An easy synthesis of enaminones in water as solvent

Article abstract of DOI:10.1055/s-2000-7608

Enaminones were prepared from β-ketoesters or 1,3-diketones and primary amines in water as solvent.

Full text of DOI:10.1055/s-2000-7608

1526
SHORT PAPER
An Easy Synthesis of Enaminones in Water as Solvent
Hélio A. Stefani,* Iguatemi M. Costa, Diogo de O. Silva
Departamento de Farmácia, Faculdade de Ciências Farmacêuticas, Universidade de São Paulo, São Paulo, SP - Brazil
Tel. 0055118183654; Fax 0055118154418; E-mail:hstefani@usp.br
Received 19 March 2000; revised 8 June 2000
Since there are two carbonyl groups in the starting mate-
rial and 2 equivalents of amine were added, there should
be several products in this reaction, i.e., the amine may re-
act with one or both of carbonyl groups. Thus, there
should be three products from b-ketoester and two from
1,3-diketone, however, only enaminones were observed
as products. This probably occurs because the acetyl por-
tion of the starting dicarbonyl compounds is more reactive
than the ester or aromatic conjugated carbonyl. When the
enaminone is formed, it is stabilized by resonance, block-
ing the formation of other products. The conjugation ef-
fect also justifies the formation of only one product from
acetylacetone.
Abstract: Enaminones were prepared from b-ketoesters or 1,3-
diketones and primary amines in water as solvent
Key words: b-ketoesters, 1,3-diketones, b-enaminones
Enaminones and related compounds possessing the struc-
tural unit N-C=C-Z (Z = COR, CO2R, CN, etc.) are versa-
tile synthetic intermediates that combine the ambident
nucleophilicity of enamines with the ambident eletrophi-
licity of enones.1
Some procedures reported for the synthesis of b-enamino-
carbonyl derivatives include the reaction of amines and
1,3-diketones supported over clay K10/ultra-sound2 or sil-
ica under microwave irradiation,3 reaction of b-amino ke-
tones in the presence of triethylamine promoted by
Pd(II),4 and reactions of a-metalated imines with esters.5
However, the generally employed method for the prepara-
tion entails the reaction between ammonia or a primary or
secondary amine with 1,3-dicarbonyl compound in ben-
zene solution with azeotropic removal of the water
formed.6-10
The probable explanation for the formation of enamin-
ones in water is their tautomeric forms (A and B) associ-
ated with the hydrogen bond.11,12 Enaminones of all types
exist predominantly in the carbonyl form and are stabi-
lized by the contribution of the zwitterionic form (C),13
which can be solvated by water preventing hydrolysis of
the formed enaminone. This explanation can be supported
by the fact that no reaction was observed using secondary
amines or simple carbonyl compounds (Scheme 2).
We report here, a simple procedure for the synthesis of b-
enamino esters and enaminoketones (1) starting from b-
ketoesters or 1,3-diketones and primary amines in water
as solvent (Scheme 1). The main advantages of this meth-
odology are: (a) the reaction is simple to perform; (b) the
reaction occurs at room temperature; (c) the yields are
good to high, (d) acid catalysis is not necessary, (e) the re-
action works for a variety of primary amines; and (f) pu-
rification of the enaminones is not necessary. With
secondary amines or simple carbonyl compounds, no re-
action was observed. The reaction worked very well to
soluble amines, but with less soluble amines the yield was
moderated and it was necessary to use high excess of
amine (3 equivalents). When b-ketoester and 1,3-dike-
tones reacted with ethylene-diamine, diaminones were
observed as products (1h and 1m).
Scheme 2
In summary, we have provided a remarkably viable alter-
native route for the synthesis of enaminones using water
as solvent. We have found, at present, only one limitation:
the low solubility of some primary amines in water pre-
vents the preparation of enaminones in good yields. The
characterization of the enaminones is very known, there-
fore, only the basic identification (NMR and IR) was
done.
Enaminones 1; General Procedure
The b-ketoester or 1,3-diketones (1 mmol) was added, at r.t., to ami-
no compound (2 mmol) in H2O (5 mL) and stirred for the time indi-
cated (Table). When the enaminone formation was completed
(monitored by GC), the reaction mixture was washed with brine to
remove excess amine and then extracted with CH2Cl2.
Scheme 1
Synthesis 2000, No. 11, 1526–1528 ISSN 0039-7881 © Thieme Stuttgart · New York

