are due to high surface areas combined with
unusually reactive morphologies. Copper oxide nanoparticles have
been of considerable interest due to the role of CuO in catalysis, in
metallurgy, and in high-temperature superconductors.25
As part of our ongoing research on nanocrystalline metal oxide-
catalyzed organic transformations,26 we herein report our results
on the use of recoverable nanocrystalline CuO (nano CuO) catalyst
for the aza-Michael addition of dibenzylamine with methyl acry-
late to produce methyl-3-(dibenzylamino) propionate in good
yields at room temperature (Scheme 1) and the reaction of piperi-
dine with ethyl diazoacetate (EDA) at room temperature resulted
in the formation of ethyl-4-piperidinylacetate with moderate
yields (Scheme 2).
the synthesis of various complex natural products, antibiotics, b-
amino alcohols, and chiral auxillaries1,2,14 and can be prepared by
conjugate addition of amines to
a,b-unsaturated compounds. A
number of methods have been reported for the 1,4-addition of
amines to electron-deficient olefins through the activation of
amines by stoichiometric or catalytic Lewis acids such as Bi(NO)3,3
Bi(OTf)3,4 Yb(OTf)3,5 La(OTf)3,6 InCl3,7 FeCl3Á6H2O, Co(OAc)2,8
Ni(ClO4)2Á6H2O,9 LiClO4,10 and copper salts.11 Different heteroge-
neous catalysts such as transition-metal doped montmorillonite
and kaolinite clays,12 silica gel13 and alumina-supported
CeCl3Á7H2O–NaI14 have been used for aza-Michael reactions. More
recently, a green approach in ionic liquids has been employed for
the conjugate addition of amines to
On the other hand, insertion of
(X = C, N, S) bonds is a reaction of considerable importance for
a
a
,b-unsaturated compounds.15
-diazo compounds into X–H
the synthesis of
a
-amino acids, peptides, and b-lactam antibiot-
Initially, nano CuO as well as commercially available bulk CuO
and Cu2O was evaluated for the aza-Michael reaction of dibenzyl-
amine and methyl acrylate and the results are summarized in Ta-
ble 1. The nano CuO was found to be a more active catalyst than
ics.16,17 The N–H insertion reaction is reported with catalysts such
as copper bronze,18 CuCN,19 Rh(OAc)2 and its derivatives,20 ruthe-
nium complexes,21 and Cu(I) homoscorpionate complexes.22 Using
Cu(I) and Ag(I) carbenoids, asymmetric version of this reaction has
also been developed.23
Industry favors catalytic processes induced by heterogeneous
catalysts over homogeneous processes in view of the ease of han-
Ph
Ph
CO2Me
Ph
Ph
CO2Me
Nano CuO
NH
N
+
MeOH, RT, 8 h
* Corresponding author. Tel./fax: +91 40 27160921.
E-mail address: mlakshmi@iict.res.in (M.L. Kantam).
Scheme 1.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.05.059

4468
M. L. Kantam et al. / Tetrahedron Letters 50 (2009) 4467–4469
Table 2
Nano CuO
DCM, RT, 24 h
The aza-Michael reaction of amines with alkenes in the presence of nano CuOa
NH
CO2C2H5
+ N2
N
CO2C2H5
Entry Amine
Olefin
Time (h) Isolated yield (%)
Scheme 2.
CN
1
2
4
4
81
79
78
85
82
77
78
80
O
O
O
NH
NH
NH
NH
NH
Table 1
Screening of reaction parameters for aza-Michael reactiona
Entry
Catalyst
Solvent
Time (h)
Yieldb (%)
CO2Me
1
2
3
4
5
6
7
8
Nano CuO
Nano CuO
Nano CuO
Nano CuO
Nano CuO
Bulk CuO
Bulk Cu2O
None
Toluene
MeCN
DCM
12
12
12
12
8
8
8
8
Trace
5
Trace
10
THF
3
6
O
MeOH
MeOH
MeOH
MeOH
74, 70c
38
42
25
CN
4
3
a
Reaction conditions: dibenzylamine(1 mmol), methyl acrylate (1.2 mmol), cat-
alyst (10 mol %), solvent (4 mL), room temperature.
b
Isolated yields.
