Ni(OAc)2: A highly efficient catalyst for the synthesis of enaminone and enamino ester derivatives under solvent-free conditions

Article abstract of DOI:10.1002/aoc.1667

Ni(OAc)₂ was found to be an efficient catalyst for the synthesis of β-enamino ketones or esters from β-dicarbonyl compounds and amines under solvent-free conditions. The reusability of the catalyst was successfully examined without noticeable loss of its catalytic activity. Copyright

Full text of DOI:10.1002/aoc.1667

Full Paper
Received: 31 October 2009
Revised: 3 April 2010
Accepted: 5 April 2010
Published online in Wiley Online Library: 23 August 2010
(wileyonlinelibrary.com) DOI 10.1002/aoc.1667
Ni(OAc)2: a highly efficient catalyst for the
synthesis of enaminone and enamino ester
derivatives under solvent-free conditions
Ju-Yan Liu∗, Gai-E Cao, Wei Xu, Jie Cao and Wei-Lu Wang
Ni(OAc)2 was found to be an efficient catalyst for the synthesis of β-enamino ketones or esters from β-dicarbonyl compounds
and amines under solvent-free conditions. The reusability of the catalyst was successfully examined without noticeable loss of
c
its catalytic activity. Copyright ꢀ 2010 John Wiley & Sons, Ltd.
Keywords: β-dicarbonyl compounds; amines; enaminones; enamino esters; nickel acetate
Introduction
reaction substrates and functional groups.[45] As a part of our
program aiming to develop selective and environmental friendly
methodologies for the preparation of fine chemicals and in
continuation of our interest in Lewis acid-catalyzed organic
reactions,[46] we herein report a green, mild and efficient method
for the regio- and chemoselective enamination of β-dicarbonyl
compounds using a catalytic amount of Ni(OAc)2 under solvent-
free conditions (Scheme 1).
Enamination of β-dicarbonyl compounds forming β-enamino
ketones and esters is an important and widely used trans-
formation in organic synthesis.[1] The latter compounds are a
highly versatile class of intermediates for the synthesis of het-
erocycles and pharmaceutical compounds, such as dopamine
auto-receptor agonists,[2] acetylcholinestersase inhibitors, oxy-
tocin antagonists[3] and anticonvulsants.[4] Owing to their wide
range of activity and importance, many synthetic methods have
been developed for the preparation of these compounds.[5–11]
Among the plethora of methods, the direct condensation
of 1,3-dicarbonyl compounds with amines is the most sim-
ple and straightforward route for their synthesis. However,
the azeotropic removal of water is usually required using
a Dean–Stark trap in a refluxing aromatic solvent.[12] Sev-
eral improved procedures have been reported using a vari-
ety of catalysts such as trimethylsilyl trifluoromethanesulfonate
Experimental
Melting points were measured on an X4 Micro-melting Point
apparatus without correction. NMR spectra were performed in
CDCl3 and recorded on a Bruker Avance 300 spectrometer. IR
spectra were obtained using a Bruker-Tensor 27 spectrometer. The
mass spectra were recorded on Thermo Finnigan LCQ Advantage
spectrometer in ESI mode-I. Elemental analyses were performed
on a Yamaco CHN corder MT-3 apparatus equipped with two
heaters. All of the obtained β-enamino ketones or esters are
known compounds and were well characterized.
(TMSTf),[13] montmorillonite K10 under microwave irradiation[14]
or ultrasound,[15] I2,[16] BF3 OEt2,[17] Al2O3,[18] Zn(ClO4)2 6H2O,
[19]
•
•
[20]
[6b]
[21]
Zn(OAc)2 2H2O,
InBr3,[6a] CoCl2 6H2O,
CeCl3 7H2O,
•
•
•
[22]
ZrOCl2 8H2O,
NaAuCl4,[23] Bi(OTf)3,[24] Sc(OTf)3,[25] CAN,[26]
•
NaHSO4,[27] HClO4 SiO2,
silica gel,[29] natural clays,[30] L-
[28]
•
General Procedure for the Preparation of β-Enamino Ketones
or Esters
Proline,[31] silicachloride,[32] silica-supportedsulfuricacid,[33] silica-
supported antimony(III) chloride,[34] phosphotungstic acid,[35] sul-
fated zirconia,[36] tin tetrachloride,[37] CAN,[38] K-7 PW11CoO40
,
[39]
A mixture of the β-dicarbonyl compound (1 mmol), the amine
(1 mmol) and Ni(OAc)2 (0.05 mmol) was stirred at room tem-
perature for the appropriate time (Table 1). The progress of the
reaction was monitored by TLC. After completion of the reaction,
ethyl acetate (10 ml) was added and the heterogeneous mixture
was filtered. The filter cake was washed with diethyl ether and
the catalyst was recovered. The organic phase was washed with
water (2 × 15 ml) and dried over anhydrous MgSO4. The solvent
copper(II) nitrate trihydrate[40] and ZrCl4.[41] Recently, this con-
densation reaction has also been performed in water,[24a,42]
PEG-water[43] or ionic liquid medium.[21,24b] Although these meth-
ods are suitable for certain synthetic conditions, many of these
procedures suffer from one or more limitations, such as long re-
action time,[29] use of non-available and expensive reagents[23–25]
and high catalyst loading.[16,20,21] Thus, the development of new
catalytic methods is highly desirable.
