Michael-type addition of azoles of broad-scale acidity to methyl acrylate

Article abstract of DOI:10.3762/bjoc.7.24

An optimisation of Michael-type addition of azole derivatives of broad-scale acidity - ranging from 5.20 to 15.00 pKa units - namely 4-nitropyrazole, 3,5-dimethyl-4-nitropyrazole, 4(5)-nitroimidazole, 4,5-diphenylimidazole, 4,5-dicyanoimidazole, 2-methyl-

Full text of DOI:10.3762/bjoc.7.24

Michael-type addition of azoles of broad-scale acidity
to methyl acrylate
Sławomir Boncel*1, Kinga Saletra1, Barbara Hefczyc2
and Krzysztof Z. Walczak*1
Letter
Open Access
Address:
Beilstein J. Org. Chem. 2011, 7, 173–178.
1Silesian University of Technology, Department of Organic Chemistry,
Bioorganic Chemistry and Biotechnology, Krzywoustego 4, 44-100
Gliwice, Poland, Tel.: +48 32 237 1792, Fax: +48 32 237 2094 and
2Silesian University of Technology, Department of Chemical Organic
Technology and Petrochemistry, Krzywoustego 4, 44-100 Gliwice,
Poland, tel.: +48 32 237 10 32, fax: +48 32 237 10 32
doi:10.3762/bjoc.7.24
Received: 27 December 2010
Accepted: 24 January 2011
Published: 08 February 2011
Associate Editor: J. N. Johnston
Email:
Sławomir Boncel* - slawomir.boncel@polsl.pl;
Kinga Saletra - kingasaletra@gmail.com;
Barbara Hefczyc - barbara.hefczyc@polsl.pl;
Krzysztof Z. Walczak* - krzysztof.walczak@polsl.pl
© 2011 Boncel et al; licensee Beilstein-Institut.
License and terms: see end of document.
* Corresponding author
Keywords:
imidazole derivatives; methyl acrylate; Michael-type addition; pyrazole
derivatives; 1,2,4-triazole derivatives
Abstract
An optimisation of Michael-type addition of azole derivatives of broad-scale acidity – ranging from 5.20 to 15.00 pKa units –
namely 4-nitropyrazole, 3,5-dimethyl-4-nitropyrazole, 4(5)-nitroimidazole, 4,5-diphenylimidazole, 4,5-dicyanoimidazole,
2-methyl-4(5)-nitroimidazole, 5(4)-bromo-2-methyl-4(5)-nitroimidazole and 3-nitro-1,2,4-triazole to methyl acrylate as an acceptor
was carried out. The optimisation process involved the use of an appropriate basic catalyst (DBU, DIPEA, NaOH, NaH, TEDA), a
donor/base/acceptor ratio and the reaction temperature. The reactions were performed in DMF as solvent. Target Michael adducts
were obtained in medium to excellent yields. Importantly, for imidazole and 1,2,4-triazole derivatives, no corresponding regioiso-
mers were obtained.
Introduction
Derivatives of azoles are important biologically active com- 1,2-Arylimidazole derivatives, e.g., 2-(3-chloro-4-methylphe-
pounds. Many, especially those containing imidazole, pyrazole nyl)-1-phenyl-4-(trifluoro-methyl)imidazole (I) are selective
and 1,2,4-triazole moieties, constitute building blocks for a cyclooxygenase (COX-2) inhibitors [1]. Metronidazole (2-(2-
variety of therapeutic agents (Figure 1).
methyl-5-nitroimidazol-1-yl)ethanol) is an antibiotic and
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Beilstein J. Org. Chem. 2011, 7, 173–178.
Figure 1: Examples of azole derivatives as important therapeutic agents.
antiprotozoal agent whose uses include, among others, the treat- reports on the synthesis of Michael-type adducts of azoles by
ment of anaerobic bacterial infections [2]. Complexes of Co(II) the use of microwave irradiation [7,24]. The optimisation of
and Cu(II) with 3-(2-nitroimidazol-1-yl)propanoic acid (III) are aza-Michael reactions with N-methylimidazole as the base cata-
radiosensitisers in cancer therapy [3]. 4,4'-(4-Ethyl-1- lyst was published in 2007 by Liu et al [25]. However, when
phenylpyrazole-3,5-diyl)diphenol (IV) and its derivatives are this catalyst was used with azoles of narrower-scale acidity (pKa
known modulators of receptors regulating the secretion of estro- range from 8.93 to 15.1) including imidazole and its 2- and
gens crucial in the pathogenesis of breast cancer [4]. 4(5)-methyl, 4(5)-nitro-, 2-methyl-4(5)-nitro- derivatives as
4-(Benzo[d][1,3]dioxol-5-ylmethyl)-1-(3-methoxybenzyl)-3- well as with 1,2,4-triazole, there was no evidence for a regiose-
phenyl-pyrazole-5-carboxylic acid (V) is an antagonist of lective course of the reactions. Furthermore, extremely high
endothelial receptors and is used as a clinical regulator of the acidic azoles, which are substrates for many important drugs,
cardiac cycle [5]. Fluconazole (VI) 2-(2,4-difluorophenyl)-1,3- have seldomly been considered as aza-Michael donors due to
bis(1,2,4-triazol-1-yl)propan-2-ol is an antifungal drug used in their poor nucleophilicity and the possible tendency of adducts
the treatment and prevention of superficial and systemic fungal to undergo retro-Michael reactions [26].
infections [6].