Yield after third cycle.
c
CO2Me
5
4
the commercial CuO and Cu2O. The use of solvents such as toluene,
acetonitrile, dichloromethane, and THF was less effective in place
of methanol. Catalyst-recycling experiments were also carried
out, using dibenzylamine and methyl acrylate as Michael acceptor.
As can be seen in (Table 1, entry 5), nano CuO can be used for three
cycles with minimal loss of activity.
CN
6
6
CH2NH2
CH2NH2
NH2
CO2Me
CO2Me
CO2Me
COMe
CO2Me
CO2Me
7
7
A variety of
a,b-unsaturated compounds such as methyl acry-
late (MA), acrylonitrile (AN), methyl vinyl ketone (MVK), and
cyclohexenone underwent 1,4-addition with a wide range of cyclic
and acyclic aliphatic amines in the presence of nano CuO at room
temperature to give the corresponding b-amino compounds or ni-
8
8
triles in high yields (Table 2). Cyclic
a,b-unsaturated ketone such
Ph
Ph
as cyclohexenone reacted with morpholine to give the correspond-
ing 1,4-adduct in good yield (Table 2, entry 3). Other amines such
as piperidine (Table 2, entries 4 and 5), benzylamine (Table 2, en-
tries 6 and 7), cyclohexylamine (Table 2, entry 8), and dibutyl-
amine (Table 2, entry 11) were reacted in equal ease with MA
and AN and gave 77–85% yields in 3–8 h. In case of primary amines,
8–12% of the bis adduct was also formed (Table 2, entries 6, 7, and
8). Sterically hindered amine, for example, dibenzylamine (Table 2,
entries 9 and 10) with MA and MVK offered 1,4-addition products
in 70–74% yields in 8 h. Though it can be seen from Table 2 that the
reaction proceeds well within 3–8 h for all substrates while aro-
matic amine such as p-methoxy aniline (Table 2, entry 12) when
treated with MA furnishes trace amount of product. The inertness
of aromatic amine is further exemplified by taking MVK and an
equimolecular mixture of p-methoxy aniline and morpholine un-
der a similar condition. As expected, aliphatic amine gave addition
product in good yields (Scheme 3). This clearly shows that nano
CuO catalyst fails in the case of aromatic amines for aza-Michael
addition reaction.
9
8
74
70
NH
NH
Ph
Ph
10
11
12
8
n-Bu
n-Bu
NH
6
82
10
Trace
MeO
NH2
a
Reaction conditions: amines (1 mmol),
a,b-unsaturated compounds (1.2 mmol),
nano CuO (10 mol %), MeOH (4 mL), room temperature.
OMe
NH2
OMe
NH2
COMe
Nano CuO, MVK
MeOH, 4h, RT
O
N
+
O
NH
+
+
Encouraged by the high catalytic activity of nano CuO in the
75%
aza-Michael reaction, we tried the catalytic insertion of
a-diazo
COMe
compounds into N–H bonds of amines using nano CuO and ethyl
diazoacetate (EDA). As illustrated in Table 3, the catalytic system
(10 mol % of nano CuO and DCM as solvent at room temperature)
proved to be efficient with a variety of amines including primary,
secondary, aliphatic, aromatic, acyclic, and cyclic amines under-
went reaction with EDA. Interestingly, cyclic amines such as mor-
pholine and piperidine (Table 3, entries 1 and 2) were found to be
more active and gave the corresponding products in moderate
yields. Bulky amines, such as dibutyl and dibenzyl amine also
afforded the products in moderate yields (Table 3, entries 3 and
4). In case of primary amines and piperazine, bis-insertion prod-
ucts were obtained in the presence of two equivalent of EDA (Table
MVK=
Scheme 3.
