Letters in Organic Chemistry, 2008, 5, 379-382
379
Morita-Baylis-Hillman Reaction in Water/Ionic Liquids under Microwave Irradiation Rodrigo O.M.A. de Souza*,a, Andréa L.F. de Souzab, Tatiana L. Fernándezb, Aires C. Silvab, Vera L.P. Pereiraa, Pierre M. Estevesb, Mario L.A.A. Vasconcellosc and Octavio A.C. Antunes*,a,b a
Núcleo de Pesquisas de Produtos Naturais,Universidade Federal do Rio de Janeiro, Cidade Universitária, CCS, Laboratório H0-27 RJ 21941-590, Brazil, bInstituto de Química, Universidade Federal do Rio de Janeiro, Cidade Universitária CT bloco A 641, RJ 21941-909, Brazil, cDepartamento de Química, Universidade Federal da Paraíba, Campus I, João Pessoa, PB 58059-900, Brazil Received December 06, 2007: Revised April 08, 2008: Accepted April 10, 2008
Abstract: The present work describes a new experimental protocol of the Morita-Baylis-Hillman reaction in H2O / Ionic Liquid media under microwave irradiation. Different proportions of ionic liquids, ([bmim][PF6] and [bmim][BF4]), and water were tested as solvents for the reaction between several aromatic aldehydes and Michael acceptors under microwave irradiation. The results show that small amounts of ionic liquid, mixed in water, can shorter reaction times keeping good yields.
Keywords: Morita-Baylis-Hillman, DABCO, ionic liquids, microwave. INTRODUCTION Microwave (MW) synthesis has received great attention in recent years [1]. Several publications have shown that microwave irradiation can accelerate the rate of chemical reactions, often with increased yields [2]. Presently, there is no doubt that there is no exclusive MW effect on the contrary, an astonishing number of papers dealing with MW mediated synthesis reinforce the fact that MW is just a rapid and efficient way of direct energy transfer to a reaction medium. Since the solvent can be heated over its boiling point, provided it is not perturbed, the overall effect in reaction rates is fantastic and can be easily anticipated using Arrhenius equation. Environmental concerns demand clean reaction process that does not use harmful organic solvents [3]. Water is no doubt the most environmentally friendly solvent. However, its use in organic reactions is rather limited because many organic materials do not dissolve in water and, in most cases, reactions proceed sluggishly. On the other hand, Ionic Liquids (ILs) [4] have been gaining exposure for their potential use as green solvents and possible replacement for traditional volatile organic solvents because of their unique chemical and physical properties of nonvolatility, non-flammability, thermal stability, controlled miscibility [5] and potential easy re-usability. In addition, since some of them are miscible in water and some are not, combined ionic liquid / water systems can constitute alternative reaction media for organic reactions in mono phase or two phases’ systems.
*Address correspondence to these authors at the Núcleo de Pesquisas de Produtos Naturais,Universidade Federal do Rio de Janeiro, Cidade Universitária, CCS, Laboratório H0-27 RJ 21941-590, Brazil; Tel: 55 21 25627248; Fax: 55 21 25627559; E-mails:
[email protected];
[email protected]
1570-1786/08 $55.00+.00
The Morita-Baylis-Hillman [6] reaction is an important C-C bond forming reaction between an activated alkene (bearing an electron withdrawing group, EWG) and an electrophile under Lewis base catalysis, such as 1,4-diazabicyclo [2.2.2] octane, DABCO. Due to the synthetic potential of the Morita-Baylis-Hillman adducts, many of which are biologically active [7], several protocols have been proposed to accelerate this reaction, such as the use of microwaves [8], ultrasound [9], addition of salts [10], high pressure [11], protic media [12] and ionic liquids [13]. RESULTS AND DISCUSSION In our continuous search for efficient methodologies for the Morita-Baylis-Hillman reaction [14], in the present study, water and ionic liquids were combined at different proportions and used as solvent mixtures aiming to obtain the desired Morita-Baylis-Hillman adducts in good yields and short reaction times under microwave irradiation (open and closed vessel). Activated and inactivated aldehydes and Michael acceptors were tested and gave moderate to good results. First, the reaction between p-nitrobenzaldehyde (1a), acrylonitrile (2a) and DABCO (Scheme 1) was undertaken in water (5 ml) (Table 1, entry 1), giving the desired MoritaBaylis-Hillman adduct (3) in >97% yield after 10 minutes. In this case, the same reaction with an increase amount of catalyst (DABCO, 2 eq.) did not lead to a significant difference in yields and reaction times (Table 1, entry 2). The effect of water in accelerating the Morita-Baylis-Hillman reaction is already known in the literature and many propositions have been raised to try to clarify this phenomenon [15,16]. However, to the best of our knowledge, water/ionic liquid systems were never studied under microwave irradiation. It is important to note that the same reaction profile under conventional heating did not lead to the formation of the Morita-Baylis-Hillman adduct 3, even after 3 hours. Evi-
© 2008 Bentham Science Publishers Ltd.
