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\DOI{10.5802/crchim.338}
\datereceived{2024-09-03}
\daterevised{2024-09-04}
\dateaccepted{2024-09-06}
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\dateposted{2025-02-13}
\begin{document}

\begin{noXML}

\CDRsetmeta{articletype}{clarification}

\title{Modern tools for the functionalization of C(sp\textsuperscript{3}) centers by
catalysis}

\alttitle{Des outils modernes pour la fonctionnalisation de centres 
C(sp\textsuperscript{3}) par catalyse}

\author{\firstname{Floris} \lastname{Buttard}\CDRorcid{0000-0002-0874-451X}\IsCorresp}
\address{INSA Rouen Normandie, Univ Rouen Normandie, CNRS, Normandie
Univ, COBRA UMR 6014, F-76000 Rouen, France}
\email[F. Buttard]{floris.buttard@univ-rouen.fr}

\author{\firstname{Tatiana} \lastname{Besset}\CDRorcid{0000-0003-4877-5270}\IsCorresp}
\addressSameAs{1}{INSA Rouen Normandie, Univ Rouen Normandie, CNRS,
Normandie Univ, COBRA UMR 6014, F-76000 Rouen, France}
\email[T. Besset]{tatiana.besset@insa-rouen.fr}

\keywords{\kwd{Synthetic methodology}
\kwd{C(sp\textsuperscript{3}) centers}
\kwd{Transition metal catalysis}
\kwd{Photochemical transformations}
\kwd{Proximal and distal functionalization}}

\altkeywords{\kwd{M\'{e}thodes de synth\`{e}se}
\kwd{Centres C(sp\textsuperscript{3})}
\kwd{Catalyse par les m\'{e}taux de transition}
\kwd{Transformations photochimiques}
\kwd{Fonctionnalisation en position proximales ou distales}}

\thanks{University of Rouen Normandy, INSA Rouen Normandy, Centre
National de la Recherche Scientifique (CNRS), European Regional
Development Fund (ERDF), Labex SynOrg (ANR-11-LABX-0029), Carnot
Institute I2C, XL-Chem Graduate School of Research  (ANR-18-EURE-0020
XL CHEM),  European Research Council (ERC) under the  European Union's
Horizon 2020 research and innovation program  (Grant Agreement No.
758710),  European Union's Horizon 2020 research and innovation program
under  Marie Sk\l{}odowska-Curie Grant Agreement Number  101034329, 
Region Normandie (WINNINGNormandy program),  French National Research
Agency  (ANR-21-CE07-0035-02 and ANR-22-CE92-0083).}

\begin{abstract}
In the quest for molecular complexity, the direct and selective
functionalization of C(sp\textsuperscript{3}) centers is of paramount importance. As
sulfur- and/or fluorine-containing molecules are particularly
important, the development of methods to (regio)selectively introduce
moieties containing these atoms on a C(sp\textsuperscript{3}) center by direct C--H
bond functionalization or decarboxylative reaction has garnered our
interest in the last few years.  Given the challenges that the direct
functionalization of C(sp\textsuperscript{3}) centers represents,  this account
summarizes our recent contributions thanks to strategies based on
transition metal catalysis and photochemistry. 
\end{abstract}

\begin{altabstract}
La fonctionnalisation directe et s\'{e}lective de centres
C(sp\textsuperscript{3}) est une approche remarquable permettant
d'obtenir des mol\'{e}cules complexes de fa\c{c}on efficace. Du fait
de l'importance des mol\'{e}cules contenant du soufre et/ou du fluor,
le d\'{e}veloppement de m\'{e}thodes pour introduire
(r\'{e}gio)s\'{e}lectivement des groupements contenant ces atomes sur
un centre C(sp\textsuperscript{3}), par fonctionnalisation directe
d'une liaison C--H ou par r\'{e}action d\'{e}carboxylante, a
suscit\'{e} un vif int\'{e}r\^{e}t au cours des derni\`{e}res
ann\'{e}es. \'{E}tant donn\'{e} les d\'{e}fis que repr\'{e}sente la
fonctionnalisation directe des centres C(sp\textsuperscript{3}), cet
article r\'{e}sume nos r\'{e}centes contributions gr\^{a}ce \`{a} des
strat\'{e}gies bas\'{e}es sur la catalyse par les m\'{e}taux de
transition et la photochimie.
\end{altabstract}

