Abstract
This chapter explores the synthesis strategies and methodologies for the preparation of fused pyrrolothiazole, pyrazolothiazole, and imidazothiazole compounds. Fused heterocyclic structures containing thiazole motifs have gathered momentous attention due to their diverse pharmacological properties and potential therapeutic applications. The synthesis of these fused heterocycles involves intricate organic transformations and multistep reactions, often requiring careful control of reaction conditions and substrate selection. Researchers have developed innovative synthetic routes, including cyclization reactions, annulation processes, and multicomponent reactions, to access these complex frameworks efficiently. Furthermore, computational studies and mechanistic investigations have provided valuable insights into the reaction mechanisms and guiding principles for the rational design of novel synthetic routes. The synthesized pyrollothiazole, pyrazolothiazole, and imidazothiazole derivatives exhibit promising biological activities, viz. anticancer, antimicrobial, antiviral, anti-inflammatory, etc. This chapter gives an ample overview of the synthetic methodologies of these fused thiazole-containing heterocycles, highlighting their potential as valuable scaffolds for drug discovery and development.
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Keywords
7.1 Introduction
Heterocyclic compounds play significant part in the cellular metabolism of whole living organisms, with a majority of fused heterocyclic compounds comprising five-membered rings exhibiting significant biological activity. Thiazole-fused heterocycles hold paramount importance in drug discovery due to their varied pharmacological profile and structural versatility. These compounds, which incorporate the thiazole ring as a core moiety, demonstrated a far-reaching range of medicinal activities, viz. antimicrobial, anticancer, anti-inflammatory, and antiviral effects [1, 2]. Thiazole-fused heterocycles also play a fundamental role in the development of pharmaceutical agents, serving as key structural motifs in many drugs [2,3,4]. Moreover, their unique structural features enable scientists to design and synthesize novel compounds with improved pharmacokinetic and pharmacodynamic profiles [5, 6]. By exploring the synthetic pathways and pharmacological activities of thiazole-fused heterocycles, researchers aim to discover new therapeutic agents to combat various diseases and address unmet medical needs [7]. Therefore, the study and development of thiazole-fused heterocycles represent a significant area of research in modern pharmaceutical sciences, offering promising avenues for the advancement of medicine and healthcare.
In this lieu, several moieties were fused with thiazole scaffold such as pyrrolothiazole, imidazothiazole, benzothiazole, pyrazolothiazole, and pyridazinothiazole, etc. (Fig. 7.1). These compounds exhibit diverse pharmacological activities and are utilized in medicinal chemistry for drug development. Thiazole-fused rings are found in various natural and synthetic compounds, serving as key structural motifs in drug molecules.
Several thiazole-fused molecules
This chapter discusses different synthetic aspects that have been employed for pyrrolo[2, 1-b]thiazole, imidazo[2, 1-b]thiazole, and pyrazolo[3, 4-d]thiazole molecules.
7.2 Synthesis of Pyrrolothiazole
The compounds bearing pyrrolothiazole were found to exhibit excellent pharmacological activities such as anticonvulsant [8], hepatoprotective [9], antitumor [10], anti-inflammatory, antipsychotic, antidiabetic [11], and so on [12]. So, there is an urgent need for advancement of effective synthetic protocols for the synthesis of this molecule. These compounds are commonly synthesized by either creating the bicyclic structure from existing pyrrole or thiazole rings using alkylation and dipolar cycloaddition reactions or by synthesizing them from acyclic precursors.
Numerous pyrrolo[2, 1-b]thiazoles (3) have been developed using a reaction of different kinds of alkenes (2) with a heterocyclizing reagent using CuI as a catalyst with bathophen as a ligand and Na2CO3 as a base in DCM solvent at 100 ℃. The reaction involved radical-mediated heteroaryl migration, initiated by single electron transfer (SET) between Cu(I) and the C–Br bond of compound 1, forming an intermediate and driving the conversion forward. Following the addition of reactant 1 to the alkene, a series of steps including ipso-heteroaryl shift and SO2 removal occur, resulting in the formation of a radical species. This radical may subsequently abstract a chlorine (Cl) or bromine (Br) atom, further influencing the reaction pathway [13] (Scheme 7.1).
