Efficient synthetic method for β-enamino esters using ultrasound

Article abstract of DOI:10.1055/s-2004-829102

β-Keto esters react with a variety of amines in the presence of 0.1 equivalents of acetic acid without any solvents under ultrasound to give good yields of the corresponding β-enamino esters.

Full text of DOI:10.1055/s-2004-829102

SHORT PAPER
1557
Efficient Synthetic Method for b-Enamino Esters Using Ultrasound
E
a
fficient
S
yntheti
a
c
Method f
r
or
b
-Ena
l
mino
E
o
sters s A. Brandt,*a Ana Cláudia M. P. da Silva,b Camila G. Pancote,b Charles L. Brito,b Maria A. B. da Silveirab
Instituto Butantan, Av. Vital Brazil, 1500, 05503-900, São Paulo, SP, Brazil
Fax +55(11)38154418; E-mail: cabrandt@usp.br
b
Departamento de Farmácia, Universidadede São Paulo, São Paulo, SP, Brazil
Received 8 December 2003; revised 12 March 2004
The usual preparation of enamines involves the nucleo-
philic addition of amines to carbonyl compounds. The im-
portance of nucleophilicity of the nitrogen to form
Abstract: b-Keto esters react with a variety of amines in the pres-
ence of 0.1 equivalents of acetic acid without any solvents under ul-
trasound to give good yields of the corresponding b-enamino esters.
Keywords: ultrasound, b-enamino esters, b-keto esters, amines
Table 1 Synthesis of b-Enamino Esters from Amines and b-Keto
Esters under Sonication
Entry Amine
1
Product
Time Isolated
b-Enaminones are very attractive molecules available
from the corresponding b-dicarbonyl compounds.1–13
They are basic and versatile structures for the synthesis of
natural therapeutic and synthetic biologically active ana-
logues including taxol,2,4,14–19 anticonvulsivant,3,14 anti-in-
flammatory,14,20 and antitumor agents,14,21 as well as
quinolone antibacterials14,22,23 and quinoline antimalari-
als. b-Enaminones also possess good stability under sim-
(h)
Yields (%)
0.2
98
2
0.5
98a
ulated physiological pH conditions and low toxicity.3,8
A
3
4
0.2
0.5
96
number of reviews have been published about the chemis-
try of enamines,24,25 their hydrolysis under a variety of
conditions, their physicochemical properties and uses.26–31
Among the methods for generating b-enaminones, con-
densation of amines and b-dicarbonyl compounds is a
classical method in which the azeotropic removal of water
92a
is affected by refluxing in aromatic solvent.2,5,6,10,13,32–36
A
5
6
0.2
2.0
96
variety of other methods utilizing Al2O3,4 SiO2,37 mont-
40
morillonite K10,38,39 and NaAuCl4 as catalysts have
been reported. However, in spite of their potential utility,
some of these methods suffer from drawbacks including
the use of non-available and costly reagents, longer reac-
tion times, higher temperatures, lower yields, use of haz-
ardous solvents (toluene or benzene), side products
(amides) and cumbersome product isolation procedures.
94a
7
8
0.2
3.0
90
In order to circumvent the problems mentioned above as
well as developing an environmentally friendly proce-
dure, we describe herein a very fast and mild procedure
for the synthesis of b-enamino esters from amines and b-
keto esters. This procedure utilizes ultrasound irradiation
in the presence of acetic acid (Scheme 1) and the results
are summarized in Table 1.
89a
9
2.0
3.0
86
10
60a
Scheme 1
SYNTHESIS 2004, No. 10, pp 1557–1559
x
x.
x
x
.
2
0
0
4
Advanced online publication: 16.06.2004
DOI: 10.1055/s-2004-829102; Art ID: M05103SS
© Georg Thieme Verlag Stuttgart · New York
a Two equivalents of amine were used.

