Microwave-assisted synthesis of nitrogen-containing heterocycles

Abstract

In the recent years, microwave (MW) radiation is widely used as a source of heating in organic synthesis. Since the discovery of the MW heating approach, MW-assisted reaction has emerged as a new green-method in organic synthesis as it provides spectacular accelerations, higher yields under milder reaction conditions, and higher product purities, and it reduces pollution of the environment through the use of solvent-free reaction protocols. N-containing heterocycles hold a special place among pharmaceutically significant natural products and synthetic compounds needed for any developed human society. Therefore, organic chemists have been engaged in extensive efforts to produce these compounds following various greener techniques, primarily to circumvent growing environmental concerns. In this review, we discuss only the MW-assisted synthesis of N-containing heterocyclic compounds.

Keywords:

• green chemistry
• microwave-assisted synthesis
• N-containing heterocycles

1. Introduction

Heterocycles form by far the largest of the classical divisions of organic chemistry. Heterocycles are essential building blocks that are frequently used in the pharmaceutical; more than 95% of pharmaceuticals contain at least one heterocyclic fragment 1. They also have application in a wide variety of industries including cosmetics, reprography, information storage, plastics, solvents, antioxidants, and vulcanization accelerators 2 3.

Amongst the heterocycles, N-based heterocycles have been the object of considerable focus, because N-containing heterocycles are structural components of many bioactive natural products such as vitamins, hormones, antibiotics, alkaloids, glycosides, and many more compounds which are of significance for human and animal health 4. Many natural drugs such as quinine, papaverine, emetine, theophylline, atropine, codeine, morphine, and reserpine are N-containing heterocycles 1 5. Therefore, N-containing heterocycles are especially considered “privileged” structures for the synthesis and development of new drugs 6 7. Traditional methods of organic synthesis are orders of magnitude too slow to satisfy the demand for these compounds 8 9. It is therefore easy to understand why the development of new methods for the synthesis of complex heterocyclic compounds continues to drive the field of synthetic organic chemistry.

Green or sustainable chemistry has now become a subject of intensive research [10–13]. The concept of “green chemistry” emerged in the early 1990s 12 and is now widely adopted to meet the fundamental scientific challenges to protect the human health and environment while simultaneously achieving commercial viability 3 14. Nonclassical methods following the principles of green chemistry 9 reduce or even eliminate the generation of hazardous substances [12–15] as well as eliminate the use of conventional volatile organic solvents. There have been tremendous successes in the synthesis of numerous numbers of heterocyclic compounds and in the development of new processes under clean, environmentally benign methodologies that are sustainable for the long term.

Microwave (MW) is one of the potential green chemistry techniques used during the recent years 16. The ability of MW-assisted organic synthesis to rapidly synthesize organic compounds is of significant benefit for library generation. Moreover, it allows modifications in selectivity (chemo-, regio-, and stereo-selectivity) and solvent-, catalyst-free conditions 17. This review outlines the use of MW, highlights the importance of a number of N-containing heterocycles, and summarizes some advances in their synthesis under MW irradiation through recent selected examples.

2. MW irradiation

A nonclassical heating technique using microwaves (MWs), termed “Bunsen burner of the 21st century”, is rapidly becoming popular and is dramatically reducing reaction times 14. The rate of acceleration observed in MW irradiation is due to material–wave interactions leading to dielectric heating. MW consists of an electric and magnetic field and thus represents electromagnetic energy. This energy can act as a nonionizing radiation that causes molecular motions of ions and rotation of the dipoles, but does not affect molecular structure 14. The applied MW field causes the molecules, on average, to temporarily spend slightly more time orienting themselves in the direction of the electric field rather than in other directions. When the field is removed, thermal agitation returns the molecules to a disordered state in the relaxation time and thermal energy is released. Hence this phenomenon relies on the ability of a substance (solvent or reactant) to absorb MWs and convert them into heat 18. This internal heating is much more homogeneous than the classical heating.

Synthesis of various N-containing heterocycles utilizing MW irradiation are now discussed under the following headings.

2.1. Pyrroles

Pyrroles are heterocycles of great importance because pyrrole is a basic substructure of numerous biologically active alkaloids and pharmaceutical products 19 20. Classically, pyrroles were synthesized by various methods viz. Knorr pyrrole synthesis 21, Paal–Knorr synthesis 22, Hantzsch pyrrole synthesis 23, etc.

Aydogan et al. 19 carried out the reaction of cis-1,4-dichloro-2-butene 1 with various amine compounds 2, amino alcohols, and amino acid esters without solvent under MW irradiation on silica gel for 2–4 min, and N-substituted homochiral pyrrole derivatives 3 (11 examples) were obtained in good yield (49–69%) instead of the expected 3-pyrrolines (Scheme 1).

short-legendScheme 1. Reaction of cis-1,4-dichloro-2-butene with various amine.

Heating an aniline 4 with 2,5-dimethoxytetrahydrofuran 5 in water (0.64 M) in a MW reactor at 150°C for 30 min resulted in the formation of the corresponding pyrroles 6 (10 examples) in water in 81–99% yield (Scheme 2). Wilson et al. 20 reported this simplified approach to the uncatalyzed Paal–Knorr condensation.

short-legendScheme 2. Microwave (MW)-induced uncatalyzed reaction of 2,5-dimethoxytetrahydrofuran with various amines in water.

Jayagobi et al. 24 have reported the synthesis of pyrano[4,5-c]pyrroles 10(a) and 10(b) by one-pot intramolecular Knoevenagel-Hetero Diels-Alder reaction of alkenyl aldehyde 7 with barbituric acid 8 in excellent yield (80%) under MW heating (Scheme 3) in 2 min in toluene. Traditional method in refluxing toluene in the presence of ethylene diaminediacetate (EDDA) provides 67% yield in 6 h.

short-legendScheme 3. Synthesis of pyrano[4,5-c]pyrroles by one-pot intramolecular Knoevenagelhetero-Diels-Alder reaction reaction under MW heating.

Deb et al. 25 have reported synthesis of ring-fused pyrrole 13 in a single operation by the reaction of 1,3-diketone 11 and cyclic aniline 12 under MW irradiation at 280°C in the presence of 0.5 equivalent of p-toluenesulfoic acid (p-TSA) with 53% yield (Scheme 4) in 10 min.

short-legendScheme 4. Synthesis of ring-fused pyrrole under MW irradiation.

Ligand-free 5-endo-dig cyclization of homopropargyl azide 14 in the presence of 20 mol% ZnCl₂ (1.0 M in ether) in CH₂Cl₂ at 105°C provided pyrroles 15 (eight examples) in high to moderate yield (91–41%) 26 in 40–60 min (Scheme 5). Conventional heating also furnished the same product but at 75°C for 16 h.

short-legendScheme 5. Synthesis of pyrroles by 5-endo-dig cyclization of homopropargyl azide.

