Letter
Controlled meta-Selective C−H Mono- and Di-Olefination of
Mandelic Acid Derivatives
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ABSTRACT: Mandelic acids represent a key structural motif
present in many drug molecules. Herein, we report the controlled
meta-selective mono- and diolefination of mandelic acids by the
careful design of the substrate and oxidant. Furthermore, free meta-
functionalized mandelic acid was generated by selectively removing
the template under mild basic conditions. The synthesis of
functionalized homatropine and cyclandelate drug derivatives was
demonstrated. Kinetic isotope effects revealed C−H activation as
the rate-limiting step.
andelic acid derivatives are biologically important
molecules that are widely present in many drugs and
in most cases the templates were not reusable since a different
functional group was generated during the deprotection.12
Although the meta-selective C−H functionalizations of aryl-
acetic acids have been reported, they are mostly limited to
α,α′-unsubstituted derivatives, with limited examples for α,α′-
alkyl-substituted derivatives. Mandelic acid (α-hydroxy phenyl-
acetic acid) derivatives were generally not a suitable reacting
partner for these transformations. Herein, we report the meta-
selective controlled mono- and diolefination of mandelic acid
derivatives with a high selectivity using an easily removable and
reusable template (Scheme 1).
We started our screening with mandelic acids that contained
nitrile, pyrimidine, oxazole, or amide directing groups as
templates with Pd(OAc)2, Ac-Gly-OH, AgOAc, and HFIP for
meta-C−H olefination. Interestingly, substrate 1a, containing a
2-cyano benzyl template, gave the expected meta-olefinated
product in a good yield (79%) and high meta-selectivity
(meta:others > 11:1) with no diolefinated byproduct. Screen-
ing other reaction conditions, such as temperature, catalyst
tion), showed the current conditions (Pd(OAc)2 catalyst, Ac-
Gly-OH ligand, AgOAc oxidant, and HFIP solvent) to be
optimal. A higher ligand loading (60 mol %) was required to
drive the reaction to completion. With the optimized
conditions in hand, we carried out the olefination of 1a with
different olefin partners. Gratifyingly, excellent meta-selectivity
M
natural products, such as homatropine, cyclandelate,1 cefalexin,
etc.2 Although several derivatives of mandelic acid have been
reported, they are mostly limited to functionalization on the
side chain with limited examples for fuctionalized phenyl rings.
In 2015, Yu et al. reported the ortho-C−H functionalization
(olefination, arylation, iodination, and acetoxylation) of
protected mandelic acid derivatives;3 however, to date there
have been no general reports for the meta-selective C−H
functionalizations of mandelic acids. Given the importance of
these structural motifs, it is highly desirable to develop a
practical method for remote meta-C−H functionalization.
Directed C−H bond functionalization is an important
strategy in organic synthesis to introduce different functional
groups on the ortho-position of an aromatic ring.4 On the other
hand, meta-C−H bond functionalization is less studied and
challenging owing to the distance between the meta-C−H
bond and the directing group and as well as the electronic
effects.5 Different strategies have been developed in the past
decade to achieve meta-selectivity using transient mediators,6
directing group templates,7 steric or electronically biased
properties of substrates and catalysts, etc.8 Among these, the
directing-group-assisted U-shaped nitrile-containing end-on
template developed by Yu et al. for meta-selective C−H
bond functionalization via the formation of a 10−12
membered cyclophane-like pretransition state is an important
technique.9 This strategy was later developed and studied by
several other groups, including Maiti, Tan, and Li, for the meta-
selective C−H functionalization of hydrocinnamic acid, benzyl
alcohol, benzylamine, benzoic acids, arylacetic acids, and
others using end-on nitrile-, pyrimidine-, and pyridine-based
templates.7,10 In many cases, the template synthesis is slightly
complex and requires harsh conditions for its removal.11 Again,
Received: June 22, 2021
Published: July 19, 2021
© 2021 American Chemical Society
Org. Lett. 2021, 23, 6014−6018
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