Ionic liquid promoted cyclocondensation reactions to the formation of isoxazoles, pyrazoles and pyrimidines

Article abstract of DOI:10.1016/j.catcom.2009.12.001

A simple one-pot procedure to obtain a series of five- and six-membered heterocycles, in three different ionic liquids ([BMIM][BF₄], [BMIM][OH] and [HMIM][HSO₄]) is described. The synthetic protocol involves the reaction between β-en

Full text of DOI:10.1016/j.catcom.2009.12.001

Catalysis Communications 11 (2010) 476–479
Contents lists available at ScienceDirect
Catalysis Communications
journal homepage: www.elsevier.com/locate/catcom
Ionic liquid promoted cyclocondensation reactions to the formation
of isoxazoles, pyrazoles and pyrimidines
*
Dayse N. Moreira, Kelvis Longhi, Clarissa P. Frizzo, Helio G. Bonacorso, Nilo Zanatta, Marcos A.P. Martins
Núcleo de Química de Heterociclos (NUQUIMHE), Departamento de Química, Universidade Federal de Santa Maria, CEP 97105-900, Santa Maria, RS, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 27 October 2009
Received in revised form 27 November 2009
Accepted 3 December 2009
Available online 6 December 2009
A simple one-pot procedure to obtain a series of five- and six-membered heterocycles, in three different
ionic liquids ([BMIM][BF4], [BMIM][OH] and [HMIM][HSO4]) is described. The synthetic protocol involves
the reaction between b-enamino ketone derived from 1,4-diacetylbenzene and hydroxylamine, hydra-
zines (R1NHNH2, where R1 = H, Ph, 4-O2N-Ph, 2,4-(O2N)2-Ph, C6F5, CO2Me, CONH2, CH2CH2OH, t-Bu) or
amidines (R2C(NH)NH2, where R2 = NH2, Ph), furnishing bis-isoxazoles, bis-pyrazoles and bis-pyrimidines
in good yields and short reaction times.
Keywords:
Ionic liquid
Ó 2009 Elsevier B.V. All rights reserved.
Cyclocondensation reaction
Heterocycles
Catalysis
1. Introduction
compounds. They are versatile synthetic intermediates that com-
bine the ambident nucleophilicity of enamines with the ambident
Often, the largest contributor to the environmental footprint of
a chemical process is the solvent used. Solvents have a significant
impact because of the quantity used, e.g., in pharmaceutical pro-
ductions they typically account for between 80% and 90% of the
mass utilization of a batch operation [1]. Consequently, replacing
conventional solvents, usually volatile organic compounds (VOCs),
with more environmentally benign media, is one of the central te-
nets of Green Chemistry [2] and a subject of significant academic
and commercial interest [3,4]. In the search for alternative sol-
vents, ionic liquids (ILs), especially those based on the imidazolium
cation, have emerged among the front runners due to their unusual
and interesting properties [5,6]. Firstly, they exhibit negligible va-
por pressure at standard conditions, eliminating concerns over
atmospheric emissions. They also dissolve a wide range of organic
and inorganic materials, have high thermal stability, are liquid over
a wide range of temperatures, and are generally nonflammable.
Thus, despite concerns over their unknown toxicities [7], they are
widely proposed as ‘green solvents’. Furthermore, the use of co-
catalysts as Brønsted and Lewis acids are an interesting alternative
to be associated with ionic liquids, as demonstrated in many cyclo-
condensation reactions [5].
eletrophilicity of enones [8].
Heterocycles, such as pyrazoles, isoxazoles and pyrimidines,
have become increasingly important because they have proven to
be extremely useful intermediates for the preparation of new
biological materials. These heterocycles are present in numerous
pharmacologically and agrochemically important compounds
[9–11].
Recently, we have successfully used ILs for the preparation of
two important heterocyclic building blocks, b-enamino ketones
and 4-alkoxy-1,1,1-trihalo-4-alken-2-ones [12–14], as well as in
the synthesis of heterocycles [5,15]. Our current review of cyclo-
condensation reactions in ionic liquid media [5] has demonstrated
that there is a lack of literature on the synthesis of pyrazoles and
isoxazoles in ionic liquid media and there are no reports of bis-het-
erocycles synthesized in this media. In the continuation of our
interest in the synthesis of heterocyclic compounds [16] and the
development of new methodologies, we describe herein the use
of ionic liquids as useful media for the reaction of b-enamino ke-
tone 1 and different 1,2- and 1,3-dinucleophiles, such as hydroxyl-
amine 2, substituted hydrazines 4 and amidines 6 (Tables 1–4).
b-Enamino ketones are readily obtainable reactants and their
chemistry has received considerable attention in recent years, once
they are key intermediates in the preparation of many heterocyclic
2. Results and discussion
Initially, we evaluated different reaction conditions for obtain-
ing bis-isoxazole 3, through the use of three ionic liquids
([BMIM][BF4], [BMIM][OH] and [HMIM][HSO4]) as the reaction
media (Table 1). Enaminone 1 and hydroxylamine hydrochloride
E-mail address: mmartins@base.ufsm.br (M.A.P. Martins).
URL: http://www.ufsm.br/nuquimhe (M.A.P. Martins).
1566-7367/$ - see front matter Ó 2009 Elsevier B.V. All rights reserved.
doi:10.1016/j.catcom.2009.12.001

