Heteropolycyclic compounds occupy a central role in medicinal and natural products chemistry
due to their extensive prevalence in these spheres as bioactive components. Their versatility and
importance have led to the extensive synthetic study and functional utility. They are found in more
than 90% of clinically used drugs. Since the discovery of heteropolycyclic compounds, numerous
synthetic methodologies have been developed to facilitate their production. Many of such synthetic
methodologies are time consuming and require expensive starting materials. The central objective
of my research project revolves around the synthesis of novel heteropolycyclic compounds,
employing cheap commercially available starting materials, developing new synthetic
methodologies, and obtaining the desired products faster. The primary objective of the study was
to synthesize γ-keto-anilides (I, VII; Figure 1) and utilize them to develop synthetic methodologies
to assemble four distinct series of heteropolycyclic compounds (Series A-D, Figure 1).
Figure 1. Four heteropolycyclic systems reported in the thesis (A-D) and the associated starting
materials/intermediates (I-IX). Chiral centers are indicated by ‘*’.
Condensation of anilines with 2-acetylbenzoic acid utilizing the carbodiimide approach, led to formation of 3-hydroxy-3-methyl-2-arylisoindolin-1-ones (II) as the major isolated product rather than the expected 2-acetylbenzanilides (I). Isolation of hemiaminal-type cyclized form of keto-anilides (II) was a boon as they can act as surrogates of tert-enamides 3-methylene-2-arylisoindolin-1-ones III (by C-C dehydration) as well as N-acyliminium (3-methyl-1-oxo-2-aryl-1H-isoindol-2-ium) ion IV (by N-C dehydration) which are required to realize the synthesis of designed series of compounds.
Synthesis of series A (3-(1H-indol-3-yl)-3-methyl-2-arylisoindolin-1-ones, Figure 1) compounds was conceptualized via electrophilic aromatic substitution of substituted indoles (electron-rich aromatics) with electrophilic N-acyliminium ions (III) obtained from 3-hydroxy-3-methyl-2-arylisoindolin-1-ones (II). With the use of p-TSA as the dehydration catalyst, the synthesis of series A compounds were realized. The reaction conditions were optimized, and 22 analogs of series A compounds were synthesized in good yields using the optimized conditions demonstrating the scope and efficiency of this reaction.
As alluded before, C-C dehydration of 3-hydroxy-3-methyl-2-arylisoindolin-1-ones (II) is expected to form tert-enamides (3-methylene-2-arylisoindolin-1-ones) (III). These tert-enamides can be visualized as electron-rich alkenes that can potentially react with electron poor dienes in an inverse electron demand Diels Alder reaction. Such a reaction between an o-quinone methide (VI) (an electron poor diene derivable from Mannich bases of 2-naphthol (V) via thermal deamination) and these tert-enamides are expected to yield compounds of series B (Figure 1).
Thermal reaction of the Mannich base 1-(morpholinomethyl)-naphthalen-2-ol (V) with 3-hydroxy-3-methyl-2-arylisoindolin-1-ones (II) in a microwave reactor using p-TSA as catalyst to yield the desired 2'-aryl-1,2-dihydrospiro[benzo[f]chromene-3,1'-isoindolin]-3'-ones (Series B) as products. The reaction conditions were optimized, and 20 analogs of series B compounds were synthesized using the optimized conditions demonstrating the versatility of this reaction.
Like o-quinone methide (VI), N-acyliminium ions IV can also be visualized as electron poor diene. Thus, an inverse electron demand Diels Alder reaction between IV (as diene) and electron rich III (as dienophile) should be possible. Since III and IV are both derivable from II, synthesis of series C compounds were envisaged by self-coupling reaction of II under dehydrating conditions (in presence of Lewis or Brønsted acids).
In the presence of a catalytic amount of BF3·Et2O, we were indeed able to obtain the cyclodimerized spiroheterocyclic products 6a'-methyl-2-aryl-6'H-spiro[isoindoline-1,5'-isoindolo[2,1-a] quinoline]-3,11'(6a'H)-diones (C). Six analogs of series C compounds were synthesized as diastereomeric mixtures using the optimized conditions. Using the same approach, 5 analogs of series D compounds were obtained utilizing levulinic anilides (VII) instead of II as the keto-anilide, where presumably tert-enamide VIII and N-acyliminium ion IX acted as the dienophile and diene pair, respectively.
All compounds were thoroughly characterized using spectrometric techniques (1H & 13C NMR and ESI HRMS).