Here, we present Michael-type addition of azoles, inter alia
The base-catalysed Michael-type addition reaction of various imidazole and 1,2,4-triazole derivatives of high acidity (pKa ≤
azoles to α,β-unsaturated carbonyl and nitro derivatives has 6.05), to methyl acrylate under optimised conditions (tempera-
been frequently exploited in the synthesis of precursors of bio- ture, type of base and donor/base/acceptor ratio) as a regioselec-
logically active compounds [3,7-15]. This reaction, although tive, efficient and useful reaction for the formation of adducts
structurally restricted to α,β-unsaturated carbonyl compounds that can be utilised in the synthesis of more complex systems
and their analogues, is advantageous due to its higher regiose- including intermediates for the pharmaceutical industry[27].
lectivity compared to alkylation reactions using alkyl halides
[16-19], alkyl sulfates [20] or oxiranes [18] under basic condi- Results and Discussion
tions, or alcohols over zeolites [21]. Moreover, it is usually 4-Nitropyrazole (1a), 3,5-dimethyl-4-nitropyrazole (1b), 4(5)-
described as a green-chemistry with an effective synthetic nitroimidazole (1c), 4,5-diphenylimidazole (1d), 4,5-
protocol and a simple work-up. In the Michael-type additions of dicyanoimidazole (1e), 2-methyl-4(5)-nitroimidazole (1f), 4(5)-
azole N–H acids, numerous catalysts such as KF/Al2O3 [8], bromo-2-methyl-5(4)-nitroimidazole (1g) and 3-nitro-1,2,4-tria-
CeCl3∙7 H2O/NaI [9], NaH or ZnCl2 [10], K2CO3 [11], anhy- zole (1h) were used as Michael donors. The azoles derivatives
drous K3PO4 [12], (NH4)2Ce(NO3)6 (CAN) [22] or ionic (1a–h) were subjected to the reaction with methyl acrylate (2)
liquids, e.g., Cu(acac)2 immobilised in [bmim][BF4] [15] have (Michael acceptor) in the presence of an appropriate base,
been used. Other reaction conditions including enzymatic catal- namely DBU (pKa = 12 [28]), diisopropylethylamine (DIPEA,
ysis (Bacillus subtilis) [13], zinc-active-site acylases from Hünig’s base, pKa = 10.75 [29]), NaOH (pKa = 15.7 [30]), NaH
Escherichia coli and Aspergillus oryzae [23] as well as ultra- (pKa = 37 [29]) or TEDA (pKa = 8.82 [31]) in polar aprotic
sonic irradiation in the presence of montmorillonite [14] have (DMF) or protic (MeOH) solvent (Scheme 1, Table 1).
also been reported. In addition, there has been several recent Although the above pKa values were determined in water, their
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Beilstein J. Org. Chem. 2011, 7, 173–178.
Scheme 1: Michael-type addition of azoles of broad-scale acidity 1a–h to methyl acrylate (2) under basic conditions.
Table 1: Optimised conditions of Michael-type addition of azoles of broad-scale acidity 1a–h to methyl acrylate (2), physical properties and yields of
the products 3a–h.
Conditions
Base / A
3
1
pKa (H2O)
A/D
Base
T [°C]
t [h]
Yield [%]
1:1
2:1
DBU
1.0
1.0
20
20
1
5
31
97
a
b
c
9.67 [34]
15.00 [35]
8.93 [36]
DIPEA
1:1
2:1
DBU
1.0
1.0
20
20
1
54
98
DIPEA
24
1:1
DBU
1.0
1.0
20
20
2
30
98
1.1:1
DIPEA
12
4:1
4:1
1:1
4:1
2:1
DIPEA
DIPEA
w/ob
1.0
1.0
—
20
80
60
65
60
192
48
0
0
d
5.70a [37]
168
24
0
NaOHb,c
NaH
0.02
1.0
8
72
60
2:1
1:1
DIPEA
DIPEA
DBU
1.0
1.0
1.0
1.0
2.5
1.2
1.2
1.2
20
60
60
65
60
60
60
60
192
120
120
24
0
0
1:1
0
2:1
NaOHc
NaHb,d
NaHb,d
NaHb,d
NaHb,d
25
0
e
5.20 [38]
1:1
144
144
144
168
1.5:1
1:2
0
14
62
1:2
f
9.64 [39]
1:1
DIPEA
1.0
20
120
97
3:1
2:1
1:1
2:1
1:2
DIPEA
DBU
1.0
1.0
60
20
20
65
60
96
72
22e
0
g
h
—
TEDA
NaOHc
NaHb,d
1.0
120
48
0
0.02
1.2
13
55
72
6.05 [18]
2:1
DIPEA
1.0
20
114
80
a30 mol % DMSO aqueous solution at 30 °C, bReaction performed under an inert (N2) atmosphere, creaction performed in MeOH, d80% solution of
NaH in mineral oil was used; etotal yield, a regioisomer 4g was obtained in 10% yield (1H NMR); A/D = acceptor to donor molar ratio.