Portela-Cubillo et al. 27 investigated iminyl radical generation and cyclization using the set of functionalized O-phenyl oxime ethers 17 promoted by MWs to produce dihydropyrrole 21 (four examples) in 68–82% yield (Scheme 6). Reaction took place at 160°C for 15 min with one equivalent of ionic liquid 1-ethyl-3-methyl-1H-imidazol-3-ium hexafluorophosphate (emimPF₆). However, it was difficult to furnish the conventional thermolyses of O-phenyl oxime ethers as reaction times had to be long, the products were not cleanly formed and yields were disappointingly low.

short-legendScheme 6. Synthesis of dihydropyrrole using O-phenyl oxime ethers.

2.2. Indole and its derivatives

Indole nuclei are broadly found in a large amount of synthetic and natural products. Indole is a popular component of fragrances and the precursor to many pharmaceuticals 28. Classically, indoles have been synthesized by various methods 29 30. The use of more environmental friendly protocols for the synthesis of indole derivatives has been reported which are mentioned below.

A series of novel 2-aryl-3,4-dihydro-2H-thieno[3,2-b]indoles 24 (22 examples) have been synthesized by Karthikeyan and his co-workers 29 regioselectively in excellent yields (85–98%) under MW irradiation (Scheme 7) at 90°C in 3–6 min. 24 were also obtained under conventional condition in refluxing ethanol but completed in 30–70 min.

short-legendScheme 7. Reaction of 5-aryldihydro-3(2H)-thiophenones and arylhydrazine hydrochloride.

The synthesis of indoles 27 (six examples) which begins with the intermediates 26 prepared from the corresponding commercially available aldehydes 25 (Scheme 8) was accomplished by Lehmann et al. 30. Formation of indoles took place with 99.9% yield at 200 W, 200°C, and 15-min irradiation time. The existing methods for the synthesis of these compounds afford only relatively low to modest yields (53–79%) in several hours.

short-legendScheme 8. Synthesis of indoles under MW irradiation.

Borthakur et al. 31 recently described this formation of various 5-hydroxybenzo[g]indole 31 (12 examples) at 140°C for 5 min in 80% yield (Scheme 9).

short-legendScheme 9. Synthesis of 2-(p-tolyl)-3-morpholino-5-hydroxybenzo[g]indoles.

Bhella et al. 32 recently reported monomode MW-assisted regio- and stereo-selective 1,3-dipolar cycloadditions of C-(3-indolyl)-N-phenylnitrone 32 with olefinic dipolarophiles 33 to afford the formation of isoxazolidines 34 (six examples) in high yields (87%) in 5 min (Scheme 10).

short-legendScheme 10. Reaction of C-(3-indolyl)-N-phenylnitrone with olefinic dipolarophiles under MW heating.

The same group 32 extended their investigations on 1,3-dipolar cycloadditions of nitrone 32 to allenic esters 35 (two examples) under MW irradiation in solvent-free conditions which afforded potentially biologically active bis-indole derivatives 36 in high yields (84–90%) in 3 min (Scheme 11).

short-legendScheme 11. Reaction of 1,3-dipolar cycloadditions of nitrone and allenic esters under MW irradiation.

Carpita et al. 33 reported differently substituted indoles 38 (22 examples) via MW-assisted cycloisomerization in water of 2-alkynylanilines 37 which is promoted by catalytic amounts of neutral or basic salts or by stoichiometric weak organic bases in good to high yields (45–66%) without any added metal catalyst in 15–30 min, and did not take place by applying conventional heating (Scheme 12). Earlier, the same group 34 produced similar indoles in moderate to good yields (16–77%) from same reactants 37 under MW irradiation in water without any added metal catalyst, acid, or base in 0.25–1.5 h.

short-legendScheme 12. MW-assisted catalytic cycloisomerization of 2-alkynylaniline derivatives.

A MW-assisted, one-pot, three-component coupling reaction for the synthesis of 2,3-disubstituted indoles 42 has been developed by Chen et al. 35 (Scheme 13). This reaction was carried out in two steps under standard Sonogashira coupling conditions which afforded a variety of 2,3-disubstituted indoles (24 examples) in 40–80 min in moderate to excellent yields (60–91%).

short-legendScheme 13. Synthesis of 2,3-disubstituted indoles under standard Sonogashira coupling conditions.

Waldmann et al. 36 described a silver-catalyzed and MW-assisted one-pot cascade reaction sequence that gives access to different alkaloid-inspired polycyclic scaffold classes including fascaplysin-type alkaloids 49 (52%) and analogs thereof 48 (53%; Scheme 14).

short-legendScheme 14. MW-assisted one-pot cascade synthesis of alkaloid-inspired polycyclic scaffold.

2.3 Imidazoles

Imidazole derivatives have attracted considerable attention in recent years as these are endowed with a wide range of pharmaceutical activities 6 37. The application of imidazoles as 1,3-disubstituted imidazole salts as ionic liquids are also well known 37. Classically, imidazoles have been synthesized by various methods [38–41].

The MW-mediated preparation of lophine (2,4,5-triphenylimidazole) 53 has been described by Crouch et al. 42 as shown in Scheme 15. When the homogenous mixture of equal molar quantities of benzaldehyde 51, benzil 52, glacial acetic acid, and ammonia was irradiated to raise the temperature from room temperature to 120°C over 10 min and then to 125°C over five more minutes, compound 53 was obtained in 90%. The existing methodology requires gram quantities of reagent, large quantities of solvent, and reaction times of greater than 1 h.

short-legendScheme 15. Reaction under MW irradiation to produce lophine.

Later, Xia et al. 43 reported a MW-assisted three-component synthesis of various 2,4,5-trisubstituted imidazoles 54 (14 examples) with good to excellent yields (74–93%) in ionic liquid 1-methyl-3-heptyl-imidazolium tetrafluoroborate ([HeMIM]BF₄), without solvent and additional acid (Scheme 16). The reaction time was dramatically reduced from several hours in conventional heating to just a few minutes under MW irradiation.

short-legendScheme 16. Synthesis of 2,4,5-trisubstituted imidazoles under solvent-free condition.

Wolkenberg et al. 44 described a simple, high-yielding (80–99%) synthesis of 2,4,5-trisubstituted imidazoles 57 from 1,2-diketones 56 and aldehydes 55 in the presence of NH₄OAc under MW irradiation at 180°C for 5 min (Scheme 17). Classical methods require harsh reaction conditions (150–200°C, 4–6 h) and suffer from low yields (40–90%), mixtures of products, and lack of generality. These compounds have utility in expedient preparations of the imidazolium alkaloid lepidiline B6 and the platelet aggregation inhibitor trifenagrel.

short-legendScheme 17. MW-assisted reactions of 1,2-diketones for the formation of 2,4,5-trisubstituted imidazoles.

Sparks and his co-workers 45 have discovered an efficient MW-assisted, one-pot, two-step synthesis of 2,4,5-triarylimidazoles 60 (15 examples) from keto-oximes 58 and aldehydes in moderate (17–37%) to good yields (40–63%) via cyclization to the N-hydroxyimidazole (Scheme 18). The novel thermally induced N–O reductive bond cleavage step takes place upon MW irradiation at 200°C for 20 min, whereas conventional methods require 2 days.

short-legendScheme 18. MW-assisted one-pot synthesis of 2,4,5-triaryl imidazoles.

