A mild, efficient and environmentally friendly method for the regio- and chemoselective synthesis of enaminones using Bi(TFA)3 as a reusable catalyst in aqueous media

Article abstract of DOI:10.1016/j.tetlet.2003.12.093

Bismuth(III) trifluoroacetate has been found to be an extremely efficient catalyst for the preparation of β-enaminones in water. In addition, by employing this catalyst, high regio- and chemoselective enamination of carbonyl compounds was achieved.

Full text of DOI:10.1016/j.tetlet.2003.12.093

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 1725–1728
A mild, efficient and environmentally friendly method for the regio-
and chemoselective synthesis of enaminones using Bi(TFA) as
a reusable catalyst in aqueous media
3
*
*
Ahmad R. Khosropour, Mohammad M. Khodaei and Mehdi Kookhazadeh
Department of Chemistry, Faculty of Science, Razi University, Kermanshah 67149, Iran
Received 11 November 2003; revised 7 December 2003; accepted 16 December 2003
Abstract—Bismuth(III) trifluoroacetate has been found to be an extremely efficient catalyst for the preparation of b-enaminones in
water. In addition, by employing this catalyst, high regio- and chemoselective enamination of carbonyl compounds was achieved.
ꢀ
2004 Elsevier Ltd. All rights reserved.
9
Enamination of b-dicarbonyl compounds forming
b-enaminones, is an important and widely used trans-
formation in organic chemistry. Such compounds are
challenging topics in organic synthesis. Many recent
papers describing the use of bismuth compounds in
organic transformations pointed out that their use is
1
10
important precursors for the synthesis of a variety of
ecologically friendly. In addition, bismuth derivatives
11
2
3
heterocycles and pharmaceutical compounds. Due to
the importance of these compounds as intermediates in
organic synthesis, a simple and high yielding one-pot
approach for this transformation is highly desirable.
have been widely used in medicine.
They have
attracted much attention because they are easy to han-
dle, are low in cost and are relatively insensitive to air
and moisture. In the course of our research on Bi(III)
salts we found that bismuth(III) trifluoroacetate is rel-
atively nontoxic, readily available at low cost and fairly
stable to water, unlike common Lewis acids (e.g.,
12
3
Despite their wide range of pharmacological activity
and synthetic applications, the synthesis of b-enami-
nones has received little attention. The most well-known
route to b-enaminones involves the direct condensation
of b-dicarbonyl compounds with amines at reflux in an
13
AlCl ), which decompose readily in aqueous media.
3
4
aromatic solvent with azetropic removal of water.
We herein report a green, mild and efficient method for
the regio- and chemoselective enamination of b-dicar-
bonyl compounds in water, in good to excellent yields,
Several improved procedures have been reported
including the reaction of amines and 1,3-dicarbonyl
compounds supported on silica with microwave irradi-
3
catalyzed with Bi(TFA) (Scheme 1).
5
6
7
ation, clay K /ultra-sound or NaAuCl . Recently,
4
10
these compounds have been prepared by direct con-
densation of b-dicarbonyl compounds and primary
amines in water as solvent. However, these methods
The experimental procedure for this reaction is
remarkably simple and does not require the use of
organic solvents or inert atmospheres. A catalytic
8
suffer from drawbacks such as long reaction times,
unsatisfactory yields, low selectivity or the use of toxic
solvents that limit these methods to small-scale synthe-
sis. Lewis acid catalyzed organic reactions in water,
because they allow environmentally friendly processes
under mild conditions, are currently one of the most
quantity of Bi(TFA) (5 mol %) and the required amine
3
were added to a stirred solution of the 1,3-dicarbonyl
compound in water, and the mixture stirred at room
temperature. The generality of this process was illus-
trated by the wide range of aromatic and aliphatic
1
R
O
O
H
Bi(TFA)3
N
1
O
R NH +
Keywords: Amines; b-Dicarbonyl compounds; Enamination; Chemo-
selective; Catalyst; Bismuth compounds.
2
2
3
H O, r.t.
R
R
2
2
R
3
R
*
Corresponding authors. Tel./fax: +98-831-422-3306/8237540; e-mail:
arkhosropour@razi.ac.ir
Scheme 1.
0
040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.12.093

