\makeatletter
\@ifundefined{HCode}
{\documentclass[screen,CRCHIM,Unicode]{cedram}
\newenvironment{noXML}{}{}
\def\tsup#1{$^{{#1}}$}
\def\tsub#1{$_{{#1}}$}
\def\ndash{\text{--}}
\usepackage[T1]{fontenc}
\def\thead{\noalign{\relax}\hline}
\def\tbody{\noalign{\relax}\hline}
\def\endthead{\noalign{\relax}\hline}
\def\xsection#1{}
\def\tabnote#1{\vskip4pt\parbox{.98\linewidth}{#1}}
\RequirePackage{etoolbox}
\def\jobid{crchim20240407}
%\graphicspath{{/tmp/\jobid_figs/web/}}
\graphicspath{{./figures/}}
\newcounter{runlevel}
\let\MakeYrStrItalic\relax
\csdef{Seqnsplit}{\\}
\def\refinput#1{}
\def\back#1{}
\def\botline{\\\hline}
\def\mn{\phantom{$-$}}
\def\0{\phantom{0}}
\def\inlinefig#1{\begin{center}\includegraphics{#1}\end{center}}
\def\xinlinefig#1{\includegraphics{#1}}
\def\tabularBreak{\hline\multicolumn{3}{r@{}}{(continued on next
 page)}\end{tabular}\end{table*}
 \begin{table*}\setcounter{table}{0}
 \tabcolsep15pt
 \caption{(continued)}
 \begin{tabular}{ccc}
 \thead
 Entry & Phosphonium salt, 2 & Phosphonate/oxide phosphine 3 (Yield(\%))\\
 \endthead}
\usepackage{multirow} 
\def\nrow#1{\@tempcnta #1\relax%
\advance\@tempcnta by 1\relax%
\xdef\lenrow{\the\@tempcnta}}
\def\morerows#1#2{\nrow{#1}\multirow{\lenrow}{*}{#2}}
\def\xmorerows#1#2{#2}
\def\ubreak{\hfill\break}
\usepackage{hyperref}
\usepackage{textcomp}
\makeatletter
\g@addto@macro{\UrlBreaks}{\UrlOrds}
\gappto{\UrlBreaks}{\UrlOrds}
\makeatother
\DOI{10.5802/crchim.349}
\datereceived{2024-05-20}
\daterevised{2024-09-06}
\datererevised{2024-09-07}
\dateaccepted{2024-09-27}
\ItHasTeXPublished
}
{\documentclass[crchim]{article}
\usepackage[T1]{fontenc}
\def\CDRdoi{10.5802/crchim.349}
\def\xmorerows#1#2{\morerows{#1}{#2}}
\def\xinlinefig#1{\inlinefig{#1}}
\def\tabularBreak{}
\let\ubreak\relax
\makeatletter
\def\CDRsupplementaryTwotypes#1#2{}
}
\makeatother

\usepackage{upgreek}

%\copyeditor{RB}

\begin{document}

\begin{noXML}

\CDRsetmeta{articletype}{research-article}

\title{Novel nucleophilic addition S\textsubscript{N}2\tralicstex{\textquotesingle}{$'$}--S\textsubscript{N}2\tralicstex{\textquotesingle}{$'$} pathway: utilizing
phosphonium salts as electrophilic agents for synthesizing new
phosphine oxides of Morita--Baylis--Hillman (MBH) adducts}

\alttitle{Nouvelle voie d'addition nucl\'eophile
S\textsubscript{N}2\tralicstex{\textquotesingle}{$'$}--S\textsubscript{N}2\tralicstex{\textquotesingle}{$'$} : utilisation de
sels de phosphonium comme agents \'electrophiles pour la synth\`ese de
nouveaux oxydes de phosphine d'adduits Morita--Baylis--Hillman (MBH)}