3, entries 5, 6, and 8). Interestingly, bulky glycine ester can also be
synthesized in moderated yields (Table 3, entry 9).
In conclusion, we have developed nano CuO catalyzed aza-Mi-
chael reaction of aliphatic amines with
pounds and synthesis of glycine esters via N–H insertion of
diazoacetate. The high catalytic activity of nano CuO may be attrib-
uted to the higher surface area (S.A: 136 m2/g) and a higher poros-
ity compared to that of commercial CuO (S.A: 1.952 m2/g) as well
a,b-unsaturated com-

M. L. Kantam et al. / Tetrahedron Letters 50 (2009) 4467–4469
4469
Table 3
reused for another cycle after vacuum drying. The centrifugate
was diluted with diethyl ether and the solvent was removed under
reduced pressure. Then it was subjected to column chromatogra-
phy to get the pure product. Isolated yield of ethyl-4-piperidinylac-
etate was 62%.
Insertion of diazoacetate into N–H bonds of amines using nano CuOa
Entry Amine
Product
Time
(h)
Yieldb
(%)
H1 NMR: 1.24–1.31 (t, 3H), 1.38–1.48 (m, 2H), 1.57–1.65 (m,
4H), 2.51 (t, 4H), 3.12 (d, 2H), 4.19 (q, 2H).
CO2C2H5
CO2C2H5
CO2C2H5
CO2C2H5
1
24
24
36
36
36
36
36
36
24
62,
58c
N
N
H
Acknowledgments
O
2
66
O
N
N
H
S.L. and J.Y. thank CSIR, New Delhi for the award of research fel-
lowships. Nanocrystalline metal oxide samples were obtained from
Nanoscale Materials Inc., Manhattan, KS 66502, USA.
Ph
Ph
Ph
3
54
N
NH
Ph
References and notes
nC4H9
nC4H9
nC4H9
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4
56
NH
N
nC4H9
CO2C2H5
5
52d
52d
60
HN
NH
N
N
C2H5O2C
CO2C2H5
CO2C2H5
N
6
7
8
NH2
CO2C2H5
NH2
NH2
NH
CO2C2H5
CO2C2H5
55d
51e
N
t
CO2 Bu
9
N
N
H
a
Reaction conditions: amine (1 mmol), EDA (1 mmol), nano CuO (10 mol %),
DCM (4 mL), room temperature.
b
Isolated yields.
Yield after third cycle.
2 mmol of EDA is used.
1 mmol tert-butyldiazoacetate is used as carbine source.
c
d
e
as the higher surface concentration of reactive sites. The catalyst is
used for three cycles with minimal loss of activity.
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(1 mmol), methyl acrylate (1.2 mmol), and nano CuO (10 mol %)
in methanol (4 mL) was maintained at room temperature under
vigorous stirring for appropriate time. After the completion of
the reaction, monitored by TLC, the reaction mixture was centri-
fuged and washed with ethyl acetate to recover the catalyst for re-
use. The combined ethyl acetate extracts were concentrated in
vacuo, and the resulting product was directly charged on silica
gel column to obtain the product. Isolated yield of methyl-3-(dib-
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(s, 4H), 7.20–7.44 (m, 10H).
´
´
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General experimental for insertion of diazo compounds into
amines: Nano CuO (10 mol %) in DCM (4 mL) was placed in an oven
dried 10 mL Schlenk flask, at room temperature under N2 atmo-
sphere. Piperidine (1 mmol) was added. To the reaction mixture
ethyl diazoacetate (1 mmol) was added dropwise for 10 min and
stirring was continued. After the completion of the reaction, as
monitored by TLC, the reaction mixture was centrifuged to sepa-
rate the catalyst. The catalyst was washed with diethyl ether and
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