1 3
Topics in Current Chemistry (2020) 378:1
of the MacMillan catalyst 2a was mandatory, as the Hayashi–Jørgensen catalysts
were not active. Commonly, it is believed that the two types of catalyst, i.e., MacMillan and Hayashi–Jørgensen, are interchangeable in an organocatalytic process,
but this is not always the case. First, as we have pointed out, the nucleophilicities
of enamines derived from the two catalysts are different: the Hayashi–Jørgensen
catalyst leads to a much more nucleophilic enamine, featuring a nucleophilic
parameter almost five orders of magnitude higher than the MacMillan-type one on
the Mayr scale [8a]. In a second instance, the Hayashi–Jørgensen catalyst is sensitive to desilylation processes, often leading to an inactive catalyst. It is important to stress that indium salts induce the formation of allylic ethers as a mixture
of diastereoisomers, as depicted in the mechanistic picture. The allylic ethers are
the resting state for the formation of the carbenium ion, which is reversibly generated by indium(III) from the allylic alcohols. In this concerted activation, the
Lewis acid acts as a promoter for the formation of the electrophilic species, i.e.,
the carbenium ion. Although coordination of the Lewis acid to the MacMillan
catalyst is possible, and in fact was observed by NMR, the study of non-linear
effects clearly showed that just a monomeric catalytic species is responsible for
the observed stereoselection. The chiral species transmitting the information is
clearly the enamine, and the linear correlation between ee of the organocatalyst
and ee of the isolated product indicates that the formation of multiple catalytic
species during the enantio-determining step is not involved. In other words, possible interactions with chiral indium complexes formed with the organocatalyst
do not influence the enantio-determining step. Furthermore, it was mentioned in
the introduction that indium is a borderline Lewis acid for its use in the presence
of water, but it can be advantageously used in the presence of strong coordinating
amines. By combining In(OTf) 3 with a MacMillan-type of catalyst, it was possible to extend the S N 1-type reactions to the stereoselective addition of propargylic
carbenium ions, generated from the corresponding alcohols (Scheme 12) [85].
Remarkably, the reaction occurs in water, and this underlines the powerful concepts related to the use of the Mayr table for setting up reactions. The most nucleophilic species, i.e., the enamine, reacts faster with the carbenium ion than water
because there are more than ten orders of magnitude between enamine and water
nucleophilicities. Furthermore, the reaction allowed the use of propargylic alcohols
carrying disubstituted triple bonds that were not reactive in the allylidene electrophilic reaction mode. Nishibayashi reported a quite similar propargylation of aldehydes with a propargylic alcohol using slightly different conditions and reporting
the use of InBr 3 or FeCl 3 to initiate the reaction [86]. In both the reports, only aryl
propargylic alcohols are employed, and also in these cases, the use of strong electron-donating groups, such as dimethylamino and methoxy groups at the para- or
ortho-position of the aryl substituent are mandatory for a good outcome of the reaction. This is due to the decrease of electrophilicity of the propargylic carbenium ion,
which can be formed in the reaction conditions. Diaryl secondary alcohols are also
suitable precursors for the generation of stabilized carbenium ions, if Lewis acids
are employed in the presence of the organocatalyst 2c (Scheme 13) [87].
The scope of organocatalytic S N 1-type reactions was widened to include benzylic and benzhydrylic carbenium ions performing the reaction in the presence of
Reprinted from the journal
45
Topics in Current Chemistry (2020) 378:1
of the MacMillan catalyst 2a was mandatory, as the Hayashi–Jørgensen catalysts
were not active. Commonly, it is believed that the two types of catalyst, i.e., MacMillan and Hayashi–Jørgensen, are interchangeable in an organocatalytic process,
but this is not always the case. First, as we have pointed out, the nucleophilicities
of enamines derived from the two catalysts are different: the Hayashi–Jørgensen
catalyst leads to a much more nucleophilic enamine, featuring a nucleophilic
parameter almost five orders of magnitude higher than the MacMillan-type one on
the Mayr scale [8a]. In a second instance, the Hayashi–Jørgensen catalyst is sensitive to desilylation processes, often leading to an inactive catalyst. It is important to stress that indium salts induce the formation of allylic ethers as a mixture
of diastereoisomers, as depicted in the mechanistic picture. The allylic ethers are
the resting state for the formation of the carbenium ion, which is reversibly generated by indium(III) from the allylic alcohols. In this concerted activation, the
Lewis acid acts as a promoter for the formation of the electrophilic species, i.e.,
the carbenium ion. Although coordination of the Lewis acid to the MacMillan
catalyst is possible, and in fact was observed by NMR, the study of non-linear
effects clearly showed that just a monomeric catalytic species is responsible for
the observed stereoselection. The chiral species transmitting the information is
clearly the enamine, and the linear correlation between ee of the organocatalyst
and ee of the isolated product indicates that the formation of multiple catalytic
species during the enantio-determining step is not involved. In other words, possible interactions with chiral indium complexes formed with the organocatalyst
do not influence the enantio-determining step. Furthermore, it was mentioned in
the introduction that indium is a borderline Lewis acid for its use in the presence
of water, but it can be advantageously used in the presence of strong coordinating
amines. By combining In(OTf) 3 with a MacMillan-type of catalyst, it was possible to extend the S N 1-type reactions to the stereoselective addition of propargylic
carbenium ions, generated from the corresponding alcohols (Scheme 12) [85].
Remarkably, the reaction occurs in water, and this underlines the powerful concepts related to the use of the Mayr table for setting up reactions. The most nucleophilic species, i.e., the enamine, reacts faster with the carbenium ion than water
because there are more than ten orders of magnitude between enamine and water
nucleophilicities. Furthermore, the reaction allowed the use of propargylic alcohols
carrying disubstituted triple bonds that were not reactive in the allylidene electrophilic reaction mode. Nishibayashi reported a quite similar propargylation of aldehydes with a propargylic alcohol using slightly different conditions and reporting
the use of InBr 3 or FeCl 3 to initiate the reaction [86]. In both the reports, only aryl
propargylic alcohols are employed, and also in these cases, the use of strong electron-donating groups, such as dimethylamino and methoxy groups at the para- or
ortho-position of the aryl substituent are mandatory for a good outcome of the reaction. This is due to the decrease of electrophilicity of the propargylic carbenium ion,
which can be formed in the reaction conditions. Diaryl secondary alcohols are also
suitable precursors for the generation of stabilized carbenium ions, if Lewis acids
are employed in the presence of the organocatalyst 2c (Scheme 13) [87].
The scope of organocatalytic S N 1-type reactions was widened to include benzylic and benzhydrylic carbenium ions performing the reaction in the presence of
Reprinted from the journal
45