Efficient copper-catalyzed Michael addition of acrylic derivatives with primary alcohols in the presence of base

Article abstract of DOI:10.1039/c2cc37595h

A novel and efficient copper-catalyzed Michael addition of acrylic derivatives with primary alcohols in the presence of base has been developed. The protocol uses readily available acrylic derivatives and primary alcohols as the starting materials, inexpensive CuCl₂ as the catalyst, and the corresponding addition products were obtained in moderate to excellent yields.

Full text of DOI:10.1039/c2cc37595h

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Efficient copper-catalyzed Michael addition of
acrylic derivatives with primary alcohols in the
presence of base†
Feng Wang,a Haijun Yang,b Hua Fu*bc and Zhichao Pei*a
Cite this: Chem. Commun., 2013,
49, 517
Received 18th October 2012,
Accepted 19th November 2012
DOI: 10.1039/c2cc37595h
www.rsc.org/chemcomm
Table 1 Copper-catalyzed Michael addition of N-phenylacrylamide (1a) with
phenylmethanol (2f) leading to 3-(benzyloxy)-N-phenylpropanamide (3f):
optimization of conditionsa
A novel and efficient copper-catalyzed Michael addition of acrylic
derivatives with primary alcohols in the presence of base has been
developed. The protocol uses readily available acrylic derivatives
and primary alcohols as the starting materials, inexpensive CuCl2
as the catalyst, and the corresponding addition products were
obtained in moderate to excellent yields.
Entry
Cat.
Base (equiv.)
Solvent
Yieldb (%)
Compounds containing carbon–oxygen bonds widely occur in
chemicals and biologically active molecules. Classical construction
of carbon–oxygen bonds is from nucleophilic substitution of highly
nucleophilic alkoxides to halogenate compounds. Recently, Michael
addition of a,b-unsaturated carbonyl compounds with alcohols has
attracted much attention,1 and some efficient methods have been
developed, such as organocatalytic,2 Lewis or Brønsted base (or acid)
catalyzed,3 N-heterocyclic carbine-catalyzed,4 DNA-based catalyzed,5
transition metal catalyzed,6 and tetra-n-butylammonium fluoride
(TBAF) promoted7 protocols. In the past few decades, copper-
catalysts have become popular because of their low-cost and
low-toxicity, and great achievement has been made through
copper-catalyzed coupling reactions by other groups8,9 and us.10
Herein, we report a novel and efficient copper-catalyzed Michael
addition of acrylic derivatives with primary alcohols in the presence
of base.
1
2
3
4
5
6
7
8
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl
Cs2CO3 (1)
K2CO3 (1)
K3PO4 (1)
KOBut (1)
—
Cs2CO3 (0.2)
Cs2CO3 (0.5)
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
ClCH2CH2Cl
CH3CN
Toluene
1,4-Dioxane
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
78
52
76
21
Trace
18
41
57
8
36
40
38
33
50
20
28
23
82c
55d
38e
9
10
11
12
13
14
15
16
17
18
19
20
CuBr
CuI
Cu(OAc)2
CuSO4
—
CuCl2
CuCl2
CuCl2
a
Reaction conditions: N-phenylacrylamide (1a) (0.5 mmol), phenyl-
methanol (2f) (0.5 mmol), catalyst (0.05 mmol), solvent (1.0 mL) under
Copper-catalyzed Michael addition of N-phenylacrylamide
(1a) with phenylmethanol (2f) leading to 3-(benzyloxy)-N-phenyl-
propanamide (3f) was used as the model to optimize conditions
including the catalysts, bases, solvents and temperature without
b
c
reflux, reaction time (12 h). Isolated yield. Phenylmethanol (2a)
(1.0 mmol). Reaction temperature (25 1C). Catalyst (0.025 mmol).
d
e
extrusion of air. As shown in Table 1, four bases were tested
using 10 mol% CuCl2 as the catalyst, CH2Cl2 as the solvent under
reflux (39 1C) (entries 1–4), and Cs2CO3 provided the highest
yield (entry 1). Only trace amount of product was observed in the
absence of base (entry 5). Yields decreased when the amount of
base was reduced (entries 6 and 7). The effect of solvents was
investigated (compare entries 1 and 8–11), and CH2Cl2 was the
most suitable (entry 1). Other copper salts were screened (entries
12–16), and they were inferior to CuCl2. Only 23% yield was
afforded in the absence of the copper-catalyst (entry 17).
a College of Science, Northwest A&F University, Yangling, Shaanxi, 712100,
P. R. China
b Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology
(Ministry of Education), Department of Chemistry, Tsinghua University,
Beijing 100084, P. R. China. E-mail: fuhua@mail.tsinghua.edu.cn,
peizhichao18@yahoo.com; Fax: +86 10-62781695
c Key Laboratory of Chemical Biology (Guangdong Province), Graduate School of
Shenzhen, Tsinghua University, Shenzhen 518057, P. R. China
† Electronic supplementary information (ESI) available: General procedure for
synthesis, characterization data, and 1H and 13C NMR spectra of compounds
3a–x. See DOI: 10.1039/c2cc37595h
c
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Table 2 Copper-catalyzed Michael addition of acrylic derivatives with primary
