Rapid Access to β‐Trifluoromethyl‐Substituted Ketones: Harnessing Inductive Effects in Wacker‐Type Oxidations of Internal Alkenes

Abstract

We present a practical trifluoromethyl-directed Wacker-type oxidation of internal alkenes that enables rapid access to b-trifluoromethyl-substituted ketones. Allylic trifluoromethyl-substituted alkenes bearing a wide range of functional groups can be oxidized in high yield and regioselectivity. The distance dependence of the regioselectivity was established by systematic variation of the number of methylene units between the double bond and the trifluoromethyl group. The regioselectivity enforced by traditional directing groups could even be reversed by introduction of a competing trifluoromethyl group. Besides being a new powerful synthetic method to prepare fluorinated molecules, this work directly probes the role of inductive effects on nucleopalladation events. Scheme 1. Regiocontrol in Wacker oxidations of internal alkenes. BQ = p-benzoquinone.

Synthesis of 5-Thio-α-GalCer Analogues with Fluorinated Acyl Chain on Lipid Residue and Their Biological Evaluation

“…We started from the synthesis of 8,8,8-trifluorooctanoic acid 17a , which will be used as acyl residue in assembly of compounds 8 and 11 . As shown in Scheme , Witting reaction of aldehyde 14 with phosphonium salt 15 obtained olefin 16 , followed by Pd­(OH) 2 -catalyzed hydrogenation to afford 8,8,8-trifluorooctanoic acid 17a in a good overall yield.…”

Developing the Saegusa–Ito Cyclisation for the Synthesis of Difluorinated Cyclohexenones

“…[30] The formation of enal 22 could involve aW acker-type processo np roduct 18 d;a lthough the Wacker reaction has recently been modified to allow aldehyde synthesis, [31] the hydroxypalladationstep normally follows Markovnikovr egiochemistry and forms ketones from terminal alkenes, but CF 2 is ap owerful electronwithdrawing substituent and may reverse the normal regiochemistry in the conversion of 18 d to 22. [32] However,t he concentrationo fw ater in our reaction mixturesi sl ikely to be quite low,m aking the conversion of 18 d to 22 very slow.T he addition of gem-dimethyl groups (at C a )a llowed an efficient cyclisation of 16 e to 18 e,b ut internal and terminal methylation prevented the cyclisation reaction, with 23 recovered from 16 c,a nd ac omplex reactionm ixture returned from 16 b.W ew ere disappointed to fail to force dienyl species 16 f to cyclise, and were also surprised at the rathers lowr eaction of cyclopropylc ongener 16 g.W e could cyclise 16 i-o successfully to give the bicyclic ketones 18 i-o;t hese annelative reactions were the fastest observed and could be carriedo ut at the lowest loadings of Pd II .A lthought he silyl enol ethers were formed as mixtures of cisand trans-diastereoisomers, the trans-fused products,w hich form from the major diastereoisomer,w ere usually isolated and are therefore shown in Ta ble 3. Exceptionally, sulfone 18 o was isolated as am ixture of trans-a nd cis-b icyclic ketones (trans/cis 87:13 by GC and 1 HNMR analyses), which reflected closely the ratio of diastereoisomers in starting material 16 o (84:16).…”