Aza-Michael Addition of Imidazoles to α,β-Unsaturated Compounds

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Aza-Michael Addition of Imidazoles to r,β-Unsaturated Compounds and Synthesis of β-Amino Alcohols via Nucleophilic Ring Opening of Epoxides Using Copper(II) Acetylacetonate (Cu(acac)2) Immobilized in Ionic Liquids M. Lakshmi Kantam,* B. Neelima, Ch. Venkat Reddy,† and Rajashree Chakravarti Inorganic and Physical Chemistry DiVision, Indian Institute of Chemical Technology, Hyderabad-500 007, India

Efficient synthesis of N-substituted imidazoles via the conjugate addition of imidazoles (aza-Michael addition) to R,β-unsaturated compounds using Cu(acac)2 immobilized in ionic liquids under ambient conditions has been reported. Similarly, β-amino alcohols are also synthesized via nucleophilic ring opening of epoxides with amines. The use of ionic liquids allows easy separation of the product and recycling of the catalyst in both reactions. 1. Introduction The conjugate addition of N-nucleophiles to R,β-unsaturated compounds is an important reaction in synthetic organic chemistry. The C-N heterocycles that contain a β-amino carbonyl functionality are essential intermediates in the synthesis of β-amino ketones, β-amino acids, β-lactam antibiotics, and chiral auxiliaries.1-3 The most common method for the preparation of these compounds is the Mannich reaction. The classical Mannich-type approaches are certainly very powerful, but they also require severe reaction conditions and are rather sluggish.4 These reactions require either acidic or basic catalysts, which seem to be detrimental to the desired synthesis.5,6 Consequently, many alternative procedures have been reported over the past few years, using InCl3,7 CeCl3‚7H2O,8 Bi(NO)3,9 Bi(OTf)3,10 Cu(OTf)2,11 LiClO4,12 and other Lewis acids.13 Most of these methods require aqueous workup for the catalyst separation. Different heterogeneous catalysts (such as clays,14 silica gel,15 copper nanoparticles,16 the alumina-supported CeCl3‚7H2O/NaI system,17 poly(ethylene glycol), ionic liquids and metal salts immobilized in ionic liquids18-20) have been used for azaMichael reactions. The conjugate addition of imidazoles to R,β-unsaturated compounds for the synthesis of N-substituted imidazoles has been a current area of investigation, in view of their pharmacological importance. The 4-nitro-isomeric compounds are pharmacologically significant as immunosuppressants, aldehyde dehydrogenase inhibitors, and radiotherapy synergists. Normally, these imidazole derivatives are synthesized by the reactions of imidazole, 2-methyl-4-nitro-1H-imidazole, or 4-nitro-1H-imidazole with suitable alkyl halides, sulfates, toluene-p-sulfonates, or Michael-type addition with unsaturated R,β-compounds.21,22 N-substituted imidazole derivatives that contain the D-glucose branch possess anticancer activity.23 Tinidazole and metronidazole, which belong to the 5-nitro N-substituted imidazole derivatives, have been widely used in the treatment of protozoal infections, such as trichomoniasis. Bioenzymes (such as alkaline protease and hydrolases) have been reported as effective catalysts for the aza-Michael addition of imidazoles.24-26 * To whom correspondence should be addressed. Tel.: +91-4027193510. Fax: +91-40-27160921. E-mail: [email protected]/ [email protected]. † Current address: 1311 Gilman Hall, Department of Chemistry, Iowa State University, Ames, IA 50011, USA.

