Synthesis of aminopyrazoles from α- oxoketene O,N-acetals using Montmorillonite K-10/Ultrasound

Article abstract of DOI:10.1055/s-2003-39398

5(3)-Amino-3(5) phenylpyrazoles 3a-f have been conveniently prepared by condensation of α-oxoketene O,N-acetals 2a-g with hydrazine using montmorillonite K-10 as solid support under sonication.

Full text of DOI:10.1055/s-2003-39398

1160
SHORT PAPER
Synthesis of Aminopyrazoles from - Oxoketene O,N-Acetals Using
Montmorillonite K-10/Ultrasound
S
ynthesis of
A
minopyr
a
azoles ra E. F. Braibante,* Hugo T. S. Braibante, Juliano K. da Roza, Danielle M. Henriques,
Luciana de Carvalho Tavares
Universidade Federal Santa Maria, Departamento de Química, Santa Maria, RS, 97105-900, Brazil
Fax +55(55)2208031; E-mail: mara@quimica.ufsm.br
Received 14 January 2003
Abstract: 5(3)-Amino-3(5) phenylpyrazoles 3a–f have been con-
veniently prepared by condensation of -oxoketene O,N-acetals
2a–g with hydrazine using montmorillonite K-10 as solid support
under sonication.
Key words: aminopyrazoles
-oxoketene O,N-Acetals
-
oxothioxo ester, montmorillonite K-10
The synthesis of heterocyclic compounds using the meth-
odology of reactions on solid supports has been an objec-
tive of study in our laboratories. We reported previously
the synthesis of a series of pyrazoles from -enamino
compounds using this methodology,1–3 where the amino
group was lost during the formation of the pyrazole rings.
In this study, we have succeeded in obtaining pyrazoles
while keeping the amino group intact, a worthwhile prod-
uct since aminopyrazoles are useful biologically active
compounds.4,5
Scheme 1
O,N-acetals has been reported in the literature.17 The re-
giochemistry of these reactions shows strong dependence
on the reaction medium and reaction conditions. When the
reaction is carried out with formic acid under reflux in tol-
uene, -oxothioxo esters are obtained. Without formic ac-
id, a mixture of -oxoketene O,N-acetals and enaminothio
esters are obtained.
The strategy used in this work to prepare aminopyrazoles
involves the cyclization of -oxoketene O,N-acetals with
hydrazine in heterogeneous media, using montmorillonite
K-10 and ultrasound sonication. The -oxoketene N,N-;
N,S-; S,S-; and O,N-acetals have been proven to be versa-
tile intermediates in the construction of a large number of
heterocycles,6–14 however, very few examples are report-
ed starting from -oxoketene O,N-acetals. In this work the
-oxoketene O,N-acetals 2a–g were obtained through the
reaction of -oxothioxo ester 1 and primary amines. The
-oxothioxo ester 1 was prepared according to reported
procedures15–17 by the reaction of potassium hydroxide
with carbon disulfide in ethanol to give potassium O-ethyl
dithiocarbonate followed by alkylation with methyl io-
dide resulting in S-methyl O-ethyl dithiocarbonate in 85%
yield (Scheme 1). The described methods for the ethoxy-
thiocarbonylation of enolates with S-methyl O-ethyl
dithiocarbonate use sodium tert-butoxide or sodium
amide as base.16,17 We tested the reaction on acetophenone
with S-methyl O-ethyl dithiocarbonate with these two
types of bases; using sodium amide in toluene gave better
yields.
In view of these limitations we decided to study these re-
actions using the methodology of solid supported reac-
tions, using montmorillonite K-10 as a solid support and
sonication under solvent free conditions, without the use
of any acid. A series of -oxoketene O,N-substituted ace-
tals 2a–g were obtained selectively by dispersing O-ethyl
3-oxo-3-phenylpropanethioate (1) and primary amines on
montmorillonite K-10 under ultrasound (Scheme 2).
Scheme 2
The cyclization of -oxoketene O,N-substituted acetals
2a–f with 80% hydrazine hydrate on montmorillonite K-
10 under ultrasound, afforded 5(3)-amino-substituted
3(5)-phenyl 1H- pyrazoles 3a–f (Scheme 3). Using these
conditions, the ring closure process occurs according the
Baldwin’s rules18 resulting in the allowed 5-exo-trig prod-
ucts. The reaction is considered to proceed by the initial
attack of hydrazine at C- , with loss of the OEt group fol-
lowed by cyclization.
The procedure for the condensation of the primary amines
with -oxothioxo esters for the synthesis of -oxoketene
Synthesis 2003, No. 8, Print: 05 06 2003.
Art Id.1437-210X,E;2003,0,08,1160,1162,ftx,en;M00103SS.pdf.
© Georg Thieme Verlag Stuttgart · New York