1726
A. R. Khosropour et al. / Tetrahedron Letters 45 (2004) 1725–1728
Table 1. Enamination of b-dicarbonyl compounds in water catalyzed by Bi(TFA)
3
1
2
3
a
b
Entry
R
R
R
Time (min)
5
Product
Yield (%)
O
c
CH (CH ) CH NH-C=CHCOC H
3 2 2 2
2 5
1
3 2 2 2
CH (CH ) CH
CH
CH
CH
CH
CH
3
3
3
3
3
OC
OC
OC
OC
OC
2
2
2
2
2
2
H
5
H
5
H
5
H
5
H
5
H
5
98
CH3
O
O
c
2
3
4
5
H
2
NCH
2
CH
2
7
10
5
C H OCCH=CNH
NH
-
C=CHCOC H
2 5
95
93
97
86
2
5
CH3
CH 3
O
HOCH
2
CH
2
HOCH CH NH-C=CHCOC H
2 2
2 5
CH3
O
C
C
6
6
H
H
5
5
CH
2
CH NH-C=CHCOC H
2
2 5
CH3
O
10
NH-C=CHCOC H
2
5
CH3
O
6
7
4-CH
3
C
6
H
4
CH
3
3
OC
45
60
CH3
NH-C=CHCOC H5
84
63
2
CH3
O
C
6
H
5
CH
Ph
NH-C=CHC-Ph
CH3
O
8
9
4-CH
3
C
6
H
4
CH
3
3
Ph
Ph
45
50
H C
NH-C=CHC-Ph
CH3
66
70
3
O
C
6
H
5
CH
2
CH
CH NH-C=CHC-Ph
2
CH3
O
NH-C=CHC-Ph
CH
O
c
1
1
1
1
1
1
1
0
1
2
3
4
5
6
H
2
NCH
2
CH
2
CH
CH
CH
CH
CH
CH
CH
3
3
3
3
3
3
3
Ph
Ph
45
30
PhCCH=C-NH
CH3
76
83
64
68
83
77
63
3
O
HOCH
2
CH
2
HOCH CH NH-C=CHC-Ph
2 2
CH3
O
c
C
6
H
5
CH
CH
CH
CH
CH
3
3
3
3
3
60
NH-C=CHC-CH3
CH3
O
c
4-CH
3
C
6
H
4
150
60
H C
NH-C=CHC-CH3
3
CH3
O
O
c
H
2
NCH
2
CH
2
CH CCH=C-NH
NH-C=CHCCH
3
3
CH3
CH3
O
c
HOCH
2
CH
2
60
HOCH CH NH-C=CHCCH
2 2 3
CH3
O
c
CH
3
CH
2
CHCH
2
180
CH CH CHNH-CH=CHCCH
3 2
3
CH3 CH3

A. R. Khosropour et al. / Tetrahedron Letters 45 (2004) 1725–1728
1727
Table 1 (continued)
1
2
3
a
b
Entry
R
R
R
Time (min)
150
Product
Yield (%)
O
CH3
H C
3
NH-
17
18
19
20
6 5
C H
82
O
O
O
O
O
H3C
CH3
NH-
CH3
4-CH
3
C
6
H
4
50
180
10 h
79
84
93
O
O
O
O
H C
O
3
CH3
NHCH2-
C
6
H
5
CH
2
O
O
O
O
H C
O
3
CH3
NHCH CH OH
2 2
2 2
HOCH CH
O
O
O
O
a
b
c
All products were identified by comparison of their physical and spectral data with those of authentic samples.
Isolated yields.
2
mmol.
primary amines and b-dicarbonyl compounds examined.
The results are shown in Table 1.
duced pressure and reused in three runs without any loss
of activity.
The reactions proceeded smoothly at room temperature
and the products were obtained in excellent yields and
chemoselectivity. Both activated and weakly activated
anilines formed enaminones in nearly quantitative
yields. Although Stefani et al. stated that the synthesis of
these compounds was limited to amines soluble in
In conclusion, the present procedure demonstrates a
new, regio- and chemoselective method for the enam-
ination of b-dicarbonyl compounds with aromatic and
aliphatic amines under mild conditions in aqueous
media where the catalyst could be recovered readily and
reused, in good to excellent yields. Furthermore, the low
toxicity of the catalyst and media, make this procedure
environmentally acceptable. Moreover, the low cost of
8
water, we have now shown that in the presence of
Bi(TFA) water insoluble amines were also converted
3
efficiently to the corresponding enaminones in good to
high yields. However, anilines with strongly electron-
withdrawing groups such as 4-nitroaniline did not yield
any product under the present reaction conditions.
Bi(TFA) , fast reaction rates and highly catalytic nature
3
of this Lewis acid as a water stable catalyst, make the
present method a practical protocol for the enamination
reaction.
Aliphatic amines also reacted efficiently to produce the
corresponding enaminones. In the case of 1,2-diamino-
ethane, 2 equiv of b-dicarbonyl compounds were used
giving products with two enaminone groups (entries 2,
General procedure. A mixture of the b-dicarbonyl com-
pound (1 mmol), the amine (1 mmol) and Bi(TFA)3
(0.05 mmol) in water (5 mL) was stirred at room tem-
perature for the appropriate time (Table 1). After
completion of the reaction as indicated by GLC or TLC,
Bi(TFA)3 was removed by filtration, washed with
1
0 and 14).
This method was successfully applied to enamination of
b-diketones (entries 7–16), linear (entries 1–6) and cyclic
b-ketoesters (entries 17–20). In all cases, amine attack
took place only at the methyl ketone carbonyl for dike-
CH
2
Cl
2
(3 · 10 mL) and dried over MgSO
4
. Evaporation
of the solvent followed by chromatography on a silica-
gel plate or silica-gel column gave the pure enaminones
in 63–98% yields.
14
3
tones and ketoesters. The use of Bi(TFA) as a hetero-
geneous catalyst showed rate enhancements, high yields
and short reaction times. The other advantage of the use
of this Lewis acid for this transformation, is the recy-
Acknowledgements
clability of the catalyst. Since Bi(TFA) is only slightly
3
soluble in water, it could be separated by simple filtra-
tion, washed with CH
We are thankful to the Razi University Research
Council for partial support of this work.
2
Cl
2
and dried at 80 ꢁC under re-

