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\DOI{10.5802/crchim.350}
\datereceived{2024-07-18}
\daterevised{2024-09-09}
\dateaccepted{2024-09-27}
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\begin{document}

\begin{noXML}

\CDRsetmeta{articletype}{review}

\title{Recent achievements in the synthesis and 
reactivity of pentafluorosulfanyl-alkynes}

\alttitle{R\'{e}alisations r\'{e}centes en synth\`{e}se et
r\'{e}activit\'{e} des alcynes pentafluorosulfanyl\'{e}s}

\author{\firstname{Floriane} \lastname{Ren\'{e}}\CDRorcid{0009-0003-3197-9960}}
\address{Universit\'e de Haute-Alsace, Universit\'e de Strasbourg,
CNRS, LIMA, UMR 7042, 3bis rue Werner, 68000 Mulhouse, France}

\author{\firstname{L\'{e}o} \lastname{Cl\'{e}ment--Comoy}\CDRorcid{0009-0003-5951-5818}}
\addressSameAs{1}{Universit\'e de Haute-Alsace, Universit\'e de Strasbourg,
CNRS, LIMA, UMR 7042, 3bis rue Werner, 68000 Mulhouse, France}

\author{\firstname{Nicolas} \lastname{Blanchard}\CDRorcid{0000-0002-3097-0548}}
\addressSameAs{1}{Universit\'e de Haute-Alsace, Universit\'e de Strasbourg,
CNRS, LIMA, UMR 7042, 3bis rue Werner, 68000 Mulhouse, France}

\author{\firstname{Vincent} \lastname{Bizet}\CDRorcid{0000-0002-0870-1747}\IsCorresp}
\addressSameAs{1}{Universit\'e de Haute-Alsace, Universit\'e de Strasbourg,
CNRS, LIMA, UMR 7042, 3bis rue Werner, 68000 Mulhouse, France}
\email[V. Bizet]{vbizet@unistra.fr}

 \shortrunauthors

\keywords{\kwd{Pentafluorosulfanyl}
\kwd{SF\textsubscript{5}-alkyne}\kwd{Cycloaddition}
\kwd{Hydrofunctionalization}\kwd{Regioselective}\kwd{Stereoselective}}

\altkeywords{\kwd{Pentafluorosulfanyle}
\kwd{Alcyne SF\textsubscript{5}}\kwd{Cycloaddition}
\kwd{Hydrofonctionnalisation}\kwd{R\'{e}gios\'{e}lectif}
\kwd{St\'{e}r\'{e}os\'{e}lectif}}

\begin{abstract}
In the dynamic field of pentafluorosulfanyl (SF\textsubscript{5}) chemistry, the
SF\textsubscript{5}-alkynes have emerged as essential, readily accessible, and
modular building blocks for the construction of a wide variety of
SF\textsubscript{5}-containing molecules. This polarized platform has been used to
perform highly regio-, chemo-, and stereoselective transformations such
as heterocycle synthesis, cycloaddition, and hydroelementation
reactions. This brief review provides an overview of recent
developments in the synthesis and reactivity of SF\textsubscript{5}-alkynes, which
are fascinating building blocks that have yet to reveal their full \unskip\break 
synthetic potential.
\end{abstract}


\begin{altabstract}
Dans le domaine dynamique de la chimie du groupement
pentafluorosulfanyle (SF\textsubscript{5}), les alcynes SF\textsubscript{5} sont apparus
comme des \'{e}l\'{e}ments de base essentiels, facilement accessibles
et modulaires pour la construction d'une grande vari\'{e}t\'{e} de
mol\'{e}cules contenant du SF\textsubscript{5}. Cette plateforme polaris\'{e}e a
\'{e}t\'{e} utilis\'{e}e pour effectuer des transformations hautement
r\'{e}gio-, chimio- et st\'{e}r\'{e}os\'{e}lectives telles que la
synth\`{e}se d'h\'{e}t\'{e}rocycles, les r\'{e}actions de cycloaddition
et d'hydro\'{e}l\'{e}mentation. Cette br\`{e}ve revue pr\'{e}sente un
aper\c{c}u des derni\`{e}res avanc\'{e}es concernant la synth\`{e}se et
la r\'{e}activit\'{e} des alcynes SF\textsubscript{5}, des briques
\'{e}l\'{e}mentaires qui n'ont pas encore r\'{e}v\'{e}l\'{e} tout leur
potentiel de synth\`{e}se.
\end{altabstract}

\maketitle


\vspace*{10pt}

\twocolumngrid

\end{noXML}


\section{Introduction}

Often compared to trifluoromethyl (CF$_{3}$), the pentafluorosulfanyl
(SF$_{5}$) group is an emerging fluorinated group that has experienced
exponential growth over the years, finding numerous applications in
life and material sciences (for reviews on SF$_{5}$,
see~\cite{1a,1b,1c,1d,1e,1f}). This is due to a unique combination of
physicochemical properties such as a large volume between CF$_{3}$ and
\textit{tert}-butyl, an octahedral geometry, a high electronegativity
(3.65 vs 3.36 for the CF$_{3}$) combined with a high lipophilicity,
which makes this SF$_{5}$ group highly polar and lipophilic.
SF$_{5}$-alkynes are readily available substrates, easily prepared from
terminal alkynes, which have been used as SF$_{5}$-building blocks in
many transformations~\cite{2}. This short review/account is the
follow-up to the review article we have published in 2022~\cite{2} and
it is mainly dedicated to the latest developments of SF$_{5}$-alkynes
from their preparation to the synthetic applications.