\maketitle

\vspace*{2pc}

\twocolumngrid

\end{noXML}

\let\rmmu\upmu

\section{Introduction}\label{sec1}
The quest for molecular complexity has garnered the interest of the
scientific community over the years. To meet this synthetic
challenge, modern tools have been designed, providing straightforward
and efficient synthetic routes. Although major advances have been made for
the functionalization of  C(sp$^{2}$) centers, the direct and selective
functionalization of C(sp$^{3}$) centers remains challenging and has
driven the curiosity of scientists to push forward in this direction
with innovative
strategies~\cite{1a,1b,1c,1d,1e,1g,1h,1i,1j,1k,1l,1m,1n,1o,1p,1q,1r,1s,1t,1u,1v,1w}.  
Given the challenges that the direct functionalization of C(sp$^{3}$)
centers represents and considering the omnipresence of sulfur- and
fluorine-containing molecules in pharmaceuticals and agrochemicals, among 
others~\cite{2}, this account summarizes our recent contributions to
selectively and efficiently forge C--S bonds thanks to strategies based
on transition metal catalysis and photochemistry, with a special focus
on C(sp$^{3}$)--S bond formation.

\section{Transition-metal-catalyzed C(sp$^{3}$)--H bond
functionalization}\label{sec2}

\subsection{Pd-catalyzed trifluoromethylthiolation of C(sp$^{3}$)
centers}\label{sec2.1}
Benefiting from the recent breakthroughs made in homogeneous catalysis
and especially how transition-metal-catalyzed C--H bond
functionalization has revolutionized the way molecules can be 
made~\cite{1a,1b,1c,1d,1e,1g,1h,1i,1j,1k,1l,1m,1n,1o,1p,1q,1r,1s,1t,1u,1v,1w}, 
we first focused on the direct construction of C--S bonds by transition
metal catalysis via C--H bond activation on aliphatic molecules. This
task is challenging considering the inert character of non-acidic
C(sp$^{3}$)--H bonds. Merging our interest in homogeneous catalysis and
organofluorine chemistry, special attention has been paid to the
SCF$_{3}$  moiety~\cite{3a,3b,3c,3d}, an emerging fluorinated group
possessing high electron-withdrawing character and good ability to
enhance molecule lipophilicity (Hansch hydrophobic parameter:  $\uppi
= 1.44$ vs $\uppi =0.88$ for CF$_{3}$)~\cite{4a,4b}. Hence,  Pd-catalyzed
C(sp$^{3}$)--H bond trifluoromethylthiolation of alkyl amides at the
${\rmbeta}$-position, under mild conditions, was developed using
electrophilic sources  (Scheme~\ref{sch1})~\cite{5}.  Optimization of
the reaction conditions revealed that the presence of a bidentate
directing group (amide derived from 8-aminoquinoline) and pivalic
acid as an additive was crucial to ensure the selectivity and
efficiency of the  process (note 
that a flow process has then been developed,
further improving the efficiency of the reaction~\cite{6}). 
Various aliphatic amides having
primary ${\rmbeta}$-C(sp$^{3}$)--H bonds were functionalized. From
${\rmalpha}$,${\rmalpha}$-dialkyl substituted amides, the reaction was
then applied to ${\rmalpha}$,${\rmalpha}$-dimethylated hydrocinnamic
acid derivatives. Even amides prepared from phenylacetic acid
derivatives or bearing ${\rmalpha}$-C--H bonds were smoothly converted
into the corresponding fluorinated product, allowing the synthesis of
the SCF$_{3}$-containing analogues of bioactive molecules such as
ibuprofen and naproxen. Note that a total control of the selectivity
was observed: monofunctionalization at  the ${\rmbeta}$-position only,
even in the presence of competitive sites (e.g., benzylic positions).
For the Munavalli reagent \textbf{I}, playing both the roles of oxidant and
SCF$_{3}$ source, a plausible mechanism is depicted in
Scheme~\ref{sch1}. After the coordination of the palladium catalyst
with the bidentate directing group (intermediate \textbf{int1}), the
metallacycle \textbf{int2} was formed (C--H bond activation event).
The latter would undergo oxidative addition in the C--SCF$_{3}$ 
bond leading to the putative Pd(IV) species \textbf{int3}, which after
reductive elimination would yield the desired product and release the
catalyst. Interestingly, the directing group can be easily cleaved
under basic reaction conditions and the SCF$_{3}$  moiety is converted
into the corresponding SOCF$_{3}$ group when treated with
$m$-chloroperbenzoic acid  ($m$-CPBA).

