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@PHDTHESIS{Pandit:1024894,
author = {Pandit, Saikat},
othercontributors = {Ritter, Tobias and Patureau, Frédéric W.},
title = {{M}etallaphotoredox-catalyzed carbon–carbon
cross-coupling of organohalides with bicyclo[1.1.1]pentyl
({BCP})-thianthrenium reagents and discovery of
thianthrenium-based bifunctional {BCP} reagent},
school = {RWTH Aachen University},
type = {Dissertation},
address = {Aachen},
publisher = {RWTH Aachen University},
reportid = {RWTH-2026-00399},
pages = {1 Online-Ressource : Illustrationen},
year = {2026},
note = {Veröffentlicht auf dem Publikationsserver der RWTH Aachen
University; Dissertation, RWTH Aachen University, 2026},
abstract = {The 1,3-disubstituted bicyclo[1.1.1]pentanes (BCPs) are
promising saturated bioisosteres of the para-substituted
benzene rings in medicinal chemistry, maintaining two exit
vectors in a 180° dihedral angle. Approximately $45\%$ of
the available drug molecules contain a benzene ring. The
replacement of a phenyl ring with the saturated bioisostere
became a valuable strategy for the improvement of
pharmacokinetic properties of the drug candidates since the
first study of the bicyclo[1.1.1]pentane (BCP) analogue of
(S)-(4-carboxyphenyl)glycine in 1996. As an example, the BCP
analog of the γ-secretase inhibitor avagacestat exhibited
increased metabolic stability, membrane permeability, and
increased aqueous solubility while retaining similar
biological activity. There are mainly two approaches for the
synthesis of the substituted BCPs, developed over the past
20 years. One is the mono- or difunctionalization of the
highly reactive [1.1.1]propellane via the radical or anionic
pathways; however, the propellane is volatile and has
limited shelf stability even at –20 °C, therefore, need
to be freshly prepared prior to use. Another approach
involves the cross-coupling strategy using BCP-based
reagents, including BCP Grignard reagents, BCP iodides, BCP
boronates, and BCP redox-active esters, to incorporate the
BCP moiety into a target molecule; however, these methods
often necessitate organometallic reagents, involve multiple
preparation steps, or lack generality and versatility for
various transformations. On the other hand, stable and
versatile alkylating BCP thianthrenium reagents were
developed to achieve diverse transformations of phenols,
alcohols, and various nitrogen nucleophiles. The high
reduction potential and facile mesolytic cleavage of the
exocyclic C–S bond in BCP thianthrenium reagents are
crucial for achieving versatile reactivity. Based on the
importance of the BCP moiety and the biaryl motifs in drug
development, we designed an efficient
metallaphotoredox-catalyzed system for the cross-coupling of
aryl bromides and the BCP thianthrenium reagents. Unlike
copper catalysis, which has been successfully used in
thianthrene and BCP chemistry, we employed the synergistic
cooperation of nickel and photoredox catalysis. The single
electron transfer (SET) between the photoredox catalyst and
BCP thianthrenium reagents generates the synthetically
useful BCP radical, and the nickel catalyst has the ability
to undergo favorable oxidative addition with aryl bromides
than copper and can undergo oxidative ligation to the BCP
radical. The combination of metallaphotoredox catalysis with
the BCP thianthrenium reagent allows a mild reaction
condition where a variety of functional groups in the aryl
bromides are tolerated. Additionally, we demonstrate the
synthetic utility of this method through the
functionalization of heteroaromatic bromides and
pharmaceutical compounds. To further diversify the
reactivity of the BCP thianthrenium reagents, we employed
the alkyl halides as a coupling partner for the reductive
C(sp3)–C(sp3) cross-coupling reaction, as the alkyl
bromides are more readily available compared to the
corresponding organometallic reagents. Unlike the common
nickel-catalyzed reductive conditions used in
cross-electrophile coupling reactions, we employed a dual
copper-photoredox catalyzed system that combines silyl
radical-mediated activation of alkyl halides. The combined
dual catalyst system addresses the homocoupling problem with
the distinct redox properties of the thianthrenium salts,
which differ from the alkyl halides. The silyl
radical-mediated halogen atom abstraction followed by copper
oxidative ligation circumvents the potentially slow
oxidative addition of the alkyl halides to copper. The
method describes a broad tolerance of functional groups, and
a range of alkyl bromides, including benzyl, primary and
secondary alkyl bromides are coupled with the BCP
thianthrenium reagents. In addition, we highlight the
synthetic utility of the current approach in late-stage
functionalization of pharmaceuticals as well as in the
construction of BCP analogs of diarylmethanes, which are
important structural motifs in pharmaceutically active
compounds. Although the available BCP reagents, including
BCP thianthrenium reagents enable the rapid preparation of
promising BCP compounds, they only have a single reaction
site and are typically used as structural linkers or end
groups. Therefore, a bifunctional BCP reagent such as the
bis-thianthrenium BCP reagent, which has two reactive sites
at both BCP bridgehead positions, would allow the
construction of diverse 1,3-disubstituted BCP derivatives.
The reaction between persistent thianthrene radical cation
and the propellane in the presence of a copper catalyst can
result in the synthesis of bis-thianthrene-substituted BCP
reagent (TT+–BCP–TT+ (BF4–)2), but the reaction
successfully works only sometimes. Therefore, it is
important to mention that we cannot claim the current
reaction approach to make the reagent reliably due to the
reproducibility issue. However, the higher reduction
potential observed for the TT+–BCP–TT+ (BF4–)2 reagent
than our previously developed CF3–BCP–TT+ BF4– reagent
would allow the selective functionalization of the
TT+–BCP–TT+ (BF4–)2 reagent under metallaphotoredox
catalysis; therefore, the construction of the diverse
disubstituted BCP derivatives is possible in two steps.
Although a considerable advancement is required for
developing a reliable synthetic approach and for the
reactivity of the TT+–BCP–TT+ (BF4–)2 reagent, this
preliminary study indicates that the TT+–BCP–TT+
(BF4–)2 reagent can be used as a bifunctional reagent for
the rapid construction of BCP derivatives with a variety of
substituents at the bridgehead positions of the BCP moiety.},
cin = {152310 / 150000},
ddc = {540},
cid = {$I:(DE-82)152310_20140620$ / $I:(DE-82)150000_20140620$},
typ = {PUB:(DE-HGF)11},
doi = {10.18154/RWTH-2026-00399},
url = {https://publications.rwth-aachen.de/record/1024894},
}
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