\author{\firstname{Haitham} \lastname{Elleuch}\CDRorcid{0000-0003-2373-6427}\IsCorresp}
\address{Laboratory of Structural Organic Chemistry and Macromolecular, 
LR99ES14, Faculty of Sciences of Tunis, University of Tunis El Manar, 
University Campus, 2092 Tunis, Tunisia}
\email{elleuchhaitham@gmail.com}
\email[H. Elleuch]{haitham.elleuch@cst.rnu.tn}

\author{\firstname{Ferid} \lastname{Yaccoubi}\CDRorcid{0000-0002-2672-1442}}
\addressSameAs{1}{Laboratory of Structural Organic Chemistry and
Macromolecular, LR99ES14, Faculty of Sciences of Tunis, University of
Tunis El Manar, University Campus, 2092 Tunis, Tunisia}
\address{Department of Chemistry, Faculty of Science and Humanity
Studies at Al Quwayiyah, Shaqra University, Al-Quwayiyah 19245, Saudi
Arabia}

\author{\firstname{Sami} \lastname{Ayari}\CDRorcid{0000-0002-1505-1922}}
\address{Laboratory of Microorganisms and Active Biomolecules,
LR03ES03, Department of Biology, Faculty of Sciences of Tunis,
University of Tunis-El Manar, 2092 El Manar I Tunis, Tunisia}

\author{\firstname{Fatma} \lastname{Saadi}\CDRorcid{0000-0001-9587-4736}}
\address{Department of Chemistry, Faculty of Science, Northern Border
University, Arar, Kingdom of Saudi Arabia}

\keywords{\kwd{Phosphonates}\kwd{Phosphine oxide}\kwd{MBH
adducts}\kwd{Alkylation}\kwd{Michaelis--Arbuzov}}

\altkeywords{\kwd{Phosphonates}\kwd{Oxyde de phosphine}\kwd{Adduits
MBH}\kwd{Alkylation}\kwd{Michaelis--Arbuzov}}

\shortrunauthors

\thanks{DGRST and Ministry of Higher Education (Tunisia), Northern Border University (Arar, KSA, project number FFR-2024-2939-01)}

\begin{abstract}
An efficient and practical approach has been developed for synthesizing
phosphonates and phosphine oxides from Morita--Baylis--Hillman (MBH)
adducts through the alkylation of trialkylphosphites and
ethoxydiphenylphosphine using phosphonium salts derived from MBH as 
powerful alkylating agents.

The alkylation proceeds via a Michaelis--Arbuzov mechanism. This
regiospecific reaction combining the S\textsubscript{N}2\tralicstex{\textquotesingle}{$'$} +
S\textsubscript{N}2\tralicstex{\textquotesingle}{$'$} = S\textsubscript{N}2 pathway was
conducted under refluxing in CHCl\textsubscript{3}, resulting in the isolation of
the products in good yields.
\vspace*{-1pt}
\end{abstract}

\begin{altabstract}
Une approche efficace et pratique a \'et\'e d\'evelopp\'ee pour
synth\'etiser des phosphonates et des oxydes de phosphine \`a partir
d'adduits de Morita--Baylis--Hillman (MBH), par alkylation de
trialkylphosphites et d'\'ethoxydiph\'enylphosphine en utilisant des
sels de phosphonium d\'eriv\'es de MBH comme puissants agents
alkylants.

L'alkylation se d\'eroule via le m\'ecanisme Michaelis--Arbuzov. Cette
r\'eaction r\'egiosp\'ecifique combinant les voies
S\textsubscript{N}2\tralicstex{\textquotesingle}{$'$} + S\textsubscript{N}2\tralicstex{\textquotesingle}{$'$} = S\textsubscript{N}2 a \'et\'e r\'ealis\'ee dans des conditions de
reflux dans CHCl\textsubscript{3}, ce qui a permis d'isoler les produits avec de
bons rendements.
\end{altabstract}

\maketitle

\twocolumngrid

\end{noXML}

\section{Introduction}

Structure-privileged phosphonates have attracted considerable attention
in the design of biologically active molecules~\cite{1}.\ These
compounds have a variety of interesting biological activities. Among
their important effects, they are used as antiviral agents;
antiretroviral, antitumoral, antibacterial~\cite{2}, anticancer,
anti-HIV~\cite{3}, and anti-influenza~\cite{4} \mbox{compounds};
vitamin~D analogues~\cite{5}; and as potent antibacterial and
antifungal agents~\cite{6}.