Leadbeater et al.27 demonstrated the conjugate addition of imidazole to methyl acrylate in the presence of a base under microwave irradiation. Sonochemical28 and microwave-assisted29 synthesis of N-substituted imidazoles has been described by Aranda et al. using basic clay catalysts. Recently, heteroMichael addition reactions have been reported in the presence of KF/Al2O3, which is a solid base catalyst, and basic ionic liquids.30 Over the past decade, room-temperature ionic liquids (RTILs) have emerged as a new class of stable and inert solvents. Indeed, this family of ionic moieties presents several interesting properties compared to classical molecular solvents such as low vapor pressure, wide liquid range, high thermal stability and possess highly conductive solvation ability for a variety of organic substrates and catalysts including Lewis acids and enzymes.31-33 In continuation of our studies using Cu(acac)2 immobilized in ionic liquids20,34,55 herein, we report the aza-Michael addition of imidazoles to R,β-unsaturated compounds to produce the corresponding N-substituted imidazoles in high yields and regioselective ring opening of epoxides with amines to produce the corresponding β-amino alcohols in high yields, using a recyclable catalytic system: Cu(acac)2 immobilized in ionic liquids (see Schemes 1 and 2). 2. Experimental Section 2.1. Chemicals. 1-Methyl imidazole, n-butyl bromide, NaBF4, NaPF6, cyclohexenone, t-butyl acrylate, and n-butyl acrylate were purchased from Aldrich or Fluka and used without further purification. Imidazoles, methyl acrylate, acrylonitrile methyl methacrylate, epoxides, and amines were purchased from S. D. Fine Chemicals, Ltd., Mumbai, India. ACME silica gel (100200 mesh) was used for column chromatography. Thin-layer chromatography (TLC) was performed on Merck precoated silica gel 60-F254 plates. All the other solvents and chemicals were obtained from commercial sources and purified using standard methods. 2.2. Synthesis of Ionic Liquids. The compounds [bmim][BF4] and [bmim][PF6]were synthesized according to the earlier literature reports.35-37 2.3. Synthesis of Copper(II) Acetylacetonate. Copper(II) acetylacetonate (Cu(acac)2) was synthesized according to the procedure developed by us.38

10.1021/ie070080g CCC: $37.00 © 2007 American Chemical Society Published on Web 06/09/2007

Ind. Eng. Chem. Res., Vol. 46, No. 25, 2007 8615 Scheme 1. Production of N-Substituted Imidazoles in High Yields, Using Cu(acac)2 Immobilized in Ionic Liquids

Table 1. Optimization of Catalytic Conditions for the Aza-Michael Addition Reactions Using Imidazole and Acrylonitrile in [bmim][BF4]a entry

Scheme 2. Regioselective Ring Opening of Epoxides with Amines, Using Cu(acac)2 Immobilized in Ionic Liquids, To Produce the Corresponding β-Amino Alcohols in High Yields

2.4. General Procedure for the Aza-Michael Reaction of Imidazole with r,β-Unsaturated Compounds Using Cu(acac)2 in Ionic Liquids. To the solution of Cu(acac)2 (0.005 g, 2 mol %) in ionic liquid (1 mL), imidazole (1 mmol) and R,β-unsaturated compound (1.2 mmol) were added and stirred at 60 °C for the appropriate time (see Table 2, presented later in this paper). After completion of the reaction, as indicated by TLC, the product was extracted with a 1:1 ethyl acetate:n-hexane mixture (3 × 10 mL). The combined organic extracts were concentrated under reduced pressure and purified by column chromatography on silica gel to afford the pure product. The recovered ionic liquid phase that contained Cu(acac)2 was dried under reduced pressure for the next runs. The products were characterized by comparison of their nuclear magnetic resonance (NMR) and mass spectra with those reported in the literature.24,26,39 2.5. General Procedure for the Ring Opening of Epoxides Using Cu(acac)2 in Ionic Liquids. To the solution of Cu(acac)2 (0.008 g, 3 mol %) in ionic liquid (1 mL), epoxide (1 mmol) and amine (1 mmol) were added and stirred at room temperature for the appropriate time. After completion of the reaction, as indicated by TLC, the product was extracted with a 1:2 ethyl acetate:n-hexane mixture (3 × 10 mL). The combined organic extracts were concentrated in vacuo, and the resulting product was purified via column chromatography on silica gel with a mixture of ethyl acetate and n-hexane (2:8) as the eluent, to afford the pure β-amino alcohol. The ionic liquid that contained Cu(acac)2 was dried under vacuum and preserved for the next run. The products were identified by comparing the spectral data with those reported in the literature.40-45 2.6. Product Identification and Analysis. The products were analyzed by NMR and mass spectroscopic techniques. NMR spectra were recorded at 200, 300, or 400 MHz with an NMR spectrometer, using tetramethylsilane (TMS) as an internal standard and CDCl3 as the solvent. Mass spectra were obtained at an ionization energy of 70 eV. All the products gave satisfactory 1H NMR and mass spectral data, in comparison with those reported in the literature.24,26,40-45 3. Results and Discussion 3.1. Aza-Michael Reaction. The conjugate addition of imidazole to acrylonitrile was conducted under different conditions, and the results are summarized in Table 1. It was observed that the reaction in ionic liquids at room temperature gave the corresponding product in moderate yield (see Table 1, entry 1), whereas high yields were realized when the reaction was