4,5-Diaryl-2-sydnonyl-1-substituted imidazoles 65 (16 examples) have been prepared by Shih et al. 46 by the one-pot condensation of 3-(4-ethoxyphenyl)-4-formylsydnone 61, benzil derivatives 62, and ammonium acetate, under MW irradiation (Scheme 19). The use of MW heating reduces reaction time (52–85% yield in 30–90 min) compared to classical heating at 90–110°C (46–77% yields in 1–3 days). When primary amines 63 added, similar treatment produced 64 (eight examples) in 2–3 h with 45–60% yields. Conventional heating also affords 64, but in 2–3 days with 20–34% yield.

short-legendScheme 19. Synthesis of 4,5-diaryl-2-sydnonyl-1-substituted imidazoles.

2-Imidazolines 69 have been synthesized by Hoz et al. 47. MW-assisted cyclization of nitriles 66 with ethylenediamine 67 which aromatize in toluene and Magtrieve^TM (oxidant) and further afforded imidazoles (five examples) in 75–105 min (Scheme 20). The use of conventional heating with MnO₂ requires longer reaction times (24–48 h) to obtain good results (76–93%).

short-legendScheme 20. MW-assisted synthesis of 2-imidazolines.

Equimolar ratio of succinic acid 70 and cyclohexane-1,2-diamine 71 were mixed together thoroughly and then subjected to MW irradiation at 850 W for 4 min to furnish the product octahydro-1H-pyrrolo-[1,2-a]benzimidazol-1-one 72 in quantitative yield (Scheme 21). This one-step process for the synthesis of tricyclic heterocyclic molecules (three examples) was reported by Sondhi et al. 48.

short-legendScheme 21. Synthesis of tricyclic heterocyclic molecules under MW irradiation.

The parent pyrrolidino[2′,3′:3,4]pyrrolidino[1,2-a]benzimidazole-2-carboxylates 78 (11 examples) have been synthesized by Meng et al. 49 utilizing a MW-assisted condensation of carbaldehyde 75 with a secondary amino ester 76 and the subsequent 1,3-dipolar cycloaddition of the S-shaped ylide 77 (Scheme 22). The reaction was carried out in xylene at 130 or 150°C for 20 min to afford the polycyclic pyrrolidine compounds 78 in (52–93%) yield. Azomethine ylide cycloadditions run under classical reaction conditions require longer reaction times and afford products in lower yields 49.

short-legendScheme 22. MW-assisted synthesis of polycyclic pyrrolidine.

2.4. Pyrazoles

Pyrazole and its derivatives have displayed broad spectrum of pharmacological and biological activities. In particular, pyrazolo[3,4-b]pyridines are useful for treatment of a wide variety of stress-related illnesses. Well-known methods for pyrazole synthesis are Pechmann pyrazole synthesis and Knorr pyrazole synthesis 50 51.

Polshettiwar et al. 52 reported MW-assisted synthesis of pyrazole derivatives 81 (eight examples) using nano-organocatalyst in water at 140°C in 20 min in high yield (84–96%; Scheme 23).

short-legendScheme 23. Synthesis of pyrazole derivatives using nano-organocatalyst by MW heating.

Hatem et al. 53 reported the synthesis of 1,3,4-triaryl-5-N-arylpyrazole-carboxamides 85 by 1,3-dipolar cycloaddition of nitrilimines 83 with 5-arylidene-2-arylimino-4-thiazolidinones 82 under solvent-free and MW-assisted conditions at 130°C for 15 min (Scheme 24).

short-legendScheme 24. Synthesis of 1,3,4-triaryl-5-N-arylpyrazole-carboxamides under MW irradiation.

Paul et al. 54 carried out reaction of 4-methylacetophenone 86 with ethyl trifluoroacetate 87 applying MW heating which afforded enol ketone 88 in 10 min at 160°C with high yield (95%). In contrast, the highest yielding (88%) non-MW conditions took 5 days. In the next step, 88 reacted with 4-methylphenylhydrazine 89 to deliver various 1,5-diarylpyrazoles 90 (nine examples) under MW irradiation at 160°C with 95% yield in the presence of silica-supported toluenesulfonic acid (Si-TsOH) in ethanol in 5 min. Whereas, under thermal conditions (100°C), 84 obtained in 7 h with 84% yield (Scheme 25).

short-legendScheme 25. Synthesis of 1,5-diarylpyrazoles in the presence of silica under MW irradiation.

Sauzem et al. 55 have synthesized 5-trifluoromethyl-4,5-dihydro-1H-pyrazoles 93 (10 examples) from one-pot cyclocondensation reaction of 4-alkoxy-1,1,1-trifluoromethyl-3-alken-2-ones 91 with the help of MW-assisted synthesis at 70°C in 4 min with high yield (82–96%; Scheme 26). Some of these compounds were effective on neurogenic pain. Conventional method entails moderate yields and a long process (ca. 24 h).

short-legendScheme 26. Synthesis of 5-trifluoromethyl-4,5-dihydro-1H-pyrazoles.

Radi et al. 56 developed multi-component MW-assisted organocatalytic domino Knoevenagel-hetero Diels-Alder reaction (DKHDA) applied for the synthesis of 2,3-dihydropyran[2,3-c]pyrazoles 98 (22 examples). When a mixture of pyrazolone 94, aldehyde 96, and ethylvinyl ether 95 was irradiated at 110°C for 30 min in the presence of the diaryl-prolinol catalyst 97 and t-BuOH as the solvent, the desired compounds 98a and 98b were obtained in 56% and 12%, respectively, and compared to the conventional heating at 80°C for 48 h for similar compounds (Scheme 27).

short-legendScheme 27. MW-assisted organocatalytic synthesis of 2,3-dihydropyran[2,3-c]pyrazoles.

Ju et al. 57 described the double alkylation of unprotected hydrazines 99 by alkyl dihalides 100 via cyclocondensation under MW irradiation. These reactions took place in aqueous media in the presence of a mild base with MW power of 70–100 W, at 120°C for 20 min to provide a series of pyrazoles 101 (11 examples) with high yield (60–80%) in a simple SN₂-like sequential heterocyclization experimental protocol which has never been fully realized under conventional reaction conditions (Scheme 28).

short-legendScheme 28. Double alkylation of hydrazine by alkyl dihalides under MW irradiation.

2.5. Pyrazolines

Pyrazoline moieties have a wide range of applications in agricultural pesticides and luminescent and fluorescent target molecules 58. Chemists use pyrazolines in bioactive moieties to synthesize new compounds possessing biological activities.