Inrecentyears,Ni(OAc)2 hasbeendiscoveredtobeanewtypeof
water-tolerant Lewis acid catalyst for organic synthesis with highly
chemo-, regio- and stereoselective results.[44] Compared with
conventional Lewis acids, it has the advantages of commercial
availability, low price (7 × 10−3 $/g), recyclability, operational
simplicity, strong tolerance to oxygen- and nitrogen-containing
∗
Correspondence to: Ju-Yan Liu, College of Chemistry and Life Science, Tianjin
Key Laboratory of Structureand Performance for Functional Molecules, Tianjin
Normal University, Tianjin 300387, China. E-mail: hsxyliy@mail.tjnu.edu.cn
College of Chemistry and Life Science, Tianjin Key Laboratory of Structure and
PerformanceforFunctionalMolecules,TianjinNormalUniversity,Tianjin,China
c
Appl. Organometal. Chem. 2010, 24, 685–691
Copyright ꢀ 2010 John Wiley & Sons, Ltd.

J.-Y. Liu et al.
–OCH3), 4.72 (s, 1H, C CH–CO), 7.03–7.22(m, 4H, Ar), 10.15 (br
s, 1H, NH). 13C NMR (CDCl3, 75 MHz): δ = 17.7 ( C–CH3), 19.8
(C6H4 –CH3), 50.3 (–OCH3), 84.5 (C CH–CO), 126.0 (C CH–CO),
126.3 (–Ar), 130.6 (–Ar), 133.8 (–Ar), 137.7 (–Ar), 159.8 (–Ar),
170.7 (–CO–). ESI-MS: m/z = 206 (M + 1)+. Anal. calcd for
C12H15NO2: C, 70.22; H, 7.37; N, 6.82. Found: C, 70.09; H, 7.57; N,
6.65.
Scheme 1. Ni(OAc)2 catalyzed enamination of β-dicarbonyl compounds.
Methyl 3-(4-ethoxy-phenylamino)-but-2-enoate(3m)
was evaporated under reduced pressure to provide the crude
product. Further purification was carried out by column chro-
matography on SiO2 with ethyl acetate–petroleum ether (1 : 4) to
afford pure β-enamino ketones or esters in moderate to excellent
yields.
A pale yellow solid, m.p.: 63–64 ◦C. IR (KBr): ν = 3440, 3112,
2943, 1647, 1595, 1511, 1481, 1395, 1359, 1248, 1164, 1058,
1004,956 cm−1. 1H NMR (CDCl3, 300 MHz): δ = 1.45 (t, J = 7.2 Hz,
3H, CH3CH2 –), 1.92 (s, 3H, C–CH3), 3.73 (s, 3H, –OCH3), 4.02
(q, J = 7.2 Hz, 2H, CH3CH2O), 4.65 (s, 1H, COCH ), 6.85 (d,
J = 8.7 Hz, 2H, Ar), 7.05 (d, J = 8.7 Hz, 2H, Ar), 10.13 (br s,
1H, NH). 13C NMR (CDCl3, 75 MHz): δ = 14.6 (CH3CH2 –), 20.1
Physical and Spectral Data for the Selected Compounds
(
C–CH3), 50.0 (–OCH3), 63.7 (CH3CH2O), 84.5 (C CH–CO),
Methyl 3-(allylamino)but-2-enoate (3d)
114.4 (C CH–CO), 126.5 (–Ar), 131.8 (–Ar), 156.8 (–Ar), 160.0
(–Ar), 170.9 (–CO–). ESI-MS: m/z = 236 (M + 1)+. Anal. calcd for
C13H17NO3: C, 66.36; H, 7.28; N, 5.95. Found: C, 66.52; H, 7.08; N,
5.87.