In addition, we have further demonstrated that Morita--Baylis--Hillman
(MBH) allylic and cyclic phosphonates exhibit a powerful antioxidant
effect~\cite{7} and display a remarkable antimutagenesis
effect~\cite{8}. Conversely, we observed the absence of antifungal
effects in these same MBH phosphonates, whereas their MBH acetate
precursors exhibit such effects~\cite{9}.

Beyond their diverse biological applications, phosphonates play pivotal
roles in organic \mbox{synthesis} \cite{10}, notably in Wittig--Horner
reactions~\cite{11,12,13},
and they can be used as complexing
agents \cite{14,15}. In the industrial field, they are recognized as
effective inhibitors that protect metals against excessive dissolution
due to corrosion~\cite{16,17,18,19}.\ Furthermore, phosphonates serve
as phosphorus-based flame retardants, primarily acting in the solid
phase of burning polymer materials. By inducing carbonization of the
polymer, they inhibit the pyrolysis process crucial for fueling
flames~\cite{20}.

The synthesis of phosphonates is based on several pathways. For
example, we synthesized MBH phosphonates by the reaction of phosphite
with MBH acetates, using DMAP or imidazole as a catalyst following an
$\text{S}_{\text{N}}2'$--$\text{S}_{\text{N}}2'$ mechanism
(Scheme~\ref{sch1}, route~A)~\cite{21}. The same reaction was applied
to MBH alcohols to synthesize the same MBH phosphonates
(Scheme~\ref{sch1}, route~B)~\cite{22}.

\begin{scheme*}
\includegraphics{sc01}
{\vspace*{.6pc}}
\caption{\label{sch1}Synthesis of phosphonates.}
{\vspace*{.9pc}}
\end{scheme*}

Other researchers have synthesized phosphonates from
dialkylmethylphosphonates with n-BuLi as a strong base in the
presence of an allylic ester~\cite{5}.

The Arbuzov reaction is a widely used method for phosphonate
synthesis. It involves the reaction of trialkylphosphite with
halogenated derivatives or derivatives bearing a leaving group,
ultimately yielding the corresponding phosphonate~\cite{23}.

It is worth noting that the Pudovik reaction, involving the reaction of
phosphites or hydrogen phosphonate with aldehydes in the presence of
a catalyst, can ultimately lead to hydroxyl
phosphonates~\cite{23,24,25}.

While surveying the literature for synthesizing phosphonates from
phosphites, we found that quaternary amine salts were used as 
alkylating agents. Notably, Yaccoubi {et~al.}\ demonstrated that the
synthesis of allylic phosphonates of acyclic 
MBH adducts was achieved by the reaction of trialkylphosphite with
quaternary amine salts~\cite{26}.

Recently, several authors have synthesized phosphonates using
phosphonium salts as starting substrates.\ Phosphonium salts have been
widely used as acceptors of nucleophiles such as amines
(Scheme~\ref{sch2}) \cite{27,28}, thiols~\cite{27,28}, aryls
(Scheme~\ref{sch2}) \cite{29,30}, and particularly
phosphites~\cite{31,32,33}.\looseness=-1

\begin{scheme*}
\includegraphics{sc02}
{\vspace*{.6pc}}
\caption{\label{sch2}Synthesis of phosphonate from phosphonium salts.}
{\vspace*{.9pc}}
\end{scheme*}