Manna et al. 59 have synthesized new 2-[1-(5,8-dihydro quinoxalino[2,3-b]indoloacetyl)-3-(1-benzofuran-2-yl)-4,5-dihydro-1H-pyrazol-5-yl] phenyl derivatives 104 (14 examples) using MW-assisted route with an excellent yield (84–98%) in 20–30 min (Scheme 29). In ordinary synthetic route (reflux), 28–72% yield was obtained in 8–9.5 h.

short-legendScheme 29. Synthesis of 2-[1-(5,8-dihydro quinoxalino[2,3-b]indoloacetyl)-3-(1-benzofuran-2-yl)-4,5-dihydro-1H-pyrazol-5-yl] phenyl derivatives.

Martins et al. 60 reported the synthesis of novel 4,5-dihydro-1H-pyrazole 107 (12 examples) from cyclocondensation reaction of enones 105 with hydrazine methyl carboxylate 106 under solvent-free conditions (Scheme 30) at 50–55°C in 6 min with 70–98% yield. Conventional heating gave only moderate yields (70–79%) in 24 h.

short-legendScheme 30. Synthesis of 4,5-dihydro-1H-pyrazole under solvent-free conditions.

2.6. Pyrazolones

Several heterocyclic compounds containing pyrazolone moiety were found to be useful intermediates for medical drugs. They have a wide range of approved biological and pharmaceutical activities 61. Among other activities, pyrazolones act as appropriate precursors for the preparation of herbicides, liquid crystals, and dyes. They are traditionally synthesized by treatment of β-ketoesters with substituted hydrazines under acidic conditions at elevated temperature 62.

Pal et al. 63 have also reported the synthesis of a series of pyrazolones 110 (12 examples) from the cyclocondensation reaction of hydrazines 109 with β-ketoesters 108 under solvent-free conditions using MW heating (Scheme 31). Compared to conventional method (in refluxing MeOH for 10 h), MW-assisted reaction completes in 2–4 min in high yield (62–89%).

short-legendScheme 31. Synthesis of pyrazolones under solvent-free conditions using MW irradiation.

Mutairi et al. 62 have irradiated the mixture of hydrazine derivatives 112 and β-keto esters 111 with MW (300 W) for 1–15 min under solvent-free condition which produced pyrazolones 113 (12 examples) in moderate to good yields (40–91%; Scheme 32). 113 are also produced under conventional condition (stirring in EtOH, at room temperature [RT] for 1–5 h).

short-legendScheme 32. Synthesis of pyrazolones under microwave irradiation.

Deshmukh et al. 64 reported a MW-assisted process to synthesize 5-aminopyrazolone 116 under solvent-free conditions (Scheme 33) with 88% yields at 130°C in 2 min. The same conversion carried out under conventional thermal heating required 4 h and furnished the products in 80% yield 64.

short-legendScheme 33. Synthesis of 5-aminopyrazolones under solvent-free condition.

2.7. Triazole

1,2,3-Triazoles are indispensable structural motifs of compounds with increasing importance in the field of pharmaceuticals, crop protection, and material sciences 65. Conventional Huisgen's 1,3-dipolar cycloaddition technique proved to be highly versatile in giving substituted 1,2,3-triazoles by the reaction between organic azides and substituted alkynes 66.

Tsai et al. 67 have synthesized 4,5-disubstituted-2H-1,2,3-triazoles 119 (14 examples) via cycloaddition reactions of azides 118 with terminal alkynes 117 following the MW procedure (75 W) in DMSO at 130°C in 4–90 min with 60–99% yields (Scheme 34). In contrast, the conventional method to get 113 requires 6–10 days.

short-legendScheme 34. Synthesis of 4,5-disubstituted-2H-1,2,3-triazoles under MW irradiation.

Yang et al. 68 have described a convenient and efficient one-pot synthesis of C-carbamoyl-1,2,3-triazoles 123 (14 examples) under MW irradiation with 72–93% yield (Scheme 35), whereas, conventional method requires long reaction time and needs purification of the intermediates.

short-legendScheme 35. Synthesis of C-carbamoyl-1,2,3-triazoles.

Meng et al. 69 have reported regioselective MW-assisted synthesis of N1-substituted 3-amino-1,2,4-triazoles 126 (10 examples) in 34–70% yields (Scheme 36).

short-legendScheme 36. Synthesis of N 1-substituted 3-amino-1,2,4-triazoles under MW irradiation.

Ball et al. 70 developed a rapid synthesis of unprecedented 1 3oxazolo[3,2-b]1 2 4triazoles 131 (eight examples) using MW irradiation by tandem alkylation/cyclization reaction of 3-bromo-1,2,4-triazoles 127 and α-haloketones 128, via intermediate enolate 130 at 100°C in 10–20 min in the presence of a base with 30–81% yields (Scheme 37).

short-legendScheme 37. Synthesis of novel [1,3]oxazolo[3,2-b][1,2,4]triazoles.

Synthesis of a triazole-linked 3′–5′ thymidine dimer 133 was reported by Lucas et al. 71 making use of 1,3-dipolar cycloaddition under MW irradiation in 1–3 min with 62–84% yield at 80°C (Scheme 38). MW-assisted route is faster than the conventional method, which requires heating at 80°C for 5 h to achieve the desired product.

short-legendScheme 38. Synthesis of a triazole-linked 3′–5′ thymidine dimmer by MW irradiation.

2.8. Pyridine

Pyridines have a wide range of applications in medicinal chemistry. Pyridine derivatives have been used as herbicides and for enrichment of cereals. Some bifunctional pyridines are used as nonlinear optical materials, electrical materials, chelating agents in metal–ligand chemistry, and as fluorescent liquid crystals 72. Despite the numerous synthetic methodologies available in the literature 72, novel methods for pyridines synthesis are still in demand.

Heating enaminones 134 with excess of ammonium acetate (as an ionic liquid), at 110°C for 20 min or irradiating under MW for 1 min at 105°C (400 W), yielded the pyridines 137 (five examples). This work was reported by Khadijah et al. 73 (Scheme 39). Yield obtained following the MW procedure is higher (65–77%) than the heating method (50–62%).

short-legendScheme 39. Synthesis of 2-aryl (or heteroaryl)-5-aroyl (or hetroaroyl)-pyridines.

A one-pot effective Kröhnke condensation reaction was carried out by Tu et al. 74 in an aqueous medium using MW irradiation (6–10 min) and ammonium acetate for the synthesis of substituted pyridines 139 (18 examples) at 130°C with 90–96% yield (Scheme 40). Heating in oil bath requires much more time (2.5–4 h) with 76–84% yield.

short-legendScheme 40. Synthesis of substituted pyridines by Kröhnke reaction using MW irradiation.

A facile solvent- and catalyst-free method for the synthesis of a series of new hydroxylated 2,4,6-trisubstituted pyridines 142 (15 examples) was obtained in high yield (83%) under MW irradiation (400 W) at 120°C for 30 min via a three-component condensation of 4-hydroxybenzaldehyde 140, acetophenone 141, and NH₄OAc (Scheme 41). This work was reported by Yin and his co-workers 75.

short-legendScheme 41. MW-assisted synthesis of 4-(2,6-diphenylpyridin-4-yl)phenol under solvent- and catalyst-free conditions.

