ZrCl4-catalyzed efficient synthesis of enaminones and enamino esters under solvent-free conditions

Article abstract of DOI:10.1007/s00706-006-0565-2

A facile synthesis of β-enaminones and enamino esters by condensation of β-dicarbonyl compounds with differently substituted amines in the presence of ZrCl₄ under solvent-free conditions is reported.

Full text of DOI:10.1007/s00706-006-0565-2

Monatshefte f €u r Chemie 138, 77–81 (2007)
DOI 10.1007/s00706-006-0565-2
Printed in The Netherlands
Short Communication
ZrCl -Catalyzed Efficient Synthesis
4
of Enaminones and Enamino Esters
under Solvent-free Conditions
Jin Lin1 and Li-Feng Zhang2
;ꢀ
1
The College of Chemistry & Material Science, Hebei Normal University, Shijiazhuang, China
2
Hebei Chemical & Pharmaceutical Vocational Technology College, Shijiazhuang, China
Received July 25, 2006; accepted (revised) August 4, 2006
Published online January 2, 2007 # Springer-Verlag 2007
Summary. A facile synthesis of ꢀ-enaminones and enamino esters by condensation of ꢀ-dicarbonyl
compounds with differently substituted amines in the presence of ZrCl under solvent-free conditions
4
is reported.
Keywords. ꢀ-Enaminones; ꢀ-Enamino esters; 1,3-Dicarbonyl compounds; Zirconium(IV) chloride;
Solvent-free conditions.
Introduction
ꢀ
-Enaminones and ꢀ-enamino esters have been extensively used as key intermedi-
ates in organic synthesis [1]. In particular, they have been employed as synthons
of different important antibacterial [2], anticonvulsant, anti-inflammatory [3], and
antitumour agents [4]. Due to their wide range application and importance, a sim-
ple and high yielding one-pot method for the synthesis of ꢀ-enaminones and
ꢀ
-enamino esters is highly desirable. The conventional approach for the prepara-
tion of ꢀ-enaminones and ꢀ-enamino esters is direct condensation of ꢀ-dicarbonyl
compounds with amines under reflux in an aromatic solvent with azeotropic re-
moval of water [5]. Various modified synthesis pathways have been reported, such
as the addition of zinc ester enolates or amide enolates to nitriles [6], tosyl imines
[
7], or imidoyl halides [8], the addition of enamines to activated carboxylic acid
derivatives [9], and the reaction of ꢀ-enamino esters with organolithium reagents
10]. Apart from these, several other improved methods for the enamination of 1,3-
[
dicarbonyl compounds have been reported using catalyst systems, such as protic
ꢀ Corresponding author. E-mail: linjin64@126.com

7
8
J. Lin and L.-F. Zhang
Scheme 1
acid [11], Lewis acid [12], iodine [13], clays [14], silica gel [15], and sulfated zirconia
[
[
16], etc. More recently, [EtNH ]NO [17], HClO ꢁ SiO [18] as well as silica chloride
3
3
4
2
19] have been used to effect this transformation. Although these methods improve
reaction conditions and shorten reaction time, in many cases still drastic conditions
are necessary for completion of the process, high temperatures and high catalyst
loading are required, or non-readily available or very expensive reagents are used.
Organic reactions under solvent-free conditions are advantageous because of
their enhanced selectivity and efficiency, ease of manipulation, and toxic or volatile
solvents are avoided [20]. Inspired by reports of catalytic applications of zirconium
tetrachloride for various organic transformations [21], we considered employing
ZrCl as a catalyst for the synthesis of ꢀ-enaminones and ꢀ-enamino esters under
4
solvent-free conditions (Scheme 1).
Results and Discussion
An initial study was performed treating ethyl acetoacetate with aniline under sol-
vent-free conditions in the presence of a catalytic amount of ZrCl (5 mol%) at
4
room temperature. To our delight, we observed the formation of ethyl 3-(pheny-
lamino)but-2-enoate (3p). Complete conversion and 95% isolated yield were ob-
tained after 30 minutes. Further studies established that 1 mol% of catalyst was also
efficient in this reaction. Reactions in solvents such as THF, CH Cl , DMF, EtOAc
2
2
gave lower yields of the desired product after prolonged reaction time. So, we
executed the reaction under solvent-free conditions.
To demonstrate the generality of this method, we next investigated the scope of
this reaction under optimized conditions and the results are summarized in Table 1.
Thus, a variety of amines including primary, benzylic, and aromatic amines were
condensed with various ꢀ-dicarbonyl compounds to produce a range of ꢀ-enam-
inones and ꢀ-enamino esters. This reaction is very clean and free from side re-
actions. Unlike reported methods, the present protocol does not require high
temperature. In general, for primary and benzylic amines the condensation reactions
usually afforded the corresponding ꢀ-enaminones and ꢀ-enamino esters in over 90%
yields in short time. However, anilines with an electron-withdrawing group (1g and
1s) afforded low yields of the products. It should be pointed out that in the reaction
of 1-benzoylacetone with amines the regioselective amination of the aliphatic car-
bonyl group (2h and 2i) was observed. When 1,3-diaminopropane was used as an
amine, two equivalents of methyl acetoacetate were required to give the product
with two enamino ester groups (3k). Moreover, the optically active amine was
converted into the corresponding ꢀ-ketoester (3n) without any racemization or in-
version. From linear ꢀ-diketones and ꢀ-ketoesters we always obtained the corre-

