Reactivity of chloroacetylated β-enamino compounds. Synthesis of heterocycles

Article abstract of DOI:10.1016/S0040-4039(02)01961-5

Ethyl (E)-(3-amino substituted)-2-chloroacetyl-2-butenoates 2c-g, N-[(Z)-1-methyl-3-oxo-1-butenyl]-2-chloroacetamide 3a and ethyl (Z)-3-chloromethyl carboxamino-2-butenoate 3c, have been prepared from β-amino α,β-unsaturated ketone 1a and esters 1c-g and chloroacetyl chloride. The reactivity of these compounds was studied by the reactions with binucleophiles, such as hydrazine and hydroxylamine, to evaluate the electrophilic centers in the formation of the polyfunctionalized heterocyclic compounds.

Full text of DOI:10.1016/S0040-4039(02)01961-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 8079–8081
Reactivity of chloroacetylated b-enamino compounds.
Synthesis of heterocycles
Mara E. F. Braibante,* Hugo T. S. Braibante, Carla C. Costa and Deme´trius B. Martins
Departamento de Qu´ımica, Universidade Federal de Santa Maria, Santa Maria, RS, 97105-900, Brazil
Received 26 June 2002; revised 3 September 2002; accepted 10 September 2002
Abstract—Ethyl (E)-(3-amino substituted)-2-chloroacetyl-2-butenoates 2c–g, N-[(Z)-1-methyl-3-oxo-1-butenyl]-2-chloroacetamide
3a and ethyl (Z)-3-chloromethyl carboxamino-2-butenoate 3c, have been prepared from b-amino a,b-unsaturated ketone 1a and
esters 1c–g and chloroacetyl chloride. The reactivity of these compounds was studied by the reactions with binucleophiles, such
as hydrazine and hydroxylamine, to evaluate the electrophilic centers in the formation of the polyfunctionalized heterocyclic
compounds. © 2002 Published by Elsevier Science Ltd.
b-Enamino compounds are important compounds
because they have found application as 1,3-bielec-
trophilic synthons in synthetic organic chemistry. Our
research group have been exploring the methodologies
suitable in the synthesis and reactivity of the b-enamino
compounds and their derivatives.1–7 The functionaliza-
tion of these compounds by the introduction of differ-
ent substituents on the nitrogen, the a-carbon7 and the
b-carbonylic carbon atoms has been studied by us,
permitting the study of the reactivity of these systems
using nucleophiles for the construction of heterocyclic
compounds. Isoxazoles, for example, are important
intermediaries in the synthesis of natural products8 and
pyrazoles are important ligands in metallo-organic
chemistry,9 and some of these compounds are used as
components of drugs, herbicides and fungicides.
with an ultrasound technique.1,2,5 Chloroacetyl chloride
permits the investigation of the competition at the
nucleophilic centers, the a-carbonylic carbon and the
nitrogen of the b-enamino compounds. There is also
the possibility of attack of these nucleophilic centers at
the C-sp2 (CꢀO) or substitution in the C-sp3 (-CH2Cl)
of the chloroacetyl chloride.
The reaction of b-enamino ketone 1a (R1=Me, R2=H)
with chloroacetyl chloride only afforded the N-
chloroacetylated compound 3a, while for the b-enam-
ino ester 1c (R1=OEt, R2=H) a mixture of C- and
N-chloroacetylated products 2c and 3c was obtained in
a 1:3 ratio. The difference of reactivity of the nucle-
ophilic centers (N- and C-a) and the absence of steric
effects on the nitrogen in the starting material probably
influenced in the regiochemistry of this reaction. For
the b-enamino esters 1d–g the C-chloroacetylated com-
pounds were isolated, demonstrating the influence of
the substituent on the nitrogen in the formation of the
products 2d–g (Scheme 1). When 1b (R1=Me, R2=Ph)
reacts with chloroacetyl chloride under the same condi-
tions,10 the N-phenyl-2-chloroacetamide was isolated.
In order to study the reactivity of the b-enamino com-
pounds with electrophiles, we used chloroacetyl chlo-
ride as a bielectrophile with a series of selected acyclic
b-enamino compounds (1a–g), obtained using the
methodology established by us, through reactions
under a solid support, montmorillonite K-10, coupled
Scheme 1.
* Corresponding author.
0040-4039/02/$ - see front matter © 2002 Published by Elsevier Science Ltd.
PII: S0040-4039(02)01961-5