\section{Pentafluorosulfanylation of alkynes}\label{sec2}

\subsection{Chloropentafluorosulfanylation}

For the last two decades, the most efficient and reliable method to
carry out chloropentafluorosulfanylation of alkynes \textbf{1} has been
the Dolbier's procedure using SF$_{5}$Cl in hexane under free radical
conditions initiated by triethylborane/oxygen~\cite{3}. Like all
methods, this one suffers from certain limitations, such as a
restricted substrate range (\textbf{2}) and the formation of some
dimeric by-products \textbf{3} (Scheme~\ref{sch1}). Since then, several
scientific groups have developed alternative conditions for the
activation and/or generation of SF$_{5}$Cl to broaden the scope and
reactivity.

\begin{scheme*}
\includegraphics{sc01}
{\vspace*{6pt}}
\caption{\label{sch1}Radical chloropentafluorosulfanylation of terminal
alkynes initiated by triethylborane.}
{\vspace*{-11pt}}
\end{scheme*}

\begin{scheme}
\includegraphics{sc02}
{\vspace*{6pt}}
\caption{\label{sch2}Radical chloropentafluorosulfanylation of terminal
alkynes initiated by EDA-complex under visible light irradiation.}
{\vspace*{-14pt}}
\end{scheme}


In 2021, Paquin and co-workers developed an alternative activation
strategy to generate the SF$_{5}$ radical from SF$_{5}$Cl by using an
electron donor--acceptor (EDA) complex and visible light irradiation
for the chloropentafluorosulfanylation of alkenes and alkynes
(Scheme~\ref{sch2})~\cite{4}. A mechanism was proposed starting with
the in-situ formation of enamine \textbf{5} from
2,2-diphenylacetaldehyde and pyrrolidine. The EDA complex \textbf{6} is
then formed by halogen bonding with the chlorine atom of SF$_{5}$Cl.
Under visible light irradiation from a 23~W compact fluorescent lamp
(CFL), the SF$_{5}$ radical is formed together with the radical
cationic enamine \textbf{7} and the chlorine anion. The SF$_{5}$
radical is selectively introduced at the terminal position of the
alkyne (to generate the vinyl radical \textbf{8}), while the chlorine
atom could originate from SF$_{5}$Cl by radical propagation or by
recombination of \textbf{8} with a chlorine radical released during the
regeneration of \textbf{5}.


In 2022, Qing and co-workers developed the synthesis of
SF$_{5}$-alkynes by radical addition of SF$_{5}$Cl to
ethynylbenziodoxolone derivatives \textbf{9} under blue light 
irradiation~\cite{5}. According to the proposed mechanism, the SF$_{5}$
radical is generated by light irradiation at 440~nm, followed by
addition onto the triple bond of the EBX reagent. The elimination of
the adduct (\textbf{10}) then allows the direct formation of a
SF$_{5}$-alkyne~\textbf{4}. This method gives access to
SF$_{5}$-alkynes in yields ranging from 49 to 76\% yield
(Scheme~\ref{sch3}).


\begin{scheme*}
\includegraphics{sc03}
{\vspace*{13pt}}
\caption{\label{sch3}Chloropentafluorosulfanylation of
ethynylbenziodoxolone derivatives under blue light irradiation.}
{\vspace*{-7pt}}
\end{scheme*}


Light activation of SF$_{5}$Cl was also used by the Paquin's group in
2023 for the addition onto alkenes and  alkynes \textbf{1}~\cite{6}.
This time, the reaction is activated by exposing the SF$_{5}$Cl
solution to black light (370~nm), which initiates the radical chain
process. This new methodology provides access to various chloro-olefins
\textbf{2} from terminal alkynes in moderate to good yields. An example
of an internal alkyne is also reported, yielding a single regio- and
stereoisomer (Scheme~\ref{sch4}).


\begin{scheme*}
\includegraphics{sc04}
{\vspace*{9pt}}
\caption{\label{sch4}Chloropentafluorosulfanylation of alkynes under
black light irradiation.}
{\vspace*{-11pt}}
\end{scheme*}


In 2024, Cahard, Bizet and co-workers published a simple regio- and
stereoselective method for the chloropentafluorosulfanylation of
alkynes with SF$_{5}$Cl in THF at ${-}$40~\textdegree C~\cite{7}. In contrast
to other methods~\cite{3,4,5,6}, performing the reaction in THF alone
was sufficient to initiate the radical addition, yielding exclusively
(\textit{E})-1-chloro-2-SF$_{5}$-alkenes \textbf{2} without the use of
radical initiator or light activation (Scheme~\ref{sch5}). The
formation of the SF$_{5}$ radical was proposed to be initiated by
hydroperoxides \textbf{11} formed from the \unskip\break autoxidation of THF with
oxygen. Addition of the SF$_{5}$ radical to the terminal position of
the alkyne resulted in a vinylic radical \textbf{8}, which was
chlorinated \unskip\break by chlorine abstraction of SF$_{5}$Cl, 
allowing the \unskip\break chain propagation. The stereochemistry of these
(\textit{E})-1-chloro-2-SF$_{5}$-alkenes \textbf{2} was definitively
established by single crystal X-ray diffraction (SCXRD). Both aromatic
and aliphatic alkynes reacted with good to excellent yields under these
conditions. This method is of great interest and complementary to
previous ones, since SF$_{5}$-alkynes with electron-deficient aromatic
rings or heteroaromatic substituents are now accessible, and the
formation of the dimeric by-product observed under Dolbier's conditions
is significantly reduced. Notably, hetero-substituted alkynes with a
silyl- or boron-motif were also competent substrates. The method is
not limited to terminal alkynes, as polarized internal alkynes such as
ynoates or ynones were efficiently converted. In this case, the
SF$_{5}$ was introduced regioselectively at the ${\upalpha}$-position
of the C${=}$O, affording the product as a single \textit{E}-isomer.