SHORT PAPER
An Easy Synthesis of Enaminones in Water as Solvent
1527
Table Enaminones 1a-o
Entry
R
R1
Reaction
Time (h)
Yield
(%)b
IR
1H NMR (300 MHz, CDCl3)
13C NMR
n (cm−1)c
d (ppm), J (Hz)d
(75 MHz, CDCl3)
d (ppm)d
1a
-OCH2CH3
-CH2CH3
6
10
7
75
65
88
1651,
1605
1.21 (t, 3 H, J = 7), 1.24 (t, 3 H,
J = 7), 1.92 (s, 3 H), 3.25 (quin, 2
H, J = 7), 4.07 (q, 2 H, J = 7), 4.42
(s, 1 H), 8.48 (br s, 1 H)
14.86, 15.82,
19.40, 37.84,
58.36, 81.54,
162.01, 170.83
1b
1c
-OCH2CH3
-OCH2CH3
-CH(CH3)2
1654,
1609
1.21 (d, 6 H, J = 6.5) 1.24 (t, 3 H,
J = 7), 1.94 (s, 3 H), 3.68 (m, 1 H),
4.08 (q, 2 H, J = 7), 4.39 (s, 1 H),
8.49 (br s, 1 H)
14.76, 19.28,
24.20, 44.53,
58.26, 81.82,
160.93, 170.70
CH2CH=CH2
1648,
1606
1.24 (t, 3 H, J = 7.1), 1.90 (s, 3 H),
3.83 (m, 2 H), 4.07 (q, 2 H, J =
7.1), 4.48 (s, 1 H), 5.15 (d, 1 H, J =
10.4), 5.21 (d, 1 H, J = 17.2),
5.80-5.92 (m, 1 H), 8.67 (br s,
1 H)
14.66, 19.03,
45.16, 58.30,
82.85, 115.79,
134.92, 161.89,
170.57
1d
1e
-OCH2CH3
-OCH2CH3
-CH2CH2OH
4
80
86
1629,
1588
1.23 (t, 3 H, J = 7.1), 1.94 (s, 3 H),
3.36 (q, 2 H, J = 5.5), 3.71 (t, 2 H,
J = 5.5), 3.84 (br s, 1 H) 4.05 (q,
2 H, J = 7.1), 4.46 (s, 1 H), 8.62 (br
s, 1 H)
14.65, 19.64,
45.22, 58.51,
61.79, 82.58,
162.32, 170.86
-c-C6H11
11
1655,
1608
1.24 (t, 3 H, J = 7.1), 1.26-1.88
(m, 10 H), 1.93 (s, 3 H), 3.29-3.33
(m, 1 H), 4.07 (q, 2 H, J = 7.1),
4.38 (s, 1 H), 8.64 (br s, 1 H)
14.73, 19.21,
24.71, 25.47,
34.56, 51.41,
58.23, 60.36,
81.78, 160.79,
170.62
1f
-OCH2CH3
-OCH2CH3
-CH2C6H5
12
25
73
65
1658,
1605
1.25 (t, 3 H, J = 7.1), 1.90 (s, 3 H),
4.09 (q, 2 H, J = 7.1), 4.41 (d, 2 H,
J = 6.4), 4.53 (s, 1 H), 7.22-7.36
(m, 5 H), 8.95 (br s, 1 H)
14.76, 19.48,
24.20, 46.89,
58.50, 83.32,
126.83, 127.46,
128.90, 138.88,
162.12, 170.72
1g
-C6H5
1644,
1589
1.28 (t, 3 H, J = 7.1), 1.98 (s, 3 H),
4.14 (q, 2 H, J = 7.1), 4.69 (s, 1 H),
7.05-7.34 (m, 5 H), 10.39 (br s,
1 H)
14.47, 20.18,
58.62, 85.93,
124.26, 124.78,
128.93, 139.22,
158.80, 170.28
1ha
1ia
1j
-OCH2CH3
-CH3
-CH2CH2NH2
-CH2CH2OH
CH2CH=CH2
0.5
14
9
95
87
74
1648,
1609
1.24 (t, 6 H, J = 7), 1.91 (s, 6 H),
3.34-3.37 (m, 4 H), 4.08 (q, 4 H,
J = 7), 4.48 (s, 2 H), 8.65 (br s,
2 H)
14.73, 19.38,
43.95, 58.60,
83.71, 161.45,
170.75
1609,
1572
1.96 (s, 3 H), 1.97 (s, 3 H), 3.40 (q,
2 H, J = 5.4), 3.75 (t, 2 H, J = 5.4),
4.42 (br s, 1 H), 4.97 (s, 1 H),
10.84 (br s, 1 H)
19.14, 28.55,
45.46, 61.35,
95.63, 164.06,
194.81
-CH3
1613,
1574
1.91 (s, 3 H), 2.00 (s, 3 H), 3.86 (br
s, 2 H), 5.01 (s, 1 H), 5.16 (d, 1 H,
J = 11.1), 5.21 (d, 1 H, J = 18.2),
5.79-5.91 (m, 2 H), 10.87 (br s,
2 H)
18.08, 28.36,
44.62, 95.18,
115.56, 133.64,
162.73, 194.54
1k
-CH3
-c-C6H11
6
88
1606,
1577
1.27-1.86 (m, 10 H), 1.95 (s, 3 H),
1.98 (s, 3 H), 3.34-3.38 (m, 1 H),
4.91 (s, 1 H), 11.00 (br s, 1 H)
18.25, 24.07,
24.99, 28.34,
33.46, 51.13,
94.59, 161.56,
193.91
Synthesis 2000, No. 11, 1526–1528 ISSN 0039-7881 © Thieme Stuttgart · New York

