Phase-Transfer-Catalyzed Alkylation of Hydantoins

Abstract

A highly efficient, cost-effective, and environmentally friendly protocol is reported for the C5-selective alkylation of hydantoins under phase-transfer catalysis. The reactions are scalable and only require a catalytic amount of tetrabutylammonium bromide (TBAB) to achieve high yields under mild reaction conditions. Moreover, the method is applicable to a wide range of electrophiles, including alkyl-, allyl-, propargyl-, and benzyl halides, as well as acrylates and dibromoalkanes, but also to virtually any hydantoin precursor. We also highlight the potential for an enantioselective adaptation using a chiral phase-transfer catalyst.

Figure 1

Hydantoin-containing clinical candidates, marketed drugs, and natural products.

Figure 2

Strategies for the C₅-functionalization of hydantoins.

Figure 3

Substrate scope. ^aConditions: 1a–u (0.25 mmol, 1 equiv), electrophile (0.75 mmol, 3 equiv), TBAB (0.005 mmol, 2 mol %), toluene (0.3 mL), 50% w/w KOH_aq (0.2 mL), rt. ^b1.2 equiv of allyl bromide was used instead of 3. ^cTBAB (0.025 mmol, 10 mol %), 50% w/w NaOH_aq (0.2 mL), rt, 48 h. ^dReaction run with t-butyl acrylate. ^eReaction run on a 5 g scale.

Figure 4

Process optimization, tetra-alkylation and enantioselective studies.