\begin{scheme*}
\includegraphics{sc01}
\vspace*{.5pc}
\caption{\label{sch1}Trifluoromethylthiolation of  C(sp$^{3}$) centers
under palladium catalysis.}
\end{scheme*}

\subsection{Directed chlorination of amides under\newline 
palladium catalysis~\cite{7}}\label{sec2.2}
As the  versatility of the above-depicted approach to
functionalize C(sp$^{3}$) centers was intriguing, the chlorination reaction was
investigated. The Pd-catalyzed directed halogenation of non-activated
C(sp$^{3}$)--H is challenging as the reductive elimination is known to
be difficult and the newly formed C--X bond might be reactive in the
presence of the catalyst. Thanks to a Pd(II)/Pd(IV) process, known to
facilitate the reductive elimination step, the Pd-catalyzed
chlorination of aliphatic amides was developed using the readily
available $N$-chlorosuccinimide (NCS) as the electrophilic Cl source 
(Scheme~\ref{sch2}). The transformation proceeded smoothly at room
temperature and favored the formation of  mono- and di-chlorinated
compounds, depending on the quantity of NCS. It is worth mentioning
that when a mixture was obtained, the two compounds were easily
separated by column chromatography. Thanks to this synthetic handle,
the synthesis of ${\rmbeta}$-lactams was realized by the treatment of 
chlorinated amides under basic conditions. This approach provided an
access to molecules of interest for pharmaceutical and agrochemical
companies. Moreover, under oxidative conditions in the presence of
ceric ammonium nitrate, the amide derived from 
8-aminoquinoline was smoothly converted into the corresponding primary
amide.

\begin{scheme*}
\includegraphics{sc02}
\vspace*{.5pc}
\caption{\label{sch2}Directed chlorination of aliphatic amides at room
temperature. Overall yields are given, and all mono- and di-chlorinated
compounds are isolated  separately.\newline 
$^{\mathrm{a}}$~Using 10 equiv of NCS.}
\end{scheme*}

\section{Photoinduced and photocatalyzed C(sp$^{3}$)--H
functionalization}\label{sec3}

\subsection{Functionalization of C(sp$^{3}$) centers by\newline 
photocatalysis~\cite{8}}\label{sec3.1}
Pursuing our efforts to access trifluoromethylthiolated molecules in a
sustainable manner, the photocatalytic
${\rmalpha}$-trifluoromethylthiolation of  $N$-acyl amines was studied
in the presence of the Munavalli reagent \textbf{I} 
(Scheme~\ref{sch3}). Despite major advances made for the C--H
functionalization at the ${\rmalpha}$-position of an amide by 
photocatalysis~\cite{9a,9b,9c,9d,9e,9f,9g,9h,9i}, there was no report
dealing with the formation of a C--S bond. We hypothesized that the
elusive acyclic fluorinated thioaminals would be synthesized by the
catalytic generation of a carbon-centered radical 
at the ${\rmalpha}$-position of a nitrogen
under visible light irradiation in the presence of a suitable
photocatalyst, followed by a reaction with a suitable SCF$_{3}$ source.
Using the low catalytic loading of an organophotocatalyst, the
functionalization of aromatic and aliphatic amides was achieved in high
yields (up to 83\% yield, 20 examples). The transformation was tolerant
to a large panel of diversely substituted benzamides as well as various
functional groups (halogens, ester, cyano). Interestingly, the reaction
was completely selective towards the formation of the desired
trifluoromethylthiolated products even in the presence of a benzyl or a
methyl group at the ${\rmalpha}$-position of the amide carbonyl. 

\begin{scheme*}
\includegraphics{sc03}
\vspace*{.5pc}
\caption{\label{sch3}Photochemical trifluoromethylthiolation of
$N$-acyl amines using the Munavalli reagent.}
\vspace*{-7pt}
\end{scheme*}

