Abstract
The organo-catalyzed enantioselective benzylation reaction of α-trifluoromethoxy indanones afforded α-benzyl-α-trifluoromethoxy indanones with a tetrasubstituted stereogenic carbon center in excellent yield with moderate enantioselectivity (up to 57% ee). Cinchona alkaloid-based chiral phase transfer catalysts were found to be effective for this transformation, and both enantiomers of α-benzyl-α-trifluoromethoxy indanones were accessed, depended on the use of cinchonidine and cinchonine-derived catalyst. The method was extended to the enantioselective allylation reaction of α-trifluoromethoxy indanones to give the allylation products in moderate yield with good enantioselectivity (up to 76% ee).
Highlights
The role of fluorine in medicinal chemistry is expanding rapidly after it was discovered that the introduction of fluorine into an organic molecule could productively influence its physical and chemical properties [1,2,3,4,5,6,7,8,9,10,11,12,13,14]
The OCF3 group is present in more than 1393 biologically active organic compounds according to a check of the PubChem database in June 2019 [21,22,23]
Compared to trifluoromethyl (CF3 ; πx = 0.88), methyl (CH3 ; πx = 0.52) and methoxy (OCH3 ) groups, the OCF3 group has the highest lipophilicity value [24,25,26,27,28,29] resulting in the potential improvement of metabolic profiles, including permeability and absorption, when it is introduced into the appropriate position of parent molecules
Summary
The role of fluorine in medicinal chemistry is expanding rapidly after it was discovered that the introduction of fluorine into an organic molecule could productively influence its physical and chemical properties [1,2,3,4,5,6,7,8,9,10,11,12,13,14]. Compared to trifluoromethyl (CF3 ; πx = 0.88), methyl (CH3 ; πx = 0.52) and methoxy (OCH3 ) groups (πx = −0.02), the OCF3 group has the highest lipophilicity value (πx = 1.04) [24,25,26,27,28,29] resulting in the potential improvement of metabolic profiles, including permeability and absorption, when it is introduced into the appropriate position of parent molecules. While the synthesis of OCF3 -containing organic compounds has improved dramatically over the last five years [37,38,39,40,41,42], a method that can be used to construct a chiral “C*–OCF3 ” unit is still extremely
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