SHORT PAPER
Synthesis of Aminopyrazoles
1161
forms were observed in the 1H NMR spectrum (Figure 1).
Duplicate signals (see Table 1) in 1H NMR spectrum were
observed for the hydrogen of the chiral group
[CH(CH3)Ph] as a quintet (5.24 ppm) and a quartet (4.53
ppm) corresponding to the forms 3f and 3f , respectively.
In the 13C NMR spectrum, the carbon of the chiral group
[CH(CH3)Ph] exhibits different chemical shifts for the
tautomeric forms, 47.59 ppm for 3f and 54.75 ppm for 3f ,
while the carbon of the methyl group appears at 21.62
ppm and at 24.45 ppm for 3f and 3f , respectively. These
assignments were confirmed by HMQC and HMBC ex-
periments. The relative proportion of the tautomers has
been established on the basis of 1H NMR spectrum, result-
ing in a ratio of 1:1 for 3f and 3f .
Scheme 3
The structures of the products were unambiguously estab-
lished based on the H and 13C NMR spectra by DEPT
1
135, HMQC and HMBC experiments. For the aminopyra-
zole 3f [R = (R)-(+)-1-phenylethylamine], two tautomeric
Table 1
-Oxoketene O,N-Acetals 2a–g and 5(3)-Amino-3(5)-phenylpyrazoles 3a–f Prepared
Yieldb mp (°C) 1H NMR (CDCl3/TMS) 13C NMR (CDCl3/TMS)
Prod-
ucta
(%)
, J (Hz)
2a
78
75–78
53–54
1.27 (t, 3 H, J = 7.0), 4.02 (q, 2 H, J = 7.0), 5.38 (s, 1 13.89, 63.58, 74.70, 126.44, 127.79, 130.13, 140.52,
H), 7.36–7.86 (m, 5 H), 6.32 (br, 1 H),10.27 (br, 1 H) 169.57, 187.51
2b
40
1.40 (t, 3 H, J = 7.0), 2.90 (d, 3 H, J = 5), 4.15 (q, 2 14.90, 26.30, 64.10, 73.80, 126.40, 127.90, 129.90,
H, J = 7.0), 5.40 (s, 1 H), 7.40 (m, 3 H), 7.80 (m, 2
140.90, 168.90, 186.20
H), 10.90 (br, 1 H)
2c
36
60
74–76
71–73
1.50 (t, 3 H, J = 7.0), 4.28 (q, 2 H, J = 7.0), 5.56 (s, 1 14.11, 64.89, 75.30, 121.37, 123.79, 126.63, 128.11,
H), 7.09–7.90 (m, 10 H), 13.16 (br, 1 H) 128.80, 130.33, 137.50, 140.31
2d
1.26 (t, 3 H, J = 7.0), 4.02 (q, 2 H, J = 7.0), 4.44 (d, 13.94, 43.69, 64.14, 73.80, 126.34, 126.88, 126.95,
2 H, J = 6.0), 5.39 (s, 1 H), 7.19–7.87 (m, 10 H),
11.43 (br, 1 H)
127.76, 128.22, 129.93, 137.90, 140.59, 168.12,
186.30
2e
2f
45
67
82
51–52
oil
1.40 (t, 3 H, J = 7.0), 3.95 (m, 2 H), 4.15 (q, 2 H),
5.25 (m, 2 H), 5.40 (s, 1 H), 7.40 (m, 3 H), 7.80 (m, 130.00, 133.70, 140.80, 168.30, 186.50
2 H), 11.50 (br, 1 H)
14.20, 42.30, 64.20, 73.90, 115.80, 126.40, 127.90,
1.25 (t, 3 H, J = 7.0), 1.56 (d, 3 H, J = 6.8), 4.05 (q, 13.95, 23.43, 50.22, 64.16, 73.97, 125.55–143.99,
2 H, J = 7.0), 4.95 (m, 1 H, J = 6.8), 5.36 (s, 1 H),
7.22–7.87 (m, 10 H), 11.46 (d, 1 H)
167.45, 186.45
2g
oil
1.20 (d, 6 H, J = 6.5), 1.29 (t, 3 H, J = 7.0), 3.85–4.06 14.60, 23.40, 42.46, 64.53, 73.90, 126.83, 128.30,
(m, 1 H), 5.32 (s, 1 H), 7.32–7.86 (m, 5 H), 11.03 (d, 130.33, 141.39,168.12, 186.21
1 H)
3a
3b
45
54
108–109 4.28 (br, 3 H), 5.86 (s, 1 H), 7.22–7.65 (m, 5 H)
9.27, 125.41, 128.23, 128.83, 130.35, 145.77, 154.21
122–124 2.80 (s, 3 H), 5.80 (s, 1 H), 6.91 (br, 2 H), 7.23–7.59 31.76, 87.38, 125.43, 127.97, 128.68, 130.86,
(m, 5 H)
146.14, 157.58
3c
3d
3e
56
45
50
153–154 6.30 (s, 1 H), 6.83–7.59 (m, 10 H), 6.29 (br, 2 H)
92.21, 115.93, 120.17, 125.55, 128.48, 128.94,
129.27, 130.02, 143.17, 145.39, 151.37
oil
4.46 (s, 1 H), 5.98 (s, 1 H), 7.07 (br, 2 H), 7.43–7.85 49.18, 87.72, 125.43, 126.98, 127.38, 127.94,
(m, 10 H)
128.37, 128.61, 130.67, 139.49, 146.07, 156.42
101–102 3.70–3.73 (m, 2 H), 5.05–5.10 (m, 1 H), 5.15–5.25
47.75, 87.72, 115.79, 125.44, 127.92, 128.63,
(m, 1 H), 5.80 (s, 1 H), 5.83–5.91 (m, 1 H), 7.23–7.58 130.80, 135.66, 146.10, 156.23
(m, 5 H)
3f
51
oil
1.61 (d, 3 H, J = 6.8), {1.57 (d, 3 H, J = 6.8)}, 5.24
21.62 {24.45}, 47.59 {54.75}, 88.55, 125.33–
(quint, 1 H, J = 6.8), {4.53 (q, 1 H, J = 6.8)}, 5.64 (s, 130.70, 142.52 {145.20}, 154.35 {160.28}c
1 H), 5.95 (br, 1 H), 7.17–8.13 (m, 10 H)c
a All compounds gave satisfactory elemental analyses: C 0.20, H 0.14; N 0.18.
b Yield of pure isolated product.
c Chemical shifts given in braces refer to duplicated signs belonging to 3f .
Synthesis 2003, No. 8, 1160–1162 ISSN 1234-567-89 © Thieme Stuttgart · New York