\begin{scheme*}
\includegraphics{sc05}
{\vspace*{8pt}}
\caption{\label{sch5}Chloropentafluorosulfanylation of alkynes using SF$_{5}$Cl in THF.}
{\vspace*{-6pt}}
\end{scheme*}


In the same year, Wang and co-workers used variously substituted
1,3-enynes \textbf{13} as starting materials for
chloropentafluorosulfanylation under copper-catalyzed
conditions~\cite{8}. Depending on the substitution, they observed the
1,2-difunctionalization (with R$^{1}$,R$^{2}$\ ${=}$\ H) to afford
\textbf{14} or the 4,3-difunctionalization (with R$^{4}$\ ${=}$\ H) to give
\textbf{15} (Scheme~\ref{sch6}). Interestingly, a phenyl substituent at
the C2 position (R$^{3}$) induced the formation of the
SF$_{5}$-substituted allene \textbf{16}. A radical pathway for this
transformation was proposed on the basis of experimental mechanistic
studies. The SF$_{5}$ radical was generated by a single electron
transfer (SET) induced by the Cu(I)--bipyridyl species. The SF$_{5}$
addition took place preferentially at the terminal position of the
olefin or alkyne, together with the formation of a vinyl (\textbf{17}),
propargyl (\textbf{18}) or allenyl radical (\textbf{19}) (due to the
formation of more stable secondary or tertiary radicals) and subsequent
chlorine abstraction, which regenerated the SF$_{5}$ radical. Several
transformations such as hydrodechlorination, hydrostannation or
dehydrochlorination under basic conditions have also been proposed as
synthetic applications. 

\begin{scheme*}
\includegraphics{sc06}
{\vspace*{6pt}}
\caption{\label{sch6}Copper-catalyzed chloropentafluorosulfanylation of 1,3-enynes.}
{\vspace*{-9pt}}
\end{scheme*}


\begin{scheme*}
\includegraphics{sc07}
{\vspace*{5pt}}
\caption{\label{sch7}In-situ generation of SF$_{5}$Cl from
$\mathrm{SF}_{5}^{-}$/TDAE$^{2+}$/F$^{-}$ salt.}
{\vspace*{-12pt}}
\end{scheme*}

Efforts to avoid the direct manipulation of the costly and toxic
SF$_{5}$Cl are ongoing, as demonstrated by the group of Tlili in 2022,
who developed the pentafluorosulfanylation of alkynes starting from
SF$_{6}$, an inert, non-toxic, but known potent greenhouse
gas  (Scheme~\ref{sch7})~\cite{9}. They developed the activation of
SF$_{6}$ using tetrakis(dimethylamino)ethylene (TDAE) under
a blue light (455~nm) irradiation. The TDAE excited state performs a
two-electron reduction on SF$_{6}$, forming the ion pair
intermediate $\mathrm{SF}_{5}^-$/TDAE$^{2+}$/F$^{-}$ (\textbf{20}). Using a
two-chamber system, the resulting intermediate can then react with
TCICA to produce SF$_{5}$Cl in situ in the first tube, which can then
be transferred to the second tube to carry out the
pentafluorosulfanylation of various alkynes \textbf{21} with moderate
to good yields with or without the use of triethylborane as a radical
initiator. 

{In another approach, De Borggraeve and co-workers developed in 2023
the in-situ generation of SF}$_{5}${Cl by oxidative fluorination of
4,4$'$-dipyridyl disulfide} \textbf{23}  {(Scheme~\ref{sch8})~\cite{10}.
The reaction was carried out in the presence of TCICA as chlorine
source and KF in acetonitrile at room temperature as reported by Pitts,
Santschi, and  Togni~\cite{11,11b}. A two-chamber reactor was used to
generate SF}$_{5}${Cl in the first chamber, which was then reacted in
the second chamber by radical addition of SF}$_{5}${Cl to alkynes}
\textbf{25}{, alkenes, and 2-diazo-1-phenylethan-1-one under Dolbier's
conditions, to afford the corresponding products} \textbf{26} {in
moderate to good\break yields.} 


\begin{scheme*}
\includegraphics{sc08}
{\vspace*{13.6pt}}
\caption{\label{sch8}In-situ generation of SF$_{5}$Cl from oxidative
fluorination of 4,4$'$-dipyridyl disulfide.}
{\vspace*{-7pt}}
\end{scheme*}