Synthesis of diverse pyrrolo[2, 1-b]thiazoles using CuI as a catalyst
A novel two-step pathway has been introduced for the synthesis of benzo[d]chromeno[3′,4′:3,4]pyrrolo[2, 1-b]thiazoles (6) using triethylamine-assisted 1,3-dipolar cycloaddition reaction of 3-nitrochromenes (5) with 2-phenacyl- or 2-alkoxycarbonylmethylbenzothiazolium bromides (4) in ethanol (EtOH) medium at room temperature (RT) followed by sequential oxidation with DDQ at reflux. The reaction was advanced through endo-[3 + 2] cycloaddition of the cyclic dipolarophiles to the in situ generated anti-form ylides [14] (Scheme 7.2).
Synthesis of benzo[d]chromeno[3′,4′:3,4]pyrrolo[2, 1-b]thiazoles
A new approach has been explored for the synthesis of pyrrolo[2, 1-b][1, 3]benzothiazoles (8, 9 and 10) through the nucleophile-caused ring contraction of 1,4-benzothiazine. The reaction involved the mixing of several nucleophiles such as arylamine, benzylamines, and alkanols, with 3-aroylpyrrolo[2, 1-c][1, 4]benzothiazine-1,2,4-triones (7) and the reaction progressed through cleavage of C-S bond of 7 in the influence of nucleophile to obtain 1-(2-thiophenyl)pyrrole analogs that underwent intramolecular cyclization to furnish the final molecule [15] (Scheme 7.3).
Synthesis of pyrrolo[2, 1-b][1, 3]benzothiazoles through the nucleophile-caused ring contraction
The synthesis of benzo[d]pyrrolo[2, 1-b]thiazoles (13) involved a (3 + 2) annulation process in which benzothiazoles (12) were reacted with donor − acceptor cyclopropanes substituted with aroyl (11), facilitated by catalytic amount of Sc(OTf)3 in 1,2-dichloroethene (1,2-DCE) at reflux condition. The annulation process resulted in the generation of dearomatized (3 + 2) adducts. Following this, there was an unforeseen occurrence of dehydrogenative and decarbethoxylative rearomatization, leading to the formation of complete aromatized products. This distinct reactivity is ascribed to the existence of an additional aroyl group within the donor − acceptor cyclopropanes [16] (Scheme 7.4).
Synthesis of benzo[d]pyrrolo[2, 1-b]thiazoles via (3 + 2) annulation
A two-stage procedure was used to create the pyrrolo[2, 1-b][1, 3]benzothiazoles (18). The first step produced a 92% product yield by employing microwave (MW) irradiation for 10 min at 40 ℃ to synthesize 2-cyano-methyl-1,3-benzothiazole (16). The compound 16 was then subjected to MW irradiation with several aldehydes at 60 ℃ in the second phase. This process produced the target compounds (18) with higher yields than traditional heating techniques. The two steps of the synthesis were a base-catalyzed Knoevenagel condensation among aldehydes and 2-cyanomethyl-1,3-benzothiazole, which produced 2-arylidenecyanomethyl 1,3-benzothiazoles (17) as first step and [4 + 1] cycloaddition of 17 to benzoyl cyanide as the second step [17] (Scheme 7.5).
Synthesis of the pyrrolo[2, 1-b][1, 3]benzothiazole derivatives via [4 + 1] cycloaddition
A different technique produced 5,6,7,8a-tetrahydropyrrolo[2, 1-b]thiazoles (22) by decarboxylating proline (19) and its analogues to form azomethine ylide in the presence of K2CO3 and phenyl glyoxal (20). This was followed by an oxidative [3 + 2] cycloaddition reaction with dialkyl trithiocarbonate (21). CuI catalyst acted as the catalyst for this reaction, which had high regiospecificity. This was probably because Cu(I) catalyst was involved in a delayed, symmetry-controlled transition state. Additionally, the reaction demonstrated exceptional tolerance to several proline substitutions, including pipecolinic acid, thiazolidine-4-carboxylic acid, and 4-hydroxyproline, yielding outstanding product yields [18] (Scheme 7.6).