A yellow oil. IR (neat): ν = 3295, 3080, 1654, 1609, 1500, 1287,
1169, 1063, 928 cm−1. 1H NMR (CDCl3, 300 MHz): δ = 1.89 [s, 3H,
C(CH3)], 3.61 (s, 3H, –OCH3), 3.82–3.87 (m, 2H, CHCH2 NH–),
4.96 (s, 1H, C CHCO), 5.12–5.23 (m, 2H,
CH2), 5.80–5.92
(m, 1H, CH2 CH–CH2), 8.65 (br s, 1H, NH). 13C NMR (CDCl3,
75 MHz): δ = 18.5 [ C(CH3)], 44.7 ( CHCH2 NH–), 49.9 (–OCH3),
82.2 ( CH2), 115.5 (CH2 CHCH2), 134.6 (–NHC CH), 161.5
(C CHCO), 170.9 (–CO–). ESI-MS: m/z = 156 (M + 1)+.
Anal. calcd for C8H13NO2: C, 61.91; H, 8.44; N, 9.03. Found: C,
62.07; H, 8.28; N, 8.91.
Methyl 3-(4-chlorophenylamino)but-2-enoate(3n)
A pale yellow solid, m.p. 60–62 ◦C. IR (KBr): ν = 3271, 2950, 1654,
1591, 1489, 1350, 1273, 1165, 1054, 940, 785 cm−1. 1H NMR (CDCl3,
300 MHz): δ = 1.96 (s, 3H, C–CH3), 3.67 (s, 3H, –OCH3), 4.72 (s,
1H, COCH ), 7.00 (d, J = 8.4 Hz, 2H, Ar), 7.26 (d, J = 8.4 Hz, 2H, Ar),
10.32 (br s, 1H, NH). 13C NMR (CDCl3, 75 MHz): δ = 20.2 ( C–CH3),
50.1 (–OCH3), 86.2 (C CH–CO), 125.5 (C CH–CO), 129.0 (–Ar),
137.5 (–Ar), 158.5 (–Ar), 162.2 (–Ar), 170.7 (–CO–). ESI-MS: 226
(M + 1)+. Anal. calcd for C11H12ClNO2: C, 58.54; H, 5.36; N, 6.21.
Found: C, 58.39; H, 5.50; N, 6.30.
Methyl 3-[3-(2-methoxycarbonyl-1-methyl-vinylamino)-
propylamino]-but-2-enoate (3h)
A pale yellow solid, m.p. 69–70 ◦C. IR (KBr): ν = 3439, 2944,
1651, 1600, 1266, 1176, 1055, 787 cm−1 1H NMR (CDCl3,
.
300 MHz): δ = 1.81 (quin, J = 6.3 Hz, 2H, –CH2CH2CH2 –),
1.93 (s, 6H, C–CH3), 3.31 (q, J = 6.3 Hz, 4H, –CH2CH2CH2 –),
3.64 (s, 6H,–OCH3), 4.45 (s, 2H, –COCH ), 8.58 (br s, 2H,
NH). 13C NMR (CDCl3, 75 MHz): δ = 19.1 (–CH2CH2CH2 –), 31.2
Methyl 3-(2,6-diisopropylphenylamino)but-2-enoate(3p)
A white crystalline solid, m.p. 130–132 ◦C. IR (KBr): ν = 3248,
2957, 1655, 1604, 1487, 1440, 1318, 1267, 1151, 1055, 911,
(
C–CH3), 39.4 (–CH2CH2CH2 –), 49.6 (–OCH3), 82.5 ( C–CH3),
806 cm−1
.
1H NMR (CDCl3, 300 MHz): δ = 1.16 [d, J = 6.6 Hz,
161.9 (–COCH ), 170.5 (–COCH ). ESI-MS: 271 (M + 1)+. Anal.
calcd for C13H22N2O4: C, 57.76; H, 8.20; N, 10.36. Found: C, 57.59;
H, 8.40; N, 10.29.
6H, –CH(CH3)2], 1.21 [d, J = 6.6 Hz, 6H, –CH(CH3)2], 1.63 (s, 3H,
C–CH3), 3.05–3.15 [m, 2H, –CH(CH3)2], 3.72 (s, 3H, –OCH3), 4.66
(s, 1H, COCH ), 7.17 (d, J = 7.8 Hz, 2H, Ar), 7.29–7.33 (m, 1H, Ar),
9.81 (br s, 1H, NH). 13C NMR (CDCl3, 75 MHz): δ = 19.5 [–CH(CH3)2],
22.7 [–CH(CH3)2], 24.5 ( C–CH3), 28.4 [–CH(CH3)2], 50.2 (–OCH3),
82.6 (C CH–CO), 123.5 (C CH–CO), 128.2 (–Ar), 133.9 (–Ar),
147.0 (–Ar), 162.0 (–Ar), 171.1 (–CO–). ESI-MS: 276 (M + 1)+. Anal.
calcd for C17H25NO2: C, 74.14; H, 9.15; N, 5.09. Found: C, 74.32; H,
9.25; N, 4.94.