\subsection{Iodopentafluorosulfanylation}

In 2023, Cahard, Bizet, Legault and co-workers developed a method for
the iodopentafluorosulfanylation of alkynes which led exclusively to
(\textit{E})-1-iodo-2-SF$_{5}$ alkenes \textbf{28} as confirmed by 
SCXRD~\cite{12}. The optimal conditions consisted in mixing a terminal
alkyne \textbf{27}, SF$_{5}$Cl, potassium iodide and 18-crown-6-ether
in THF at ${-}$78~\textdegree C resulting in regio- and stereoselective
access to unprecedented (\textit{E})-1-iodo-2-SF$_{5}$ alkenes
\textbf{28} (Scheme~\ref{sch9}). The addition of 18-crown-6-ether
improved the nucleophilicity of the iodide and the use of THF instead
of hexane significantly increased conversion and yield. Conducting the
reaction at ${-}$78~\textdegree C was necessary to avoid the formation of the
diiodo alkene side product. Other sources of iodide were also tested
but were not as efficient as potassium iodide in achieving this
conversion. For aromatic alkynes and one internal alkyne, only
1-iodo-2-SF$_{5}$-products were observed, whereas aliphatic alkynes
gave mixtures of 1-iodo- and 1-chloro-2-SF$_{5}$-alkenes due to a
competing reaction pathway with SF$_{5}$Cl in this case. A detailed
mechanistic investigation was carried out and supported by DFT
calculations. It was found that a radical chain mechanism is more
likely to be responsible for the addition of SF$_{5}$ at the terminal
position of the alkyne, whereas an anionic mechanism would give the
opposite regioselectivity. It was clearly shown that the formation of
SF$_{5}$I, as a reagent itself, cannot be thermodynamically
\unskip\break feasible and that the most probable reaction
\unskip\break pathway is as follows: after the in-situ generation of
the $\mathrm{SF}_{5}^{-}$ (\textbf{30}, observed by $^{19}$F NMR), the
latter is oxidized by a single electron transfer (SET) with
$\mathrm{I}_{3}^\bullet$ to form the $\mathrm{SF}_{5}^\bullet$ radical
which undergoes classical radical addition onto alkyne (\textbf{27a})
to give a vinyl radical \textbf{32a}. The abstraction of iodine from
ICl is then much more favored with aromatic substrates than the
abstraction of chlorine\break (\textbf{28a} vs \textbf{33a}). 

\begin{scheme*}
\includegraphics{sc09}
{\vspace*{10pt}}
\caption{\label{sch9}Iodopentafluorosulfanylation of alkynes using
SF$_{5}$Cl, KI and 18-crown-6-ether in THF.}
{\vspace*{-12pt}}
\end{scheme*}

\subsection{Hydropentafluorosulfanylation}

In 2022, Paquin, Champagne, and co-workers reported a photoinitiated
\textit{anti}-hydropentafluorosulfanylation of terminal alkynes in
favor of the \textit{Z} isomer \textbf{35} (${>}$85\% 
\textit{Z}-selective)~\cite{13}. The reaction required SF$_{5}$Cl as a
source of SF$_{5}$ radical and (TMS)$_{3}$SiH acting as a hydrogen atom
donor (HAD) species (Scheme~\ref{sch10}). Due to the competitive
chlorine abstraction by the vinylic radical resulting in
1-chloro-2-SF$_{5}$ alkenes, gaseous SF$_{5}$Cl was added incrementally
to artificially lower its concentration, thereby favoring the hydrogen
atom transfer (HAT). Using a black light CFL bulb, a SF$_{5}$ radical
is generated from the photochemical activation of SF$_{5}$Cl. Its
addition to terminal alkynes gives a bent or a linear vinylic radical
(\textbf{36}, \textbf{36$'$}), depending on the nature of the
substituent, which is then captured by the HAD that provides
\textbf{35}. A wide range of substrates were used, such as aromatic or
aliphatic alkynes, and even ynones, which showed good reactivity under
these conditions. A detailed DFT calculation study showed that the
selectivity is due to the intrinsic preference of SF$_{5}$-substituted
vinylic radicals to adopt a \textit{cis}-geometry, and to the reduced
distortion in the transition structures.

\begin{scheme*}
\includegraphics{sc10}
{\vspace*{6pt}}
\caption{\label{sch10}Photoinitiated hydropentafluorosulfanylation of
alkynes using SF$_{5}$Cl and (TMS)$_{3}$SiH.}
{\vspace*{-10pt}}
\end{scheme*}


\begin{scheme*}
\includegraphics{sc11}
{\vspace*{6pt}}
\caption{\label{sch11}Synthesis of 2-SF$_{5}$-(aza)indoles and further derivatization.}
{\vspace*{-8pt}}
\end{scheme*}

\begin{scheme*}
{\vspace*{2pt}}
\includegraphics{sc12}
{\vspace*{8pt}}
\caption{\label{sch12}Synthesis of SF$_{5}$-pyrazoles under flow conditions.}
{\vspace*{-8pt}}
\end{scheme*}


\section{Cycloaddition and cyclization reactions of
SF$_{5}$-alkynes}\label{sec3}


