Organic molecules are mainly composed of the carboncarbon backbone, but the functions of these molecules have been mostly observed deriving from the presence of heteroatoms. Compounds containing oxygen-, nitrogen- and sulfur- are of utmost importance due to their interesting and diverse biological activities. Among these structures, benzo-fused heterocycles are worthy of attention due to their numerous applications in pharmaceuticals and material science [66-71]. For example, PMX 610, the benzothiazole derivative, is used as an anti-tumour agent [69]. The bis-benzoxazoles, exemplifying UK-1 and its derivatives, represent anticancer or anti-inflammatory activities [70, 72].
There were three basic approaches to achieve these benzo-fused heterocycles. The first method was related to the intramolecular cross coupling of an anilides.
Scheme 1.3. Cross coupling approaches to form benzazoles [73-76].
This approach included an intramolecular cyclization of anilides containing a leaving group at the o-position promoted by a transition-metal catalyst such as Cu, Pd [73-76].
Thus, it was found inconvenient to synthesize benzimidazoles and benzothiazoles with this method due to the requirement of commercially unavailable starting materials such as amidines or thiocarbonyl. Oxidative dehydrogenation reactions [77] were improved later, but these methods also had their own drawbacks involving the requirement of
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reactive and toxic reagents, less-common substrates, transition-metal catalysts as well as strong oxidants.
Scheme 1.4. Synthesis of 4H-3,1-benzoxazines [78].
Hence, Phillip reaction for the synthesis of these benzo-fused heterocycles showed interest. Those methods included the condensation of o-thio/hydroxy/aminoaniline with either aldehyde or carboxylic acid and its derivatives (acyl chloride, ester, amide, nitrile and so forth).
Scheme 1.5. Phillip’s method in the synthesis of benzazoles [79].
Mineral acid, especially H3PO4, has been reported to be a highly effective reagent for promoting this type of condensation. [79]. Due to the importance of this method, the reaction was also studied in the presence of various Lewis acid catalysts such as ZrCl4, SnCl4, TiCl4, ZrOCl2.9H2O, In(Otf)3.
Scheme 1.6. Plausible reaction for Phillip benzazole synthesis [80].
Despite significant advancements in this field, the construction of these benzo-fused
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heterocycles was still a major challenge for organic chemists because these methods suffered from one or more of the disadvantages such as high thermal conditions (often more than 200oC), long reaction time (over 10 hours), difficulty in product separation and giving low yield in the preparation of 2-aryl substituted benzimidazoles [81-85].
As a result, Cu-MOFs and Fe-MOFs have been used as catalysts for the synthesis of these fused heterocycles. A porous MOF-537 with molecular formula Cu2(TPPB)2(DMF)6 was used as a catalyst for the transformation of amidines to 2- phenylbenzimidazoles [86].
Scheme 1.7. Conversion of amidine to 2-phenylbenzimidazole [86].
The target product was detected in 96% yield when a mixed solvent of DMSO/DMF was used. Of note, benzoic acid was employed as acidic additive. The use of benzoic acid was attributed to the suppression of decomposition products under these reaction conditions. Substituent effect on the formation of 2-phenylbenzimidazoles was studied.
The results indicated that substituted amidines containing electron-withdrawing groups or electron donating groups in ortho, meta, para position offered only moderate product yields under optimized conditions. For plausible mechanism, the author supposed that the CH functionalization of amidine underwent via two possible pathways.
Figure 1.9. Two possible paths for the conversion of amidine [86].
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In the first path, MOF-537 was coordinated to amidines and then followed by electrophilic addition of copper center to N-phenyl ring to offer (B). After that, (B) underwent reductive elimination and re-aromatization to give (D). In the second pathway, a copper nitrene intermediate (C) was formed instead of intermediate (B) via reaction of the amidine with MOF-537. Later, this intermediate underwent various steps, including insertion of the nitrogen into a C–H bond of amidine, electrocyclic ring closure and [1,3]-shift of a hydrogen to afford the final product (D). The moderate to high yields of benzimidazoles provided under these reaction conditions were attributed to the coordination ability as well as stabilizing intermediates (B) or (C) of MOF-537.
Cu2(OBA)2(BPY) was used as a heterogeneous catalyst in one-pot domino reaction between 2-aminobenzyl alcohol and propiophenone to form phenyl(quinolin-3- yl)methanone [87].
Scheme 1.8. Reaction between 2-aminobenzyl alcohol and propiophenone [87].
It should be noted that Cu2(OBA)2(BPY) displayed higher catalytic efficiency than Cu(BDC), Cu-MOF-74 and MOF-199. These results were attributed to the basic nitrogen atoms in BPY ligands which would facilitate the dehydrogenation on the alpha carbon in propiophenone in the catalytic cycle [87]. As seen in the scheme 1.9, Ln- Cu(II)-enolate complex (A) was initially formed by coordination of copper species with ketone. Then, (A) generated Cu(I) species and α-C-centered radical (B) via single electron transfer process. This radical (B) reacted with TEMPO to form α-TEMPO- substituted ketone (C), which was then released TEMPOH to afford α, β-unsaturated ketone (D). β-Aminoketone (F) was formed by the reaction between (D) and aldehyde (E). Enaminone (G), which was formed by dehydrogenation of (F), was transformed into product via an intramolecular enamine–ketone condensation.
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Scheme 1.9. Referred mechanism for reaction between 2-aminobenzyl alcohol and propiophenone [87].