Synthesis of Enaminones and Enamino Esters
79
Table 1. ZrCl -catalyzed synthesis of ꢀ-enaminones and ꢀ-enamino esters
4
1
2
R
3
4
R
a
Entry
R
R
Time=min
Yield=%
a
b
c
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
Me
CH (CH )
3
18
15
12
10
12
12
240
60
50
12
15
10
10
12
45
40
40
40
180
25
30
30
40
90
80
93
94
96
95
93
92
81
85
81
94
2 3
PhCH2
Me
Ph
d
e
Me
4-Me-C H
6
4
Me
4-OMe-C H
6
4
f
Me
4-OEt-C H
6
4
g
h
I
Me
4-Cl-C H
6
4
Ph
Ph
Ph
3-Me-C H
6
4
j
OEt
OMe
OEt
OMe
OEt
OMe
OEt
OMe
OEt
OEt
CH (CH )
3
2 3
b
k
l
H NCH CH CH
2
95
94
94
93
95
95
92
91
85
95
95
92
92
92
93
2
2
2
C H
3
5
m
n
o
p
q
r
PhCH2
(R)-PhCH(CH3)
Ph
Ph
4-OMe-C H
6
4
4
4-OMe-C H
6
s
4-Br-C H
6
4
t
(CH ) O
2
PhCH2
2
u
v
w
x
y
(CH ) O
2
Ph
2
(CH ) O
2
4-Me-C H
6
2
4
4
(CH ) O
2
2-Me-C H
6
2
(CH2)3
(CH2)3
OEt
OEt
Ph
4-OMe-C H
6
4
a
b
Isolated yield; 2 equiv of ꢀ-dicarbonyl compounds (with respect to propane-1,3-diamine)
were used
sponding ꢀ-enaminones and ꢀ-enamino esters having a (Z)-configuration of the
carbon-carbon double bond due to the formation of intramolecular hydrogen
1
bonding, as evidenced by H NMR analysis following the procedure reported by
Das et al. [18].
In conclusion, we demonstrated that ZrCl is a remarkably efficient catalyst for
4
the synthesis of ꢀ-enaminones and ꢀ-enamino esters from ꢀ-dicarbonyl com-
pounds and amines. The present method is associated with several advantages such
as mild conditions, short reaction times, excellent yields of products, simple
workup procedure, and low cost of catalyst. The use of solvent-free reaction con-
ditions employed in the present protocol makes it environmentally friendly and
suitable for large scale synthesis.
Experimental
Melting points were recorded on a X-4 apparatus. IR spectra were recorded on a Perkin Elmer 781
1
spectrophotometer. H NMR spectra were recorded with a Bruker spectrometer at 300 MHz using TMS
as internal standard. Elemental analyses were performed on an elementar vario EL analyser. Their
results agreed favourably with the calculated values.