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Beilstein J. Org. Chem. 2011, 7, 173–178.
relative basicity is usually in good agreement in other polar In the case of the reaction of 1d, an imidazole derivative of
solvents, e.g., there is a linear relationship between pKa values acidity three orders of magnitude higher compared to 1c, no
in water and DMF for the set of N-centred organic bases reaction was observed in the presence of an equimolar amount
expressed by the equation: pKa (DMF) = 0.9463 pKa (water) + of DIPEA and even with a four-fold molar excess of the
1.4154 [32,33]. This semi-empirical relationship enables an acceptor at ambient or elevated temperature. We then carried
initial selection of a base required for a sufficient level of out an additional trial in the absence of a deprotonating agent at
deprotonation of N–H azole acids.
elevated temperature on the assumption that due to the
increased acidity of 1d, a small concentration of the anionic
1a and 1b as weak N–H acids required an equimolar amount of form would be sufficient for completion of the reaction.
a strong base (DBU) and reacted with 2 in stoichiometric However, gain no reaction was observed. On the other hand, the
proportions to give the appropriate products 3a and 3b in high use of a catalytic amount of NaOH at elevated temperature
purity but in low/medium yields. The presence of the unreacted furnished only a small amount of the expected product 3d.
substrates 1a, 1b in the post-reaction mixtures points to the ten- However, when 1d was treated with a double molar excess of
dency of the adducts to undergo the reverse reaction – a retro- the acceptor in the presence of NaH at elevated temperature, the
Michael reaction – in equilibrium with Michael-type addition. expected product was isolated in good yield (60%). The reac-
By contrast, DIPEA, with a lower pKa gave the same adducts 3a tion of the most acidic imidazole derivative within the group 1e
and 3b in excellent yields. For 1b (the azole with the lowest was more complicated to optimise. DBU, DIPEA and NaOH all
acidity) a similar yield to 1a was achieved only after a signifi- appeared as ineffective basic catalysts and only when a double
cantly prolonged reaction time due to its lower concentration of molar excess of the donor was used in the presence of NaH was
the anionic form in the reaction mixture. For 1c, analogous a satisfactory yield of 3e obtained. Similarly, for 1g only the
behaviour was observed when treated with 2 in the presence of former conditions gave 3g in good yield (62%). Interestingly, a
DBU. Here again, a use of DIPEA, instead of DBU, in a slight regioisomeric product of the addition, i.e., methyl 3-(4-bromo-
molar excess with respect to the azole furnished 3c in excellent 2-methyl-5-nitroimidazol-1-yl)propanoate (4g) was not
yield. These conditions were also adequate in the reactions of 1f obtained when NaH was used as a catalyst. However, when
and 1h with 2 and gave the corresponding products 3f and 3h DIPEA was used as a base, this regioisomer was obtained in ca.
respectively, in excellent yields. No regioisomers were obtained 10% yield, as determined by 1H NMR spectroscopy. The struc-
for these C-nitro azole derivatives. The structure of 3c was tures of all the products were established by means of 1H and
established by an independent synthesis from 1,4-dinitroimida- 13C NMR spectroscopy.
zole (4) and β-alanine methyl ester hydrochloride (5). This latter
reaction proceeds via an ANRORC mechanism (Addition of It is worth noting that in none of the reactions polymerisation or
Nucleophile, Ring Opening, Ring Closure) [40,41] (Scheme 2). hydrolysis of methyl acrylate was observed. Nevertheless,
Product 3c obtained by the two independent routes, possessed decreased yields for azole adducts when DBU or NaH were
identical physicochemical and spectral properties. The observed used as catalysts at elevated temperature could originate from a
difference in yields, 98% for Michael-type addition and 60% for reversibility of the Michael reaction since unreacted azoles were
ANRORC, arises from some unidentified side reactions.
isolated. This observation is in a good agreement with our
Scheme 2: Chemical evidence for a regioselective Michael-type addition of 4(5)-nitroimidazole (1c) to methyl acrylate (2) based on the ANRORC
reaction of 1,4-dinitroimidazole (4) with β-alanine methyl ester hydrochloride (5).
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Beilstein J. Org. Chem. 2011, 7, 173–178.
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Supporting Information File 1
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Authors thank the Ministry of Science and Higher Education in
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