Another benzo-fused heterocycle, 2,3-dihydro-2,2,4-trimethyl-1H-1,5-benzodiazepine, was formed in the cyclocondensation of 1,2-phenylenediamine with acetone using MOF-235 as catalyst [88].
Scheme 1.10. Reaction between 1,2-phenylenediamine and acetone to form 2,3- dihydro-2,2,4-trimethyl-1H-1,5-benzodiazepine [88].
It was observed that metal sites played significant roles in the activity of MOF-235. The catalytic performance of MOF-235 was compared with those of other MOFs containing different metal sites, including MOF-5, Mn(BDC) and Ni2(BDC)2(DABCO). The nickel-based MOF, Ni2(BDC)2(DABCO), gave no trace amount of product after 180
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min. Less than 10% conversion was detected after 180 min in the case of the zinc-based MOF-5 and manganese-based Mn(BDC).
Reaction between 1,2-phenylenediamine and acetone, which was catalyzed by MIL- 100(Fe) to form benzodiazepine, was reported by Jhung [89]. Reaction mechanism was proposed involving the catalysis of Lewis acid sites in the frameworks.
Scheme 1.11. Proposed mechanism for reaction between 1,2-phenylenediamine and acetone catalyzed by MIL-100 (Fe) to form benzodiazepine [89].
Among benzo-fused heterocycles, quinazolines and quinazolinones are an important class of compounds with large spectrum of therapeutic potentials. 2-Phenylquinazolin- 4(3H)-one was synthesized via a two-step process including iron-catalyzed the decarboxylation of phenylacetic acid, and subsequent oxidative cyclization with 2- aminobenzamide [90].
Scheme 1.12. Synthesis of 2-phenylquinazolin-4(3H)-one via a one-pot, two-step process [90].
The first step was catalyzed by VNU-21, which was constructed form FeCl2 and mixed-
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linkers of 1,3,5-benzenetricarboxylic acid and 4,4’-ethynylenedibenzoic acid. Mixed- valence iron species of Fe2+and Fe3+, resulted in VNU-21 framework, were both active for oxidative Csp3H bond activation of phenylacetic acid to produce benzaldehyde.
After that, the catalyst was removed by filtration, and followed by adding a solution of 2- aminobenzamide to the reactor. It was interesting that the transformation starting with phenylacetic acid under these reaction conditions gave no trace amount of benzoic acid while a large amount of benzoic acid as a by-product was formed in a catalyst-free cyclization of benzaldehyde with 2-aminobenzamide. Probable reaction mechanism was proposed via radical pathway.
Scheme 1.13. Probable reaction mechanism [90].
2-Phenylquinazolin-4(3H)-one was also synthesized via the reaction of benzyl alcohol with o-aminobenzamide, which was catalyzed by Fe(BTC) [91].
Scheme 1.14. Tandem process for the conversion of benzyl alcohol to 2-phenylquinazolin-4(3H)-ones [91].
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The target product was obtained in 82% isolated yield when TBHP was employed as an oxidant. The decrease of product yield was observed in the case of using H2O2 as oxidant. It was attributed to the instability of H2O2 compared with that of TBHP under these catalytic reaction conditions.
As can be seen in the proposed mechanism, there were three pathways to obtain the benzaldehyde product. The pathway (1) occurred via the carbocation formation. The pathway (2) included the formation of a gem-diol-like structure which was then dehydrated to form benzaldehyde. The other pathway passed through a hydrogen-atom abstraction from (C) by the t-BuOOã or t-BuOã radicals. After that, activated aldehyde reacted with o-aminobenzamide to give 2-phenylquinazolin-4(3H)-ones.
Scheme 1.15. Plausible reaction mechanism [91].
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A bimetallic (Zr, Fe) MOF denoted as Fe@PCN-222(Fe) was prepared by modification of PCN-222(Fe) with FeCl3. The synthesized Fe@PCN-222(Fe) was used as an efficient catalyst for a one-pot reaction between benzyl alcohol and 2-aminobenzamide through a tandem oxidation/cyclization/oxidation under visible light. The target product, 2- phenylquinazolin-4(3H)-one, was obtained in 79% isolated yield when the reaction was carried out in the presence of a mixed solvent of DMSO/water for 32 hours under oxygen atmosphere [92].
Scheme 1.16. Reaction of benzyl alcohol and 2-aminobenzamide [92].
The catalytic activity of the bimetallic MOF was superior as compared to that of homogeneous catalysts (FeTCPPCl, iron and zirconium salts) and related heterogeneous catalysts (PCN-222(Fe), UiO-66, Fe(BTC)). These results were attributed to the presence of the hexagonal mesochannels in MOF framework. The mesoporosity enabled the reaction to occur in the interior of Fe@PCN-222(Fe) pores [92].
Scheme 1.17. Plausible reaction mechanism [92].
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In general, copper and iron-based MOFs have been used as catalysts in some limited protocols for the synthesis of benzo-fused heterocycles. Benzimidazoles were synthesized by oxidative dehydrogenation of amidines catalyzed by MOF-537.
Quinazolinone derivatives were synthesized by the reaction between o- aminobenzamides and carboxylic acids/aldehydes/alcohols catalyzed by some Fe- MOFs with Lewis acid sites such as Fe@PCN-222(Fe), VNU-21, Fe-BTC.
As could be seen that the synthesis of quinazoline, benzoxazine, benzazole derivatives catalyzed by copper, iron-based MOFs was quite limited. Therefore, different synthetic approaches need to be further developed to obtain these valuable skeletons.