1558
C. A. Brandt et al.
SHORT PAPER
H), 3.19 (q, 2 H, J = 6.7 Hz), 4.08 (q, 2 H, J = 7.1 Hz), 4.42 (s, 1 H),
8.56 (br s, 1 H, NH).
enamines has been documented and it can be determined
by stereoeletronic effects of amines.41–44 As shown in
Table 1, the reactions where more nucleophilic amines 13C NMR (75 MHz, CDCl3): d = 13.6, 14.3, 18.9, 22.2, 26.2, 30.1,
31.2, 42.7, 57.8, 81.5, 161.5, 170.3.
were used (i.e. benzylamine, cyclohexylamine, and hexyl-
amine) gave the products in almost quantitative yields in
a short period of time. However, when very weak amines
like aniline were used, the reaction proceeded more slow-
ly but was more effective than other methods in terms of
Ethyl (2Z)-3-(Cyclohexylamino)but-2-enoate45 (Entry 5)
Yellow oil, bp 110–115 °C/0.35 Torr.
IR (film): 1654, 1607 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.24 (t, 3 H, J = 7.1 Hz), 1.26–
yields and reaction time. For instance, entry 9 (aniline and
1.89 (m, 10 H), 1.93 (s, 3 H), 3.29–3.34 (m, 1 H), 4.08 (q, 2 H,
ethyl acetoacetate) gave the enamine in 86% instead of
J = 7.1 Hz), 4.39 (s, 1 H), 8.64 (br s, 1 H, NH).
13C NMR (75 MHz, CDCl3): d = 14.7, 19.1, 24.6, 25.4, 34.5, 51.4,
50–65% yield (previously reported methods).39,45 The Z
geometry in these compounds is secured by intramolecu-
lar hydrogen bonding (in 1H NMR, the NH hydrogen atom
58.1, 60.4, 81.8, 160.8, 170.5.
is typically shifted downfield, from 10.5 to 8.5 ppm). Ad-
ditionally, there are distinct advantages of this methodol-
ogy since it provides regioselective products. Longer
reaction times by heating methodology resulted in greater
Ethyl (2Z)-3-(Isopropylamino)but-2-enoate45 (Entry 7)
Yellow oil, bp 75 °C/2.00 Torr.
IR (film): 1656, 1608 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.21 (d, 6 H, J = 6.4 Hz), 1.24 (t,
3 H, J = 7.1 Hz), 1.92 (s, 3 H), 3.63–3.74 (m, 1 H), 4.08 (q, 2 H,
J = 7.1 Hz), 4.42 (s, 1 H), 8.48 (br s, 1 H, NH).
13C NMR (75 MHz, CDCl3): d = 14.5, 19.1, 24.0, 44.3, 58.0, 81.6,
amounts of amides, since the enamines are converted into
the amides with one equivalent of water at high tempera-
ture,1 providing in this case lower selectivity.
In conclusion, we propose a novel and efficient approach
160.7, 170.5.
for rapid synthesis of the b-enamino esters using acetic
acid as an inexpensive and environmentally benign cata-
lytic system. Advantages of this method are mild reaction
conditions, economical procedure, improved yields and
enhanced reaction rates, simple experimental and separa-
tion procedures.
Ethyl (2Z)-3-Anilinobut-2-enoate45 (Entry 9)
Yellow oil, bp 125–130 °C/0.20 Torr.
IR (film): 1648, 1589 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.24 (t, 3 H, J = 7.1 Hz), 1.99 (s,
3 H), 4.17 (q, 2 H, J = 7.1 Hz), 4.69 (s, 1 H), 7.08 (d, 2 H, J = 7.5
Hz), 7.15 (t, 1 H, J = 7.5 Hz), 7.32 (t, 2 H, J = 7.5 Hz), 10.38 (br s,
1 H, NH).
13C NMR (75 MHz, CDCl3): d = 14.7, 20.5, 58.9, 86.2, 124.6,
125.1, 129.2, 139.5, 159.1, 170.6.
1H and 13C NMR spectra were recorded on a Bruker DPX 300 spec-
trometer in CDCl3/Me4Si. Capillary CG analyses were performed