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de Souza et al.
OH CN
CHO
water CN
+
MW, DABCO
O2N
O2N
2a
1a
3
Scheme 1.
dently, energy transfer using MW proved to be much more effective.
After these results, we started to explore less activated Michael acceptors, as methyl acrylate (2b) and t-butyl acrylate (2c), in the reaction with p-nitrobenzaldehyde (1a) catalyzed by 2 eq. of DABCO on open vessels. The results are summarized in Scheme 2, Table 2. Yields up to 90% were obtained and [bmim][PF6] showed superior performance.
We started using [bmim][PF6] as additive to investigate the effect of addition of small amounts of this compound in water in the reaction between p-nitrobenzaldehyde (1a), acrylonitrile (2a) and DABCO. Gratefully, we found that addition of very small quantities of [bmim][PF6] (0.1 ml to 5.0 ml of water) is enough to afford 70% reduction in reaction time keeping yields higher than 97% (Table 1, entry 3). With an increased amount of DABCO (2 eq.), the reaction time can be even shorter keeping similar yield (Table 1, entry 4). [Bmim][BF4] was also evaluated (Table 1, entry 5) at the best conditions obtained for [bmim][PF6], but the reaction time was longer than that obtained with [bmim][PF6].
Benzaldehyde (1b), 4-fluorobenzaldehyde (1c), 2- pyridinecarboxyaldehyde (1e) and piperonal (1d) (Scheme 3) were also evaluated for Morita-Baylis-Hillman reaction under microwave irradiation (Table 3). These less activated electrophiles lead to moderate to good conversions (35 to 60 min). In all cases, we used 0.1 ml of [bmim][PF6] and 2 eq. of DABCO which were the best reaction conditions observed previously. As anticipated, reactions with acrylonitrile afforded better yields.
The use of pressure is a known way of accelerating the Morita-Baylis-Hillman reaction [11]. Therefore, we envisaged that combining microwave irradiation with pressure (40 psi), which is easily reached using the present equipment, could improve the reaction rate. Since this was the case, so combining MW activation with pressure actually led to very fast reaction times. Again the use of [bmim][PF6] (Table 1, entry 6) gave better results than the use of [bmim][BF4] (Table 1, entry 7).
Table 1.
a
CONCLUSION In conclusion, the present paper discloses a novel protocol to the Morita-Baylis-Hillman reaction under microwave irradiation where the addition of small amounts of ionic liquids, [bmim][PF6] or [bmim][BF4] (0.1 ml), particularly the former, shows a great improvement in reaction time, leading to the DABCO catalyzed Morita-Baylis-Hillman products (3, 5-14) in good yields.
Results on the Reaction between p-nitrobenzaldehyde (1a), Acrylonitrile (2a) and DABCO in Water/Ionic Liquid Entry
Ionic Liquid
Eq. DABCO
Reaction Time
Yield (%)a
1
-
1
10 minutesa
>97b
2
-
2
7 minutesa
>97b
3
[bmim][PF6]c
1
3 minutesa
>97b
4
[bmim][PF6]c
2
2 minutesa
>97b
5
[bmim][BF4] c
2
7 minutesa
>97b
6
[bmim][PF6]c
2
20 secondsd
>97b
7
[bmim][BF4] c
2
40 secondsd
>97b
open vessel, bisolated yield, c0.1 mL of ionic liquid in 5 mL of water, dunder pressure, 40 psi.