But, treatment of hydroxyl-substituted aryl ketone (4-acetylphenol) 143 (five examples) with benzaldehyde 51 under the same conditions afforded bis-hydroxyl compound 144 in 82% yields (Scheme 42).

short-legendScheme 42. MW-assisted synthesis of bis-hydroxyl compound under solvent- and catalyst-free conditions.

Yan et al. 76 described a modified Kröhnke procedure of annulated pyridine derivatives 148 (10 examples) in one-pot reactions of N-phenacylpyridinium bromide 145 with aromatic aldehydes 147 and cyclic ketones 146 in the presence of ammonium acetate and acetic acid under MW irradiation in 2–4 min with 70–80% yield (Scheme 43). 148 compounds were produced in 84% yields by heating a mixture of five reaction components at 90°C for 3 h.

short-legendScheme 43. MW-assisted synthesis of annulated pyridines.

The chemoselective synthesis of thiazolo[3,2-a]pyridine derivatives 152 and 153 was achieved by Shi et al. 77 in water via MW-assisted three-component reactions of malononitrile 149, aromatic aldehydes 150, and 2-mercaptoacetic acid 151 with molar ratios of 2:1:1.5 and 2:2.2:1, respectively (Scheme 44). 130 was obtained at 90°C with 80–89% yield in 6–9 min and 131 was produced at 100°C with 82–89% yield in 6–7 min.

short-legendScheme 44. Synthesis of thiazolo[3,2-a]pyridine derivatives under MW irradiation.

A highly efficient, MW-assisted, regioselective one-pot three component synthesis of trisubstituted pyridines 158 (eight examples) and 7,7-dimethyl-2-aryl-5,6,7,8-tetrahydroquinoline-5-ones 156 (five examples) from enaminones 154 in the presence of potassium dodecatungstocobaltate trihydrate, K₅CoW₁₂O₄₀.3H₂O (as a reusable heterogeneous catalyst) within 3–6 min with an excellent yield (up to 98%) under solvent-free conditions was reported by Kantevari et al. 78 (Scheme 45).

short-legendScheme 45. Regioselective one-pot three component synthesis of trisubstituted pyridines and 7,7-dimethyl-2-aryl-5,6,7,8-tetrahydroquinoline-5-ones under solvent-free MW irradiation conditions.

2.9. Quinoline

Quinoline derivatives occur in various natural products, especially in alkaloids and are often used for the design of many synthetic compounds with diverse pharmacological properties 79. A number of methods of quinoline synthesis viz. Skraup, Doebner-von Miller, Friedlander, Pfitzinger, Conrad-Limpach, Combes have been known since the late 1800s 80.

Muscia et al. 81 synthesized a series of substituted quinolines 161 (10 examples) in good yields (50–89%) via the Friedländer reaction by the reaction of 2-aminoacetophenone 159 or benzophenones with a variety of ketones 160 and keto esters and a catalytic amount of hydrochloric acid within a time period of 1.5–12 min following the MW procedure (Scheme 46). Conventional synthesis requires prolong heating (6 h) at 100°C.

short-legendScheme 46. Synthesis of substituted quinolines via the Friedländer reaction catalyzed by hydrochloric acid.

Balamurugan et al. 82 also have reported regioselective 2,9-diaryl-2,3-dihydrothieno[3,2-b]quinolines 164 (18 examples) via the Friedländer reaction (Scheme 47). A mixture of 5-aryldihydro-3(2H)-thiophenone 163, 2-aminoaryl ketone 162, and trifluoroacetic acid was irradiated in an MW oven at 100°C (40 W) for 30 min. This reaction proceeded more rapidly and afforded better yields (60–98%) than the thermal reaction at 100°C (60–85% yields in 2–3 h).

short-legendScheme 47. Synthesis of substituted quinolines by Friedländer reaction catalyzed by trifluoroacetic acid.

Fluorine-containing spiro[piperidine-4,4′-pyrano[3,2-c]quinolines] 168 (14 examples) were synthesized by Dandia et al. 83 through a rapid one-pot multi-component reaction under MW irradiation (Scheme 48) with an excellent yield (80–96%) and short reaction time (3–10 min), whereas conventional heating needs 5–12 h to get 68–76% yield.

short-legendScheme 48. Synthesis of spiro[piperidine-4,4′-pyrano[3,2-c]quinolines].

Mali et al. 84 has recently developed a one-pot water-mediated synthetic route to produce quinoline derivatives 171 (eight examples) using both thermal and MW energy resources (Scheme 49). MW-assisted route offers high yields (87–93%), short reaction times (1.5–2.5 h) compared to conventional heating which affords 85–91% yield within 7–10 h.

short-legendScheme 49. Synthesis of quinoline derivatives by MW heating.

Tu et al. 85 synthesized N-substituted furo[3,4-b]quinoline derivatives 175 (28 examples) via a three-component reaction of an aldehyde 172, an enamineone 174, and tetronic acid 173 in glacial acetic acid without any catalyst (Scheme 50). Following the MW procedure at 100°C, the reaction time was strikingly shortened to 5–9 min from 3 to 5 h required under traditional heating conditions, and the yields were increased to 90–98% from 37% to 56%.

short-legendScheme 50. Synthesis of N-substituted furo[3,4-b]quinoline derivatives.

2,3-Dihydro-1H-pyrrolo[3,2-c]quinoline 179 (13 examples) core from substituted 2-iodoanilines 176 and 2,3-dihydro-1H-pyrrole 177 was achieved using 10 mol% Pd(PPh₃)₄ and K₂CO₃ in 1,4-dioxane at 170°C for 1 h in an MW oven in 60% yield (Scheme 51). But, the reaction of 176 and 177 in refluxing toluene for 24 h produces 179 in 44% 86.

short-legendScheme 51. Synthesis of 2,3-dihydro-1H-pyrrolo[3,2-c]quinoline by MW heating.

An efficient synthesis of 4-aminoaryl/alkyl-7-chloroquinolines 182 (14 examples) and 2-aminoaryl/alkylbenzothiazoles 184 (seven examples) has been developed by MW-accelerated regioselective aromatic nucleophilic substitution of 4,7-dichloroquinoline 180 (or 2-chlorobenzothiazole 183) with aliphatic and aromatic amines 181 under solvent-free conditions in the absence of added protic or Lewis acid catalyst with 70–95% yield in 10 min (Scheme 52 and 53). Conventional heating at 100°C affords with 20–40% conversion in 1 h 87.

short-legendScheme 52. Reaction of 4,7-dichloroquinoline with aromatic amines under micro-mode irradiation for the formation of 4-aminophenyl-7-chloroquinoline.

short-legendScheme 53. Reaction of 2-chlorobenzothiazole with various amines under MW heating to produce 2-aminophenylbenzothiazoles.

