American Chemical Society
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On the Probability That Ring-Forming Multicomponent Reactions Are Intrinsically Green: Setting Thresholds for Intrinsic Greenness Based on Design Strategy and Experimental Reaction Performance

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journal contribution
posted on 2013-05-06, 00:00 authored by John Andraos
This paper describes in detail the determination of the likelihood that a given generalized chemical reaction may be considered intrinsically “green” based on design strategy. Justification is given for setting threshold constraints on reaction yield and kernel reaction mass efficiency (RME) performances at greater than 80% and greater than 61.8%, respectively, for intrinsically green reactions. These criteria are applied to a survey of 60 named ring-forming multicomponent reactions (MCRs) and 2000+ such reactions reported in the literature from 2003 to 2011. Patterns among various ring construction motifs are discussed. Results show that 5- and 6-membered monocyclic rings are most commonly made by [2+2+1] and [3+2+1] cycloadditions where 57% and 76% of them, respectively, have a 100% chance of being intrinsically green from a design perspective. Similarly, the [4.3.0] and [4.4.0] skeletons are the most common fused bicyclic structures made by MCR strategies where 38% and 59% of them, respectively, have a 100% chance of being intrinsically green. The syntheses of various heterocyclic ring structures made by MCRs have also been surveyed using this new criterion. The application of this probability analysis is also demonstrated for the total synthesis of ring containing scaffold structures of praziquantel and frondosin B, two compounds of pharmaceutical interest made using MCRs. The direction of future research in MCR development is also briefly discussed.