1 2 3 4 5 6 7 8 9 10 11

catalyst

temperature (°C)

time (h)

conversion (%)b

Cu(acac)2 Cu(acac)2 Cu(acac)2 Cu(acac)2 Cu(acac)2 Cu(acac)2 Cu(acac)2

35 60 60 60 35 35 60 60 70 70 70

12 6 12 12 6 12 6 6 6 6 6

66 60 90 88c 63 77 95 90c 45d 50e 80f

a Reaction conditions: 1 mmol imidazole, 1 mmol acrylonitrile, room temperature, and 1 mL [bmim][BF4]. b Conversions calculated by 1H NMR spectroscopy. c [bmim][PF6] was used as solvent in place of [bmim][BF4]. d Toluene was used as solvent in place of [bmim][BF ]. e CHCl was used 4 3 as solvent in place of [bmim][BF4]. f DMSO was used as solvent in place of [bmim][BF4].

conducted at 60 °C in [bmim][BF4], albeit with longer reaction times (see Table 1, entries 2-4). We have recently reported the use of Cu(acac)2 immobilized in ionic liquid for the azaMichael addition of amines to R,β-unsaturated compounds.20 Similar strategy has been adopted for the reaction of imidazole with acrylonitrile using Cu(acac)2 immobilized in ionic liquids. As expected, high yields of N-substituted imidazoles were obtained in shorter reaction times (see Table 1, entries 5-8). The use of organic solvents such as toluene and chloroform were less effective (see Table 1, entries 9 and 10) in place of ionic liquids, whereas the use of a hydrophilic high polar solvent (such as dimethyl sulfoxide, DMSO) resulted in 80% product conversion (see Table 1, entry 11) in the same length of time. Both [bmim][BF4] and [bmim][PF6] were equally effective as ionic liquids for the reaction (data given in Table 1, entry 7). The conjugate addition of imidazole with a variety of R,βunsaturated compounds was investigated separately in ionic liquids alone and in Cu(acac)2 immobilized in ionic liquids (see Table 2). The yields of corresponding N-substituted imidazoles in both cases were almost similar; however, the reaction in ionic liquids without the copper catalyst required longer reaction times. Different R,β-unsaturated compounds (such as acrylates, nitriles, and cyclic enones) underwent reaction with imidazole to give the corresponding addition products in good yields. Both simple acrylates and long-chain acrylates were equally effective for the conjugate additions with imidazole (see Table 2, entries 1-3). Bulky esters such as tert-butyl acrylate afforded the product in good yield (see Table 2, entry 4). Generally, acrylonitrile, methyl vinyl ketone, methyl methacrylate, and cyclohexenone reacted readily with imidazole (see Table 2, entries 5-8). Importantly, substituted imidazoles were determined to be equally effective for the reaction (see Table 2, entries 9-12). Under similar reaction conditions, benzimidazole reacted with acrylonitrile, affording the product in good yield (see Table 2, entry 13). The ionic liquid phase that contained Cu(acac)2 was recovered and reused with consistent activity (see Table 2, entry 7). The isolated yields in the second, third, and fourth cycles were determined to be 92%, 90%, and 90%, respectively. The literature shows that the substituted Michael acceptors (such as methyl methacrylate) are known to be less reactive, because of the strong steric hindrance, to realize good isolated yields.30b However, the present system performed excellently in the case of methyl methacrylate, indicating its effectiveness in aza-Michael reactions (see Table 2, entry 6); this may be attributed to the advantageous synergistic benefit