1728
A. R. Khosropour et al. / Tetrahedron Letters 45 (2004) 1725–1728
Ikegami, T.; Matano, Y. Synthesis 1997, 249; (d) Marshall,
References and notes
J. A. Chemtracts 1997, 1064; (e) Reglinski, J. In Chemistry
of Arsenic, Antimony and Bismuth; Norman, N. C., Ed.;
Blackie Academic and Professional: New York, 1998; pp
1
2
. The Chemistry of Enamines, Part 1; Rappoport, Z., Ed.;
John Wiley & Sons: New York, 1994.
. (a) Alan, C.; Spivey, A. C.; Srikaran, R.; Diaper, C. M.;
David, J.; Turner, D. Org. Biomol. Chem. 2003, 1638; (b)
Hassneen, H. M.; Abdallah, T. A. Molecules 2003, 8, 333;
4
03–440.
1
3. (a) Mohammadpoor-Baltork, I.; Khodaei, M. M.; Nikoo-
far, K. Tetrahedron Lett. 2003, 44, 591; (b) Mohammad-
poor-Baltork, I.; Khosropour, A. R. Monatsh. Chem.
(
c) Michael, J. P.; Koning, C. B.; Gravestock, D.; Hosken,
2
002, 133, 189; (c) Mohammadpoor-Baltork, I.; Aliyan,
G. D.; Howard, A. S.; Jungmann, C. M.; Krause, R. W.
M.; Parsons, A. S.; Pelly, S. C.; Stanbury, T. V. Pure Appl.
Chem. 1999, 71, 979.
H.; Khosropour, A. R. Tetrahedron 2001, 57, 5851; (d)
Mohammadpoor-Baltork, I.; Khosropour, A. R. Mole-
cules 2001, 6, 996; (e) Mohammadpoor-Baltork, I.;
Khosropour, A. R.; Aliyan, H. J. Chem. Res. (S) 2001,
780; (f) Mohammadpoor-Baltork, I.; Khosropour, A. R.;
Aliyan, H. Synth. Commun. 2001, 22, 3411.
3
. (a) Sweeney, T. R.; Strube, R. E. In BurgerÔs Medicinal
Chemistry, Part II, 4th ed.; Wolff, M. E., Ed.; 4th ed.;
Wiley: New York, 1979; p 333; (b) Foster, J. E.;
Nicholson, J. M.; Butcher, R.; Stables, J. P.; Edafiogho,
I. O.; Goodwin, A. M.; Henson, M. C.; Smith, C. A.;
Scott, K. R. Bioorg. Med. Chem. 1999, 7, 2415; (c)
Edafiogho, I. O.; Moore, J. A.; Alexander, M. S.; Scott, K.
R. J. Pharm. Sci. 1994, 83, 1155.
. (a) Baraldi, P. G.; Simoni, D.; Manfredini, S. Synthesis
1983, 902; (b) Martin, D. F.; Janusonis, G. A.; Martin,
B. B. J. Am. Chem. Soc. 1961, 83, 73.
. Rechsteiner, B.; Texier-Boullet, F.; Hamelin, J. Tetra-
hedron Lett. 1993, 34, 5071.
1
4. Analytical data for products 10, 13, 17, 20. Compound 10
mp 177–179 ꢁC; mmax(KBr) 3360, 3120, 1525, 1512, 1080,
ꢀ1
8
H 3
00, 748, 705 cm ; d (200 MHz, CDCl ) 11.6 (s, 2H,
NH), 8.17–7.1 (m, 10H, Ph), 5.7 (s, 2H, @CH–), 3.82–3.3
m, 4H, –CH ), 2.1 (s, 6H, CH ); d (50 MHz, CDCl
88.7, 165.4, 140.5, 131.1, 128.7, 127.4, 93.4, 44.2, 19.7.
Anal. Calcd for C22 : C, 75.63; H, 6.94; N, 9.16.
Found: C, 75.24; H, 6.8; N, 8.4. Compound 13 mp 58–
(
1
2
3