8080
M. E. F. Braibante et al. / Tetrahedron Letters 43 (2002) 8079–8081
Table 2. Synthesis of heterocyclic compounds 4–6
For the reaction with 1e, a mixture of 2e and N-phenyl-
2-chloroacetamide was obtained, by loss of the main
skeleton of the b-enamino compound 1e. After purifica-
tion, 2e was obtained as the minor (10%) product and
N-phenyl-2-chloroacetamide was obtained as the major
(60%) product. To prove the influence of the substi-
tuted group on the nitrogen, reaction of the b-enamino
ester with a linked bulky group on the nitrogen (i-Pr)
and chloroacetyl chloride was performed. Analysis of
the reaction showed the formation of the C-
chloroacetylated product only, confirming that steric
factors have influenced the regiochemistry of the
formed products (Table 1).
Compd
Time (h)
Yielda (%)
Mp (°C)
4
5
6
24
16
4
15
35
45
128–132
Oil
Oil
a Yield of pure isolated compounds.
tuted nitrogen of the phenyl hydrazine to the b-carbon,
followed by cyclization the other nitrogen to the
methylenic carbon of the chloroacetyl chloride.
When 2c or 2d were treated with hydroxylamine hydro-
chloride, ethyl-5-chloromethyl 4-isoxazolecarboxylate
(6) was isolated, independent of the substitution on the
nitrogen in 2, because the cyclization always proceeded
with the loss of the amino group. This was also
observed in the formation of the 5. The structures of
heterocycles 4–6 (Table 2) were confirmed by NMR
spectral analysis.12
The reactivity of the chloroacetylated b-enamino com-
pounds obtained 2c and 2d was studied by the reactions
of these compounds with phenyl hydrazine, hydrazine
and hydroxylamine, in order to evaluate the elec-
trophilic centers in the formation of the polyfunctional-
ized heterocyclic compounds. The reaction of the 2c or
2d with phenyl hydrazine and hydrazine was carried out
under reflux in ethanol11 to give ethyl-6-methyl-4-oxo-
2-phenyl-1,2,3,4-tetrahydro-5-pyridazinecarboxylate (4)
and ethyl 5-chloromethyl-3-methyl-1H-4-pyrazolecar-
boxylate (5), respectively (Scheme 2).
These results showed the versatility of chloroacetylated
b-enamino compounds as building blocks to obtain
polyfunctionalized heterocyclic compounds.
The formation of 4 was unexpected and it can be
considered to proceed by the attack of the unsubsti-
Acknowledgements
Table 1. Synthesis of chloroacetylated b-enamino com-
pounds 2c–g and 3a,c
We are grateful to the Fundac¸a˜o de Amparo a` Pesquisa
do Estado do Rio Grande do Sul (FAPERGS) for the
financial support and to the Conselho Nacional de
Desenvolvimento Cient´ıfico e Tecnolo´gico (CNPq)
(C.C.) for fellowships.
Compd
R1
R2
Yielda (%)
Mp (°C)
2c
2d
2e
2f
2g
3a
3c
OEt
OEt
OEt
OEt
OEt
Me
H
15
60
10
35
30
70
45
131–132
49–51
60–61
Oil
83–85
68–69
56–57
Me
Ph
Bn
Allyl
H
References
OEt
H
1. Braibante, M. E. F.; Braibante, H. S.; Salvatore, S. Qu´ım.
Nova 1990, 13, 67.
a Yield of pure isolated compounds.
Scheme 2.