Methyl 3-(p-tolylamino)but-2-enoate (3k)
A pale yellow solid, m.p. 58–59 ◦C. IR (KBr): ν = 3259, 2946,
1652, 1590, 1484, 1385, 1363, 1271, 1185, 1163, 1052, 910 cm−1
.
1H NMR (CDCl3, 300 MHz): δ = 1.94 (s, 3H, C–CH3), 2.35 (s,
3H, C6H4 –CH3), 3.68 (s, 3H, –OCH3), 4.65 (s, 1H, C CH–CO),
6.98 (d, J = 8.1 Hz, 2H, –Ar), 7.12 (d, J = 8.1 Hz, 2H, –Ar),
10.23 (br s, 1H, NH). 13C NMR (CDCl3, 75 MHz): δ = 20.3
(R)-4-(1-phenylethylamino)pent-3-en-2-one (3 w)
(
C–CH3), 20.8 (C6H4 –CH3), 50.2 (–OCH3), 85.1 (C CH–CO),
A yellow oil; [α]D20: −836 (c = 0.66, EtOH). IR (neat): ν = 3448,
2973, 2925, 1610, 1578, 1506, 1438, 1355, 1295, 1137, 1017, 858,
746 cm−1. 1H NMR (CDCl3, 300 MHz): δ = 1.54 (d, J = 6.9 Hz, 3H,
–CHCH3), 1.76(s, 3H, C–CH3), 2.04(s, 3H, –COCH3), 4.60–4.69(m,
1H, CH3CHNH), 4.99 (s, 1H, COCH ), 7.22–7.34 (m, 5H, Ar), 11.26
(br s, 1H, NH). 13C NMR (CDCl3, 75 MHz): δ = 18.8 (–CHCH3), 24.2
124.3 (C CH–CO), 129.6 (–Ar), 130.6 (–Ar), 136.8 (–Ar), 159.3
(–Ar), 170.9 (–CO–). ESI-MS: m/z = 206 (M + 1)+. Anal. calcd for
C12H15NO2: C, 70.22; H, 7.37; N, 6.82. Found: C, 70.27; H, 7.40; N,
6.69.
Methyl 3-(o-tolylamino)but-2-enoate (3l)
(
C–CH3), 28.6 (–COCH3), 52.5 (CH3CHNH), 95.5 (C CH–CO),
A pale yellow solid, m.p. 26–28 ◦C. IR (KBr): ν = 3440, 3113, 1596,
1401, 1265, 1162, 1059, 915, 787 cm−1. 1H NMR (CDCl3, 300 MHz):
δ = 1.84 (s, 3H, C–CH3), 2.25 (s, 3H, C6H4 –CH3), 3.67 (s, 3H,
125.4 (C CH–CO), 126.9 (Ar), 128.4 (Ar), 144.1 (Ar), 162.5 (Ar),
194.8 (–CO–). Anal. calcd for C13H17NO: C, 76.81; H, 8.43; N, 6.89.
Found: C, 76.85; H, 8.50; N, 6.83.
c
wileyonlinelibrary.com/journal/aoc
Copyright ꢀ 2010 John Wiley & Sons, Ltd.
Appl. Organometal. Chem. 2010, 24, 685–691

Ni(OAc)2
Table 1. Synthesis of β-enamino ketones and β-enamino esters using Ni(OAc)2 under solvent-free conditions
Entry
Product
Time (min)
4
Yield (%)a
99
Reference
31
a
b
c
5
5
98
95
6a
6a
d
e
8
8
95
96
6a
22
f
9
90
74
6a
6a
g
300
h
9
5
96
97
6a
31
i
j
18
17
97
94
28
31
k
c
Appl. Organometal. Chem. 2010, 24, 685–691
Copyright ꢀ 2010 John Wiley & Sons, Ltd.
wileyonlinelibrary.com/journal/aoc

J.-Y. Liu et al.
