Copper-catalyzed aldol-type addition of ketones to aromatic nitriles: A simple approach to enaminone synthesis

Article abstract of DOI:10.1039/c3cc40466h

An efficient method for the synthesis of enaminones is described. The aldol-type addition of ketones to aromatic nitriles proceeded smoothly in the presence of a simple copper catalyst system (CuI-2,2′-bipyridine-NaO ^tBu) in N,N-dimethylformamide. Enaminones in satisfactory to excellent yields were produced using this technique. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c3cc40466h

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Copper-catalyzed aldol-type addition of ketones to
aromatic nitriles: a simple approach to enaminone
synthesis†
Xiaoqiang Yu,*a Longxiang Wang,a Xiujuan Feng,a Ming Bao*a and
Yoshinori Yamamotoab
Cite this: Chem. Commun., 2013,
49, 2885
Received 19th January 2013,
Accepted 19th February 2013
DOI: 10.1039/c3cc40466h
www.rsc.org/chemcomm
An efficient method for the synthesis of enaminones is described. of the cyano group to a Lewis acid catalyst was reportedly stronger
The aldol-type addition of ketones to aromatic nitriles proceeded than that of the carbonyl group.12,14 We hypothesized that the
smoothly in the presence of a simple copper catalyst system (CuI– reaction selectivity could be controlled by using an appropriate
2,20-bipyridine–NaOtBu) in N,N-dimethylformamide. Enaminones in Lewis acid catalyst. The catalyst would be selectively coordinated
satisfactory to excellent yields were produced using this technique. to the cyano group to enhance the reactivity of the aromatic
nitrile, thereby suppressing the self-condensation of ketone.
Enaminones are important synthetic intermediates and building
Several Lewis acid catalyst systems were investigated to test this
blocks for drug development1 and natural product synthesis.2 For hypothesis. The aldol-type addition reaction of acetophenone (1a)
example, enaminones have been successfully used for synthesis of to benzonitrile (2a) was chosen as a model to optimize the reaction
drugs (anticonvulsants,3 anti-inflammatory agents,4 and antitumor conditions. The results are summarized in Table 1. Lewis acid
agents5) and bioactive heterocycles (pyridinones,6a quinolones,6b catalysts ZnCl2, CoCl2, NiCl2, copper(II) trifluoromethanesulfonate
pyrroles,6c isoxazoles,6d indole,6e and polyazaheterocycles6f). There- [Cu(OTf)2], copper(II) acetate [Cu(OAc)2], CuCl, CuBr, and CuI were
fore, the development of convenient and efficient methods for the initially examined in the absence of a ligand by using NaOtBu as
synthesis of enaminones has attracted considerable attention. Over the base. Among these catalysts, CuI exhibited the highest catalytic
the past decades, numerous techniques have been developed for the selectivity (entry 8 vs. entries 1–7). Nitrogen-containing ligands
construction of enaminones, including the direct condensation pyridine (L1), ethane-1,2-diamine (L2), N1,N1,N2,N2-tetramethyl-
reaction of 1,3-dicarbonyl compounds with amines or excess ethane-1,2-diamine (L3), 2,20-bipyridine (L4), and 1,10-phenanthro-
ammonium salts;7–9 aldol-type addition reaction of 1,3-dicarbonyl line (L5) were then investigated using CuI as the Lewis acid catalyst
compounds to activated nitrile compounds catalyzed by Lewis (entries 9–13).15 L4 proved to be the best ligand for the selective
catalysts;10 and others.11 In addition, C–H activation has recently synthesis of enaminone 3a. Low yield or no formation of 3a was
been successfully employed in the synthesis of enaminones.12 observed when the bases NaOH, KOH, K2CO3, and Cs2CO3 were
Despite the success of these approaches in obtaining various used instead of NaOtBu (entries 14–17). The solvent (entries 12, 18,
enaminones, synthesis of enaminones frequently suffers from and 19) and temperature (entries 12, 20, and 21) were finally
certain disadvantages such as harsh reaction conditions, unsatis- screened. N,N-Dimethyl formamide (DMF) and 80 1C were identi-
factory yields, and the need to use special starting materials.
fied as the best solvent and reaction temperature, respectively.