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Table 2. Aza-Michael Reaction of Imidazoles with r,β-Unsaturated Compounds Using Cu(acac)2 in [bmim][BF4]a

a Reaction conditions: 1 mmol imidazole, 1.2 mmol R,β-unsaturated compound, and 2 mol % Cu(acac) in 1 mL of [bmim][BF ] at 60 °C, with a reaction 2 4 time of 6 h. b Isolated yields after column chromatography. c Reaction using [bmim][BF4] alone. d Yield after fourth cycle.

of ionic liquids in combination with a copper catalyst. Very recently, Lin and co-workers,30b and Xia and co-workers,30c reported the use of a strongly basic task-specific ionic liquid ([Bmim]OH) for the aza-Michael reactions of N-heterocycles. The yields obtained using the basic ionic liquid [Bmim]OH were comparable to the yields obtained via our method. 3.2. Nucleophilic Ring Opening of Epoxides. β-Amino alcohols are versatile intermediates in the synthesis of biologically active natural products and pharmaceuticals, and as chiral auxiliaries in asymmetric synthesis.46-48 The classical approach for the synthesis of these compounds involves the nucleophilic ring opening of epoxides with amines. However, these reactions require high temperature, longer reaction times, and a large excess of amine.49 Several alternative methods have been developed using metal amides,49 metal salts,50 metal alkoxides,41 metal triflates,41 metal halides,42 and heterogeneous catalysts such as alumina,51 zirconium sulfophenyl phosphonate,43 silica,44

and clays.52 Despite their synthetic elegance, some of the previously described methods involve the use of stoichiometric amounts of reagents, longer reaction times, poor regioselectivity, and undesirable side reactions, and some generate copious amounts of solid metal waste. The widespread interest of ionic liquids (ILs) in catalysis53,54 and our continued search for new alternatives for selective organic transformations prompted us to investigate these important reactions using ILs.34,55 Recently, ionic liquids have been reported to mediate the ring opening of epoxides with amines, although longer reaction times are required.56 Herein, we also report the regioselective ring opening of epoxides with amines to produce the corresponding β-amino alcohols in high yields using a recyclable catalytic system (Cu(acac)2 immobilized in ionic liquids; see Scheme 2). To best of our knowledge, the ring opening of epoxides with amines, involving

Ind. Eng. Chem. Res., Vol. 46, No. 25, 2007 8617 Table 3. Ring Opening of Styrene Oxide with Aniline under Different Reaction Conditionsa entry

copper salt

solvent

yield (%)b

1 2 3 4 5

Cu(acac)2 CuCl2 Cu(acac)2 Cu(acac)2

[bmim][BF4] [bmim][BF4] [bmim][PF6] [bmim][BF4] CH2Cl2

92 40 85 30c 30, 85c

Table 5. Ring Opening of Various Epoxides with Aniline and Morpholine Using Cu(acac)2 in [bmim][BF4]a

a Reaction conditions: 1 mmol styrene oxide, 1 mmol aniline, 3 mol % copper catalyst in 1 mL of [bmim][BF4], with a reaction time of 15 min, at room temperature. b Isolated yields of isomer 3. c Isolated yield of isomer 3 after 1 h.

Table 4. Ring Opening of Styrene Oxide with Different Amines Using Cu(acac)2 in [bmim][BF4]a

a Reaction conditions: 1 mmol epoxide, 1 mmol amine, 3 mol % Cu(acac)2 in [bmim][BF4], at room temperature. b Ratio of regioisomers (3:4) were determined via gas chromatography. c Isolated yields.

a Reaction conditions: 1 mmol styrene oxide, 1 mmol aniline, 3 mol % copper catalyst in 1 mL of [bmim][BF4], at room temperature. b Ratio of regioisomers (3:4) were determined by gas chromatography. c Isolated yield after column chromatography. d Yield after fourth cycle.