C
3
)
4
24 2 2
H N O
5
6
7
8
9
5
1
9 ꢁC; mmax(KBr) 3340, 3012, 2952, 2900, 2860, 1606, 1595,
ꢀ
1
H 3
558, 1268, 1015, 803 cm ; d (200 MHz, CDCl ) 12.41
. Valduga, C. J.; Squizani, A.; Braibante, H. S.; Braibante,
M. E. F. Synthesis 1998, 1019.
. Arcadi, A.; Bianchi, G.; Di Giuseppe, S.; Marinelli, F.
Green Chem. 2003, 64.
. Stefani, H. A.; Costa, I. M.; Silva, D. O. Synthesis 2000,
(
2
(
1
7
s, 1H, NH), 7.23–6.9 (m, 4H, Ar), 5.16 (s, 1H, @CH–),
.31 (s, 3H, CH ), 2.11 (s, 3H, CH ), 1.92 (s, 3H, CH ); d
50 MHz, CDCl ) 195.8, 171.0, 160.7, 136.4, 135.0, 129.9,
24.9, 60.5, 29.3, 20.7. Anal. Calcd for C12 15NO: C,
6.16; H, 7.99; N, 7.40. Found: C, 75.8; H, 7.9; N, 7.1.
3
3
3
C
3
H
1526.
Compound 17 mp 90–92 ꢁC; mmax(KBr) 3250, 3030, 2900,
. (a) Li, C. J.; Chang, T. H. Organic Reactions in Aqueous
Media; Wiley: New York, 1997; (b) Grieco, P. A. Organic
Synthesis in Water; Blackie Academic and Professional:
London, 1998; (c) Santelli, M.; Pons, J.-M. Lewis Acids
and Selectivity in Organic Synthesis; CRC: Boca Raton,
FL, 1995.
ꢀ1
1
674, 1634, 1247, 1019, 920 cm ; d
0.1 (br, 1H, NH), 7–7.41 (m, 5H, Ar), 4.42–4.3 (t,
), 3.07–2.89 (t, J ¼ 8:1 Hz, 2H, @C–
–), 2.1 (s, 3H, CH ); d (50 MHz, CDCl ) 174.3,
53.9, 147.8, 139.6, 129.6, 125.3, 124.6, 89.7, 65.8, 26.9.
Anal. Calcd for C12 : C, 70.92; H, 6.45; N, 6.89.
Found: C, 70.5; H, 6.5; N, 7.0. Compound 20 mp 110–
H 3
(200 MHz, CDCl )
1
J ¼ 8:2 Hz, 2H, OCH
2
CH
2
3
C
3
1
H13NO
2
1
0. (a) Cunha, S. B.; Lima, R.; Souza, A. R. Tetrahedron Lett.
002, 43, 49; (b) Keramane, E. M.; Boyer, B.; Roque, J. P.
2
1
7
4
3
2
11 ꢁC; mmax(KBr) 3240, 2923, 1668, 1584, 1250, 1012, 955,
Tetrahedron 2001, 57, 1909; (c) Keramane, E. M.; Boyer,
B.; Roque, J. P. Tetrahedron Lett. 2001, 42, 855.
1. Comprehensive Coordination Chemistry; Wilkinson, G.,
Gillard, R. D., McCleverty, J. A., Eds.; Pergamon:
London, 1987; Vol. 3, pp 292–313.
2. (a) Srivastava, N.; Banik, B. K. J. Org. Chem. 2003, 68,
2109; (b) Eash, K. J.; Pulia, M. S.; Wieland, L. C.; Mohan,
R. S. J. Org. Chem. 2000, 65, 8399; (c) Suzuki, H.;
ꢀ1
H 3
63 cm ; d (200 MHz, CDCl ) 8.32 (br, 1H, NH), 4.33–
.22 (t, J ¼ 8:7 Hz, 2H), 3.8–3.69 (t, J ¼ 5:8 Hz, 2H),
1
.47–3.36 (q, J ¼ 5:1, 5.2 Hz, 2H), 3.18 (br, 1H, OH), 2.9–
.8 (t, J ¼ 7:3 Hz, 2H), 2.1 (s, 3H, CH
3
); d
C
(50 MHz,
CDCl
Anal. Calcd for C
Found: C, 56.0; H, 7.7; N, 8.3.
3
) 174.8, 158.4, 156.9, 85.2, 65.8, 62.1 45.7, 26.9.
1
8 3
H13NO
: C, 56.13; H, 7.65; N, 8.18.