To the best of our knowledge, the aldol-type addition reaction Therefore, the subsequent aldol-type addition reactions of ketones
of ketones to aromatic nitriles to produce enaminones has not to aromatic nitriles were performed in the presence of CuI and L4
been systematically researched.13 Poor reaction selectivity was by using NaOtBu as the base in DMF at 80 1C for 12 h.
found when a mixture of ketone and aromatic nitrile was treated
The aldol-type addition reactions of ketones 1a–1m to 2a
in the presence of a Lewis acid catalyst under basic conditions; were performed under optimized conditions to determine the
both self-condensation of ketone and aldol-type addition of scope of ketone substrates. The results are summarized in
ketone to aromatic nitrile were observed. The coordination ability Table 2. The desired product enaminone 3a was isolated in 72%
yield from the reaction of 1a with 2a (entry 1). Satisfactory yields
a State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian
116023, China. E-mail: yuxiaoqiang@dlut.edu.cn, mingbao@dlut.edu.cn;
Fax: +86-0411-84986181; Tel: +86-0411-84986180
similar to that of 3a were observed when 1-(p-tolyl)ethanone
(1b), 1-(o-tolyl)ethanone (1c), 1-(4-methoxyphenyl)ethanone
(1d), 1-(4-(dimethylamino)phenyl)ethanone (1e), and 1-(4-(butyl-
amino)phenyl)ethanone (1f) were tested under optimized reaction
conditions (entries 2–6 vs. entry 1, 65–82%). However, the reactions of
1-(4-fluorophenyl)ethanone (1g) and 1-(4-chlorophenyl)ethanone (1h)
b WPI-AIMR (WPI-Advanced Institute for Materials Research), Tohoku University,
Sendai 980-8577, Japan
† Electronic supplementary information (ESI) available: Experimental procedures
and spectroscopic data for isolated compounds. See DOI: 10.1039/c3cc40466h
c
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Table 1 Reaction condition screeninga
Table 2 Copper-catalyzed aldol-type addition of various ketones to benzo-
nitrilea
Entry
1
Ketone 1
Product 3
Yieldb (%)
72
Yieldb (%)
3a
Yieldc (%)
1a
1b
1c
1d
3a
3b
3c
Entry
Catalyst
Ligand
Base
4a + 4a0
1
2
3
4
5
6
7
8
ZnCl2
CoCl2
NiCl2
Cu(OTf)2
Cu(OAc)2
CuCl
CuBr
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
None
None
None
None
None
None
None
None
L1
L2
L3
L4
L5
L4
L4
L4
L4
L4
L4
L4
L4
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOH
KOH
K2CO3
Cs2CO3
NaOtBu
NaOtBu
NaOtBu
NaOtBu
25
15
4
57
38
24
39
37
43
37
31
45
52
41
12
2
3
4
82
71
74
58
62
49
62
70
55
56
60
83
50
12
13
NDd
NDd
50
69
79
85
9
3d
3e
3f
10
11
12
13
14
15
16
17
18e
19f
20g
21h
36
5
75
1e
1f
Trace
Trace
NDd
Trace
43
14
27
6
7
8
65
67c
65c
1g
3g
3h
CuI
24
a
Reaction conditions: Lewis acid catalyst (10 mol%), ligand (11 mol%),
acetophenone (1a, 0.6 mmol, 72.0 mg), benzonitrile (2a, 0.5 mmol,
51.5 mg), and base (2.0 mmol) in DMF (1.0 mL) at 80 1C for 12 h. GC
yield based on 2a. (E)-4-Phenylbut-3-en-2-one was used as an internal
b
1h
1i
c
standard. GC yield based on 1a. (E)-4-Phenylbut-3-en-2-one was
d
e
used as an internal standard. Not determined. THF was used as
3i
3j
f
g
9
30
the solvent. Dioxane was used as the solvent. The reaction was
h
conducted at 70 1C. The reaction was conducted at 90 1C.
1j
10
11
12
65
1k
1l
3k
3l
51
required an extended time (24 h) to complete despite increases
in catalyst loading and the amount of ketone substrate to
20 mol% and two equivalents, respectively (entries 7 and 8, 67%
and 65% yields). These results indicate that the reactivity of
aromatic ketones should be lowered by an electron-withdrawing
group linked to a benzene ring. Although the ketone substrate
1-(thiophen-2-yl)ethanone (1i) disappeared within 12 h, the desired
product enaminone 3i was isolated in only 30% yield (entry 9).