Detailed mechanistic studies were conducted. They revealed that the
active SCF$_{3}$ species was the in situ generated SCF$_{3}$
dimer and supported a proton-coupled electron transfer (PCET). Indeed,
the following plausible mechanism for this trifluoromethylthiolation
reaction was suggested. The irradiation induces the excited state of
the tetrakis(9H-carbazol-9-yl) isophthalonitrile (4CzIPN) photocatalyst,
which reduces the electrophilic SCF$_{3}$ source via a single
electron transfer, leading to the generation of a SCF$_{3}$
radical that can recombine to form the (SCF$_{3}$)$_{2}$ dimer along
with the oxidized photocatalyst (4-CzIPN$\bullet^{+}$). In the
presence of the released phthalimide anion, a 
PCET followed by 1,2-hydrogen atom transfer (HAT) occurred, allowing the
formation of a primary radical at the ${\rmalpha}$-position of the
nitrogen. The latter would react with the (SCF$_{3}$)$_{2}$ dimer to
furnish the desired product along with the ${}^{\bullet}$SCF$_{3}$
radical.

Over the last few years, our group has also been interested in developing
new synthetic methods to incorporate a thiocyanate moiety on various 
substrates~\cite{10a,10b,10c,10d,10e}. Thiocyanates are not only highly
biorelevant compounds (for general reviews on thiocyanates, 
see~\cite{11a,11b,11c,11d,11e,11f,11g,11h}), as this functional group is present in several
bioactive  molecules~\cite{2}, but are also valuable synthetic
linchpins that can be used to access various sulfur-containing products
of biological  interest~\cite{13a,13b,13c}. In this context, in
\mbox{collaboration} with the Lebel group, we have designed a divergent
synthesis of alkyl thiocyanates and isothiocyanates from readily
available carboxylic acids  via a photocatalyzed
decarboxylative  transformation~\cite{10e}. The formation of
thiocyanates or their isothiocyanate isomers can be tuned by the choice
of additives. In the presence of 2,4,6-triphenylpyrylium
tetrafluoroborate  as the organophotocatalyst, under blue light
irradiation, \textit{N}-thiocyanatosaccharin \textbf{II} as the 
thiocyanating agent, and a catalytic amount of sodium carbonate, a large
panel of aliphatic carboxylic acids were smoothly converted into the
corresponding alkyl thiocyanates;  most yields were above 60\% 
(Scheme~\ref{sch4}). The reaction conditions were shown to be
compatible with a wide range of functional groups, with ketones,
halides, heterocycles, and azides remaining inert. Besides, highly
biorelevant thiocyanates could be synthesized through this method as
well, starting from bioactive carboxylic acids, such as the synthesis
of an analogue of \mbox{ibuprofen}. \looseness=-1

\begin{scheme*}
\includegraphics{sc04}
\vspace*{.5pc}
\caption{\label{sch4}Divergent 
synthesis of alkyl thiocyanates and isothiocyanates from readily
available carboxylic acids by photocatalysis.}
\vspace*{-.5pc}
\end{scheme*}

The mechanism of this transformation was proposed to involve a
single-electron oxidation of the carboxylate formed by deprotonation
of the corresponding carboxylic acid, leading to the radical
intermediate \textbf{int1} upon decarboxylation. Reaction with the
thiocyanate source \textbf{II} then allowed the formation of the final
thiocyanate product and the intermediate \textbf{int2}, which was
subsequently reduced to \textbf{int3}, regenerating \textbf{cat1}. A
radical chain propagation process involving HAT
with \textbf{int2} was also shown to be possible under the reaction
conditions.

In the presence of a catalytic amount of acetic acid instead of sodium
carbonate and under otherwise identical reaction conditions, the
isothiocyanate products were obtained in high yields (53--91\% yields).
Their formation likely arose from the isomerization of the thiocyanates
under these reaction conditions. 

\subsection{A light-driven process for the distal\newline 
functionalization of C(sp$^{3}$) centers}\label{sec3.2}
Our group has also been involved in the development of new synthetic
methods for the straightforward introduction of various fluorinated
functional groups and, in particular, emerging fluorinated moieties.
Although considerable progress has been recently made for the
functionalization of various substrates with biorelevant SCF$_2$R
functional groups~\cite{14a,14b,14c,14d,14e},  significant challenges
still remained for such functionalization of non-activated
C(sp$^{3}$)--H positions on aliphatic chains. In this context, a
radical reaction represents an attractive tool for the regioselective
functionalization of C(sp$^{3}$)--H centers with fluorinated 
moieties~\cite{14a}. 