2.10. Pyrimidine

Pyrimidine derivatives serve both as biomimetic and reactive pharmacophores due to their diverse medicinal properties. The importance of partially hydrogenated pyrimidine derivatives in medicinal chemistry is widely known 88. Most popular method for pyrimidine synthesis is Biginelli reaction 89. In order to improve the yields obtained in the described classic conditions for the synthesis of pyrimidines, much effort has been made.

Various 2-unsubstituted 4-(substituted)anilinothieno[2,3-d]pyrimidines 190 (14 examples) were synthesized by Phoujdar et al. 90 through the chlorination of the corresponding 2-unsubstituted-thieno[2,3-d]-pyrimidin-4-ones 187, followed by the nucleophilic displacement of the 4-Cl group of 188, with a variety of anilines 189. Compared to conventional method in refluxing iso-propanol that completes in 5–9 h with 59–85% yield, the entire four-step MW-assisted reactions require 2 h in high yield (Scheme 54).

short-legendScheme 54. Synthesis of 2-unsubstituted 4-(substituted)anilinothieno[2,3-d]pyrimidines by MW irradiation.

Novel chromeno[2,3-b] pyrimidine derivatives 194 (11 examples) were obtained by Rai et al. 91. MW irradiation of intermediate 193 with different amines in acetic acid gave 194 within 5 min in reasonably good yields (64–75%; Scheme 55). All these compounds were screened for their antimicrobial activity.

short-legendScheme 55. Synthesis of chromeno[2,3-b] pyrimidine derivatives.

2,4,6-Triarylpyrimidines 197 were synthesized by Bagley et al. 92 by MW-assisted tandem oxidation/heterocyclocondensation using BaMnO₄ (Scheme 56) at 145°C in 45 min. In contrast, traditional method under conductive heating by cyclocondensation of 195 and 196 at reflux in EtOH in the presence of NaOH, moisture, and air for 10 h produces 197 in 0-40% yield.

short-legendScheme 56. MW-assisted synthesis of 2,4,6-triarylpyrimidines.

Shaaban 93 has synthesized 6-thienoyl-7-(trifluoromethyl)-1 2 4triazolo[4,3-a]pyrimidine 201 in 91% yields (and 6-thienoyl-7-(trifluoromethyl) benzimidazo[1,2-a]pyrimidine 202 in 83% yields) by MW irradiation of 4,4,4-trifluoro-1-(thien-2-yl)butane-1,3-dione 198, 3-amino-1,2,4-triazole 199 (or 2-amino-benzimidazole 200), and triethylorthoformate at 100°C for 5 min (Scheme 57). Most of the thermal syntheses of such compounds consume a lot of time and/or lack of high selectivity 93.

short-legendScheme 57. Synthesis of pyrazolo[1,5-a]pyrimidine derivatives by MW heating.

6-(2-Hydroxybenzoyl)-5-methyl-7-phenylpyrazolo[1,5-a]pyrimidines 205 (eight examples) have been synthesized directly by the solvent-free reaction between 5-amino-1H-pyrazoles 203 and 3-benzoyl-2-methyl-4H-chromen-4-one 204 using MW-assisted route in 2 min in 88–93% yield (Scheme 58). This work was reported by Quiroga et al. 94. Conventional heating at 180°C for 20 min gives the product in 70–76% yield.

short-legendScheme 58. Solvent-free synthesis of 6-(2-hydroxybenzoyl)-5-methyl-7-phenylpyrazolo[1,5-a]pyrimidines.

Aminopyrimidines 208 and 210 were made by reaction of 206 with guanidine 207 and thiourea 209, respectively (Scheme 59). Urea 30 and thiourea 209 were also used to obtain a wide variety of pyrazolyl-substituted pyrimidines 212 and 213 (Scheme 60). These reactions were reported by Hoz et al. 95. All reactions were performed under MW irradiation, and reaction times were in the range of 20–60 min. These conditions gave good yields of 208 and 210 (38–56%) and 212 and 213 (58–70%).

short-legendScheme 59. Synthesis of aminopyrimidines.

short-legendScheme 60. Synthesis of pyrazolyl-substituted pyrimidines.

Daniels et al. 96 synthesized a series of functionalized pyrazolo[3,4-d]pyrimidines 219 (seven examples) on MW irradiation (Scheme 61). The last reaction step that required >48 h at reflux and provided 40–65% yield under conventional method has been optimized to 20 min with 74–91% yields on MW heating.

short-legendScheme 61. MW-assisted synthesis of pyrazolo[3,4-d]pyrimidines.

Arya et al. 97 synthesized fluorinated spiro [indole-3,2′-pyrido[1,2-a]thiazolo[5,4-e]pyrimidines] 222 (four examples) and spiro [indole-3,2′-thiazolo[4,5-d]pyrimidines] 223 (four examples) under MWs in the presence of montmorillonite KSF (Mont. KSF). Micheal addition of 2-aminopyridine 221 and arylidenes derivatives 220 yielded 222 in the presence of Mont. KSF in 85–91% yield in 5–6 min. Reaction of arylidenes derivatives 220 with thiourea 209 afforded 223 in 85–90% yield in 3–5 min (Scheme 62).

short-legendScheme 62. MW-asisted synthesis of spiro [indole-3,2′-pyrido[1,2-a]thiazolo[5,4-e]pyrimidines] and spiro [indole-3,2′-thiazolo[4,5-d]pyrimidines].

2.11. Pyrimidinones

There is a continuous widespread interest in the synthesis of pyrimidinones because of the diverse biological properties associated with this system 98 99. Synthetic procedures are generally based on the modifications of the century-old Biginelli's reaction 89, involving an acid catalyzed three-component condensation of a 1,3-dicarbonyl compound, aldehyde, and urea.

Shingare et al. 100 synthesized various pyrimido[4,5-d]pyrimidine-2,4,7-triones 226, 227 (16 examples) by multicomponent reaction of aldehyde 225, urea 30/thiourea 209, barbituric acid 224, and alumina (Al₂O₃) on MW irradiation (600 W) within a time of 25–40 sec (Scheme 63). Traditional procedures typically involved longer reaction time and less yield 100.

short-legendScheme 63. MW-assisted synthesis of various pyrimido[4,5-d]pyrimidine-2,4,7-triones.

An efficient, simple MW-assisted synthesis of 3,4-dihydropyrimidinones 230 (14 examples) in excellent yields was obtained in the presence of water without additional solvent/acid catalyst in 2 min with 88–98% yield. This reaction has been reported by Singhal et al. 101 as shown in Scheme 64. The same reaction was also been executed under conventional heating which was found to be much slower (gets completed in 45–75 min).

short-legendScheme 64. Solvent-free synthesis of dihydropyrimidinones under both MW irradiation.

Mojtahedi et al. 102 reported the preparation of pyrimidinones 232 (four examples) and thiopyrimidinones 233 (three examples) in solvent-free and MW-assisted conditions (Scheme 65) with good yields (53–81%) in 2–6 min. Conventional method, in refluxing ethanol (containing metallic sodium), completes within 6–7 h with 4–78% yields.

short-legendScheme 65. MW-assisted synthesis of pyrimidinones under solvent-free conditions.