OH CO2R
CHO
water / ionic liquid +
CO2R
O2N 1a
Scheme 2.
2b, R= Me 2c, R= t-Bu
MW, DABCO 60 minutes
O2N 4a, R= Me 4b, R= t-Bu
Morita-Baylis-Hillman Reaction in Water/Ionic Liquids
Table 2.
381
Results on the Reaction between p-nitrobenzaldehyde (1a), Methyl Acrylate (2b) or tert-butyl acrylate (2c) and 2 eq. of DABCO in Open Vessel Water/Ionic Liquid Media Entry
R
Ionic Liquida
Conversionb
1
Methyl
[bmim][PF6]
4a, 90 %
2
Methyl
[bmim][BF4]
4a, 36 %
3
tert-butyl
[bmim][PF6]
4b, 77 %
tert-butyl
[bmim][BF4]
4b, 61 %
4 a
Letters in Organic Chemistry, 2008, Vol. 5, No. 5
b
0.1 mL of ionic liquid in 5 mL of water based on GC-MS analysis.
OH Ar
CHO
water / ionic liquid +
EWG
EWG
Ar
MW, 2 eq. DABCO
1b-e 2a, EWG= CN 2b, EWG= CO2CH3 2c, EWG= CO2C(CH3)3
60 minutes
5a-h
Scheme 3. Table 3.
a
Results on the Reaction between Several Aldehydes (1b-e) and Different Michael Acceptors (2a-c) under Catalysis of 2 eq. of DABCO in Open Vessel Water/Ionic Liquid Media
Entry
Aldehyde
EWG
Reaction Time
Conversiona
1
Benzaldehyde (1b)
CN
60 min
5a, 70 %
2
Benzaldehyde (1b)
CO2CH3
60 min
5b, 58 %
3
Benzaldehyde (1b)
CO2C(CH 3)3
60 min
5c, 40 %
4
4-fluorobenzaldehyde
CN
60 min
5d, 62 %
5
Piperonal
CN
60 min
5e, 56 %
6
Piperonal
CO2CH3
60 min
5f, 35 %
7
2-pyridinecarboxyaldehyde
CN
35 min
5g, 82 %
8
2-pyridinecarboxyaldehyde
CO2CH3
40 min
5h, 78 %
based on GC-MS analysis.
EXPERIMENTAL All experiments were conducted in a monomode microwave CEM Discover®. The Morita-Baylis-Hillman reactions were carried out in the microwave oven (150W). The reactions were monitored by TLC and were carried out at 150oC using a solvent (water / ionic liquid; 5 mL), aldehyde (0.6 mmol), activated alkene (0.6 mmol) (methyl acrylate, tertbutyl acrylate or acrylonitrile) and 1 or 2 equivalents of DABCO. The reaction medium was extracted with ethyl acetate (3 x 30 ml). The organic phase was dried with Na2SO4 and concentrated under reduced pressure. Conversion was obtained by GC-MS analysis and the structures of all the substances were confirmed by NMR data.
Methyl 3-hydroxy-2-methylene-3-(4-nitrophenyl) propanoate (4a) [9] H NMR (CDCl3, 200MHz): = 8.71 (d, 2 H, J = 8.75 Hz), 7.54 (d, 2H, J = 8.82 Hz), 6.38 (s, 1 H), 5.89 (s, 1 H), 5.62 (d, J=5.86 Hz, 1H), 3.73 (s, 3 H), 3.4 (d. J=6.34, 1H, exchangeable with D2O). 1
tert-Butyl 3-hydroxy-2-methylene-3-(4-nitrophenyl) propanoate (4b) [18] H NMR (CDCl3,200 MHz): = 8.35 (d, 2 H, J = 8.5 Hz), 7.66 (d, 2 H, J = 8.6 Hz), 6.41 (s, 1 H), 5.70 (s, 1 H), 5.56 (d, 1 H, J = 5.72 Hz), 3.39 (d, J = 6.25 Hz, exchangeable with D2O), 2,15 (s, 9 H). 1
3-Hydroxy-2-methylene-3-(4-nitrophenyl)propanenitrile (3) [14]
3-Hydroxy-2-methylene-3-phenyl propanenitrile (5a) [14]
H NMR (CDCl3, 200 MHz): = 8.51 (d, 2 H, J = 7.6 Hz), 8.0 (d, 2H, J = 7.55 Hz), 6.15 (s, 1 H), 5.82 (s, 1 H), 5.2 (d, 1 H, J = 5.81 Hz), 2.0 (m, 1 H, exchangeable with D2O).