SF$_{5}$-Alkynes are very versatile small building blocks that have
been found to be relevant reaction partners in {[}4${+}$2{]} Diels--Alder
cycloadditions and 1,3-dipolar cycloadditions~\cite{2}. In 2021, Bizet,
Blanchard and co-workers reported an efficient synthesis of
2-SF$_{5}$-(aza)indoles \textbf{39} starting from 2-ethynyl aniline
derivatives \textbf{37} via a 3-step telescoped procedure 
(Scheme~\ref{sch11})~\cite{14}.  The first step is the classical
radical addition of SF$_{5}$Cl to a 2-ethynyl aniline \textbf{37}
initiated by triethylborane to give intermediate \textbf{38}. The
reaction was very efficient in ethyl acetate, and required room
temperature to reach completion. The reaction was therefore carried out
in sealed tubes to keep the gas in solution. Treatment with
LiOH${\cdot}$H$_{2}$O in DMSO produced a cascade of dehydrochlorination,
5-\textit{endo}-dig cyclization, and deprotection of the tosyl
fragment, giving 2-SF$_{5}$-indole \textbf{39} in good to high yields.
The sequence was then deconstructed and carried out stepwise. The
dehydrochlorination was highly selective using LiHMDS as base and the
corresponding alkynes \textbf{40} were formed in almost quantitative
yields. The 5-\textit{endo}-dig cyclization was then carried out with
K$_{3}$PO$_{4}$, with conservation of the tosyl fragment expected for
substrates with strong electron-withdrawing groups, where a mixture of
NH \textbf{39} and N--Ts indoles \textbf{41} was observed. Downstream
functionalizations at the N and C3 positions provided various
\textit{N}-protected and 3-halogenated 2-SF$_{5}$-indoles, which were further
involved in Negishi and Heck cross-couplings, or even allylation and
cyanation after halogen/metal exchange. In addition to the synthetic
part, several physicochemical measurements were carried out with
2-R$_{\mathrm{f}}$-indoles (R$_{\mathrm{f}}$\ ${=}$\ H, Me, F, CF$_{3}$, and
SF$_{5}$) in order to better evaluate the impact of the SF$_{5}$ motif.
Differential scanning calorimetry (DSC) measurements showed that
2-SF$_{5}$-indoles \textbf{39} are high-energy materials with an onset
of exotherm above 165~\textdegree C with an enthalpy of ${-}$1180~kJ/kg,
compared to the 2-F-indoles (${>}$120~\textdegree C, ${-}$623~kJ/kg) and 
2-CF$_{3}$-indoles (${>}$325~\textdegree C, ${-}$403~kJ/kg). However, the
synthesis of 2-SF$_{5}$-indoles has a rather large safety margin gap
(${>}$120~\textdegree C) between the temperature of the reaction sequence
(up to 40~\textdegree C max.) and the exotherm. The mutagenic potential
of 2-SF$_{5}$-indoles was evaluated by a classical biological test
known as the ``Ames test'', using different histidine-requiring
bacterial strains of \textit{Salmonella typhimurium} carrying mutations
in the genes in the absence and presence of a liver metabolizing
system. No evidence of mutagenicity was observed with
2-SF$_{5}$-indoles, which means that they can potentially be used for
further development in drug design. Finally, the pKa and logP of the
2-R$_{\mathrm{f}}$-indoles were measured by Leito's group, which showed
a 2.3 pKa unit difference between the 2-SF$_{5}$- and
2-CF$_{3}$-indoles (pKa ${=}$ 24.44 for SF$_{5}$ vs 26.76 for CF$_{3}$ in
MeCN), confirming that SF$_{5}$ is a stronger electron-withdrawing
group than CF$_{3}$, while the lipophilicity is in the same range (3.8
${\pm}$ 0.2 for SF$_{5}$ vs 3.5 ${\pm}$ 0.2 for CF$_{3}$).


\begin{scheme*}
\includegraphics{sc13}
{\vspace*{8pt}}
\caption{\label{sch13}Palladium-catalyzed synthesis of
2-SF$_{5}$-indenols and further derivatizations.}
{\vspace*{-10pt}}
\end{scheme*}


In 2024, the Paquin's group proposed a synthesis of substituted
SF$_{5}$-pyrazoles by 1,3-dipolar cycloaddition of ethyl diazoacetate
with SF$_{5}$-alkynes under flow conditions
(Scheme~\ref{sch12})~\cite{15}. The use of flow conditions was
motivated by the potential hazards associated with the heating of diazo
compounds. Although both isomers \textbf{44} and \textbf{45} of the
pyrazoles were obtained in all the cases, the \unskip\break regioselectivity was
mainly induced by the substituent on the SF$_{5}$-alkynes.
3-SF$_{5}$-Pyrazoles \textbf{44} were the main products obtained from
alkyl-substituted SF$_{5}$-alkynes, whereas aryl-substituted
SF$_{5}$-alkynes preferentially gave 4-SF$_{5}$-pyrazoles \textbf{45},
regardless of the electronic nature of the substituents. The
methodology was extended to CF$_{3}$-pyrazoles, this time with reversed
regioselectivity. Some post-functionalization reactions were
successfully applied to these pyrazoles, such as acetylation to give
\textit{N}-acetylpyrazole whereas the ester moiety was \unskip\break reduced to a
terminal alcohol or hydrolyzed to form a carboxylic acid group. 