Synthesis of 5,6,7,8a-tetrahydropyrrolo[2, 1-b]thiazoles via azomethine ylide intermediate
In a two-step, one-pot approach supported by DMAP, 2,3-dihydropyrrolo[2, 1-b]thiazoles were synthesized using ethyl 2-(thiazolidin-2-ylidene)acetate (25) as a substrate. This substrate was mixed with several cyclic 1,3-dicarbonyl molecules (24), and phenyl glyoxal (23) to produce pyrrolo[2, 1-b]thiazole derivatives, in moderate to excellent yield. Interestingly, pyrrolo[2, 1-b]thiazole (26) showed a conjugated benzene diene molecule in its enol form. Moreover, an attempt has been made to create a polyheteroaromatic core using photochemical cyclization. This endeavor led to the formation of the anticipated polyheterocycle (28), achieving a 44% yield when exposed to ultraviolet (UV) irradiation at 365 nm [19] (Scheme 7.7).
Synthesis of 2,3-dihydropyrrolo[2, 1-b]thiazoles using ethyl 2-(thiazolidin-2-ylidene)acetate
The synthesis of pyrrolothiazoles entailed the interaction between amphiphilic dithioloimines (29) and arynes or alkynes (30) featuring electron-withdrawing groups. Under standard conditions, the reaction employed Cs2CO3 in acetonitrile at RT, resulting in favorable yields of the targeted pyrrolothiazoles (31) [20] (Scheme 7.8). In different method, synthesis of pyrrolo[2, 1-b]thiazole-5,6-dicarboxylate (33) was achieved through the reaction of triazoloepothilone (32) with dimethyl acetylenedicarboxylate (DMAD) in DCM at RT with 87% yield [21] (Scheme 7.9).
Synthesis of pyrrolothiazoles using dithioloimines
Synthesis of pyrrolo[2, 1-b]thiazole-5,6-dicarboxylate
By using an innovative synthesis approach, pyrrolo[2, 1-b]thiazoles attached with a protected carbohydrate moiety have been obtained in which MW irradiation helped with the N-alkylation step. A two-step method has been developed to synthesize pyrrolo[2, 1-b]thiazoles substituted with a protected carbohydrate moiety using substituted thiazoles as a starting material. To generate target compounds (36), DIPEA was added after MW irradiation in THF initially mediated the N-alkylation phase [22] (Scheme 7.10).
Synthesis of pyrrolo[2, 1-b]thiazoles substituted with a protected carbohydrate moiety
7.3 Synthesis of Pyrazolothiazoles
Pyrazolothiazoles comprise molecules with a fused structure of pyrazole and thiazole rings. Currently, three systems within this category have been explored in scientific literature, depicted as pyrazolo[4, 3-d]thiazoles, pyrazolo[3, 4-d]thiazoles and pyrazolo[5, 1-b]thiazoles (Fig. 7.2). Research indicates that pyrazolothiazoles possess varied biological functionalities, including their role as an antagonist of the corticotropin-releasing factor 1 [CRF(1)] receptor [23], anti-tubercular activities [24], antimicrobial [25] and protein kinase modulators for cancer [26], and other medical conditions.
Different kinds of pyrazolothiazoles
Generally, two methods have been employed for synthesizing these types of molecules. One approach involves annulating the pyrazole ring around an existing thiazole molecule, while the other entails annulating the thiazole ring around an existing pyrazole ring. It's noteworthy that the formation of the pyrazole ring around the thiazole ring is more commonly utilized in synthesis [27]. This section describes various procedures that have been developed for the synthesis of pyrazolothiazole moiety in recent times.