Khunt et al. 103 developed a solvent-free MW-assisted process for the preparation of tetrahydropyrimidinones 236 and tetrahydrothiopyrimidinones 237 employing equimolar amounts of neat 1,3-dicarbonyl compounds 234, different aromatic aldehydes 235 and urea 30 (or thiourea 209; Scheme 66). The reaction mixture was irradiated at 110–120°C with MW for 1.5–6.5 min with 78–85% yield (15 examples). In contrast, conventional thermal heating method involving THF (as solvent) and InCl₃ (as catalyst) furnishes the products in hours.

short-legendScheme 66. Synthesis of tetrahydropyrimidinones and tetrahydrothiopyrimidinones by MW heating.

Dihydropyrimidinones 240 and 241 (15 examples) were synthesized by aqueous Biginelli protocol using polystyrenesulfonic acid (PSSA) as a catalyst under MW irradiation 104 at 80°C for 20 min with an excellent yield of 86–92% (Scheme 67). This reaction proceeds without using any phase-transfer catalyst (PTC). Conventional heating condition (oil bath) requires 5–6 h for completion.

short-legendScheme 67. Biginelli reaction in an aqueous medium.

2.12. Quinazoline

Quinazoline and its derivatives are a class of heteroaromatic compounds that have drawn much attention because of their biological and pharmaceutical activities 105.

Rad-Moghadam et al. 106 synthesized various quinazolines 244 (five examples) under both MW irradiation and conventional heating conditions from a mixture of 2-aminobenzonitrile 242, orthoester 243, and ammonium acetate under solvent-free conditions (Scheme 68). MW method offers products in high yields (82–89%), in 5–7 min, whereas conventional method occurs in oil bath at 120°C, in 30–80 min with 83–92% yield.

short-legendScheme 68. Synthesis of quinazolines under solvent-free conditions.

2-(Aminoaryl)alkanone O-phenyl oximes 245 and carbonyl compounds 246 in toluene solution with emimPF₆ as ionic liquid were irradiated with MWs (Scheme 69) at 160°C for 30 min to afford dihydroquinazolines 247 (five examples) in high yields (72–94%). This reaction was reported by Portela-Cubillo and his coworkers 107. When 0.3 equivalents of ZnCl₂ is included in the mixture, quinazolines 248 (eight examples) are obtained instead. With the exception of the CuCl₂ catalyzed reaction of aldehydes with anthranilamide, methods of forming the quinazoline ring either require multi-step preparations of special reagents/reactants or give moderate yields 107.

short-legendScheme 69. Synthesis of dihydroquinazolines and quinazolines under MW irradiation.

An effective route to the formation of benzimidazo[2,1-b]quinazolin-12(5H)-ones 251 (11 examples) from o-aryl isothiocyanate esters 249 and o-phenylenediamines 250 has been reported by Carpenter et al. 108 in 91–98% overall yield via tandem DIC-mediated benzimidazole cyclization and MW-assisted benzimidazoquinazolinone cyclization with barium hydroxide (Scheme 70). Common approaches to 251require ~200°C and give low yields or sometimes together with byproduct.

short-legendScheme 70. MW-assisted synthesis of benzimidazo[2,1-b]quinazolin-12(5H)-ones.

2.13. Miscellaneous

Fused 1,3-oxazin-6-ones constitute an interesting class of pharmacologically active compounds because they have shown a multitude of biological activities 109. A MW-assisted solid-phase synthesis of heteroannulated 1,3-oxazin-6-ones 260 has been developed by Che et al. 109 (Scheme 71). Overall reaction time has been dramatically shortened when compared to the conventional procedures.

short-legendScheme 71. MW-assisted synthesis of oxazinone derivative.

Sondhi et al. 48 recently reported the new products 2-(2-aminophenyl)isoquinoline-1,3(2H,4H)-dione 263 (three examples) and 11H-benzimidazo [1,2b]isoquinoline-11-one 264 (three examples) from the reaction between 2-(carboxymethyl)benzoic acid 261 and diamines 71 (or 262) under MW irradiation that gets completed within 5–6 min in 99% yield (Scheme 72).

short-legendScheme 72. MW-promoted synthesis of tetracyclic heterocyclic molecules.

In the similar way, the same group 48 has investigated the condensation reaction of phthalic acid 265 and diamines 71 (or 262) under MW irradiation that gives another set of tetracyclic heterocyclic compound 266 (three examples), in good yields (95–98%) in 4–5 min (Scheme 73).

short-legendScheme 73. Synthesis of tetracyclic heterocycles by MW irradiation.

Pyrazolo[3,4-b]pyridin-6-ones have been shown to be inhibitors of cyclin-dependent protein kinase-2 (cdk-2), cyclin-dependent protein kinase-5 (cdk-5), and phosphatidylinositol 3-kinase (PI3-K) 110. Thus, these compounds have potential in the treatment of bipolar disorder, diabetes, dementia, Alzheimer's disease, schizophrenia, depression, and cancer 110. Rodrigues-Santos et al. 111 have reported the synthesis of pyrazolo[3,4-b]pyridin-6-ones 270 (12 examples) both by the conventional method and by MW irradiation (Scheme 74). 270 were obtained in moderate to good yields (50–85%) using the conventional methanol reflux method in 4–24 h. Using this MW method, 270 were produced in moderate yield (50–65%), which is low compared to the conventional methodology, but is 12–96 times faster than conventional method.

short-legendScheme 74. Synthesis of pyrazolo[3,4-b]pyridin-6-ones under MW irradiation.

Regio- and chemoselective synthesis of 1,4,6,7,8,9-hexahydro-1H-pyrazolo[3,4-b]quinolin-5-ones 274 (eight examples) and 5a-hydroxy-4,5,5a,6,7,8-hexahydropyrazolo[4,3-c]quinolizin-9-ones 275 (nine examples) starting from 5-amino-3-phenylpyrazole 271, cyclic 1,3-dicarbonyl compounds 273, and aromatic aldehydes 272 under MW irradiation is described by the Chebanov et al. 112. Whereas in most cases, the three-component coupling in ethanol under reflux conditions provides mixtures of both possible regioisomers pyrazoloquinolinones and pyrazoloquinazolinones in varying ratios (Scheme 75). 274 were produced in 15 min at 150°C with 70–91% yield using MW-assisted route and 275 were obtained in the presence of t-BuOK instead of Et₃N in 15 min with 38-75% yield.

short-legendScheme 75. MW-assisted synthesis of 4-aryl-3-phenyl-1,4,6,7,8,9-hexahydro-1H-pyrazolo[3,4-b]quinolin-5-ones and 4-aryl-5a-hydroxy-3-phenyl-4,5,5a,6,7,8-hexahydropyrazolo[4,3-c]quinolizin-9-ones.