In 2024, the Bizet group reported the palladium-catalyzed synthesis of
2-SF$_{5}$-indenols and indenamines \textbf{48} from SF$_{5}$-alkynes
\textbf{47} and 2-formyl phenylboronic acid derivatives \textbf{46}
(Scheme~\ref{sch13})~\cite{16}. The scope of the reaction is very
general and can be realized either from a boronic acid, a
boronic ester or even a potassium trifluoroborate salt in similar
yields. The proposed mechanism proceeds by a transmetallation between
the L--Pd--OR species (\textbf{I}) and the boronic acid \textbf{46} to
generate the intermediate \textbf{III}, which, after coordination with
the SF$_{5}$-alkyne (\textbf{IV}), undergoes a regioselective migratory
insertion (\textbf{V}) controlled by the polarization of the
SF$_{5}$-alkyne towards the SF$_{5}$. Then, migratory insertion to the
formyl fragment (\textbf{VI}) and ligand exchange with the alcoholic
solvent yields the 2-SF$_{5}$-indenol. The 2-SF$_{5}$-indenol
\textbf{48} was further oxidized with MnO$_{2}$ to give the
corresponding 2-SF$_{5}$-indenone \textbf{49}. \mbox{Downstream}
functionalizations such as nitration reaction, 1,2 and 1,4-nucleophilic
additions with N- and S-nucleophiles were designed. The
1,4-nucleophilic addition (\textbf{50}) was found to be highly
diastereoselective due to the steric constraint imposed by the bulky
SF$_{5}$ group.

\begin{scheme*}
{\vspace*{-2pt}}
\includegraphics{sc14}
{\vspace*{6pt}}
\caption{\label{sch14}Hydroamination of triisopropylsilyl acetylene-SF$_{5}$ 
using secondary amines, AcOH and KF.}
{\vspace*{-8pt}}
\end{scheme*}

\section{Hydrofunctionalization of SF$_{5}$-alkynes}\label{sec4}

The Rombach group investigated the reactivity of triisopropylsilyl
acetylene sulfur pentafluoride (TASP). They first reported a
diastereoselective hydroamination reaction for the synthesis of
(\textit{E})-${\upbeta}$-SF$_{5}$-enamines \textbf{52}
(Scheme~\ref{sch14})~\cite{17}.  The product is formed by a one-pot
sequence of in-situ deprotection of the TIPS with potassium fluoride in
the presence of acetic acid, leading to the formation of several
intermediates including enolacetate \textbf{51}. The hydroamination
step is carried out with acyclic or cyclic secondary amines yielding
exclusively (\textit{E})-${\upbeta}$-SF$_{5}$-enamines \textbf{52}. A
very small energy difference was calculated by DFT between the
\textit{E}- and \textit{Z}-nucleophilic addition to SF$_{5}$-acetylene,
making this pathway unlikely. The enolacetate \textbf{51} is proposed
as a reactive intermediate leading to the formation of the
thermodynamically most stable \textit{E}-enamines
\textbf{52}.

\begin{scheme*}
\includegraphics{sc15}
{\vspace*{6pt}}
\caption{\label{sch15}Hydrothiolation of triisopropylsilyl acetylene-SF$_{5}$ 
using thiols, AcOH, and CsF.}
{\vspace*{-10pt}}
\end{scheme*}

\begin{scheme*}
\includegraphics{sc16}
{\vspace*{6pt}}
\caption{\label{sch16}Regio- and stereoselective hydroelementation of
SF$_{5}$-alkynes with N, O, S-nucleophiles.}
{\vspace*{-10pt}}
\end{scheme*}


Shortly afterwards, the same group succeeded in using TASP in a
hydrothiolation reaction. The ${\upbeta}$-SF$_{5}$-vinyl sulfides
\textbf{54} were obtained under similar conditions by mixing TASP with
a thiol as \unskip\break nucleophile, acetic acid and cesium fluoride in acetonitrile
(Scheme~\ref{sch15})~\cite{18}. These conditions were applied to a wide
range of thiol derivatives including \unskip\break aromatic, heteroaromatic, and
aliphatic thiols. Even tertiary alkyl SF$_{5}$-vinyl sulfides could be
obtained with slightly modified reaction conditions. In contrast with
the hydroamination, the hydrothiolation yields only the
(\textit{Z})-isomer. In this case, the proposed mechanism based on DFT
calculations suggested an ionic pathway with direct nucleophilic attack
of the thiol on SF$_{5}$-acetylene \textbf{53}.


\begin{scheme*}
{\vspace*{6pt}}
\includegraphics{sc17}
{\vspace*{6pt}}
\caption{\label{sch17}Hydrofluorination of SF$_{5}$-alkynes with TBAF solution.}
{\vspace*{-10pt}}
\end{scheme*}