D.N. Moreira et al. / Catalysis Communications 11 (2010) 476–479
477
Table 1
ratio of the reactants and the temperature of the reaction (90 °C)
used to synthesize product 3 were employed for all subsequent
reactions.
Optimization of the synthesis of 3.
O
Me
In the reaction between 1 and 2 using [BMIM][BF4], the bis-
isoxazole 3 was obtained in a moderate yield (Table 1, entry 1).
However, when HCl (10 mol%) was added there was an improve-
ment in yield and a decrease in the reaction time (Table 1, entry
2). We then changed the catalyst system to [HMIM][HSO4], an ionic
liquid that combines polar properties with the Brønsted acidic
function (Table 1, entry 3). This IL led to the desired product in sim-
ilar yield, although the use of a co-catalyst was not necessary. Thus,
[HMIM][HSO4] played a dual role, that is, as an acid catalyst and
solvent for the cyclocondensation reaction. The ionic liquid [BMI-
M][OH] was also employed, but in this case it was observed that
both a 1,3- and 1,5-regioisomer were formed (where the phenyl
substituent is attached at C3 or C5, respectively), and the ratio be-
tween them was around 1:3, respectively. In order to evaluate the
solvent effect, we performed the reaction of 1 and 2 in dimethyl-
formamide (DMF) at 90 °C (Table 1, entry 5), however the product
3 was obtained in lower yields. Product 3 was previous obtained by
Lang and Lin [17] (Table 1, entry 6), however, our methodology led
to a decreased reaction time, while avoiding the use of molecular
solvent. The mechanism of the product formation occurs through
an attack in the enaminone b-carbon by the NH2 group, followed
by the addition of the OH group to the carbonyl carbon to give
the product 3, which in agreement with the literature [18].
Bis-pyrazole 5a was initially synthesized by the reaction of
hydrazine sulfate 4a and 1 in [BMIM][BF4], with and without HCl
(Table 2, entries 1 and 2). We observed that no product was at-
tained when the co-catalyst was not employed. The employment
of [HMIM][HSO4] (Table 2, entry 3) promoted the reaction effi-
ciently, with a similar yield when compared with the catalytic sys-
tem [BMIM][BF4]/HCl and without the need of an acid co-catalyst.
The reaction was also performed in [BMIM][OH] (Table 2, entry 4),
however the product 5a was obtained in a lower yield than that
found with the other ILs. The synthesis of product 5a was previous
reported in the literature [17] using ethanol as solvent during 3 h
at room temperature, however, our methodology led to a de-
creased reaction time and better yields (Table 2, entry 5).
Me
N
N
Me
N
Me
O
O
1
O
N
+
3
NH2OH
HCl
2
Entry
Solvent
Acid
Time (h)
Yield (%)a
1
2
3
4
5
6
[BMIM][BF4]
[BMIM][BF4]
[HMIM][HSO4]
[BMIM][OH]
DMF
–
0.5
62
87
HCl
–
0.25
0.25
0.25
0.25
5
84
–
68b
79
HCl
–
Dioxane/water
80c
a
b
c
Yield of isolated product.
Yield of isolated mixture of 1,3- and 1,5-regioisomers.
Data from literature [17].
Table 2
Optimization of the synthesis of 5a.
O
Me
Me
N
N
Me
N
Me
N
H
H
N
O
1
N
+
5a
NH2NH2 H2SO4
4a
Entry
Solvent
Acid
Time (h)
Yield (%)a
1
2
3
4
5
[BMIM][BF4]
[BMIM][BF4]
[HMIM][HSO4]
[BMIM][OH]
EtOH
–
0.5
0.5
0.5
0.5
3
–
HCl
–
84
78
71
75b
–
–
a
Yield of isolated product.
Data from literature [17].
b
After the establishment of the best conditions for the synthesis
of 5a, the reaction was extended to aryl (4b–e), carbonyl (4f,g) and
alkyl hydrazines (4h,i). In order to evaluate the solvent effect, the
reaction of
1 and phenyl hydrazine 4b was performed in
Table 3
[BMIM][BF4], [HMIM][HSO4] and in dimethylformamide (DMF),
under similar conditions. Making a comparison among the sol-
vents, it is clear the importance of both ionic liquids (Table 3, en-
tries 1 and 2), since they drive the reaction for obtaining only
one product, while the use of DMF furnished a mixture of 1,3-
and 1,5-isomers (1:5) (Table 3, entries 3).
Optimization of the synthesis of 5b.
O
Me
Me
N
N
Me
N
N
Me
Ph
O
1
N
N
Ph
Aryl-1H-pyrazoles 5b–e were also obtained in better yields in
[HMIM][HSO4] than [BMIM][BF4]/HCl and the synthesis of these
compounds was not influenced by the presence of electron-with-
drawing groups (EWG) in the phenyl ring of hydrazine (Table 4, en-
tries 1–6). The reaction of methyl hydrazinocarboxylate 4f with 1
was firstly performed in [BMIM][BF4]/HCl, however the product
was obtained as a mixture of 1,3- and 1,5-isomers (1:6). Then,
we tested [HMIM][HSO4] which furnished 5f as a single product
(Table 4, entry 7). During the optimization of reaction conditions
to synthesize 5g, it was observed that this product is very suscep-
tible to the media employed, regarding both temperature and co-
catalyst. These factors caused the loss of the C(O)NH2 group and re-
sulted in the formation of the NH-pyrazole or a mixture of the de-
sired product and the NH-pyrazole in a ratio of 1:1. In this case, a
Brønsted catalyst was very hard and so it was substituted by a Le-
wis catalyst. The best result was achieved with the catalytic system
[BMIM][BF4]/BF3 OEt2 (20 mol%), at 70 °C during 2 h, which fur-
+
5b
NH2NHPh
4b
Entry
Solvent
Acid
Time (min)
Yield (%)a
1
2
3
[BMIM][BF4]
[HMIM][HSO4]
DMF
HCl
–
HCl
0.5
0.5
0.5
83
87
87b
a
Yield of isolated product.
Yield of isolated mixture of 1,3- and 1,5-regioisomers.
b
2 were used in a molar ratio of 1:1.2, respectively and the amount
of ionic liquid used was equivalent to the amount of dinucleophile,
which was enough to obtain a homogeneous media. The molar