In our study, we synthesized the phosphonium salts of
MBH adducts using the Wittig
method~\cite{34}. It is important to note that the MBH acetates
utilized in our previous work necessitate additional reagents for their
synthesis, and their purification on silica gel with organic solvents
is time-consuming and expensive. Our quest was to find a faster and
more cost-effective approach to synthesize phosphine oxides with good
yields and without relying on MBH acetates. Recognizing the versatility
of our MBH phosphonium salts and seeking to expand their applicability,
we report herein a novel method involving the reaction of
trialkylphosphites and ethoxydiphenylphosphine as powerful nucleophilic
agents with phosphonium salts for synthesizing phosphonates and
phosphine oxides from MBH. These compounds hold promise for exhibiting
diverse biological properties~\cite{7,8}.

\section{Result and discussion} \label{sec2}
\subsection{Preparation of phosphonium salts} \label{sec2.1}

The phosphonium salts were prepared following the method described by
our group~\cite{34}. Treatment of primary MBH alcohol \textbf{1a}
(R${=}$H) with aqueous HBr (48\%) (5~equiv) and triphenylphosphine
(1~equiv) in CH$_{2}$Cl$_{2}$ at room temperature produces \textbf{2a}
as a white solid, within 20~min, which was isolated and recrystallized
with ethyl acetate (Scheme~\ref{sch3}). The reaction is general, and
\textbf{2b--2d} were obtained with yields up to~94\%.

\begin{scheme*}
\includegraphics{sc03}
{\vspace*{.6pc}}
\caption{\label{sch3}Synthesis of phosphonium salts \textbf{2a--j}.}
{\vspace*{.9pc}}
\end{scheme*}

\subsection{Alkylation of phosphites with phosphonium salts of MBH}
\label{sec2.2}

To synthesize the allylic phosphonates of MBH \textbf{3}
(Scheme~\ref{sch4}) from the phosphonium salts of MBH~\textbf{2}, we
drew inspiration from prior work~\cite{31,32,33}.

\begin{scheme*}
\includegraphics{sc04}
{\vspace*{.6pc}}
\caption{\label{sch4}Synthesis of Morita--Baylis--Hillman
phosphonates.}
{\vspace*{-1pc}}
\end{scheme*}

First, we used DMAP as an additive to catalyze the reaction as
demonstrated in our previous work~\cite{21}. Ethoxydiphenylphosphine
reacted with the phosphonium \textbf{2a} salt in the presence of DMAP
(1~equiv) in refluxing CHCl$_{3}$. Unfortunately, despite a 24~h
reflux, the reaction did not proceed. Subsequently, we replaced DMAP by
imidazole (1~equiv) and repeated the reaction in refluxing chloroform.
However, even after 24~h, we recovered the starting materials.
Consequently, we concluded that neither DMAP nor imidazole is effective
under these reaction\break conditions.

\begin{scheme*}
{\vspace*{.8pc}}
\includegraphics{sc05}
{\vspace*{6pt}}
\caption{\label{sch5}Reaction mechanism and synthesis of
Morita--Baylis--Hillman oxide phosphine.}
\end{scheme*}

\begin{scheme*}
\includegraphics{sc06}
{\vspace*{.6pc}}
\caption{\label{sch6}Synthesis of MBH acetates from MBH alcohols.}
{\vspace*{-.8pc}}
\end{scheme*}

In our second attempt, we replaced DMAP and imidazole by DBU (1~equiv)
and conducted the reaction with the mixture in refluxing CHCl$_{3}$.\ 
Utilizing trialkylphosphite by default allowed us to \mbox{establish}
the reaction time, as the phosphonium salts tend to be sticky on 
thin-layer chromatography (TLC) plates, making it difficult to observe
the reaction progress. Under these conditions, the trialkylphosphite
reacted with the phosphonium salts of MBH, resulting exclusively, and
with very good yield, in the corresponding phosphine oxides and
phosphonates.

