Mild and efficient method for synthesis of eaminones using ytterbium triflate as catalyst

Article abstract of DOI:10.1080/00397911.2010.493722

A mild and efficient procedure for synthesis of-enaminones by the condensation of-dicarbonyl compounds and amines using ytterbium triflate [Yb(OTf)₃] as catalyst is described. The catalyst can be easily recovered and reused without loss of activity. Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397911.2010.493722

Synthetic Communications1, 40: 2506–2512, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.493722
MILD AND EFFICIENT METHOD FOR SYNTHESIS
OF EAMINONES USING YTTERBIUM TRIFLATE
AS CATALYST
Rener Chen, Ping Li, Jianjun Li, and Weike Su
Zhejiang Key Laboratory of Pharmaceutical Engineering, College of
Pharmaceutical Sciences, Zhejiang University of Technology,
Hangzhou, China
A mild and efficient procedure for synthesis of b-enaminones by the condensation of
b-dicarbonyl compounds and amines using ytterbium triflate [Yb(OTf)3] as catalyst
is described. The catalyst can be easily recovered and reused without loss of activity.
Keywords: Amine; b-dicarbonyl compounds; b-enaminones; ytterbium triflate
Enaminones are important precursors for the synthesis of a variety of heterocycles[1]
and pharmaceutical compounds.[2] They are known to possess a variety of medicinal
properties including anticonvulsant, antimalarial, anti-inflammatory, and cardio-
vascular effects. Because of the importance of these compounds as intermediates
in organic synthesis, several methods for the preparation of b-enaminones have been
reported.[2] The conventional method for the synthesis of enaminones is the direct
condensation of b-dicarbonyl compounds with amines under reflux in an aromatic
solvent with azetropic removal of water.[3] Recently, improved procedures have been
reported using all kinds of catalysts such as silica=microwave irradiation,[4] clay
K10=ultrasound irradiation,[5] NaAuAl4,[6] Bi(TFA)3,[7] Zn(ClO4)2 ꢀ 6H2O,[8] CeCl3 ꢀ
7H2O,[9] ionic liquids,[10] and I2.[11] Nevertheless, some of the approaches currently
available suffer from one or more drawbacks such as the use of expensive or less
easily available reagents, vigorous reaction conditions, long reaction times, unsatis-
factory yields, or poor selectivity. Taking into consideration of all these limitations
and the wide range of activity of enaminones, there is still a need to develop a
suitable method for the synthesis of enaminones.
In the past few years, we were interested in the use of metal triflates as Lewis
acid promoters in various organic transformations.[12] In the course of our research
on metal triflates, we found that they are relatively nontoxic, fairly stable, and
efficient catalysts. Herein, we report the use of metal triflates as recyclable catalysts
Received April 13, 2007.
Address correspondence to Jianjun Li, Key Laboratory of Pharmaceutical Engineering of Ministry
of Education, College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou 310014,
China. E-mail: lijianjun@zjut.edu.cn
2506

SYNTHESIS OF EAMINONES
2507
Scheme 1. The synthesis of b-enaminones.
for the synthesis of b-enaminones using cyclohexane-1,3-dione and amine under mild
reaction conditions (Scheme 1).
We began our study by comparing the catalytic activity of different metal
triflates. Most the catalysts listed in Table 1 were active and stable, and Yb(OTf)3
proved to be the most efficient because the reaction could be carried out in excellent
yield. The best reaction conditions require the presence of a small amount of
Yb(OTf)3 (2 mol%). In addition, because the Yb(OTf)3 was weakly soluble in
CH2Cl2 and the products had high solubility in CH2Cl2, the products could be
extracted with CH2Cl2. The catalyst was separated by filtration and dried at
150 ꢁC. The catalyst could be reused for four times without loss of activity
(Table 1, entry 13).
The results presented in Table 2 indicated the scope and generality of the
method, which is efficient not only for aromatic amines but also for aliphatic amines.
The electron-withdrawing group on aromatic amines would draw back the reaction
(Table 2, entry 1). The protocol was also successfully applied to enamination of
linear b-diketones (Scheme 2; Table 2, entry 11) and linear b-ketoesters (Scheme 2;
Table 2, entries 12 and 13). In most cases, the reaction proceeded rapidly and
smoothly at room temperature in comparison to other methods, and the products
were obtained in excellent yields.
A probable mechanism for the synthesis involving cyclohexane-1,3-dione may
be postulated as shown in Scheme 3. First, the amino group attacks the carbomyl
Table 1. Preparation of 3-phenylamino-cyclohex-2-enone (3e) under different conditionsa
Entry
Catalyst
Cat. amount (mol%)
Yield of 3e (%)b
1
4
—
—
1
2
3
4
5
2
2
2
2
2
30
70
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Zn(OTf)2
Cu(OTf)2
Eu(OTf)2
Y(OTf)2
Yb(OTf)3
5
96
96
6
7
96
97
8
9
85
93
10
11
12
13c
92
94
96, 95, 95, 95
aReaction conditions: cyclohexane-1,3-dione (5 mmol), aniline (5 mmol), CH3CN as solvent (2 mL),
room temperature for 20 min.
bIsolated yields.
cThe catalyst was reused for four times.