M. E. F. Braibante et al. / Tetrahedron Letters 43 (2002) 8079–8081
8081
2. Braibante, M. E. F.; Braibante, H. S.; Missio, L.; Andri-
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3. Braibante, M. E. F.; Braibante, H. S.; Missio, L. J.
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4. Braibante, M. E. F.; Braibante, H. S.; Valduga, C. J. J.
Heterocyclic Chem. 1997, 34, 1453.
11. Ethyl
(E)-(3-amino
substituted)-2-chloroacetyl-2-
butenoates 2c or 2d (1 mmol) were mixed with phenyl
hydrazine or hydrazine hydrochloride or hydroxylamine
hydrochloride (2 mmol) in ethanol (2 mL). The mixture
was refluxed for 24 h for to give 4, 16 h to give 5 and 4
h to give 6. These were extracted with ethyl acetate, then
the organic layer was washed with water (3×10 mL),
dried over magnesium sulfate, filtered and the solvent was
removed in vacuo to yield the crude products. Product 4
was purified by recrystallization from diisopropyl ether,
while compounds 5 and 6 were purified by column chro-
matography on silica gel (Vetec, 70–230 mesh) using 40%
dichloromethane/ethyl acetate as eluent for 5 and 10%
dichloromethane/ethyl acetate as eluent for 6.
5. Braibante, M. E. F.; Braibante, H. S.; Valduga, C. J.;
Squizani, A. Synthesis 1998, 1019.
6. Braibante, M. E. F.; Braibante, H. S.; Valduga, C. J.;
Santis, D. B. J. Heterocyclic Chem. 1999, 36, 505.
7. Braibante, M. E. F.; Braibante, H. S.; Rosso, G. B.; da
Roza, J. K. Synthesis 2001, 1935.
8. Baraldi, P. G.; Barco, A.; Benetti, S.; Pollini, G. P.;
Simoni, D. Synthesis 1987, 857.
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10. General experimental procedure for the preparation of 2c–g
and 3a,c: b-Enamino compounds 1a–g (9 mmol) were
dissolved in chloroform (30 mL), cooled to −10°C and
chloroacetyl chloride (21 mmol) was added dropwise. The
solution was stirred at 0°C for 2–3 h, then neutralized
with sodium carbonate, washed with water, dried over
magnesium sulfate, filtered and the solvent was removed
in vacuo to yield the crude products. Compounds 2d and
3a were purified by recrystallization from diisopropyl
ether. Compounds 2e–g were purified by column chro-
matography on silica gel (Vetec, 70–230 mesh) using 1%
dichloromethane/ethyl acetate as eluent, resulting in the
following yields of products: 2e (10%), N-phenyl-2-
chloroacetamide (60%), 2f (35%), and 2g (30%). The
mixture of 2c and 3c was separated by filtration with hot
hexane, affording solid 2c (15%). The solvent was then
evaporated, resulting in the formation of 3c (45%).
12. Selected spectral data for compound 4: 1H NMR (200
MHz, CDCl3): l 1.46 (3H, t, CH3, J=7.0), 2.53 (3H, s,
CH3), 4.34 (2H, q, CH2, J=7.0), 4.70 (2H, s, CH2),
7.26–7.52 (5H, m, Ph); 13C NMR (50 MHz, CDCl3): l
14.7 (CH3), 29.75 (CH3), 55.72 (C-3), 65.25 (O-CH2),
109.14 (C-5), 125.52 (Carom), 128.82 (Carom), 129.36
(Carom), 137.92 (Carom), 147.37 (C-6), 162.42 (CꢀO),
196.22 (CꢀO). Compound 5: 1H NMR (200 MHz,
CDCl3): l 1.38 (3H, t, CH3, J=7.0), 2.53 (3H, s, CH3),
4.34 (2H, q, CH2, J=7.0), 4.86 (2H, s, CH2), 9.0 (1H, br,
NH); 13C NMR (50 MHz, CDCl3): l 11.88 (CH3), 14.13
(CH3), 37.53 (CH2-Cl), 60.15 (O-CH2), 108.76 (C-4),
146.52 (C-3), 149.66 (C-5), 163.55 (CꢀO). Compound 6:
1H NMR (200 MHz, CDCl3): l 1.40 (3H, t, CH3,
J=7.0), 2.47 (3H, s, CH3), 4.37 (2H, q, CH2, J=7.0),
4.89 (2H, s, CH2); 13C NMR (50 MHz, CDCl3): l
11.28 (CH3), 13.79 (CH3), 33.21 (CH2-Cl), 60.89 (O-
CH2), 109.72 (C-4), 159.79 (C-3), 160.87 (CꢀO), 170.95
(C-5).