478
D.N. Moreira et al. / Catalysis Communications 11 (2010) 476–479
Table 4
Conditions for the synthesis of compounds 5 and 7.
R1
N
N
O
N
Me
N
R2C(NH)NH2
N
R1NHNH2
N
R2
Me
N
N
5c-g
R1
R2
N
Me
Me
N
O
N
R1
N
N
1
7a,b
R1
N
5h-i
Entry
R1
Product
Ionic liquid
Catalyst
Time (h)
Yield (%)b
1
2
3
4
5
6
7
8
4-O2N-Ph
4-O2N-Ph
2,4-(O2N)2-Ph
2,4-(O2N)2-Ph
C6F5
C6F5
CO2Me
CONH2
CH2CH2OH
t-Bu
5c
5c
5d
5d
5e
5e
5f
5g
5h
5i
[BMIM][BF4]
[HMIM][HSO4]
[BMIM][BF4]
[HMIM][HSO4]
[BMIM][BF4]
[HMIM][HSO4]
[HMIM][HSO4]
[BMIM][BF4]
[BMIM][BF4]
[HMIM][HSO4]
[BMIM][BF4]
HCl
–
HCl
–
HCl
–
–
1
1
74
78
84
88
82
86
60
70
82
79
72
1.5
1.5
1.5
1.5
3
2
0.5
1
BF3ꢀOEt2
9
10
11
–
–
–
t-Bu
5i
1
R2
Producta
Ionic liquid
Catalyst
Time (h)
Yield (%)b
12
13
NH2
Ph
7a
7b
[BMIM][BF4]
[BMIM][BF4]
NaOH
NaOH
1
1
61
68
a
All the reactions were carried out at 90 °C, except for compound 5g which was performed at 70 °C.
Yield of isolated product.
b
nished 5g in good yield (Table 4, entry 8). X-ray data [19] demon-
strated that 5f was obtained as the 1,3-isomer (Fig. 1). This state-
ment was also confirmed by the fragmentation pattern in the
mass spectrometry, where the lost of the fragment [CNCO2Me]+ꢀ
(m/z 240) referent to the pyrazole cleavage was observed. This
behavior was observed when electron-withdrawing groups were
attached in the N1-atom.
For alkyl hydrazine 4h the use of HCl together with [BMIM][BF4]
was not necessary, probably due to the inductive effect of alkyl
groups (Table 4, entry 9). The reaction with hydrazine 4i was car-
ried out in both [BMIM][BF4] and [HMIM][HSO4] (Table 4, entries
10 and 11, respectively) and similar results were observed. X-ray
data [20] demonstrated that 5i was obtained as the 1,5-isomer
(Fig. 2). This statement was also confirmed by the fragmentation
pattern in the mass spectrometry, where the lost of both tert-butyl
groups (m/z 210) and the fragment [CN]+ꢀ (m/z 181) referent to the
pyrazole cleavage was observed. This behavior was observed when
electron-donating groups were attached in the N1-atom. A similar
mechanism pathway for the formation of compounds 5 is de-
scribed in the reference [18].
Fig. 2. ORTEP of compound 5i.
[BMIM][BF4], however, the addition of a base (NaOH) was neces-
sary for the total conversion of the starting material (Table 4, en-
tries 12 and 13). One probable route might be a first attack of
the NH-group of the amidine on the enaminone b-carbon, which
on subsequent intramolecular cyclization followed by elimination
of water that generates the corresponding pyrimidine 7, as de-
picted in the Scheme 1 [21]. In an attempt to avoid the use of
NaOH, this reaction was performed in [BMIM][OH], however all
b-enamino ketone 1 was recovered.
Pyrimidines 7 were synthesized from guanidine and benzami-
dine hydrochloride (R2 = NH2, Ph) with b-enamino ketone 1, in
Thus, it is possible to affirm that the ionic liquids allowed the
reaction to proceed in a shorter reaction time than did molecular
solvents. We believe that this enhancement of the reaction rate
is a result of the decrease of activation energy in the slow reaction
step caused by the general ionic liquid effect. This would be ex-
pected for reactions such as condensation, which involve activated
Fig. 1. ORTEP of compound 5f.