Pyrazoloquinazolinones 279 (eight examples) were also produced (with 54–70% yield) by the same group [112] when the three-component condensation was executed in the presence of trimethylsilylchloride (Me₃SiCl) as reaction mediator at higher temperature (170 ° C) for 30 min (Scheme 76). Reaction involving the condensation of these three reactants in refluxing ethanol at ~80°C is rather unpredictable 112.

short-legendScheme 76. Synthesis of pyrazoloquinazolinone using MW irradiation.

A new heterocycle tetracyclic pyrimido[4,5-c]carbazole 282 was prepared by Debray et al. 113 in three steps from 3-aminocarbazole 280 (Scheme 77). A mixture of 281 and montmorillonite K-10 (K-10) clay was irradiated in an MW oven at 80°C for 1 h to furnish 282 in 77% yield. In classical methods, the Friedel–Craft type cyclization of 281 catalyzed by Me₃SiCl in dimethylformamide (DMF) works well; however, the efficiency of the work-up is very sensitive to the nature of the R group, and sometimes produce lower yields.

short-legendScheme 77. MW-assisted synthesis of tetracyclic pyrimido[4,5-c] carbazole.

Nucleosides play important roles in various biological processes. Kinase inhibitors, C6-cycloamine-substituted purines and their analogs 285 (42 examples) were synthesized by Qu et al. 114 via a mild aqueous MW protocol that afforded the desired compounds at 100°C in 8 min in higher purity and yield (73–94%), making this methodology suitable for rapid drug discovery (Scheme 78). Traditional routes often involve long reaction time (15% yield after 24 h), toxic-solvent, and labor-intensive operation 114.

short-legendScheme 78. Synthesis of C6-cycloamine-substituted purines and their analogs using MW irradiation in aqueous medium.

Pyrazole nucleus in fusion with benzopyrans confers pharmacological properties 115. Benzopyrano[4,3-c]pyrazoles 289 (seven examples) were synthesized by heterocondensation reaction between in situ-generated 3-arylidene-2,4-chromanediones 287 and N-substituted hydrazine 288 moieties under MW irradiation conditions in 2–4.5 min (Scheme 79). This high yielding (75–85%) protocol was reported by Kidwai et al. 115. Under conventional method, second stage requires 5–8 h to obtain 45–78% yield.

short-legendScheme 79. Synthesis of benzopyrano[4,3-c]pyrazoles under MW irradiation in aqueous medium.

Spiro-amino acids incorporated into bioactive peptides are useful for both restricting the flexibility of the peptide and providing information on the topographical requirements of peptide receptors. An efficient method for the synthesis of spiro-2,5-diketopiperazines (spiro-DKPs) 293 (four examples) was developed by Jam and his co-workers 116 by cyclization of Boc-protected dipeptides 292 containing spiro-amino acids using MW heating in water in the presence of O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) at 160°C in 10 min with 80–86% (Scheme 80). Older methods used for peptide bond formation are inefficient with sterically congested amino acid residues like spiro-amino acids, offer low yield and need excess of reagents to complete the reaction 116.

short-legendScheme 80. Synthesis of spiro-2,5-diketopiperazines by MW protocol.

Das and his co-workers 117 reported a simple and general solventless reaction for the synthesis of 9-substituted acridines 297 (11 examples), by a modification of classical Bernthsen reaction (Scheme 81), using p-TSA as the catalyst using MW irradiation method. This paves the way for an environmentally benign condition without compromising viability and speed. The reaction time has been dramatically reduced to 4 min with 80% yield at 450 W than the conventional method (75% yields in 20 h).

short-legendScheme 81. Synthesis of a 9-substituted acridines using the catalyst under MW radiation.

Tu et al. 74 have developed a first facile and clean Kröhnke reaction for the synthesis of 4′-aryl-2,2′:6′,2″-terpyridines 299 (11 examples) in water under both MW irradiation or conventional heating conditions at 130°C (Scheme 82). The use of MW irradiation at 200 W significantly reduces the reaction time to 16 min from 240 min required under conventional synthesis and improves the reaction yields 82–93% from 71% to 81%.

short-legendScheme 82. Synthesis of 4′-aryl-2,2′:6′,2″-terpyridines in aqueous media.

Triazines and tetrazoles are important class of nitrogen heterocycles that form an integral part of therapeutically interesting compounds which display diverse biological activities. Shie et al. 118 reported a method for the direct conversion of aldehydes to triazines 304 (five examples, 69–83% yields) and tetrazoles 302 (five examples, 70–83% yields) with high optical purity via cycloadditions of intermediate nitriles with dicyandiamide and sodium azide under MW irradiation (Scheme 83). Formation of triazines and tetrazoles requires refluxing (e.g., ~100°C) for a prolonged period (12–48 h) in traditional methods.

short-legendScheme 83. Synthesis of triazines and tetrazoles using MW heating.

The benzoxazole moiety is an important pharmacophore due to the biological activity (melatonin receptor agonist and cyclooxygenase inhibitory, anticancer antimycobacterial, elastase inhibitory, etc.) displayed by 2-substituted benzoxazoles 119. Chakraborti et al. 119 120 described an efficient new methodology for the synthesis of 2-substituted benzoxazoles 308 (16 examples)/benzothiazoles 309 (18 examples) from carboxylic acids 307 by direct condensation with 2-aminothiophenol 306/2-aminophenol 305 following the MW procedure in absence of any metal catalyst and under solvent-free conditions (Scheme 84). Reaction of 2-aminophenol 305 with various carboxylic acids 307 under MW irradiation in a domestic MW oven using micro-mode operation and full power for 20 min provided good yields (up to 90%). In contrast, the conventional methodologies suffer from harsh reaction condition (refluxing at higher temperature ~200°C for days/hours).

short-legendScheme 84. Synthesis of benzothiazole/benzoxazoles under MW irradiation.

Investigation 119 by this group reveals that in the case of dicarboxylic acids 310, the reaction proceeds via the formation of the corresponding anhydride and affords predominant formation of the mono-benzoxazole 311 (Scheme 85).

short-legendScheme 85. MW-coupling direct condensation of 2-aminophenol with dicarboxylic acids for the formation of mono-benzoxazole.

4. Conclusion

The development of more environment-friendly methodologies is certainly a very current topic. Synthetic organic reactions performed under MW irradiation are gaining popularity, because this technique offers simple, clean, fast, efficient and economic for the synthesis of a large number of organic compounds including N-containing heterocycles. This technique enables a number of reactions to be completed under mild reaction condition, in shorter reaction times, and with higher yields that either do not occur under conventional heating or occur at much higher temperatures. We herein describe the current developments in the synthesis of N-containing heterocyclic compounds using MW heating. We believe that in the coming future many more MW-assisted reactions could be done on industrial scales thereby increasing the overall efficiency of the processes. The future for the application of MW technology looks bright because of its efficiency and its potential to contribute to clean products.

Acknowledgements

We thank DST, New Delhi, India (Ref: SR/WOS-A/CS-29/2010) for financial support. Prof. Gautam Mandal, Department of Physics, TIFR, India, is also gratefully acknowledged for his assistance.