1528
H. A. Stefani et al.
SHORT PAPER
Table (continued)
Entry
R
R1
Reaction
Time (h)
Yield
(%)b
IR
1H NMR (300 MHz, CDCl3)
13C NMR
n (cm−1)c
d (ppm), J (Hz)d
(75 MHz, CDCl3)
d (ppm)d
1la
-CH3
-C6H5
24
60
1610,
1587
1.99 (s, 3 H), 2.10 (s, 3 H), 5.19 (s,
1 H), 7.08-7.36 (m, 5 H), 12.48
(br s, 1 H)
19.75, 29.08,
97.53, 124.66,
125.47, 129.01,
138.66, 160.16,
196.06
1ma
1na
-CH3
-CH2CH2NH2
-CH2CH2OH
10
4
60
78
1613,
1580
1.84 (s, 6 H), 1.92 (s, 6 H), 3.34-
3.37 (m, 4 H), 4.92 (s, 2 H), 10.82
(br s, 2 H)
18.41, 28.58,
43.24, 95.87,
162.63, 195.16
-C6H5
1598,
1547
1.99 (s, 3 H), 3.44 (q, 2 H, J = 5.4),
3.79 (t, 2 H, J = 5.4), 5.63 (s, 1 H),
7.35-7.41 (m, 3 H), 7.80-7.84 (m,
2 H)
19.58, 45.66,
61.48, 92.64,
126.90, 128.17,
128.32, 130.50,
140.32, 165.80,
187.67
1o
-C6H5
CH2CH=CH2
10
71
1595,
1543
2.03 (s, 3H), 3.89-3.94 (m, 2 H),
5.19 (d, 1 H, J = 10.4), 5.26 (d,
1 H, J = 17.1), 5.70 (s, 1 H), 5.81-
5.95 (m, 1 H), 7.33-7.40 (m, 3 H),
7.82-7.89 (m, 2 H), 11.48 (br s,
1 H)
19.13, 45.35,
92.38, 116.44,
126.89, 128.14,
130.46, 133.72,
140.34, 165.03,
187.86
aSolid products, mp (oC): 126 (1h), 72 (1i), 47 (1l), 105 (1m), 81 (1n).
bIsolated yields.
cCarbonyl and hydrogen-bonded carbonyl signals. Measured on a FT-IR Hewlett Packard.
dRecorded on a Bruker DPX 300 NMR spectrometer.
(6) Greenhill, J. V. J. Chem. Soc. C 1971, 2699.
(7) Roberts, E.; Turner, E. E. J. Chem. Soc. 1927, 1832.
Acknowledgement
(8) Martin, D. F.; Janusonis, G. A.; Martin, B. B. J. Am. Chem.
Soc. 1961, 83, 73.
We are grateful to FAPESP, CNPQ, and CAPES for financial sup-
port.
(9) Holtzclaw, H. F., Jr.; Collman, J. P.; Alire, R. M. J. Am. Chem.
Soc. 1958, 80, 1100.
(10) Baraldi, P. G.; Simoni, D.; Manfredini, S. Synthesis 1983,
902.
(11) Ohmine, I.; Saito, S. Acc. Chem. Res. 1999, 32, 741.
(12) Dudek, G. O. J. Org. Chem. 1965, 30, 548.
(13) Cone, E. J.; Garner, R. H.; Hayes, A. W. J. Org. Chem. 1972,
37, 4436.
References
(1) Greenhill, J. V. Chem. Soc. Rev. 1977, 6, 277.
(2) Braibante, M. E. F.; Braibante, H. S.; Salvatore, S. Quím.
Nova 1990, 13, 67.
(3) Rechsteiner, B.; Texier-Boullet, F.; Hamelin, J. Tetrahedron
Lett. 1993, 34, 5071.
(4) Murahashi, S.-I.; Mitsue, Y.; Tsumiyama, T. Bull. Chem. Soc.
Jpn. 1987, 60, 3285.
(5) Bartoli, G.; Cimarelli, C.; Palmieri, G.; Bosco, M.; Dalpozzo,
R. Synthesis 1990, 895.
Article Identifier:
1437-210X,E;2000,0,11,1526,1528,ftx,en;M05300SS.pdf
Synthesis 2000, No. 11, 1526–1528 ISSN 0039-7881 © Thieme Stuttgart · New York