The yield increased from 78% to 82% when 2 equiv. of phenyl-
methanol (2a) was used as the partner of N-phenylacrylamide
(1a). The reaction provided 55% yield when it was carried out at
room temperature (25 1C). When 5 mol% CuCl2 was used as the
catalyst, the yield decreased to 38% (entry 20). Therefore, the
optimized copper-catalyzed conditions are as follows: 10 mol%
CuCl2 as the catalyst, one equiv. of Cs2CO3 as the base, CH2Cl2 as
the solvent at 39 1C without extrusion of air.
alcoholsa
Entry
1
1
2
3 (Yieldb)
With the optimized copper-catalyzed conditions in hand, the
scope for Michael addition of acrylic derivatives with primary
alcohols was investigated. As shown in Table 2, the examined
substrates provided moderate to excellent yields. For substituted
acrylamides (1a–h), their reactivity was affected by steric hindrance
and electronic effect of the substrates. The substrates containing
bigger groups and higher electronic density exhibited lower
reactivity. A stronger base, CH3ONa, was required for the reaction
of (E)-N-phenylhex-2-enamide (1f) with CH3OH (entry 18), and
1-(piperidin-1-yl)prop-2-en-1-one (1g) gave lower yield (48%) under
the standard conditions (entry 19). For acrylic esters (1i and 1j), the
Michael addition afforded higher yields (entries 21–23). Unfortu-
nately, the ester bonds were hydrolyzed into the corresponding
acids because of addition of water from the solvent and reagents.
For primary alcohols, steric hindrance was a key factor. For
example octan-1-ol (2d) gave lower yield (entry 4). The reactions
could tolerate some functional groups including amide bond
(entries 1–20), CF3 (entry 5), ether (entry 8), C–Br bond (entry 9),
nitro (entry 10), alkenyl (entry 11), alkyne group (entry 12) and
oxygen heterocycle (entry 13) in the substrates.
2
3
4
5
6
1a
1a
1a
1a
1a
7
8
1a
1a
According to the above results, a possible mechanism for
copper-catalyzed Michael addition of acrylic derivatives with
primary alcohols in the presence of base is proposed in
Scheme 1. Treatment of primary alcohol (2) with CuCl2 in the
presence of Cs2CO3 provides I, and coordination of I with 1 leads
to II.11 Michael addition of the alkoxyl anion to the acrylic
derivative provides III, and reaction of III with 2 gives IV leaving
the copper catalyst–alkoxyl complex I that enters the catalytic cycle
again. Finally, isomerization of IV affords the target product (3).
We attempted the copper-catalyzed Michael addition of
(E)-but-2-enenitrile (1k) with phenylmethanol (2f) under the
standard conditions, and the corresponding product (3x) was
obtained in 96% yield (Scheme 2). Therefore, the present
method can be used in the Michael addition of other alkenes
containing a-electron-withdrawing groups.
9
1a
1a
10
11
12
13
1a
1a
1a
14
2b
In conclusion, we have developed an easy and efficient
copper-catalyzed Michael addition of acrylic derivatives with
primary alcohols in the presence of base. The protocol uses
readily available acrylic derivatives and primary alcohols as the
starting materials, CuCl2 as the catalyst, Cs2CO3 as the base,
and CH2Cl2 as the solvent, the reactions were performed well
under mild conditions without extrusion of air, and the corres-
ponding addition products with carbon–oxygen bonds were
obtained in moderate to excellent yields. The method could
tolerate some functional groups in the substrates. This is the
first example for copper-catalyzed Michael addition with weak
primary alcohols thus far. Therefore, the present method will
find wide applications in various fields.
15
16
2b
2b
17c
2b
18d
19
2a
2b
c
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´
Table 2 (continued )
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Entry
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3 (Yieldb)
2b
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22
2b
2a
2b
23
1j
a
Reaction conditions: 1 (2.0 mmol), 2 (4.0 mmol), CuCl2 (0.2 mmol),
Cs2CO3 (2.0 mmol), CH2Cl2 (4.0 mL) under reflux, reaction time (12 h).
b
c
d
Isolated yield. Under a nitrogen atmosphere. CH3ONa (2.0 mmol)
as the base, CH3OH (4.0 mL) as the solvent under reflux.
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Scheme 1 A possible mechanism for copper-catalyzed Michael addition of acrylic
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Scheme 2 Copper-catalyzed Michael addition of (E)-but-2-enenitrile (1k) with
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The authors wish to thank the Scientific Research Foundation
of Northwest A&F University (Z111020903), the National Natural
Science Foundation of China (Grant No. 21105054, 20972083
and 21172128) and the Ministry of Science and Technology of
China (Grant No. 2012CB722605) for financial support.
Notes and references
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c
This journal is The Royal Society of Chemistry 2013
Chem. Commun., 2013, 49, 517--519 519