8
0
J. Lin and L.-F. Zhang
General Procedure for the Synthesis of ꢀ-Enaminones and ꢀ-Enamino Esters 3
ZrCl (23 mg, 0.1 mmol) was added to a mixture of ꢀ-dicarbonyl compound (10 mmol) and amine
4
(
10 mmol). The mixture was stirred magnetically under solvent-free conditions at room temperature.
3
After completion of the reaction (monitored by TLC), 20 cm ethyl acetate were added to the reaction
3
mixture and the organic phase was washed with 2ꢂ10cm brine. The combined organic layer was
dried (MgSO ) and concentrated under vacuum to obtain a product in almost pure form. Further
4
purification was carried out by column chromatography over silica gel using ethyl acetate:n-hexane
(2:8) as the eluent.
Ethyl 3-(cyclopropylamino)but-2-enoate (3l, C H NO )
9
15
2
Yellowish oil; IR (neat): ꢁꢀ ¼ 3292, 2981, 1688, 1655, 1610, 1492, 1440, 1340, 1268, 1161, 1027,
ꢃ1
1
9
03 cm ; H NMR (CDCl ): ꢂ ¼ 0.56–0.63 (m, 2H), 0.72–0.80 (m, 2H), 1.24 (t, J ¼ 7.2Hz, 3H),
3
2
.06 (s, 3H), 2.53–2.62 (m, 1H), 4.08 (q, J ¼ 7.2Hz, 2H), 4.49 (s, 1H), 8.55 (br s, 1H, NH) ppm.
Ethyl (R)-3-(1-phenylethylamino)but-2-enoate (3n, C H NO )
1
4
19
2
2
D
0
2
ꢃ1
Colorless liquid; ½ꢃꢄ : ꢃ630 cm g (c ¼ 1.02, EtOH); IR (neat): ꢁꢀ ¼ 3279, 2979, 1650, 1610, 1494,
ꢃ1
1
1
445, 1385, 1265, 1054, 844, 785 cm ; H NMR (CDCl , 300 MHz): ꢂ ¼ 1.30 (t, J ¼ 7.2 Hz, 3H),
3
1
.54 (d, J ¼ 6.9 Hz, 3H), 1.79 (s, 3H), 4.15 (q, J ¼ 7.2Hz, 2H), 4.89 (s, 1H), 4.66 (m, 1H), 7.23–7.38
(
m, 5H), 9.02 (br s, 1H, NH) ppm.
Ethyl 3-(4-methoxyphenylamino)but-2-enoate (3r, C H NO )
3
1
3
17
ꢅ
Pale yellow solid, mp 44.5–45.5 C; IR (KBr): ꢁꢀ ¼ 3265, 2950, 2836, 1655, 1614, 1514, 1246, 1161,
ꢃ1
1
1
035, 977, 786 cm ; H NMR (CDCl , 300 MHz): ꢂ ¼ 1.27 (t, J ¼ 7.2 Hz, 3H), 1.87 (s, 3H), 3.79
3
(
(
s, 3H), 4.15 (q, J ¼ 7.2Hz, 2H), 4.64 (s, 1H), 6.85 (d, J ¼ 8.1 Hz, 2H), 7.02 (d, J ¼ 8.1 Hz, 2H), 10.18
br s, 1H, NH) ppm.
Ethyl 3-(4-bromophenylamino)but-2-enoate (3s, C H BrNO )
2
1
2
14
ꢅ
Pale yellow solid, mp 52.5–53 C; IR (KBr): ꢁꢀ ¼ 3275, 2979, 1650, 1611, 1581, 1480, 1385, 1261,
ꢃ1
1
1
2
064, 853, 789 cm ; HNMR (CDCl ): ꢂ ¼ 1.29 (t, J ¼ 7.2 Hz, 3H), 1.99 (s, 3H), 4.16 (q, J ¼ 7.2 Hz,
3
H), 4.72 (s, 1H), 6.95 (d, J ¼ 8.1 Hz, 2H), 7.43 (d, J ¼ 8.1 Hz, 2H), 10.35 (br s, 1H, NH) ppm.
3
-(1-(3-Toluidino)ethylidene)dihydrofuran-2(3H)-one (3w, C H NO )
1
3
15
2
ꢅ
Pale yellow solid, mp 121–122 C; IR (KBr): ꢁꢀ ¼ 3465, 2978, 1632, 1514, 1460, 1359, 1283, 1124,
ꢃ1
1
1
2
022, 954, 760 cm ; H NMR (300MHz, CDCl ): ꢂ ¼ 2.02 (s, 3H), 2.33 (s, 3H), 2.80 (t, J ¼ 7.2 Hz,
3
H), 4.32 (t, J ¼ 7.2 Hz, 2H), 6.85–6.88 (m, 2H), 6.96 (d, J ¼ 7.2 Hz, 1H), 7.20 (t, J ¼ 7.2 Hz, 1H), 9.95
(br s, 1H, NH) ppm.
Acknowledgement
The financial support for this work from Hebei Normal University (L2005B18) is gratefully
acknowledged.
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