Simultaneously and independently, the Bizet group has reported the
regio- and stereoselective hydroelementation of SF$_{5}$ alkynes
\textbf{56} with O-, N-, and S-nucleophiles \textbf{57}, where the
nucleophile is introduced exclusively at the C$_{\upbeta}$ of the
SF$_{5}$-alkynes, giving in all cases the
${\upbeta}$,\textit{Z}-product \textbf{58}, whatever the nature of the
nucleophile (Scheme~\ref{sch16})~\cite{19}. The reaction was carried
out in the presence of a base to maintain good reactivity for all the
nucleophiles; it was shown that the same procedure could be applied
directly from the SF$_{5}$-chloro-olefins \textbf{55}, giving the same
selectivity by successive dehydrochlorination/hydroelementation steps
in a single pot. With reactive nucleophiles such as pyrrolidine or
\mbox{piperidine,} the hydrolysis of the intermediate enamine \textbf{60} was
carried out with HBF$_{4}$ solution yielding the corresponding SF$_{5}$
ketones \textbf{61} in moderate to good yields. Experimental and
computational mechanistic studies were performed and confirmed an ionic
mechanism in which the nucleophile, deprotonated by the base
(\textbf{62}), selectively attacks the triple bonds at the most
electron deficient C$_{\upbeta}$ of the SF$_{5}$-alkynes, while the
intermediate carbanion \textbf{63} is rapidly reprotonated in the
reaction medium. The origin of the selectivity was explained by DFT
calculations considering several aspects. The privileged attack at the
C$_{\upbeta}$ is favored because of the polarization of the
SF$_{5}$-alkyne and the slightly electrophilic character of this
position, as shown by the calculation of natural charges from a Natural
Population Analysis (NPA) of the SF$_{5}$-alkyne \textbf{56}, which are
${+}$0.09 for the C$_{\upbeta}$ and ${-}$0.030 for the C$_{\upalpha}$ (with
R ${=}$ \textit{p}-Ph-C$_{6}$H$_{4}$). Moreover, the \textit{Z}-isomer
\textbf{58} appeared to be kinetically favored
(${\rmDelta}$G$^{\ddagger} = 21.7$~kcal/mol) compared to the
\textit{E}-isomer (${\rmDelta}{\rmDelta}$G$^{\ddagger} \approx
5$~kcal/mol), while the ${\upbeta}$-selectivity was confirmed by a
greater steric repulsion (${\rmDelta}{E}_{\mathrm{Pauli}}$) in the
attack on C$_{\upalpha}$. Some downstream functionalizations of
\textbf{58} were revealed, such as cross-coupling reactions,
halogenations, and \mbox{reductions.} The SF$_{5}$-ketones \textbf{61} were
also subjected to Bayer--Villiger oxidation and reduction with
NaBH$_{4}$ to give the corresponding ester or alcohol in good to high
yields. 



In 2024, Shibata and co-workers developed a regio- and stereoselective
hydrofluorination of RSF$_{4}$- and SF$_{5}$-alkynes to give
(\textit{Z})-RSF$_{4}$- and (\textit{Z})-SF$_{5}$-vinyl fluorides
(Scheme~\ref{sch17})~\cite{20}, using the SF$_{5}$-alkyne \textbf{64}
as the electrophile with TBAF${\cdot}$3H$_{2}$O as the fluoride source
(nucleophile). The reaction was found to be efficient with
aryl-substituted SF$_{5}$-alkynes, giving good yields, while alkyl
derivatives showed a poor stability. The mechanism of the reaction was
discussed using DFT calculations and confirmed that the formation of
the ${\upbeta}$,\textit{Z}-isomer \textbf{67} was favored by
3.7~kcal/mol, which explains the very high selectivity. The proposed
mechanism starts with a nucleophilic attack of the fluoride on the
electron-deficient C$_{\upbeta}$ (\textbf{65}), which generates a
carbanion on C$_{\upalpha}$ (\textbf{66}), which is rapidly protonated
with water. The \textit{Z}/\textit{E} \mbox{interconversion} was calculated to
be strongly disfavored (${\rmDelta}$G$^{\ddag} = 49.8$~kcal/mol).

