KHMDS/Triglyme Cryptate as an Alternative to Phosphazene Base in Stereodivergent Pentafluoroethylation of N-Sulfinylimines Using HFC-125

Abstract

A protocol for the stereodivergent pentafluoroethylation of N-sulfinylimines using HFC-125 with KHMDS/triglyme has been developed. Both diastereomers of the pentafluoroethylated amines can be selectively synthesized based on the presence or absence of triglyme. This additive-controlled protocol allows the KHMDS/triglyme cryptate to be a straightforward and cheap alternative to previously reported base-controlled stereodivergent trifluoromethylation using potassium hexamethyldisilazide (KHMDS) versus P4- t Bu.

Current State of Microflow Trifluoromethylation Reactions

“…The same group also reported a stereodivergent pentafluoroethylation of N ‐sulfinylimines using HFC‐125 (Figure 41 [57b] . Using the same microflow system as before, N ‐sulfinylimine underwent a flow trifluoromethylation reaction with HFC‐125 in the presence of KHMDS at −30 °C in triglyme to afford the corresponding pentafluoroethylated product in a good yield (75 %) with high diastereoselectivity (( R , Ss ) diastereomer, 92 : 8).…”

“…Most pentafluoroethylation reactions were developed by adapting batch trifluoromethylation procedures using pentafluoroethyl halides (C 2 F 5 X), [54] R 3 Si−C 2 F 5 , [55] M−C 2 F 5 , [56] and HC 2 F 5 [57] . Conversely, relatively few flow pentafluoroethylation reactions are known [46,57b,58–59] …”

Fluorinated Imines in Tandem and Cycloaddition Reactions

“…When the reaction was carried out in the presence of P 4 ‐ t Bu diamine ( R s ,S )‐ 5 a nonchelated transition state could explain the results, whereas the use of KHMDS provided trifluoromethylated N ‐sulfinamides ( R s ,R )‐ 5 explicable by a chelated transition state. The vicinal diamines could also be selectively deprotected in two steps furnishing free diamines ( S,S )‐ 6 in good yields (Scheme 10b) [29] …”

Reactions Using Freons and Halothane as Halofluoroalkyl/Halofluoroalkenyl Building Blocks

“…During pentafluoroethylation, similar stereoselective synthesis can be achieved by changing the reaction temperature and additives used, although only KHMDS could be used as the base, indicating that the transition state is the same as for trifluoromethylation (Figure 24B). [112] …”

“…During pentafluoroethylation, similar stereoselective synthesis can be achieved by changing the reaction temperature and additives used, although only KHMDS could be used as the base, indicating that the transition state is the same as for trifluoromethylation (Figure 24B). [112] Halothane treated with t-BuOK and Li/NaHMDS gives 2bromo-2-chloro-1,1,1-trifluoroethyl anions that undergo 1,2addition to give halofluoroethylalcohol and 1,4-addition to give cyclopent-2-ene-1-ones (Scheme 13). [81,[113][114][115] For example, Kumadaki et al and Bunch et al discovered that using an amide base allows a 2-bromo-2-chloro-1,1,1-trifluoroethyl group to be added to anisaldehyde and cyclohexanone with 83 % and 96 % yields, respectively.…”