Table 1. (Continued)
Entry
Product
Time (min)
21
Yield (%)a
92
Reference
6a
l
m
n
11
240
400
96
89b
69b
6a
31
6a
o
p
270
82b
6a
q
r
4
5
99b
98b
24
6a
s
t
9
98
28
6a
240
86b
u
v
10
96
6a
6a
420
65b
c
wileyonlinelibrary.com/journal/aoc
Copyright ꢀ 2010 John Wiley & Sons, Ltd.
Appl. Organometal. Chem. 2010, 24, 685–691

Ni(OAc)2
Table 1. (Continued)
Entry
Product
Time (min)
6
Yield (%)a
95b
Reference
6a
w
x
y
z
51
60
87
79b
95
6a
29
29
93
a Yields are given for isolated products.
b The reactions were performed at 60 ◦C.
3-(4-Ethoxy-phenylamino)-1-phenyl-but-2-en-1-one(3x)
of catalytic amounts of Ni(OAc)2 (5 mol%) under solvent-free
conditions and the results are shown in Table 1. The reactions
were fast (4 min to 420 min) and clean with moderate to high
isolated yield (65–99%). For example, ethyl 3-(butylamino)but-
2-enoate (3a) and methyl 3-(isopropylamino)but-2-enoate (3b)
were obtained in 99 and 98% yield, respectively. The nucleophilic
addition of amines to carbonyl compounds, catalyzed by Ni(OAc)2,
was found to be dependent on steric and electronic factors of β-
keto esters and amines. The reaction between aniline and cyclic
β-keto esters with a substituent different from hydrogen in the α-
position(3yand3z)tooklongercomparedwiththecorresponding
reaction with ethyl acetoacetate (3j) under similar conditions.
Since a keto carbonyl group is more electrophilic than an ester
group, this reaction was highly chemoselective, evidenced by
the formation of 3y–3z in high yield (93–95%). The presence
of electron-donating and electron-withdrawing groups on the
aromatic ring of substituted anilines makes an obvious difference
to the reaction rate.
Substitution of an electron-withdrawing group onto the
aromatic ring severely retards this condensation reaction (3n and
3t). Anilines bearing strong electron-withdrawing groups, such as
4-nitroaniline(3oand3v), providedthecorresponding β-enamino
ester and ketone in only 69 and 65% yield at 60 ◦C, respectively,
which showed an obvious electronic effect. Ortho-substituted
anilines, whatever the nature of the substituted groups, required
a longer reaction period. It was suggested that the yields were
significantly decreased when the size of the ortho-substituent
groups was large. For instance, 2,6-diisopropylaniline (3p) was
found to be less active and gave the desired β-keto esters in 82%
yield even after 4.5 h. This may be due to the steric hindrance
performed by the 2,6-diisopropyl groups of the aniline towards
the approaching β-keto ester.
A yellow solid, m.p. 86-87 ◦C. IR (KBr): ν = 3418, 2976, 1598,
1503, 1475, 1437, 1370, 1321, 825cm−1. 1H NMR (CDCl3, 300 MHz):
δ = 1.41 (t, J = 6.9 Hz, 3H, –OCH2CH3), 2.05 (s, 3H, C–CH3),
4.05 (q, J = 6.9 Hz, 2H, –OCH2CH3), 5.85 (s, 1H, –COCH), 6.89 (d,
J = 9.0 Hz, 2H, Ar), 7.07 (d, J = 9.0 Hz, 2H, Ar), 7.42–7.45 (m, 3H,
Ar), 7.89–7.92 (m, 2H, Ar), 12.94 (br s, 1H, NH).
13C NMR (CDCl3, 75 MHz): δ = 14.6 (–CH2CH3), 20.1 ( C–CH3),
63.8 (–OCH2CH3), 93.4 (–COCH), 114.9 ( C–CH3), 126.6 (Ar), 127.2
(Ar), 128.3 (Ar), 130.9 (Ar), 131.4 (Ar), 140.5 (Ar), 157.6(Ar), 163.5(Ar),
188.2 (–CO–). ESI-MS: 282 (M + 1)+. Anal. calcd for C18H19NO2: C,
76.84; H, 6.81; N, 4.98. Found: C, 75.69; H, 6.90; N, 5.01.