D.N. Moreira et al. / Catalysis Communications 11 (2010) 476–479
479
R2
HN
Me
NH2
O
NH
R2
O
H
N
N
H
Me
N
N
R2
Me
-2Me2NH
Me
NH
1
R2
NH
O
O
H2N
R2
R2
H
O
NH2
R2
N
N
N
N
N
OH
OH
R2
N
-2H2O
7
NH2
O
N
N
N
N
H
R2
R2
Scheme 1.
complexes (highly polar or charge concentrated) and could become
more stable and long-lived in this media [5,15].
Appendix A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.catcom.2009.12.001.
3. Conclusion
In summary, we have demonstrated that ionic liquids can be
used as an efficient media for cyclocondensation reactions of b-
enamino ketones and different 1,2- and 1,3-dinucleophiles. The
heterocycles synthesized in this study were obtained in high regio-
seletivity, good yields and short reaction times.
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4.2. Synthesis of 5,50-bis-isoxazoles 3, 5,50-bis-pyrazoles 5a–b,h–i and
3,30-bis-pyrazoles 5c–g
A mixture of 1 (1.0 mmol), hydroxylamine hydrochloride 2 or
hydrazine 4 (1.2 mmol) and the appropriated IL (1.2 mmol) was
stirred at 70–90 °C in a pre-heated oil bath for 0.25–2 h. After cool-
ing, the reaction mixture was washed with water (10 mL) and the
solid product was filtered off and dried under vacuum.
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4.3. Synthesis of 5,50-bis-pyrimidines 7
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[19] Crystallographic data for structure 5f, reported in this paper, have been
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Union Road, Cambridge CB2 1EZ, UK (Fax: +44 1223 336033 or e-mail:
deposit@ccdc.cam.ac.uk).
A mixture of 1 (1.0 mmol), amidine 6 (1.2 mmol), NaOH
(1.2 mmol) or BF3ꢀOEt2 and the appropriated ionic liquid (1.2 mmol)
was stirred at 90 °C in a pre-heated oil bath for 1–1.5 h. After cooling,
the reaction mixture was washed with water (10 mL) and the solid
product was filtered off and dried under vacuum.
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deposited with the Cambridge Crystallographic Data Center (CCDC 729766).
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Union Road, Cambridge CB2 1EZ, UK (Fax: +44 1223 336033 or e-mail:
deposit@ccdc.cam.ac.uk).
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Acknowledgments
The authors thank the Conselho Nacional de Desenvolvimento
Científico e Tecnológico (CNPq), Coordenação de Aperfeiçoamento
de Pessoal de Nível Superior (CAPES) and Fundação de Apoio à Pes-
quisa do Estado do Rio Grande do Sul (FAPERGS) for financial sup-
port. The fellowships from CNPq and CAPES are also acknowledged.
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