1 H NMR (CDCl3, 200 MHz): = 7.4–7.2 (m, 5 H) 6.15 (s, 1 H), 5.95 (s, 1 H), 5.3 (s, 1 H), 2.0 (s, 1 H, exchangeable with D2O).
1
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Letters in Organic Chemistry, 2008, Vol. 5, No. 5
Methyl (5b) [9]
3-Hydroxy-2-methylene-3-phenyl
de Souza et al.
propanoate
REFERENCES [1]
1
H NMR (CDCl3, 200 MHz): = 7.4–7.2 (m, 5 H), 6.30 (s, 1 H),5.90 (s, 1H), 5.45 (s, 1H), 3.70 (s, 3 H), 3.15 (s, 1H). tert-butyl 3-Hydroxy-2-methylene-3-phenyl propanoate (5c) [18] H NMR (CDCl3, 200MHz): = 7.8-7.5 (m, 5H), 6.38 (s, 1 H), 5.89 (s, 1 H), 5.62 (s, 1H), 2.0 (s, 9 H). 1
3-Hydroxy-2-methylene-3-(4-fluorophenyl) propanenitrile (5d) [9] H NMR (CDCl3, 200 MHz): = 7.6 (m, 1H), 7.4 (m, 1H), 7.3 (m, 1H), 7.1 (m, 1H), 6.21 (s, 1 H), 5.92 (s, 1 H), 5.66 (s, 1 H), 2.90 (s, 1H, exchangeable with D2O).
[2] [3] [4] [5] [6]
[7]
1
3-Hydroxy-2-methylene-3-(3,4-methylenedioxyphenyl) propanenitrile (5e) [14] H NMR (CDCl3, 200 MHz): = 6.9–6.6 (m, 3H) 6.1 (d, J=1.46 Hz, 1 H), 6.0 (d, J=1.46 Hz, 1H),5.82 (s, 2 H), 5.20 (s, 1 H), 2.6 (s, 1H, exchangeable with D2O). 1
Methyl 3-Hydroxy-2-methylene-3-(3,4-methylenedioxy phenyl) propanoate (5f) [9] HNMR (CDCl3, 200 MHz): = 7.1–6.8 (m, 3 H), 6.3 (d, J=1.43 Hz, 1 H), 6.1 (d, J=1.43 Hz, 1H) 5.82 (s, 2H), 5.40 (s, 1 H), 3.66 (s, 3 H), 2.2 (s, 1H, exchangeable with D 2O).
[8] [9] [10] [11] [12] [13]
[14]
1
3-Hydroxy-2-methylene-3-(2-pyridinyl)propanenitrile (5g) [14]
[15] [16] [17]
H NMR (CDCl3, 200MHz): = 8.44 (d, 2 H, J = 4.36 Hz), 7.35 (d, 2 H, J = 4.51 Hz), 6.22 (s, 1 H), 6.05 (s, 1H), 5.30 (s, 1 H). 1
Methyl-3-Hydroxy-2-methylene-3-(2-pyridyl)propanoate (5h) [9, 14] 1 H NMR (CDCl3, 200MHz): = 8.43 (d, 2 H, J = 4.55 Hz), 7.40 (d, 2 H, J = 4.58 Hz), 6.39 (s, 1 H), 6.00 (s, 1 H), 5.70 (1 H, s), 3.66 (s,3 H).
ACKNOWLEDGEMENTS Financial support from FINEP, CNPq, CAPES and FAPERJ, Brazilian Governmental Financing Agencies, is gratefully acknowledged.
[18]
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