Microwave assisted synthesis of 5-hydroxymethylfurfural (5-HMF) over sulfonic acid anchored solid acid catalysts in isopropyl alcohol (IPA) offers specific advantages. Comparison of catalysts with different backbones stipulates a profound effect on the selectivity of fructose dehydration in IPA. The catalyst with an aliphatic backbone has a higher yield than the catalyst with a styrenic backbone. Of the tested catalyst, the DBT-ICT-Centre for Energy Biosciences, Institute of Chemical Technology Catalyst #2 (DICAT-2) in IPA resulted in 85% yield with >95% conversion in 120 s. The modeling analysis depicted the characteristic role of the aliphatic backbone for obtaining higher selectivity in IPA. Moreover, the use of IPA is ecologically preferred and it also facilitates product, solvent, and catalyst separation. The structural and morphological characterization with a recyclability study for five consecutive runs showed consistency in yield and conversion. The turnover number (TON), turnover frequency (TOF), E-factor, and process mass intensity (PMI) indicate an environmentally safer and industrially viable process.