7.3.1 Synthesis of Pyrazolo[3,4-d]thiazoles
The reaction of hydrazines with 1,3-difunctional electrophilic precursors is recognized to be the primary method for producing functionalized and fused pyrazoles. By using this approach, pyrazolo[3, 4-d]-thiazoles (38) were created by condensation of 5-acyl-4-bromo-2-(methylsulfanyl)thiazole (37) with arylhydrazine or hydrazine to form the pyrazole ring, which was then followed by an intramolecular cyclization catalyzed by copper [28].Then the synthesized compounds were functionalized by reacting with several monosubstituted aromatic boronic acids via Liebeskind–Srogl cross-coupling reaction, using palladium complex as a catalyst under MW irradiation [29] (Scheme 7.11).
Synthesis of pyrazolo[3, 4-d]-thiazoles and their post-functionalization
A 5-aminothiazolo[3, 2-a]pyridine derivative (40) was effectively converted into pyrazolo[3,4:4,5]thiazolo[3, 2-a]pyridine (41a, b) by reacting with hydrazine or arylhydrazine in EtOH solvent at reflux condition via intramolecular cyclocondensation followed by the oxidation of cycloadduct [30] (Scheme 7.12). In other study, the pyrazole ring was annulated on thiazolo[3, 2-a]pyrimidine ring structure through reacting phenyl hydrazine with arylidine compounds 43a-e in EtOH solution under reflux condition using piperidine as a catalyst [31] (Scheme 7.13).
Synthesis and plausible mechanism of synthesis of pyrazolo[3,4:4,5]thiazolo[3, 2-a]pyridine
Synthesis of pyrazolo[3, 4-d]-thiazoles via pyrazole ring annulation
In another approach, two pyrazolo[3, 4-d]-thiazoles (46a and b) were synthesized by reacting chalcone 45 with phenyl hydrazine (PhNHNH2) and hydrazine hydrate (NH2NH2) using EtOH as a solvent and hydrochloric acid as a catalyst [32] (Scheme 7.14). In a study, first thiazole ring derivatives (52) were synthesized by reacting various aldehydes with 4-(1H-benzo[d]imidazol-2-yl)thiazol-2-amine (51) using EtOH as a solvent and glacial acetic acid (AcOH) as a catalyst afforded compound (52) which again reacted with thioglycolic acid and several aldehydes in the presence of zinc chloride in 1,4-dioxane solvent under reflux. Then, the pyrazole ring was annulated on thiazole ring by the condensation of 53 with hydrazine hydrate using glacial AcOH and anhydrous sodium acetate at reflux. In this reaction, 51 was synthesized by condensation of 47 and 48 followed by oxidation of synthesized compound 49 into compound 50 that further reacted with thiourea and yielded 51 [33] (Scheme 7.15).
Synthesis of chalcone-substituted pyrazolo[3, 4-d]-thiazoles
Schematic synthesis of pyrazolo[3, 4-d]-thiazoles using 4-(1H-benzo[d]imidazol-2-yl)thiazol-2-amine
The pyrazolo[3, 4,d]thiazoles (59) were synthesized using the condensation of thiazol-2-yl possessing 2-imino-thiazolidin-4-ones (57) with various aldehydes in EtOH and sodium acetate that further cyclized with NH2NH2 in AcOH [34] (Scheme 7.16). The pyrazolo[3, 4,d]thiazoles (61a-c) were synthesized through the reaction of 4-((5-((dimethylamino)methylene)-4-oxo-4,5-dihydrothiazol-2-yl)amino) benzene sulfonamide (60) with either PhNHNH2, hydrazinecarbothioamide or NH2NH2 in EtOH medium in the presence of Et3N under reflux condition followed by cyclization and aromatization [35] (Scheme 7.17).
Synthesis of pyrazolo[3, 4,d]thiazoles by condensation of thiazol-2-yl-substituted 2-imino-thiazolidin-4-ones
Synthesis of pyrazolo[3, 4,d]thiazoles by condensation of 4-((5-((dimethylamino)methylene)-4-oxo-4,5-dihydrothiazol-2-yl)amino) benzene sulfonamide
Hantzsch reaction was used for the synthesis of pyrazolo[3, 4-d]thiazole-5-thione analogs (63) through annulation of thiazole ring by reaction of 3-methyl-1-tosyl-1H-pyrazol-5(4H)-one (62) and methyl/phenylisothiocyanate with elemental sulfur in the solvent system of dimethylformamide (DMF)/EtOH using influence of Et3N as a catalyst at reflux conditions [36] (Scheme 7.18).