Finally, by determining the reaction time, and to avoid wasting the
prepared phosphonium salts, phosphonium \textbf{2a--2e} salts (1~equiv)
were made to react with trialkylphosphite or ethoxydiphenylphosphine
(1.1~equiv) in the presence of 1~equiv of DBU in refluxing CHCl$_{3}$.
This reaction is completed after 1~h, yielding MBH phosphonates in very
good yields (90--99\%) (Scheme~\ref{sch4}, Table~\ref{tab1}).

\begin{table*}[p!]%tab1
\tabcolsep15pt
\caption{\label{tab1}Synthesis of phosphine oxides and phosphonates
\textbf{3a--m} from phosphonium salts \textbf{2a--m}}
\begin{tabular}{ccc}
\thead
Entry & Phosphonium salt 2 & Phosphonate/oxide phosphine 3 (Yield (\%))\\
\endthead
\01 & \raisebox{5.8pc}{}\xinlinefig{fx01} & \xinlinefig{fx02}\vspace*{1.5pc}\\
\02 & \xinlinefig{fx03} & \xinlinefig{fx04}\vspace*{1.5pc}\\
\03 & \xinlinefig{fx05} & \xinlinefig{fx06}\vspace*{1.5pc}\\
\04 & \xinlinefig{fx07} & \xinlinefig{fx08}\vspace*{1.5pc}\\
\05 & \xinlinefig{fx09} & \xinlinefig{fx10}\vspace*{1.5pc}\\
\06 & \xinlinefig{fx11} & \xinlinefig{fx12}\\\tabularBreak
\07 & \xinlinefig{fx13} & \raisebox{9.5pc}{}\xinlinefig{fx14}\vspace*{1pc}\\
\08 & \xinlinefig{fx15} & \xinlinefig{fx16}\vspace*{1pc}\\
\09 & \xinlinefig{fx17} & \xinlinefig{fx18}\vspace*{1pc}\\
10 & \xinlinefig{fx19} & \xinlinefig{fx20}\vspace*{1pc}\\
11 & \xinlinefig{fx21} & \xinlinefig{fx22}\\\tabularBreak
12 & \xinlinefig{fx23} & \raisebox{7.5pc}{}\xinlinefig{fx24}\vspace*{1.2pc}\\
13 & \xinlinefig{fx25} & \xinlinefig{fx26}
\botline
\end{tabular}
\end{table*}

The reaction mechanism involves a 1,4-addition of DBU to the
cyclohexenone moiety, accompanied by the cleavage of the C--P bond and
subsequent elimination of P(Ph)$_{3}$ via an $\text{S}_{\mathrm{N}}2'$
mechanism. Simultaneously, the trialkylphosphite attacks the opposite
side of the C${=}$C double bond by following an
$\text{S}_{\mathrm{N}}2'$ mechanism. This leads to a repositioning of
the electrons towards their original configuration, resulting in the
elimination of DBU. Ultimately, an Arbuzov-type rearrangement occurs,
leading to the formation of phosphine oxide (Scheme~\ref{sch5}).

The succession of two $\text{S}_{\mathrm{N}}2'$ mechanisms generates an
$\text{S}_{\mathrm{N}}2$ type mechanism.

This method exemplifies the principles of reducing resource use, such
as solvents of the process, to produce MBH acetates efficiently.
Conversely, a straightforward purification of the phosphonium salts was
achieved through simple washing with a small volume of ethyl acetate or
ether. Moreover, their heightened electrophilicity, in comparison to
MBH acetates, broadens their applicability in organic chemistry,
extending beyond the Wittig reaction to include a wider range of
synthetic reactions.