2508
R. CHEN ET AL.
a
Table 2. Preparation of b-enaminones catalyzed by Yb(OTf)3
Entry
1b
Reaction time (min)
Products
Yield (%)c [Ref.]
60
30
30
84[14]
2
3
91[4b]
92[17]
4
5
6
20
20
20
95[4b]
96[10]
94[15]
7
8
20
10
97[4b]
98[2b]
9
10
10
97[16]
10
96[4b]
(Continued )

SYNTHESIS OF EAMINONES
2509
Table 2. Continued
Entry
11
Reaction time (min)
Products
Yield (%)c [Ref.]
20
90[4b]
12
13
20
20
93[18]
93[13]
aReaction conditions: b-dicarbonyl compound (5 mmol), amine (5 mmol), Yb(OTf)3 (0.10 mmol),
CH3CN as solvent (2 mL), room temperature.
bReaction temperature: 60 ꢁC.
cIsolated yields.
Scheme 2. The direct condensation of cyclohexane-1,3-dione and amine catalyzed by ytterbium triflate.
Scheme 3. Proposed mechanism for the condensation reaction of cyclohexane-1,3-dione and amine.

2510
R. CHEN ET AL.
group of cyclohexane-1,3-dione, which is activated by Yb(OTf)3, giving the inter-
mediate 6, which was intramolecular dehydrated to give the corresponding product 3.
In conclusion, we have developed a novel and efficient method for the synthesis
of b-enaminones by treating b-dicarbonyl compounds with amines in the presence
of Yb(OTf)3. The mildness of the conversion, simple experimental procedure,
good yields, short reaction times, and reusability of the catalyst are the noteworthy
advantages of the protocol.
EXPERIMENTAL
All reagents were used as received. 1H NMR spectra were recorded on a
Varian 400-MHz instrument using dimethylsulfoxide (DMSO) as the solvent.
Chemical shifts were expressed in parts per million using tetramethylsilane (TMS)
as an internal standard.
General Procedure for the Preparation of b-Enaminones
A mixture of the b-dicarbonyl compounds (5 mmol), amine 2 (5 mmol), and
Yb(OTf)3 (0.10 mmol, 0.062 g) in acetonitrile (2 mL) was stirred at room temperature
(or 60 ꢁC; Table 2, entry 1) for the appropriate time (Table 2). After completion of
the reaction as indicated by thin-layer chromatography (TLC), the mixture was
diluted by CH2Cl2 (20 mL). The insoluble catalyst was separated by filtration
and rinsed with CH2Cl2. Then it was dried at 150 ꢁC for 2 h to give a white solid,
which could be reused without loss of activity. The organic liquid was concentrated
under reduced pressure and then recrystallized from petroleum ester and ethyl
acetate (V=V ¼ 3:1) to give pure products 3.
Spectral Data of Selected Compounds
1
3-(4-Nitrophenylamino)cyclohex-2-enone 3a. H NMR (400MHz,
DMSO): d 9.34 (s, 1 H, NH), 8.22 (d, J ¼ 8.8 Hz, 2H, ArH), 7.38 (d, J ¼ 8.8 Hz, 2 H,
=
ArH), 5.69 (s, 1 H, CH C), 2.58 (t, J ¼ 6.0 Hz, 2 H, CH2), 2.26 (t, J ¼ 6.4 Hz,
2 H, CH2), 1.94 (q, J ¼ 6.0 Hz, 2 H, CH2). 13C NMR (100MHz, DMSO): 196.7,
159.4, 146.2, 141.6, 125.2 120.3, 102.4, 36.4, 28.6, 21.3.
3-(3-Chloro-2-methylphenylamino)cyclohex-2-enone
3c. 1H
NMR
(400 MHz, DMSO): d 8.71 (s, 1 H, NH), 7.38 (d, J ¼ 8.4 Hz, 1 H, ArH), 7.26
=
(t, J ¼ 8.0 Hz, 1 H, ArH), 7.15 (d, J ¼ 8.0 Hz, 1 H, ArH), 4.58 (s, 1 H, CH C), 2.53
(t, J ¼ 6.0 Hz, 2 H, CH2), 2.20 (s, 3 H, CH3), 2.15 (t, J ¼ 6.0 Hz, 2 H, CH2),
1.90 (q, J ¼ 6.0 Hz, 2 H, CH2). 13C NMR (100 MHz, DMSO): 195.3, 163.7, 138.6,
134.4, 132.4, 127.5, 127.2, 126.0, 97.8, 36.4, 27.9, 21.6, 14.9.
3-(p-Toluidino)cyclohex-2-enone 3e. 1H NMR (400 MHz, DMSO): d 8.79
(s, 1 H, NH), 7.17 (d, J ¼ 8.0 Hz, 2 H, ArH), 7.06 (d, J ¼ 8.4 Hz, 2 H, ArH), 5.26 (s,
=
1 H, CH C), 2.49 (t, J ¼ 6.0 Hz, 2 H, CH2), 2.28 (s, 3H, CH3), 2.15 (t, J ¼ 6.4 Hz, 2H,
CH2), 1.87 (q, J ¼ 6.0 Hz, 2 H, CH2). 13C NMR (100 MHz, DMSO): 195.6, 162.3,
136.4, 133.7, 129.6, 123.2, 97.6, 36.4, 28.5, 21.6, 20.5.

