393
2.3 Hetero-functionalization of Carboxylic Acid Equivalents
via Bidentate Directing Groups
Since the influential work by Daugulis on 8-aminoquinoline-directed C–H bond
functionalization of arenes under palladium catalysis, the bidentate directing groupassisted C–H functionalization has emerged as a fascinating area of research in
organic chemistry [52]. A series of N,N-, N,O-, and N,S-bidentate directing groups
were developed for the hetero-functionalization of aliphatic carboxylic acids [14,
53–55]. Due to stronger chelating aptitude of bidentate directing groups towards
transition metals compared to that of monodentate counterparts, the formation of
metallacycle intermediates is thermodynamically more favored. In addition, simple
installation and cleavage of those directing groups augment the practical applicability of the catalytic approaches [54, 55].
C–O bond formation: The directed C(sp
3
)–H bond oxy-functionalization under
the assistance of a bidentate chelating group is one of the most explored heterofunctionalization approaches for carboxylic acids. In 2005, Corey et al. reported the
first example of a palladium-catalyzed direct acetoxylation of α-amino acids via
transforming them into 8-aminoquinoline-derived amides [56]. Common α-amino
acids, including leucine, alanine, β-phenylalanine, etc., were acetoxylated with acetic anhydride at the β-carbon center with regard to the 8-aminoquinoline amide
giving an expedient entry to β-hydroxy- and β-acetoxy-α-amino acids that serve as
versatile building blocks for numerous bioactive compounds (Scheme 16) [57–60].
The rate of this C–H oxidation process was notably enhanced by the presence of
Mn
2+
that was believed to form Mn 3 O(OAc) 7 under oxidative condition, hence acting as a Lewis acid to ease the palladacycle 60 formation.
A copper-catalyzed strategy for the acetoxylation of methyl groups in simple
carboxamides was also described with the aid of 8-aminoquinoline directing auxiliary. Hence, Cu(OAc) 2 in conjunction with AgOAc promotes the β-acetoxylation of
terminal methyl groups in respect to the bidentate 8-aminoquinolinyl amide substituent (Scheme 17) [61]. However, a mixture of mono- and bis-acetoxylated products was resulted for substrates bearing two chemically alike methyl groups at
β-position. The cleavage of the chelating auxiliary can be performed under mild
reaction condition to afford the primary amide.
The C(sp
3
)–H acetoxylation of carboxylic acids was also reported to proceed
under the influence of another bidentate coordinating substituent, S-methyl-S-2pyridylsulfoximine (MPyS) [62, 63]. In this case the five-fused five-membered palladacycle intermediate is formed via the coordination of the directing group through
pyridyl and sulfoximine nitrogens to the palladium center. Gratifyingly, the reaction
condition was tuned to obtain mono-acetoxylated products at room temperature and
bis-acetoxylated products at an elevated temperature (70 °C) (Scheme 18). The free
β-hydroxy carboxylic acids can be accessed via the removal of the exquisite
S-methyl-S-2-pyridylsulfoximine (MPyS) auxiliary from the acetoxylated
carboxamides.
C(sp
3
)–H Bond Hetero-functionalization of Aliphatic Carboxylic Acid Equivalents…
2.3 Hetero-functionalization of Carboxylic Acid Equivalents
via Bidentate Directing Groups
Since the influential work by Daugulis on 8-aminoquinoline-directed C–H bond
functionalization of arenes under palladium catalysis, the bidentate directing groupassisted C–H functionalization has emerged as a fascinating area of research in
organic chemistry [52]. A series of N,N-, N,O-, and N,S-bidentate directing groups
were developed for the hetero-functionalization of aliphatic carboxylic acids [14,
53–55]. Due to stronger chelating aptitude of bidentate directing groups towards
transition metals compared to that of monodentate counterparts, the formation of
metallacycle intermediates is thermodynamically more favored. In addition, simple
installation and cleavage of those directing groups augment the practical applicability of the catalytic approaches [54, 55].
C–O bond formation: The directed C(sp
3
)–H bond oxy-functionalization under
the assistance of a bidentate chelating group is one of the most explored heterofunctionalization approaches for carboxylic acids. In 2005, Corey et al. reported the
first example of a palladium-catalyzed direct acetoxylation of α-amino acids via
transforming them into 8-aminoquinoline-derived amides [56]. Common α-amino
acids, including leucine, alanine, β-phenylalanine, etc., were acetoxylated with acetic anhydride at the β-carbon center with regard to the 8-aminoquinoline amide
giving an expedient entry to β-hydroxy- and β-acetoxy-α-amino acids that serve as
versatile building blocks for numerous bioactive compounds (Scheme 16) [57–60].
The rate of this C–H oxidation process was notably enhanced by the presence of
Mn
2+
that was believed to form Mn 3 O(OAc) 7 under oxidative condition, hence acting as a Lewis acid to ease the palladacycle 60 formation.
A copper-catalyzed strategy for the acetoxylation of methyl groups in simple
carboxamides was also described with the aid of 8-aminoquinoline directing auxiliary. Hence, Cu(OAc) 2 in conjunction with AgOAc promotes the β-acetoxylation of
terminal methyl groups in respect to the bidentate 8-aminoquinolinyl amide substituent (Scheme 17) [61]. However, a mixture of mono- and bis-acetoxylated products was resulted for substrates bearing two chemically alike methyl groups at
β-position. The cleavage of the chelating auxiliary can be performed under mild
reaction condition to afford the primary amide.
The C(sp
3
)–H acetoxylation of carboxylic acids was also reported to proceed
under the influence of another bidentate coordinating substituent, S-methyl-S-2pyridylsulfoximine (MPyS) [62, 63]. In this case the five-fused five-membered palladacycle intermediate is formed via the coordination of the directing group through
pyridyl and sulfoximine nitrogens to the palladium center. Gratifyingly, the reaction
condition was tuned to obtain mono-acetoxylated products at room temperature and
bis-acetoxylated products at an elevated temperature (70 °C) (Scheme 18). The free
β-hydroxy carboxylic acids can be accessed via the removal of the exquisite
S-methyl-S-2-pyridylsulfoximine (MPyS) auxiliary from the acetoxylated
carboxamides.
C(sp
3
)–H Bond Hetero-functionalization of Aliphatic Carboxylic Acid Equivalents…