Tetrafluoroborate(1-) - an overview

2.8 Use of Ionic Liquid-Supported Diamine

In order to demonstrate the advantages of IL-supported synthesis over the conventional solution-phase synthesis, Sun and coworkers examined reactions between various IL-grafted diamines and different substrates (Schemes12 and 13) [43–53]. Privileged structures of IL-immobilized diamines 97 and 99 were synthesized from 4-fluoro-3-nitrobenzoic acid and 4-(bromomethyl)-3-nitrobenzoic acid, respectively over three steps (Scheme 14). The ionic liquid 3-hydroxyethyl (1-methylinidazolium)-tetrafluoroborate ([hydemim][BF4]) 1 was selected as appropriate IL support in all multistep transformations. Benzoic acid 94 coupled with IL 1 through esterification followed by ipso-fluoro and bromo displacement by primary amines and subsequent nitro reduction afforded ortho-phenylenediamines 97 and 99.

IL-anchored ortho-phenylenediamine 97 was used as a common scaffold to construct skeletal diversity of novel heterocyclic molecules using various acids, isothiocyanate, and cyanogen bromide (Scheme 12). IL-supported 97 condensation with 3-nitrobenzoic acids followed by cyclization gave benzimidazole heterocycles 100. The ipso-fluoro displacement by primary amine and subsequent nitro reduction resulted benzimidazole-linked o-phenylenediamine 101. IL-grafted 101 was selected as a common scaffold to the synthesis of 2-alkyl-substituted bis-benzimidazole 102, and pyrrole[1,2-a]benzimidazolones 103 using various keto acids in one step (Scheme 12) [43]. IL-supported pyrrole[1,2-a]benzimidazolones 103 were treated with Lawesson’s reagents to afford thiopyrido-benzimidazolone 106.

The scope of the cyclization reaction of o-phenylenediamines 97 with isothiocyanates was extended and shown in Scheme 12. The substituted isothiocyanates reacted with IL-anchored o-phenylenediamines 97 to obtain monothiourea, further activated by methyl iodide to undergo cyclodesulfurization to obtain 2-substituted aminobenzimidazoles 110 in one pot (Scheme 12) [44].

Sun et al. have also reported microwave-assisted synthetic process for bis-benzimidazolyl benzoxazole synthesis. IL-grafted 3-amino-4-hydroxy benzimidazolyl 100 was subjected with thiocarbonyl diimidazole under microwave irradiation followed by S-alkylation by various alkyl bromides at ambient temperature to afford IL-bound bis-benzimidazolyl benzoxazole 108 and subsequently basic methanolysis to remove IL support (Scheme 12) [45]. Present strategy is useful to obtain IL-intermediate and final product by simple operation, and short reaction time is observed under microwave dielectric heating.

To extend the scope of this cascade strategy, IL-grafted diamines 97 were subjected with α-ketobenzoic acid to offer IL-supported isoindolobenzimidazolones 111, followed by treatment with Lawesson’s reagent to obtain thiopyrrolobenzimidazolone 112 [46]. Notably, cascade reaction was systemically applied for the synthesis of bis-heterocyclic libraries. The successive removal of IL-tag through basic methanolysis afforded 102, 103, 106, and 112.

IL-supported one-pot multicomponent reaction for the construction of bi-heterocyclic-fused pyrrolo[1,2-a]benzimidazoles 114 under microwave irradiation were reported by Sun and coworkers (Scheme 12) [47]. The IL-anchored diamines 97 were coupled with cyanoacetic acid followed by cyclodehydration to generate key intermediate 2-substituted benzimidazoles 113. IL-supported 113 reacted with aldehyde and isocyanide through Knoevenagel condensation followed by [4   +   1] cycloaddition in one-pot affording pyrrolo[1,2-a]benzimidazole 114. Remarkably, this is the first time applied IL support and isocyanide-based multicomponent react for the synthesis of fused tricyclic heterocycles under microwave irradiation.

The next scope of this attempt was the construction of novel benzimidazole-fused dihydropyrimidine 116 and pyrimido[1,2-a]benzimidazoles 117 through multicomponent reactions (Scheme 12). The key intermediate, 2-aminobenzimidazoles 115 were constructed by using cyanogen bromide through cyclization of ortho-phenylenediamine 97. The multicomponent reaction between IL-grafted 2-aminobenzimidazoles, aldehyde, and electron-deficient acetylenes for the synthesis of dihydropyrimidobenzimidazole 116 is also presented in Scheme 12 [48]. The reaction involves imine formation followed by Mannich reaction and subsequent intramolecular electrophilic aromatic substitution. Further sigmatropic rearrangement toward the formation of a more stable conjugate system through stabilization of the ionic intermediate to furnish dihydropyrimidobenzimidazole 116 was also achieved. Multicomponent synthesis of benzimidazole iminopyrimidines 118 by using IL-supported 2-aminobenzoimidazole 115, malononitrile, and benzaldehyde under microwave irradiation through Knoevenagel condensation, Michael addition, followed by intramolecular cyclization afforded tricyclic ring system 117 [49]. Notably, one-pot multicomponent rearrangement reaction under basic conditions worked well for the library synthesis of 116 and 117.

Sun et al. [51] have further reported the scope of the cyclization reaction of privileged scaffolds, IL-tagged diamines 99. Microwave-assisted IL-supported synthesis toward dihydro- and tetrahydroquinazoline analogs was demonstrated in Scheme 14 [50]. In order to construct quinazoline framework, IL-supported 99 was condensed with one-carbon electrophile aldehydes and isothiocyanates resulting tetrahydroquinazoline 120 and dihydroquinazoline 122, respectively. To extend the scope of this cyclization reaction, treatment of the same starting material with α-ketobenzoic acids or γ-ketoaliphatic acid in the presence of acetic acid afforded isoindolo[1,2-a]quinazoles 119 under microwave irradiation (Scheme 14) [51]. Removal of IL support from quinazolines moiety under transesterification conditions furnished heterocycles 119, 121, and 123 with varied molecular complexity. The present methods offer more effective platforms to access structurally diverse heterocycles.