Ethyl 2-(phenylamino)cyclopent-1-enecarboxylate (3z)
A yellow oil. IR (KBr): ν = 3288, 2955, 1654, 1620, 1506, 1478,
1264, 1170, 1046, 751 cm−1. 1H NMR (CDCl3, 300 MHz): δ = 1.31
(t, J = 7.2 Hz, 3H, –CH2CH3), 1.82–1.91 (m, 2H, –CH2CH2CH2 –),
2.54 (t, J = 7.5 Hz, 2H, –CH2CH2CH2 –), 2.78 (t, J = 7.2 Hz, 2H,
–CH2CH2CH2 –), 4.19 (q, J = 7.2 Hz, 2H, –CH2CH3), 7.01–7.28 (m,
5H, Ar), 9.58 (br s, 1H, NH). 13C NMR (CDCl3, 75 MHz): δ = 14.5
(–CH2CH3), 21.8 (–CH2CH2CH2 –), 28.6 (–CH2CH2CH2 –), 33.5
(–CH2CH2CH2 –), 58.8 (–CH2CH3), 97.6 ( C–NH), 120.5 ( CCO),
123.1 (Ar), 129.3 (Ar), 140.8 (Ar), 160.1 (Ar), 168.5 (–CO–). Anal.
calcd for C14H17NO2: C, 72.70; H, 7.41; N, 6.06. Found: C, 72.65; H,
7.39; N, 6.18.
Results and Discussion
To demonstrate the generality and scope of this method, various
cyclic and acyclic β-dicarbonyl compounds such as methyl
acetoacetate, ethyl acetoacetate, 2-acetybutyrolactone and ethyl
2-oxocyclopentanecarboxylate were treated with a range of
primary, secondary, benzylic and aromatic amines in the presence
Generally, aliphatic amines are more reactive than aromatic
amines. In the case of 1,3-diaminopropane, two equivalents of
β-keto ester were used, producing the product with two enamino
c
Appl. Organometal. Chem. 2010, 24, 685–691
Copyright ꢀ 2010 John Wiley & Sons, Ltd.
wileyonlinelibrary.com/journal/aoc

J.-Y. Liu et al.
and esters under solvent-free conditions. The advantages include
mild reaction conditions, enhanced reaction rates, low loading of
catalyst, and operational and experimental simplicity.
Table 2. Comparison of the effect of catalysts for the synthesis of
4-(phenylamino)pent-3-en-2-one (3s)
Catalyst
Catalyst/solvent
loading
Time
Yield (%) Reference
Acknowledgments
Zn(OAc)2· 2H2O/CH2Cl2
InBr3
5 mol%
1 mol%
5 mol%
5 mol%
10 mg
2 days
10 min
4 h
86
94
95
95
95
76
95
98
20
6a
19
6b
29
21
22
WearegratefulforfinancialsupportfromtheResearchFoundation
for the Doctoral Program of Tianjin Normal University (5RL091).
Zn(ClO4)2· 6H2O/CH2Cl2
CoCl2· 6H2O
15 min
35 h
Silica gel/solvent-free
References
CeCl3· 7H2O/solvent-free 10 mol% 35 min
ZrOCl2· 8H2O/solvent-free 2 mol%
Ni(OAc)2/solvent-free 5 mol%
10 min
9 min
[1] a) Z. Rappoport, The Chemistry of Enamines, Part 1, John Wiley &
Sons: New York, 1994; b) C. M. Kascheres, J. Braz. Chem. Soc. 2003,
41, 945.
[2] B. W. Caprathe, J. C. Jaen, L. D. Wise, T. G. Heffner, T. A. Pugsley, L. T.
Melzer, M. Parvez, J. Med. Chem. 1991, 34, 2736.
[3] F. Gatta, M. R. Delguidice, M. Pomponi, M. Marta, Heterocycles 1992,
34, 991.
[4] K. R. Scott, I. O. Edafiogho, E. L. Richardson, V. A. Farrar, J. A. Moore,
E. I. Tietz, C. N. Hinko, H. Chang, A. EI-Assadi, J. M. Nicholson, J. Med.
Chem. 1993, 36, 1947.
[5] R. S. Bhosale, P. A. Suryawanshi, S. A. Ingle, M. N. Lokhande, S. P.
More, S. B. Mane, S. V. Bhosale, R. P. Pawar, Synlett 2006, 933.
[6] a) Z. H. Zhang, L. Yin, Y. M. Wang, Adv. Synth. Catal. 2006, 348, 184;
b) Z. H. Zhang, J. Y. Hu, J. Braz. Chem. Soc. 2006, 17, 1447.
[7] S. G. Hegde, C. R. Jones, J. Heterocycl. Chem. 1993, 30, 1501.
[8] P. Lue, J. V. Greenhill, Adv. Heterocycl. Chem. 1997, 67, 215.
[9] A. R. Katritzky, A. E. Hayden, K. Kirichenko, P. Pelphrey, Y. Ji, J. Org.
Chem. 2004, 69, 5108.