a combination of the chosen catalyst and ionic liquids, is unprecedented. The ionic liquids, [bmim][BF4] and [bmim][PF6], were synthesized according to the procedure reported in the literature and are analytically pure.57 Initially, the catalytic activity was tested for the ring opening of styrene oxide with aniline under a variety of reaction conditions and the results are disclosed in Table 3. Cu(acac)2 is determined to be a more effective catalyst in ILs, compared to CuCl2 in ILs (see Table 3, entries 1 and 2). Furthermore, in recognition of the fact that ILs alone are capable of catalyzing the reaction, an experiment was conducted without copper species. No product formation was observed after 15

min; however, after prolonged reaction time (see Table 3, entry 4), 30% product was obtained. Reaction in CH2Cl2 required a longer reaction time (see Table 3, entry 5). Under the optimized reaction conditions, styrene oxide underwent reaction with a wide range of amines, in the presence of 3 mol % Cu(acac)2 immobilized in 1 mL of ionic liquid at room temperature, to give the corresponding β-amino alcohols in good yields with high regioselectivities. The regioselectivity was determined by gas chromatography, and the results are illustrated in Table 4. Aryl amines underwent reaction with styrene oxide in a regioselective manner to give the corresponding β-amino alcohols (3) with preferential nucleophilic attack at the benzylic position (see Table 4, entries 1-3). Aliphatic amines on reaction with styrene oxide gave the product in good yields with an opposite regiochemistry of aromatic substrate (see Table 4, entries 4-8). Thus, aromatic amines, being less nucleophilic, react preferentially at the benzylic carbon of styrene oxide, whereas in the case of aliphatic amines, the preferential attack of the amine occurs at the terminal carbon of styrene oxide, because of the increased nucleophilicity favoring the SN2 process.42 The methodology was further extended to the ring opening of aliphatic epoxides and substituted styrene oxide with amines, and the results are summarized in Table 5. In the case of cyclohexene oxide, only the trans-diastereoisomer was obtained (see entries 1 and 2 in Table 5). The reaction between decyl oxirane and aniline afforded the corresponding amino alcohol (4) in good yields (see entry 3). Therefore, the attack of nucleophile is governed by the nature of the epoxide and the stability of the carbanion. The ionic liquid phase that contained [bmim][BF4] and Cu(acac)2 was recovered quantitatively via simple extraction of the product with organic solvent. The recovered ionic liquid phase that contained the catalyst was reused for several cycles with consistent activity (see Table 4, entry 1). 4. Conclusions In conclusion, a facile, recyclable, and clean aza-Michael reaction of imidazoles with a variety of R,β-unsaturated