on a HP 6890 series chromatograph equipped with a split/splitless
injector and FID detector. An ultrasound bath (water), Thornton,
50/60 Hz, 110/220 V, was used.
Ethyl(2Z)-2-[1-(Benzylamino)ethylidene]pent-4-enoate2 (Entry
2)
Yellow oil, bp 125–130 °C/0.15 Torr.
IR (film): 1645, 1598 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.25 (t, 3 H, J = 7.0 Hz), 1.91 (s,
3 H), 3.01 (d, 2 H, J = 5.4 Hz), 4.12 (q, 2 H, J = 7.0 Hz), 4.43 (d, 2
H, J = 5.9 Hz), 4.89–4.97 (m, 2 H), 5.76–5.88 (m, 1 H), 7.26–7.32
(m, 5 H), 9.77 (br s, 1 H, NH).
Preparation of b-Enamino Esters; Typical Procedure
A mixture of ethyl acetoacetate or ethyl 2-acetylpent-4-enoate (2
mmol), amine (2 mmol) and acetic acid (0.2 mmol) was placed in
an ultrasound bath USC 700, 40 KHz, 100 W (the temperature of the
bath never exceeding 30 °C) for the time (by capillary GC analysis)
reported in Table 1. At the end of the reaction, EtOH (5 mL) was
added, the solution was dried (Na2SO4), filtered and concentrated in
vacuo. The residue was distilled after the removal of unreacted
starting material by Kugelrohr apparatus at reduced pressure to give
the pure product as a yellow oil.
13C NMR (75 MHz, CDCl3): d = 14.5, 14.7, 31.2, 46.9, 58.6, 90.3,
112.9, 126.7, 127.0, 128.6, 138.3, 139.1, 162.5, 170.6.
Ethyl (2Z)-2-[1-(Hexylamino)ethylidene]pent-4-enoate2 (Entry
4)
Ethyl (2Z)-3-(Benzylamino)but-2-enoate45 (Entry 1)
Yellow oil, bp 110–115 °C/0.20 Torr.
Yellow oil, bp 120–125 °C/0.15 Torr.
IR (film): 1655, 1605 cm–1.
IR (film): 1645, 1598 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.25 (t, 3 H, J = 7.1 Hz), 1.90 (s,
3 H), 4.10 (q, 2 H, J = 7.1 Hz), 4.42 (d, 2 H, J = 6.4 Hz), 4.55 (s, 1
H), 7.22–7.40 (m, 5 H), 8.95 (br s, 1 H, NH).
13C NMR (75 MHz, CDCl3): d = 14.7, 19.5, 24.1, 46.8, 58.5, 83.2,
126.8, 127.4, 128.8, 138.8, 162.0, 170.6.
1H NMR (300 MHz, CDCl3): d = 0.89 (t, 3 H, J = 6.7 Hz), 1.24 (t,
3 H, J = 7.0 Hz), 1.22–1.41 (m, 6 H), 1.52–1.61 (m, 2 H), 1.94 (s, 3
H), 2.99 (d, 2 H, J = 5.7 Hz), 3.18 (t, 2 H, J = 7.0 Hz), 4.11 (q, 2 H,
J = 7.0 Hz), 4.91–4.97 (m, 2 H), 5.75–5.88 (m, 1 H), 9.36 (br s, 1 H,
NH).
13C NMR (75 MHz, CDCl3): d = 13.2, 13.9, 21.9, 25.9, 29.7, 30.6,
30.9, 42.6, 58.3, 88.2, 111.8, 137.9, 159.9, 169.8.
Ethyl (2Z)-3-(Hexylamino)but-2-enoate45 (Entry 3)
Yellow oil, bp 105–110 °C/0.20 Torr.
IR (film): 1655, 1606 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.89 (t, 3 H, J = 6.7 Hz), 1.24 (t,
3 H, J = 7.1 Hz), 1.22–1.41 (m, 6 H), 1.51–1.60 (m, 2 H), 1.91 (s, 3
Ethyl (2Z)-2-[1-(Cyclohexylamino)ethylidene]pent-4-enoate2
(Entry 6)
Yellow oil, bp 105–110 °C/0.35 Torr.
IR (film): 1644, 1597 cm–1.
Synthesis 2004, No. 10, 1557–1559 © Thieme Stuttgart · New York

SHORT PAPER
Efficient Synthetic Method for b-Enamino Esters
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1559
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112.6, 138.5, 159.7, 170.6.
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Acknowledgment
The authors would like to thank CNPq for financial support.
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Synthesis 2004, No. 10, 1557–1559 © Thieme Stuttgart · New York