2.3 γ-Arylation of Amine Derivatives
Based on the original study of Daugulis and co-workers, who introduced the
picolinamide bidentate directing group for the palladium-catalyzed γ-C(sp
3 )–H
arylation of amine derivatives [20], He and Chen reported major improvements
which facilitate synthetic applications [50]. Indeed, they developed milder conditions (80
C, with t-BuOH or trifluoroethanol as the solvent), which are compatible
with sensitive functional groups and stereogenic centers found in complex molecule
settings. Furthermore, based on precedents in peptide chemistry [52], they developed a modified picolinamide directing group which can be removed through
intramolecular acyl transfer under mildly acidic conditions. The importance of
these modifications was demonstrated through to the formal synthesis of (+)obafluorin (Scheme 6). The synthetic sequence started from the readily available
threonine derivative 25, which was engaged in the optimized γ-C–H arylation
conditions to afford the desired arylated product 26 in 60% yield. The directing
group was then smoothly removed under acidic treatment to provide aminoester 27,
which served as an intermediate in the formal synthesis of (+)-obafluorin.
In 2013, Chen and co-workers reported a streamlined approach for the synthesis
of tetrahydroquinolines (THQs) via the sequential functionalization of remote C–H
bonds [53]. Starting from readily available aryl iodide and aliphatic amine precursors, this strategy involved a three-step sequence including palladium-catalyzed
γ-C(sp
3 )–H arylation, followed by a previously optimized metal-free ε-C(sp
2 )–H
iodination reaction [54] and a more classical Cu-catalyzed intramolecular C–N
coupling. To test the efficacy of this novel procedure, the authors applied it to the
total synthesis of the antimalarial alkaloid (+)-angustureine (Scheme 7) [55]. NAlkylpicolinamide 28 was easily accessible from commercially available (S)-(+)-3Scheme 5 Total synthesis of podophyllotoxin via Pd-catalyzed directed C–H arylation
140
D. Dailler et al.
Based on the original study of Daugulis and co-workers, who introduced the
picolinamide bidentate directing group for the palladium-catalyzed γ-C(sp
3 )–H
arylation of amine derivatives [20], He and Chen reported major improvements
which facilitate synthetic applications [50]. Indeed, they developed milder conditions (80
C, with t-BuOH or trifluoroethanol as the solvent), which are compatible
with sensitive functional groups and stereogenic centers found in complex molecule
settings. Furthermore, based on precedents in peptide chemistry [52], they developed a modified picolinamide directing group which can be removed through
intramolecular acyl transfer under mildly acidic conditions. The importance of
these modifications was demonstrated through to the formal synthesis of (+)obafluorin (Scheme 6). The synthetic sequence started from the readily available
threonine derivative 25, which was engaged in the optimized γ-C–H arylation
conditions to afford the desired arylated product 26 in 60% yield. The directing
group was then smoothly removed under acidic treatment to provide aminoester 27,
which served as an intermediate in the formal synthesis of (+)-obafluorin.
In 2013, Chen and co-workers reported a streamlined approach for the synthesis
of tetrahydroquinolines (THQs) via the sequential functionalization of remote C–H
bonds [53]. Starting from readily available aryl iodide and aliphatic amine precursors, this strategy involved a three-step sequence including palladium-catalyzed
γ-C(sp
3 )–H arylation, followed by a previously optimized metal-free ε-C(sp
2 )–H
iodination reaction [54] and a more classical Cu-catalyzed intramolecular C–N
coupling. To test the efficacy of this novel procedure, the authors applied it to the
total synthesis of the antimalarial alkaloid (+)-angustureine (Scheme 7) [55]. NAlkylpicolinamide 28 was easily accessible from commercially available (S)-(+)-3Scheme 5 Total synthesis of podophyllotoxin via Pd-catalyzed directed C–H arylation
140
D. Dailler et al.