Inspired by the use of hypervalent iodide reagents as radical promoters
from  alcohols~\cite{15}, we have developed a new synthetic approach
for the regioselective ${\rmdelta}$-functionalization of free alcohols
with various SCF$_2$R moieties under mild reaction conditions, enabled
by 1,5-HAT~\cite{16,17}.  In the presence
of phenyliodine diacetate (PIDA) and the reagents
\textbf{III}--\textbf{VI} under blue light irradiation, free alcohols
(primary, secondary, and tertiary) were converted into the corresponding
products bearing the fluorinated moiety at the ${\rmdelta}$-position
from the alcohols (Scheme~\ref{sch5}).
This approach was successfully applied for the
introduction of SCF$_{3}$~\cite{7}, SCF$_2$PO(OEt)$_2$~\cite{17},
SCF$_2$CO$_2$Et~\cite{17}, and SCF$_2$H~\cite{17} moieties 
in the presence of the corresponding sulfonyl-SCF$_2$R reagents.
The reaction conditions were shown to be compatible with various
functional groups, such as azides, protected amines, and esters. The
mechanism of the reaction was proposed to involve the formation of the
hypervalent iodide intermediate \textbf{int1} from PIDA and the alcohol
substrate, followed by its homolysis under blue light irradiation
producing the alkoxy radical \textbf{int2}. The latter may subsequently
undergo 1,5-HAT to furnish the C-centered radical intermediate
\textbf{int3}, which can react with the
sulfonyl--SCF$_2$R reagent 
(\textbf{III}--\textbf{VI}) to form the functionalized alcohol. For
purification purposes, the free alcohol products were in situ
acetylated to obtain the final products.

\begin{scheme*}
\includegraphics{sc05}
\vspace*{.5pc}
\caption{\label{sch5}1,5-HAT enabled the construction of a
carbon--SCF$_{2}$R bond on aliphatic alcohols at a remote position.}
\vspace*{-8pt}
\end{scheme*}

\section{Conclusion}\label{sec4}
Over the years, major advances have been made in the functionalization
of C(sp$^{3}$) centers by using modern tools. Hence, methods based on
transition metal catalysis, photocatalysis, and transition-metal-free
processes were developed. With these contributions, the construction of
C(sp$^{3}$)--SR (R $=$ CF$_{3}$, CF$_{2}$FG, CN) and C(sp$^{3}$)--Cl at
proximal and distal positions was possible, expanding the chemical
space of compounds of interest for academia 
and industries. 

\section*{Declaration of interests}
The authors do not work for, advise, own shares in, or receive funds
from any organization that  could  \mbox{benefit} from this article,
and have declared no affiliations other than their research
organizations.

\section*{Funding}
This work has been partially supported by  University of Rouen
Normandy,  INSA Rouen Normandy,  Centre National de la Recherche
Scientifique (CNRS),  European Regional Development Fund (ERDF),  Labex
SynOrg  (ANR-11-LABX-0029),  Carnot \mbox{Institute} I2C,  XL-Chem Graduate School
of Research   (ANR-18-EURE-0020 XL CHEM), and  Region
Normandie.  TB thanks the  European Research Council (ERC) under the 
European Union's Horizon 2020
research and innovation program  (Grant
Agreement No. 758710).  FB thanks the  European Union's Horizon 2020
research and innovation program  under  Marie Sk\l{}odowska-Curie
Grant Agreement Number  101034329,  and the  Region Normandie
(WINNINGNormandy program) for funding.  The French National Research
Agency  (ANR-21-CE07-0035-02 and ANR-22-CE92-0083)  is gratefully
acknowledged for generous financial support.

\CDRGrant[Labex SynOrg]{ANR-11-LABX-0029}
\CDRGrant[XL-Chem]{ANR-18-EURE-0020}
\CDRGrant[ERC]{758710}
\CDRGrant[EU]{101034329}
\CDRGrant[ANR]{ANR-21-CE07-0035-02}
\CDRGrant[ANR]{ANR-22-CE92-0083}

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