Synthesis of pyrazolo[3, 4-d]thiazole-5-thione derivatives
The annulation of thiazole moiety for the synthesis of 3-(pyridin-3-yl)-1-p-tolyl-1H-pyrazolo [3, 4-d]thiazol-5-amine (65) was achieved through reacting KSCN with 3-(pyridin-3-yl)-1-p-tolyl-1H- pyrazol-5-amine (64) in the influence of glacial AcOH and bromine. Then, 3-(pyridin-3-yl)-1-p-tolyl-1H-pyrazolo[3, 4-d]thiazol-5-amine (65) was employed as versatile precursor for the synthesis of novel fused heterocyclic moieties containing imidazoles or pyrimidines (66–73) [37] (Scheme 7.19).
Synthesis of 3-(pyridin-3-yl)-1-p-tolyl-1H-pyrazolo [3, 4-d]thiazol-5-amine and their post-functionalization
7.3.2 Synthesis of Pyrazolo[4,3-d]thiazoles
Pyrazolo[4, 3-d]thiazole derivatives (75) were synthesized by the condensation of hydrazone derivative (74) with different halo compounds such as chloroacetone, chloroacetamide, or chloroacetonitrile using EtOH as a solvent and triethylamine as a catalyst under reflux condition followed by cyclization and tautomerism to form pyrazole ring [38] (Scheme 7.20).
Synthesis of pyrazolo[4, 3-d]thiazole derivatives
7.3.3 Synthesis of Pyrazolo[5,1-d]thiazoles
Fused pyrazolo[5, 1-b]thiazole aldehyde (80) were synthesized by multiple step reactions that include synthesis of 3-methylpyrazolone (77) from the condensation of ethyl acetoacetate with hydrazine hydrate in EtOH that again reacted at 110 ℃ with ethyl bromoacetate and obtained pyrazolone-acetate (78). Further, pyrazolone-acetate underwent formylation via Vilsmeier–Haack reaction using DMF and phosphorus oxychloride and afforded pyrazolone-acetate-substituted aldehyde (79). At last, prepared aldehyde was reacted with potassium hydroxide and CS2 in DMSO solvent in the presence of iodomethane furnished the fused pyrazolo[5, 1-b]thiazole aldehyde (80) [39] (Scheme 7.21).
Synthesis of fused pyrazolo[5, 1-b]thiazole aldehyde
7.3.4 Synthesis of Imidazothiazole
The imidazothiazole core demonstrates versatile therapeutic applications, including antihelminthic [40, 41], antitumor [42,43,44,45], anti-inflammatory [46], cardiotonic [47], antiviral [48], antiparasitic [49], anti-hypertensive [50], fungicidal [51,52,53], antibacterial [54,55,56], and antioxidant properties [57]. Notably, Levamisole, a crucial imidazothiazole derivative, is extensively utilized in cancer therapy (Fig. 7.3). Additionally, imidazothiazoles serve as potent IDO1 inhibitors, aiding in cancer treatment [57]. Furthermore, derivatives of imidazothiazoles (imidazo[2, 1-b]thiazole and imodazo[1, 2-c]thiazole (Fig. 7.3) exhibit potential as HIV-1 RT inhibitors, emphasizing their significance in medicinal chemistry [59]. These diverse pharmacological roles underscore the usefulness of imidazothiazole moieties in drug discovery. Consequently, the synthesis of these moiety holds predominant importance in organic chemistry. This section presents several approaches that have been incorporated for the development of imidazothiazole analogs.
Different kinds of imidazothiazole and biologically active compounds
An effective approach has been explored for the synthesis of imidazo[2, 1-b][1, 3]thiazole compounds (84 and 85) by condensation of (2Z)-1,3-diaryl-4-bromobut-2-en-1-one analogs (81) with 2-aminothiazoles (82) in the presence of base. The reaction underwent through Michael addition via cyclization using base as a catalyst [60] (Scheme 7.22).