{
\advance\baselineskip by .22pt


{At the same time, Bizet and co-workers reported a stereodivergent
hydrohalogenation of SF}$_{5}$-{alkynes, providing access to a wide
range of ${\upbeta}$,}{\textit{Z}}- {and
${\upbeta}$,}{\textit{E}}{-halogenated SF}$_{5}$-{alkenes}
\textbf{69}--\textbf{76} {with all the halogens (Scheme~\ref{sch18})~\cite{21}.
They postulated that the SF}$_{5}${-alkynes} \textbf{68} {might be
ambiphilic, reacting as both an electrophile and a nucleophile. The
regioselectivity of the reaction was controlled by the polarization of
the triple bond induced by the SF}$_{5}$ {moiety, leading to the fully
selective introduction of halides on the electron-deficient
C}$_{\upbeta}$ {to the SF}$_{5}${. On the other hand, the
stereoselectivity was determined by the reaction conditions. For the
hydroiodination in the presence of a strong acid such as HI, the
reaction was fully selective for the
${\upbeta}$,}{\textit{E}}{-isomer} \textbf{69}{, whereas in the
presence of NaI and acetic acid as a soft acid, the \unskip\break reaction was fully
selective for the ${\upbeta}$,}{\textit{Z}}-{isomer} \textbf{73}{. The
two conditions sets were exemplified with many substrates and these
methods were extended to the other halogens. Some difficulties were
encountered with other halides, but these were solved by replacing HX
solution with trifluoroacetic acid (TFA) with ammonium or phosphonium
halide salts (with I-}\textbf{69}{, Br-}\textbf{70}{, and
Cl-}\textbf{71}) to improve solubility. Similarly, improved reactivity
and selectivity were obtained by replacing NaX with ammonium or
phosphonium halide salt (with I-\textbf{73}{, Br-}\textbf{74}{, and
Cl-}\textbf{75}) in acetic acid. Fluorination was somewhat more
challenging, but like Shibata we observed that TBAF solution without
acid was efficient enough to form the
${\upbeta}$,{\textit{Z}}{-fluoroolefin} \textbf{76}{, while the use of
a pyridinium BF}$_{4}$ {salt was used to access the
${\upbeta}$,}{\textit{E}}{-fluoroolefin} \textbf{72}{. Two different
reaction mechanisms have been proposed: in the first one (red arrows),
the alkyne plays the role of the nucleophile and is protonated by the
strong acid (HI or TFA); then, the intermediate carbocation}
\textbf{78} {reacts with the halide on the most accessible face (on the
opposite side to SF}$_{5}$ {due to steric hindrance) to form the}
${\upbeta}$,{\textit{E}}{-SF}$_{5}${-haloolefin} \textbf{79}{. In the
second one (blue arrows), the alkyne plays the role of the electrophile
and the halides (I, Br, Cl) perform a nucleophilic addition on the
C}$_{\upbeta}$ {to generate a carbanion} \textbf{80} {which is
protonated with the acetic acid, selectively yielding the}
${\upbeta}$,{\textit{Z}}{-SF}$_{5}${-haloolefin} \textbf{81}
{(Scheme~\ref{sch18}).  These two mechanisms were validated by DFT
calculations, indicating that the} {\textit{Z}}{-stereoselectivity is
solely due to the lower energy \unskip\break required to distort the reactant,
whereas a stronger interaction between the reactants in the formation
of} {\textit{E}}{-alkenyl halides is due to a smaller overlap between
their main occupied orbitals, ultimately leading to lower Pauli
repulsion. This ambiphilic reactivity has also been exploited to
perform dihalogenations of SF}$_{5}$ {alkynes with I}$_{2}${, ICl, and
Br}$_{2}$ (\textbf{77}). The reaction with aryl-substituted
SF$_{5}${-alkynes proved to be particularly efficient for these three
reactants, whereas only the 1,2-dibromination gave the desired product
with alkyl-SF}$_{5}${-alkynes. A highly selective}
{\textit{cis}}{-dihalogenation was observed in all cases, which was
even fully regioselective in the case of ICl with incorporation of the
iodine on C}$_{\upalpha}$ {and the chlorine on C}$_{\upbeta}${. The
\begin{scheme*}
\includegraphics{sc18}
{\vspace*{4pt}}
\caption{\label{sch18}Regioselective and stereodivergent
hydrohalogenation and dehalogenation of SF$_{5}$-alkynes.}
{\vspace*{-12pt}}
\end{scheme*}
reaction mechanism was calculated for the 1,2-dibromination (green
arrows) and confirmed that the reaction proceeds by the attack of the
alkyne on Br}$^{+}${, with formation of a C}$_{\upalpha}${--Br bond and
a carbocation on C}$_{\upbeta}$ (\textbf{83}), then the attack of the
halide (Br$^{-}$ from $\mathrm{Br}_{3}^{-}$) on the least hindered face of the
carbocation at C$_{\upbeta}$ {(on the \mbox{opposite} side of the SF}$_{5}$),
giving the {\textit{cis}}-dibrominated \unskip\break product \textbf{84}.

\begin{scheme*}
\includegraphics{sc19}
{\vspace*{6pt}}
\caption{\label{sch19}Functionalization of ${\upbeta}$,Z-iodo-SF$_{5}$-olefin.}
{\vspace*{-8pt}}
\end{scheme*}

Finally, post-functionalization of
${\upbeta}$,\textit{Z}-iodo-SF$_{5}$-{\ubreak}olefin \textbf{73} was developed
for the first time (Scheme~\ref{sch19}), including Pd-catalyzed
Negishi, Sonogashira, Stille and Suzuki cross-coupling reactions
(\textbf{85-88}), Cu-catalyzed cyanation (\textbf{89}), Pd-catalyzed
reduction or radical-initiated reduction (\textbf{90}-\textbf{91}),
giving moderate to high yields. The reactivity of the
${\upbeta}$,\textit{E}-iodo-SF$_{5}$-olefin \textbf{69} was also
investigated but it proved to be much more sensitive to basic
conditions, leading in some cases mainly to dehydrohalogenation or
decomposition.

}

\section{Conclusion}\label{sec5}

Several groups are actively working in the vibrant field of
pentafluorosulfanyl chemistry. The keen \unskip\break interest in this motif is due
to the unique properties of SF$_{5}$ such as geometry, volume,
electronegativity, lipophilicity, and stability. Although usually
considered as a ``super CF$_{3}$'', the reactivity and selectivity
conferred by the SF$_{5}$ substituent is fundamentally different. In
this review, new synthetic achievements in the synthesis and use of
SF$_{5}$-alkynes have been reported and we have shown that this small
building block is highly versatile for the design of more complex
molecules. Many challenges remain to be addressed and we along others
are working hard to generalize the applications of SF$_{5}$ in various
fields, \unskip\break including biological and medicinal chemistry, \unskip\break 
catalysis, and materials science.

\section*{Declaration of interests}

The authors do not work for, advise, own shares in, or receive funds
from any organization that  could benefit from this article, and have
declared no affiliations other than their research 
organizations.

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