Improved Method for the Diimide Reduction of Multiple Bonds on Solid-Supported Substrates

Abstract

A mild and improved method for reducing multiple bonds on various resins with diimide is described. The simple procedure readily generates diimide from 2-nitrobenzenesulfonohydrazide and triethylamine at room temperature. A number of representative multiple bonds in various steric and electronic environments were examined, including polar double bonds such as carbonyl and azo, for ease and selectivity of reduction. A general trend of reactivity was identified which revealed, inter alia, that terminal olefins, 1,2-disubstituted olefins, electron-poor olefins, and terminal alkynes were the most easily reduced.The range of useful reactions available for solid-phase organic synthesis has expanded significantly in the past decade. 1 However, one area that has received comparatively little attention is the reduction of multiple bonds on solid supported substrates. Carbon-carbon multiple bonds have rarely been reduced on the solid-phase, largely due to the inherent incompatibility with traditional heterogeneous catalytic hydrogenation conditions, as a consequence of the unfavorable kinetics of solid-on-solid reactions. 2 Even with non-crosslinked polymers, catalytic hydrogenation, though successful, is rare. 3a,b There is one recent report of successful homogeneous hydrogenation with Wilkinson's catalyst at 60 psi in a polypeptide substrate on a modified Rink amide resin. 3c Diimide reduction, on the other hand, would appear to offer an attractive solution to this important problem. 4 The reasons are manifold: diimide can be generated from numerous precursors; it is compatible with most In connection with a program of research designed to create compound libraries inspired by medium-ring natural products, including the powerful antitumor agent octalactin A, 5 we required the synthesis and subsequent reduction of several THP-linked 6 unsaturated primary and secondary alcohols, such as those depicted in Scheme 1. Cognizant of the inherent difficulties with hetereogenous catalytic hydrogenation, we initially looked to homogeneous hydrogenation using the Wilkinson, Crabtree, and similar catalysts. Unfortunately, after repeated attempts with Wilkinson's catalyst, no detectable reduction products could be isolated, and it was further found that metallic rhodium was precipitated over the course of the reaction, indicating slow decomposition of the catalyst. After several additional failed hydrogenation attempts with the other catalysts, we turned our attention to diimide reduction. The only previous report concerning the use of diimide with solid supported systems examined cinnamic or styryl derivatives with a stable ester linked Merrifield-type resin. 7 The relatively harsh reaction conditions required for complete reductions (e.g., 100 °C in DMF) were unlikely to be compatible with our more labile linkers. Accordingly, we decided to investigate other diimide-forming reaction protocols that would be suitable for use with our supports. Additionally, we were interested in examining the scope of diimide reduction with ...

Total Synthesis of Tryprostatins A and B

“…After the Sonogashira coupling between 7 and 2-iodoformanilide (9), partial reduction of the triple bond was examined. Whereas the use of the Lindlar catalyst, Pd/C, nickel boride, [9] or diimide [10] resulted in no reaction or overreduction, treatment with Zn/LiCuBr 2 in ethanol [11] gave the desired product 11 along with the corresponding amine. The use of 2,2,2-trifluoroethanol [12] as the solvent suppressed the undesired solvolysis and improved the yield of 11 to 99 %.…”

A Pot-Economical Approach to the Total Synthesis of Sch-725674

“…After RCM completion (30 min), the solvent was changed 17 to 1,2-dichloroethane (DCE) and the n -pentyl-substituted CM partner 9 was introduced to the same pot, followed by a second addition of HG-II (4 mol %). The CM event proceeded for 5 h under reflux and subsequent chemoselective diimide reduction at the external olefin was achieved by addition of o -nitrobenzenesulfonylhydrazine ( o -NBSH) 18 into the reaction mixture. This one-pot, three-reaction, sequential operation provided bicyclic phosphate 10 in 59% yield over one-pot, representing an average yield of 84% per reaction (84% av/rxn).…”

Synthetic studies to lyngbouilloside: a phosphate tether-mediated synthesis of the macrolactone core

“…The reaction was continued at 90 °C with simultaneous evaporation of low boiling solvent from the previous reaction to reach optimal concentration (~ 0.1 M) for cross-metathesis (Scheme 3). Subsequent chemo-selective diimide reduction, by simple addition of o -NBSH 16 and Et 3 N into the reaction mixture, provided the bicyclic phosphate phosphate 13 in 65% overall yield, representing an 87% average yield/reaction in the one-pot, sequential protocol. Next, a Pd-catalyzed, reductive allylic transposition was carried out to regioselectively open the phosphate tether with hydride [Pd(OAc) 2 /Bu 3 PHBF 4 , HCOOH, Et 3 N, then methylation with TMSCHN 2 in MeOH] affording monocyclic phosphate ester in excellent overall yield (82%) and regioselectivity.…”