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compounds, and the synthesis of β-amino alcohols via regioselective ring opening of epoxides with amines, using Cu(acac)2 immobilized in ionic liquids, has been developed. The simplicity of operation, the mild conditions, and the environmentally benign nature of the reaction allows easy application to a wide range of substrates.58 Acknowledgment The authors thank the CSIR for financial support under the Task Force Project CMM-0005. Authors B.N. and R.C. thank the Council of Scientific and Industrial Research (CSIR), India, for research fellowships. Literature Cited (1) Bartoli, G.; Cimarelli, C.; Marcantoni, E.; Palmieri, G.; Petrini, M. Chemo- and diastereoselective reduction of β-enamino esters: A convenient synthesis of both cis- and trans-γ-amino alcohols and β-amino esters. J. Org. Chem. 1994, 59, 5328. (2) Eliel, E. L.; He, X. C. Highly stereoselective syntheses involving N-alkyl-4,4,7-R-trimethyl-trans-octahydro-1,3-benzooxazine intermediates. J. Org. Chem. 1990, 55, 2114. (3) Cardillo, G.; Tomasini, C. Asymmetric synthesis of β-aminoacids and R-substituted β-aminoacids. Chem. Soc. ReV. 1996, 117. (4) Arend, M.; Westermann, B.; Risch, N. Modern variants of the Mannich reaction. Angew. Chem., Int. Ed. 1998, 37, 1044. (5) Bull, S. D.; Davies, S. G.; Delgado-Ballester, S.; Fenton, G.; Kelly, P. M.; Smith, A. D. The asymmetric synthesis of β-haloaryl-β-aminoacid derivatives. Synlett 2000, 1257. (6) Davies, S. G.; McCarthy, T. D. An asymmetric synthesis of N-protected β-amino aldehydes and β-amino ketones. Synlett 1995, 700. (7) Loh, T.-P.; Wei, L.-L. Indium trichloride catalyzed conjugate addition of amines to R,β-ethylenic compounds in water. Synlett 1998, 975. (8) Bartoli, G.; Bosco, M.; Marcantoni, E.; Pertrini, M.; Sanbri, L.; Torregiani, E. Conjugate addition of amines to R,β-enones promoted by CeCl3‚7H2O-NaI system supported in silica gel. J. Org. Chem. 2001, 66, 9052. (9) Srivastava, N.; Banik, B. K. Bismuth nitrate catalyzed versatile Michael reactions. J. Org. Chem. 2003, 68, 2109. (10) Varala. R.; Alam, M. M.; Adapa, S. R. Chemoselective Michael type addition of aliphatic amines to R,β-ethylenic compounds using bismuth triflate catalyst. Synlett 2003, 720. (11) Xu, L. W.; Li, J. W.; Xia, C. G.; Zhou, S. L.; Hu, X. X. Efficient copper-catalyzed chemo selective conjugate addition of aliphatic amines to R,β-unsaturated compounds in water. Synlett 2003, 2425. (12) Azizi, N.; Saidi, M. R. LiClO4 accelerated Michael addition of amines to R,β-unsaturated olefins under solvent-free conditions. Tetrahedron 2004, 60, 383. (13) Xu, L. W.; Li, L.; Xia, C. G. Transiton-metal based lewis acid catalysis of aza-Michael additions of amines to R,β-unsaturated electrophiles in water. HelV. Chim. Acta 2004, 87, 1522. (14) Shaikh, N. S.; Despande, V. H.; Bedekar, A. V. Clay catalyzed chemoselective Michael type addition of aliphatic amines to R,β-ethylenic compounds. Tetrahedron 2001, 57, 9045. (15) Basu, B.; Das, P.; Hossain, I. Synthesis of β-aminoesters via azaMichael addition of amines to alkenes promoted on silica: A useful and recyclable surface. Synlett 2004, 2630. (16) Verma, A. K.; Kumar, R.; Choudhary, P.; Saxena, A.; Shankar, R.; Mozumdar, S.; Chandra, R. Cu-nanoparticles: a chemoselective catalyst for the aza-Michael reactions of N-alkyl and N-arylpiperazines with acrylonitrile. Tetrahedron Lett. 2005, 46, 5229. (17) Bartoli, G.; Bartolacci, M.; Giuliani, A.; Marcantoni, E.; Massaccesi, M.; Torregiani, E. Improved heteroatom nucleophilic addition to electronpoor alkenes promoted by CeCl3‚7H2O/NaI system supported on alumina in solvent-free conditions. J. Org. Chem. 2005, 70, 169. (18) Yadav, J. S.; Reddy, B. V. S.; Basak, A. K.; Narsaiah, A. V. AzaMichael reactions in ionic liquids. A facile synthesis of β-amino compounds. Chem. Lett. 2003, 32, 988. (19) (a) Gu, Y.; Ogawa, C.; Kobayashi, S. Silica supported sodium sulfonate with ionic liquid: A neutral catalyst system for Michael reactions of indoles in water. Org. Lett. 2007, 9, 175. (b) Ranu, B. C.; Banerjee. S. Significant rate acceleration of the aza-Michael reaction in water. Tetrahedron Lett. 2007, 48, 141. (c) Surendra, K.; Srilakshmi Krishnaveni, N.; Sridhar, R.; Rama Rao, K. β-Cyclodextrin promoted aza-Michael addition of amines to conjugated alkenes in water. Tetrahedron Lett. 2006,

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ReceiVed for reView January 13, 2007 ReVised manuscript receiVed May 3, 2007 Accepted May 4, 2007 IE070080G