Synthesis of imidazo[2, 1-b] [1, 3] thiazoles
In a different work, aldehyde with various methyl ketone was subjected to Claisen–Schmidt condensation to create derivatives of imidazothiazoles replaced with chalcone. Through cyclocondensation of 2-aminothiazole (82) and an α-halogenated carbonyl molecule (86) in the presence of EtOH, imidazo[2, 1-b]thiazole (87) was produced. Imidazo[2, 1-b]thiazole carbaldehyde (88) was produced using the Vilsmeier–Haack reaction with the resultant product 87 in phosphoryl chloride (POCl3) and DMF. Further, the chalcone derivatives (89) were synthesized by the reaction of aromatic aldehyde 88 and different methyl ketones in the presence of KOH and EtOH [61] (Scheme 7.23).
Synthesis of imidazo[2, 1-b]thiazole by cyclocondensation between 2-aminothiazole and an α-halogenated carbonyl compound
In order to synthesize imidazothiazole derivatives, α-bromo-3(4)-methoxyacetophenone (90) was cyclized with 2-amino-thiazole (82) in EtOH at reflux to produce intermediates (91). These intermediates were then reacted with 4-iodo-2-(methylthio)pyrimidine in the influence of caesium carbonate, triphenylphosphine as a ligand, and palladium (II) acetate as a catalyst to form compounds. Oxone was used to produce the methylsulfide's subsequent oxidation to sulfone. The next step was to use boron tribromide to remove the methoxy group from molecules, which produced the equivalent hydroxyl counterparts. The required target derivatives (92) were obtained in the last stage by adding alkyl halide or sulfamoyl chloride using potassium carbonate or sodium hydride, respectively [62] (Scheme 7.24).
Synthesis of imidazo[2, 1-b]thiazole by cyclization of α-bromo-3(4)-methoxyacetophenone with 2-amino-thiazole
3-Methyl-imidazo[2, 1-b]thiazole-based analogs (97) were prepared in two steps, initially precursor 2-amino-4-methylthiazole-5-carboxylate (95) was synthesized by the reaction of thiourea (93) with 2-chloroacetoacetate (94) in EtOH medium at reflux, then it was reacted with different 2-bromo-1-(4-substituted phenyl)ethanone analogs (96) at 60 ℃ in acetone solvent and yielded the target compounds (97) [63] (Scheme 7.25).
Synthesis of 3-methyl-imidazo[2, 1-b]thiazole-based analogs
When 2-mercaptoimidazole (98) underwent reaction with aliphatic alpha-halogenoketones in EtOH or butanol in the absence of alkali, it led to a cyclization reaction, resulting in the production of imidazo[2, 1-b]thiazoles (100) [64] (Scheme 7.26).
Synthesis of imidazo[2, 1-b]thiazoles using 2-mercaptoimidazole
For the synthesis of triazole-substituted imidazothiazole analogs (106), a multi-step reaction strategy was employed. The process initiated with the treatment of 4-(4-bromophenyl)thiazol-2-amine (101) using ethyl bromoacetate and DMF-dimethylacetamide (DMA), leading to the formation of intermediate 102. Subsequently, intermediate 102 underwent an intramolecular cyclization, followed by reduction, resulting in the formation of compound 103. This compound, in turn, reacted with DPPA to yield azide 105. Expanding the scope, alkynes were carefully selected, and target compounds (106) were synthesized through the utilization of click chemistry reactions under classical conditions. The comprehensive approach provides insights into the systematic and controlled synthesis of these specialized imidazothiazoles [58] (Scheme 7.27).
Synthesis of triazole-substituted imidazothiazoles
When 3′-nitroacetophenone (107) reacts with N-bromosuccinamide in DMF, α-bromination takes place, yielding compound 107. Subsequently, compound 108 underwent reflux with 2-aminothiazole (82) in MeOH, resulting in the formation of compound 109. This synthetic pathway outlines the stepwise conversion of 3′-nitroacetophenone into the targeted compound 109 through controlled chemical reactions [65] (Scheme 7.28).