[10] G. Bartoli, C. Cimarelli, R. Dalpozzo, G. Palmieri, Tetrahedron 1995,
51, 8613.
[11] D. S. Reddy, T. V. Rajale, R. K. Shivakumar, J. Iqbal, Tetrahedron Lett.
2005, 46, 979.
[12] a) P. G. Baraldi, D. Simoni, S. Manfredini, Synthesis 1983, 902; b)
T. Potesˇil, J. Chromatogr. 1984, 312, 387; c) E. J. Cone, R. H. Garner,
A. W. Hayes, J. Org. Chem. 1972, 37, 4436.
[13] C. P. Cartaya-Marin, D. G. Henderson, R. W. Soeder, Synth. Commun.
1997, 27, 4275.
ester groups (3h). Optically active amine was converted into the
corresponding β-enamino compounds without any racemization
or inversion (3 w). The less reactive 1-benzoylacetone reacted
with ethoxy aniline to obtain exclusively a single regioisomer
(3x). Additionally, secondary amines also gave low conversion,
as confirmed by the fact that the condensation reaction of
acetylacetone and morpholine provided the β-enamino ketone
product in Generally, aliphatic amines are more reactive than.
aromatic amines. In the case of 1,3-diaminopropane, two
equivalents of β-keto ester were used producing the product
with two enamino ester groups (3h). Optically active amine
was converted into the corresponding β-enamino compounds
without any racemization or inversion (3 w). The less reactive 1-
benzoylacetone reacted with ethoxy aniline to obtain exclusively a
single regioisomer (3x). Additionally, secondary amines also gave
low conversion as confirmed by the fact that the condensation
reaction of acetylacetone and morpholine provided the β-
enamino ketone product in 74% yield and required a long reaction
time (3g). In some cases, the condensation of acetylacetone
with aliphatic amines produced a precipitate (3q and 3r), which
resultedfromtheformationofacarbinolaminederivative.[47] These
compounds were relatively unstable and they were dehydrated by
heating to give β-enamino ketones. In all reactions, the products
were obtained with the (Z)-form configuration. The proton of the
-NH- group appearing at a lower field (δ > 8.2) indicated the
classical intramolecular hydrogen-bonding interactions between
the amino proton and the carbonyl oxygen, which stabilized the
products (3 in Scheme 1). Therefore, this condensation reaction
was stereospecific.
[14] a) B. Rechsteimer, F. Texier-Boullet, J. Hamelin, Tetrahedron Lett.
1993, 34, 5071; b) H. T. S. Braibante, M. E. F. Braibante, G. B. Rosso,
D. A. Oriques, J. Braz. Chem. Soc. 2003, 14, 994.
[15] C. J.Valduga,A.Squizani,H. S.Braibante,M. E. F.Braibante,Synthesis
1998, 1019.
[16] C. R. Hauser, G. A. Reynolds, J. Am. Chem. Soc. 1948, 70, 2402; b)
S. Gogoi, R. Bhuyan, N. C. Barua, Synth. Commun. 2005, 35, 2811.
[17] B. Stefane, S. Polanc, Synlett 2004, 698.
[18] F. Texier-Bouliet, Synthesis 1985, 679.
[19] G. Bartoli, M. Bosco, M. Locatelli, E. Marcantoni, P. Melchiorre,
L. Sambri, Synlett 2004, 239.
[20] R. K. Vohra, J. L. Renaud, C. Bruneau, Collect. Czech. Chem. Commun.
2005, 70, 1943.
[21] M. M. Khodaei, A. R. Khosropour, M. Kookhazadeh, Synlett 2004,
1980.
[22] Z. H. Zhang, T. S. Li, J. J. Li, Catal. Commun. 2007, 8, 1615.
[23] A. Arcadi, G. Bianchi, S. Di Giuseppe, F. Marinelli, Green Chem. 2003,
5, 64.
[24] a) A. R. Khosropour, M. M. Khodaei, M. Kookhazadeh, Tetrahedron
Lett. 2004, 45, 1725; b) M. M. Khodaei, A. R. Khosropour,
M. Kookhazadeh, Can. J. Chem. 2005, 83, 209.
[25] J. S. Yadav, V. N. Kumar, R. S. Rao, A. D. Priyadarshini, P. P. Rao, B. V. S.
Reddy, K. Nagaiah, J. Mol. Catal. A: Chem. 2006, 256, 234.
[26] V. Sridharan, C. Avendano, J. C. Menendez, Synlett 2007, 881.
[27] H. S. Wang, J. Y. Miao, Chin. J. Org. Chem. 2007, 27, 266.