Enaminone 3j was obtained in a moderate yield when 3,4-dihydro-
naphthalen-1(2H)-one (1j) was tested (entry 10, 65% yield). Aliphatic
ketones, cyclohexanone (1k) and pentan-2-one (1l), were then used
in the addition reaction. Enaminones 3k and 3l were obtained in
53c
NRd
3m
1m
13
a
Reaction conditions: CuI (10 mol%, 9.5 mg), L4 (11 mol%, 9.5 mg), ketone
(1, 0.6 mmol, 1.2 equiv.), benzonitrile (2a, 0.5 mmol, 51.5 mg), NaOtBu
(2.0 mmol, 96.0 mg) in 1 mL of DMF at 80 1C for 12 h. b Isolated yield.
c
Reaction conditions: CuI (20 mol%, 19.0 mg), L4 (22 mol%, 19 mg),
benzonitrile (2a, 0.5 mmol, 51.5 mg), ketone (1, 1.0 mmol, 2 equiv.), NaOtBu
(3.3 mmol, 160 mg) in 1.5 mL of DMF at 80 1C for 24 h. d No reaction.
51% and 53% yields, respectively (entries 11 and 12). The reaction of or 4-(trifluoromethyl)benzonitrile (2c) proceeded smoothly to
unsymmetrical ketone 3l regioselectively occurred on the less produce the enaminones 3n and 3o in excellent yields (entries 1
sterically hindered a-carbon atom. As expected, no reaction was and 2; 89% and 95%, respectively). The desired product 3p was
observed when propiophenone (1m) was examined (entry 13).
also obtained in excellent yield (93%) from the reaction of 1d with
The reactions of the ketone substrates 1a and 1d with the 2b (entry 3). Nitrile substrates, 4-methylbenzonitrile (2d) and
aromatic nitriles 2b–2g were then examined to explore the 4-methoxybenzonitrile (2e), exhibited low reactivities in this
scope of nitrile substrates. The results are shown in Table 3. type of addition reaction. Moderate yields of the enaminones 3q
As expected, the reactions of 1a with 4-chlorobenzonitrile (2b) and 3r were observed in the reactions of 1a with either 2d or 2e
c
2886 Chem. Commun., 2013, 49, 2885--2887
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Table 3 Copper-catalyzed aldol-type addition of aromatic ketones 1a and 1b to
various aromatic nitrilesa
Notes and references
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Yieldb
(%)
Entry Ketone 1 Nitrile 2
Product 3
1
2
1a
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89
3n
3o
2b
2c
95
93
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5
1a
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61c
70c
¨
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2f
3s
3t
6
7
1a
1a
1d
73
85
87
2g
2g
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3u
a
ˇ
Reaction conditions: CuI (10 mol%, 9.5 mg), L4 (11 mol%, 9.5 mg), ketone
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(1a or 1d, 0.6 mmol, 1.2 equiv., 72.0 mg or 90.0 mg), aromatic nitrile (2,
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19 mg), aromatic nitrile (2, 0.5 mmol), acetophenone (1a, 1.0 mmol, 2 equiv.,
120.1 mg), NaOtBu (3.3 mmol, 160 mg) in 1.5 mL of DMF at 80 1C for 24 h.
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(entries 4 and 5; 61% and 70% yields, respectively). These results
suggest that the reactivity of the nitrile substrate was remarkably
influenced by the electronic property of the substituent linked to
the benzene ring of nitrile. Enaminones 3n, 3q, and 3r are isomers
of enaminones 3h, 3b, and 3d, respectively. These isomers were
selectively synthesized by the present method. Reactions of hetero-
aryl nitriles, 2-chloroisonicotinonitrile (2f) and picolinonitrile (2g),
were finally examined. The enaminone products 3s–3u were
obtained in 73%, 85%, and 87% yields, respectively (entries 6–8).
In summary, a general method for synthesis of enaminones was
developed using simple and readily available starting materials,
namely, ketones and aromatic nitriles. The copper-catalyzed aldol-
type addition of ketones to aromatic nitriles proceeded smoothly
under mild conditions and produced enaminones in satisfactory to
excellent yields. The affordability of the catalyst, wide availability of
the starting materials, mild reaction conditions, and simplicity of
the procedure render the present methodology more useful in
organic synthesis. The use of 2,20-bipyridine as a ligand plays a
key role in the control of reaction selectivity.
We are grateful to the National Natural Science Foundation
of China (No. 21002010 and 21072023) for their financial
support.
c
This journal is The Royal Society of Chemistry 2013
Chem. Commun., 2013, 49, 2885--2887 2887