Synthesis of imidazothiazole derivatives using 3′-nitroacetophenone
2-Acetyl-(3-methyl-6-(substituted)-imidazo[2, 1-b]thiazoles (113 and 114) were synthesized by the cyclization of phenacylbromide derivative (111) with 5-acetyl-2-amino-4-methylthiazole (110), which further underwent condensation with thiosemicarbazide and thiocarbohydrazide in refluxing EtOH/HCl, respectively [66] (Scheme 7.29).
Synthesis of 2-acetyl-(3-methyl-6-(substituted)-imidazo[2, 1-b]thiazole
In a different approach, imidazo[2, 1-b]thiazoles (116) were synthesized through reacting 2-aminothiazole (82) with 2-bromoacetophenone (115) in acetone under reflux followed by addition of HCl [67] (Scheme 7.30).
Synthesis of imidazo[2, 1-b]thiazoles
In another study, 2-aminothiazole (82) reacted with ethyl 4-bromoacetoacetate (117) in the influence of sodium bicarbonate as a catalyst and mixture of 1,4-dioxane and EtOH as solvent system afforded the ethyl imidazo[2, 1-b] thiazole-6-yl acetate (118) in significant yield [68] (Scheme 7.31).
Synthesis of ethyl imidazo[2, 1-b] thiazole-6-yl acetate
A series of benzoxazole-substituted imidazo[2, 1-b][1, 3]thiazole-2-carboxamide derivatives (121a-c) were synthesized by the condensation of 1,3-thiazole-5-carboxamides 119a-c with benzoxazole 120 in n-butanol at reflux condition followed by cyclization [69] (Scheme 7.32).
Synthesis of benzoxazole-substituted imidazo[2, 1-b][1, 3]thiazole-2-carboxamides
Imidazothiazole derivatives were synthesized in two-step reaction in which initially thiourea (93) was condensed with ethyl bromopyruvate (122) in EtOH under reflux which afforded ethyl-2-aminothiazole-4-carboxylate (123) as an intermediate, which further reacted with several phenacyl bromides (124a-e) in EtOH medium and underwent cyclization reaction to obtain the desired compounds (125a-e) [70] (Scheme 7.33).
Synthesis of imidazothiazole derivatives via two-step approach
7.3.5 Conclusion
The synthesis of fused pyrollothiazole, pyrazolothiazole, and imidazothiazole compounds represents a significant advancement in heterocyclic chemistry with profound implications for drug discovery and development. Through innovative synthetic methodologies, researchers have successfully accessed these complex heterocyclic scaffolds, paving the way for the exploration of their diverse pharmacological properties.
The biological significance of these compounds is underscored by their therapeutic potential across various diseases, including cancer, infectious diseases, inflammation, and neurological disorders. Leveraging the synthetic versatility of these frameworks, medicinal chemists can tailor molecular structures to optimize drug-like properties and enhance biological activity, thereby accelerating the development of novel therapeutics.
Moreover, computational modeling and mechanistic studies have provided invaluable insights into reaction pathways and structure–activity relationships, facilitating rational design strategies for the synthesis of next-generation analogs with improved pharmacokinetic profiles and target selectivity.
In conclusion, the synthesis of fused pyrollothiazole, pyrazolothiazole, and imidazothiazole derivatives represents a dynamic field at the intersection of organic synthesis and medicinal chemistry, offering exciting opportunities for the discovery of therapeutically relevant compounds with enhanced efficacy and safety profiles.
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Teli, P., Rundla, H.K., Agarwal, L.K., Jangid, D.K., Agarwal, S. (2024). Synthesis and Biological Evaluation of Some Fused Pyrrolothiazoles, Pyrazolothiazoles, and Imidazothiazoles. In: Ameta, K.L. (eds) S-Heterocycles. Springer, Singapore. https://doi.org/10.1007/978-981-97-4308-7_7
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