[28] B. Das, K. Venkateswarlu, A. Majhi, M. R. Reddy, K. N. Reddy, Y. K.
Rao, K. Ravikumar, B. Sridhar, J. Mol. Catal. A: Chem. 2006, 246, 276.
[29] Y. H. Gao, Q. H. Zhang, J. X. Xu, Synth. Commun. 2004, 34, 909.
[30] F. C. Silva, M. C. B. V. De Souza, V. F. Ferreira, S. J. Sabino, O. A. C.
Antunes, Catal. Commun. 2004, 5, 151.
•
In comparison with other catalysts such as Zn(OAc)2 2H2O,
•
•
•
InBr3, Zn(ClO4)2 6H2O, CoCl2 H2O, silica gel, CeCl3 7H2O and
•
ZrOCl2 8H2O, which were recently used in the enamination of
β-dicarbonyl compounds, Ni(OAc)2 employed here exhibits more
effective catalytic activity than those previously reported in terms
of the amount of catalyst, yields and reaction time (Table 2).
Recyclability of the catalyst was also studied through a
condensation reaction of aniline and ethyl acetoacetate as model
substrates. The catalyst was simply filtered from the reaction
mixture, and Ni(OAc)·2xH2O was recovered after washing with
ether and air drying. This was reused for the preparation of 3j in
five runs without significant loss of activity.
[31] K. Dhiman, M. Adinath, H. Alakananda, Chin.J.Chem. 2008, 26, 1545.
[32] A. R. Gholap, N. S. Chakor, T. Daniel, R. J. Lahoti, K. V. Srinivasan,
J. Mol. Catal. A: Chem. 2006, 245, 37.
Conclusions
In conclusion, Ni(OAc)2 has been employed for the first time as a
[33] X. Chen, J. She, Z. C. Shang, J. Wu, P. Z. Zhang, Synth. Commun.
novel and efficient catalyst for the synthesis of β-enamino ketones
2009, 39, 947.
c
wileyonlinelibrary.com/journal/aoc
Copyright ꢀ 2010 John Wiley & Sons, Ltd.
Appl. Organometal. Chem. 2010, 24, 685–691

Ni(OAc)2
[34] L. F. Zhang, S. T. Yang, Russ. J. Org. Chem. 2009, 45, 18.
[35] G. C. Li, J. Chem. Res. 2007, 696.
[44] a) T. Zhao, Y. Han, Y. Sun, Fuel Process. Technol. 2000, 62, 187;
b) M. Abla, J. C. Choi, T. Sakakura, Green Chem. 2004, 6, 524; c)
C. F. Cheng, Z. C Lai, Y. J. Lee, Tetrahedron 2008, 64, 4347; d)
C. M. Tang, Y. Zeng, P. Cao, X. G. Yang, G. Y. Wang, Catal. Lett. 2009,
129, 189.
[45] a) Z. Li, S. L. Zhang, Y. Fu, Q. X. Guo, L. Liu, J. Am. Chem. Soc. 2009,
131, 8815; b) J. Canivet, J. Yamaguchi, I. Ban, K. Itami, Org.Lett. 2009,
11, 1733.
[36] Z. H. Zhang, L. M. Song, J. Chem. Res. 2005, 817.
[37] Z. H. Zhang, Z. C. Ma, L. P. Mo, Indian J. Chem. 2007, 46B, 535.
[38] L. P. Mo, S. F. Liu, W. Z. Li, J. Chin. Chem. Soc. 2007, 54, 879.
[39] H. A. Oskooie, M. M. Heravi, N. M. Javadi, K. Bakhtiari, F. F.
Bamoharram, Synth. Commun. 2008, 38, 2864.
[40] G. C. Li, Monatsh. Chem. 2008, 139, 789.
[41] J. Lin, L. F. Zhang, Monatsh. Chem. 2007, 138, 77.
[42] H. A. Stefani, I. M. Costa, D. de O Silva, Synthesis 2000, 1526.
[43] B. P. Bandgar, S. A. Patil, B. L. Korbad, S. B. Bandgar, B. S. Hote, Aust.
J. Chem. 2008, 61, 552.
[46] Z. H. Zhang, L. Yin, Y. M. Wang, J. Y. Liu, Y. Li, Green Chem. 2004, 6,
563.
[47] F. C. Pennington, W. D. Kehret, J. Org. Chem. 1967, 32, 2034.
c
Appl. Organometal. Chem. 2010, 24, 685–691
Copyright ꢀ 2010 John Wiley & Sons, Ltd.
wileyonlinelibrary.com/journal/aoc