SYNTHESIS OF EAMINONES
2511
3-(4-Methoxyphenylamino)cyclohex-2-enone 3g. 1H NMR (400 MHz,
DMSO): d 8.69 (s, 1 H, NH), 7.10 (d, J ¼ 8.8 Hz, 2 H, ArH), 6.95 (d, J ¼ 8.8 Hz,
=
2 H, ArH), 5.11 (s, 1 H, CH C), 3.75 (s, 3 H, OCH3), 2.47 (t, J ¼ 6.0 Hz, 2 H,
CH2), 2.14 (t, J ¼ 6.4 Hz, 2 H, CH2), 1.87 (q, J ¼ 6.4 Hz, 2 H, CH2). 13C NMR
(100 MHz, DMSO): 195.3, 163.0, 156.4, 131.6, 125.3, 114.4, 97.0, 55.2, 36.4,
28.4, 21.6.
3-(Benzylamino)cyclohex-2-enone 3h. 1H NMR (400 MHz, DMSO): d
=
7.54 (t, J ¼ 5.2 Hz, 1 H, NH), 7.36–7.24 (m, 5 H, ArH), 4.80 (s, 1 H, CH C), 4.20
(d, J ¼ 6.0 Hz, 2 H, CH2), 2.38 (t, J ¼ 6.4 Hz, 2 H, CH2), 2.06 (t, J ¼ 6.4 Hz, 2 H,
CH2), 1.79 (q, J ¼ 6.4 Hz, 2 H, CH2). 13C NMR (100 MHz, DMSO): 194.5, 164.4,
138.1, 128.4, 127.3, 127.0, 95.6, 45.6, 36.5, 28.4, 21.7.
3-(tert-Butylamino)cyclohex-2-enone 3i. 1H NMR (400 MHz, DMSO):
=
d 7.18 (brs, 1 H, NH), 4.71 (s, 1 H, CH C), 2.06–1.96 (m, 4 H, 2 ꢂ CH2), 1.73
(q, J ¼ 6.4 Hz, 2 H, CH2), 1.20 (s, 9 H, 3 ꢂ CH3). 13C NMR (100 MHz, DMSO):
191.1, 101.6, 49.6, 34.9, 28.5, 21.7.
ACKNOWLEDGMENTS
We are grateful to the National Basic Research Program (No. 2003CB114402)
and the National Natural Science Foundation of China (Nos. 20476098 and
20676123) for financial support.
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