1162
M. E. F. Braibante et al.
SHORT PAPER
drich 230–400 mesh) CH2Cl2–EtOAc (10%) as eluent to give ana-
lytically pure pyrazoles (Table 1).
Acknowledgments
We are grateful to the Conselho Nacional de Desenvolvimento
Científico e Tecnológico (CNPq), Brazil and Fundação de Amparo
a Pesquisa do Estado do Rio Grande do Sul (FAPERGS-01/0506.6)
for financial support and to FAPERGS (D.H) and CNPq-PIBIC for
fellowships to D.M.H., J.K.R and L.C.T. We thank Dr. Robert Bur-
row for helpful comments on the manuscript.
Figure 1 Structure of tautomeric forms 3f and 3f
These results demonstrate that the use of the methodology
with montmorillonite K-10 is a valuable improvement
over the classical methods due to the availability of the
acid sites, milder conditions, and higher selectivity.
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O-Ethyl 3-oxo-3-phenylpropanethioate (1; 208 mg, 1 mmol) in
CH2Cl2 (1 mL) was dispersed on montmorillonite K-10 (0.3 g, Flu-
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5(3)-Amino-Substituted 3(5)-Phenyl-1H-pyrazoles 3a–f; Gener-
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Hydrazine hydrate (80%, 2 mmol) was added dropwise to the ap-
propriate -oxoketene O,N-acetal 2 (1 mmol) in CH2Cl2 (1 mL) dis-
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Synthesis 2003, No. 8, 1160–1162 ISSN 1234-567-89 © Thieme Stuttgart · New York