Abstract
D. General experimental procedure for the synthesis of benzothiazoles
4.2. Strategies for quinoxaline and quinoline synthesis
Conventionally, quinoxalines are prepared by the acid catalysed condensation of o-phenylenediamines with 1,2-dicarbonyl compounds22 (Scheme 4.1, A). Several strategies for the synthesis of quinoxalines derivatives are reported in literature. These strategies are included the reaction of o-phenylenediamines with α-hydroxy ketones23 (Scheme 4.1, B), epoxides24 (Scheme 4.1, C), α-bromoketones25 (Scheme 4.1, D), α- tosyloxy ketones26 (Scheme 4.1, E), α-ketocarboxylic acids27 (Scheme 4.1, F), oxalic acid28 (Scheme 4.1, G), diazenyl butenes,29 (Scheme 4.1, H), hydroxy acetylenes30 (Scheme 4.1, I), alkynes,31 (Scheme 4.1, J), vicinal diols32 (Scheme 4.1, K), or diazoketones33 (Scheme 4.1, L). However, most of these reactions have their own limitations such as the involvement of the heavy metal catalysts, the use stoichiometric amount of oxidant/base, incompatibility with pre-functionalized substrates and the use of harsh reaction conditions. Thus, these cannot be largely applied because of their environmental and/or economic issues.
Scheme 4.1: Different conventional methods for the synthesis of quinoxaline.
Very recently, acceptorless dehydrogenation approach has been largely applied to synthesize quinoxalines34 in presence of metal catalyst through metal-ligand cooperation process. These protocols do not require stoichiometric oxidant and hence these are considered as waste-free processes (Scheme 4.2).
Scheme 4.2: Acceptorless dehydrogenation approach for the synthesis of quinoxaline.
In 2006, Cho and co-worker reported35 RuCl2(PPh3)3 catalysed oxidative cyclization o-phenylenediamines with various 1,2-diols to give quinoxaline derivatives in moderate to good yield (Scheme 4.3). Excess amount of KOH (4 equiv. with respect to 1,2-diaminobenzene) was used for these transformations.
Scheme 4.3: The synthesis of quinoxaline by Ru-complex from 1,2-diaminobenzene and 1,2-diol.
In 2014, Kempe and co-workers developed tridentate Ir-PNP pincer complex 3.6a catalysed36 dehydrogenative syntheses of quinoxaline derivatives at relatively lower reaction temperature (90 °C).
Very recently, Kundu and co-workers demonstrated earth-abundant Co(II) complex 1.12c catalysed37 synthesis of quinoxalines via dehydrogenative coupling of vicinal diols with o-phenylenediamine or 2-nitroanilines at 150 °C in presence of relatively lower amount of base.
Scheme 4.5: The synthesis of quinoxaline by Co-complex from 1,2-diaminobenzene and 1,2-diol.
In the same year, the group of Milstein developed the acridine PNP based manganese complex 1.12f to synthesize such type of compounds38 in presence of a catalytic amount of base at 150°C.
Scheme 4.6: The synthesis of quinoxaline by Mn-complex from 1,2-diaminobenzene and 1,2-diol.
Consequently, the construction of quinolines have also been developed over the past few years using various efficient strategies such as the Skraup synthesis, Friedländer synthesis, Gould-Jacobs synthesis, Conrad-Limpach and Doebner-von Miller synthesis. Among them, the Friedländer annulation39 has attracted much attention as it involves straightforward condensation of 2-aminobenzaldehydes/ketones with different carbonyl compounds having an active α-methylene group followed by intramolecular cyclization. However, limited availability o-aminobenzaldehydes and harsh reaction condition are the two major drawbacks of this synthetic strategy.
Moreover, 2-aminobenzaldehydes are prone to self-condensation and hence highly unstable.
An alternative environmentally benign and atom-economical approach to synthesize quinoline derivatives is the dehydrogenative coupling40 of 2-aminobenzyl alcohols with ketones/alcohols (Scheme 4.7). The reaction occurs without the involvement of toxic strong oxidants and it generates environmentally benign hydrogen gas and H2O as by-products.
Scheme 4.7: The synthesis of quinoline via dehydrogenative annulations.
Over the past few decades, different transition metal complexes have been utilized for the dehydrogenative synthesis of various differently substituted quinoxaline, pyrazine and quinoline derivatives. Among them, the novel metal complexes (Ru, Ir etc) have been found to be most suitable for the synthesis of such heterocycles. Recently, earth-abundant transition metal complexes (Fe, Co, Mn) are also utilised for similar kind reaction to avoid the high cost and limited availability of noble metal salts. Some of the reported strategies are shown here.
In 2007, Verpoort et al. reported Ru-catalysed41 synthesis of quinoline derivatives from 2-aminobenzylalcohol and ketones derivatives in presence of KOH in dioxane medium. They have used 2 equivalent of ketone with respect to the 2- aminobenzylalcohol.
Scheme 4.8: Synthesis of quinoline by Ru-complexes from 2-aminobenzyl alcohol and ketone derivatives
Li et al. developed tridentate Ir-complexes40a 4.8a-c to catalyse dehydrogenative Friedländer synthesis in water, using almost an equimolar amount of 2- aminobenzylalcohol and ketones.
Scheme 4.9: Dehydrogenative quinoline synthesis by Ir-complexes from 2-aminobenzyl alcohol and ketone derivatives.
In 2015, Sortais and co-workers reported iron catalysed42 modified Friedländer annulation. There protocol offers limited substrate scope with moderate yield of the product.
Scheme 4.10: Fe-complexes catalysed synthesis of quinoline from 2-aminobenzyl alcohol and ketone derivatives.
Scheme 4.11: Cobalt catalysed modified Friedländer annulation reaction from 2-aminobenzyl alcohol and ketone derivatives.
In 2017, Zheng and co-workers illustrated Co-catalysed43 dehydrogenative Friedländer synthesis of quinoline in toluene medium and got only 46-60 % yields the
quinoline derivatives (Scheme 4.11). Very recently, the dehydrogenative annulation reactions for the synthesis of quinoline directly from 2-aminobenzyl alcohol and a secondary alcohol are reported. In 2013, the group of Milstein40b developed an elegant method to synthesize quinoline from 2-aminobenzyl alcohol and secondary alcohol using Ru-PNP complex in traditional solvent with higher amount of base (2 mmol) respect to the substrate.
Scheme 4.12: Synthesis of quinoline by Ru-complexes from 2-aminobenzyl alcohol and secondary alcohol.
In 2016, Kirchner and groups first reported Mn-based PNP-pincer complexes44 1.12e, 4.11a-b catalysed dehydrogenative condensation 2-aminobenzyl alcohol and secondary alcohol to form quinoline derivatives. The mixture of tBuOK (2.1 mmol) and KOH (1 mmol) is highly essential for this reaction and they found a significant decrease in the yield of the desired product in the absence of KOH.
Scheme 4.13: Mn-complexes catalysed dehydrogenative synthesis of quinoline from 2-aminobenzyl alcohol and secondary alcohol.
Many metal complexes were applied for the dehydrogenative synthesis of quinoxaline, pyrazine and quinoline. However, the use of earth-abundant non-toxic manganese complexes towards the synthesis of these heterocycles are limited and mainly effective in presence of highly sophisticated phosphine containing ligands. Thus, there is an ample scope to study the dehydrogenative synthesis of such type of heterocycles in presence of newly synthesized NNS-Mn complexes.