Typically, MBH acetates are synthesized from \mbox{alcohols} \textbf{1}
(Scheme~\ref{sch6})~\cite{21} using acetic anhydride, Et$_{3}$N, and
DMAP. The resulting MBH acetates were then neutralized with HCl and
extracted with CH$_{2}$Cl$_{2}$. Subsequently, purification involves
chromatographic column separation on silica, requiring considerable
quantities of the organic solvent (such as petroleum ether or ether) to
remove various impurities. In contrast, the phosphonium salts
necessitate only a simple washing with ether or ethyl acetate, and in
much small amounts for purification. This efficient method proves
invaluable for synthesizing phosphine oxides and phosphonates, which
can be involved in diverse biological and chemical applications, while
ensuring the prevention of secondary reactions. Moreover, it eliminates
the need for multiple reagents and catalysts like acetic anhydride,
Et$_{3}$N, and DMAP, thereby simplifying the synthesis process,
accelerating it, and reducing costs significantly (Scheme~\ref{sch6}). 

The results and yields are reported in Table~\ref{tab1}.

\subsection{Conclusion} \label{sec2.3}

In this study, we have developed a method that prioritizes atom economy
and minimizes the need of a solvent for purification in the synthesis of
phosphine oxides and allylic phosphonates of 
MBH adducts. To this end, we employed phosphonium salts \textbf{2} as
reagents capable of undergoing a single-step reaction with
trialkylphosphites and ethoxydiphenylphosphine. Besides their utility in
the Wittig reaction, the resulting products hold promise for their
strong complexation abilities. Previous research has emphasized the
reliability of similar compounds in facilitating the assembly of
complex molecular architectures~\cite{14,15,35,36,37}.

\section{Experimental section} \label{sec3}
\subsection{General considerations} \label{sec3.1}
\subsubsection{Materials and methods}

${}^{1}$H NMR and ${}^{13}$C NMR spectra were recorded at 300 and
75~MHz, respectively, in CDCl$_{3}$, using TMS as an internal standard
(chemical shifts in $\updelta$ values, $J$ in Hz). High-resolution mass
spectra (HRMS) were recorded as TOF-HRMS on a micromass spectrometer.
Analytical TLC was performed using silica gel 60 F254 precoated plates.
Visualization was achieved by UV light (254~nm). Flash chromatography
was performed using silica gel 60 and a gradient solvent system
(petroleum ether/ether) as the eluent.

\subsection{Synthesis of phosphonium salts 2} \label{sec3.2}

In a round-bottom flask, a combination of
2-hydroxymethylcyclohex-2-en-1-one (\textbf{1a}) (1~g, 7.93 mmol,
1~equiv) and triphenylphosphine (2.49~g, 9.51~mmol, 1.1~equiv) in
CH$_{2}$Cl$_{2}$ (20~mL) and an aqueous solution containing 48\% HBr
(5~mL, 39.65~mmol) were introduced. The resulting mixture was stirred
at room temperature for 20~min, during which the progress of the
reaction was monitored using TLC. Once the reaction was completed, the
mixture underwent hydrolysis with H$_{2}$O, followed by multiple
extractions with CH$_{2}$Cl$_{2}$. After drying the organic phase over
MgSO$_{4}$, the solvent was evaporated, yielding a white solid. This
solid was subjected to recrystallization using EtOAc, filtered through
a sintered glass, and rinsed with Et$_{2}$O, resulting in the isolation
of pure \textbf{2a--m} as a white solid.

\subsection{Synthesis of phosphonates 3} \label{sec3.3}

In a small round-bottom flask equipped with a stirrer and reflux
condenser, phosphonium salt \textbf{2} (1.55~mmol, 1~equiv) was
dissolved in CHCl$_{3}$, followed by the addition of trialkylphosphite
or ethoxydiphenylphosphine (1.70~mmol, 1.5~equiv) and DBU (0.155~mmol,
0.1~equiv). The mixture is then refluxed for 1~h. The progress of the
reaction was monitored using TLC. Upon completion, the reaction mixture
was neutralized with a 4~N HCl aqueous solution and extracted with
CH$_{2}$Cl$_{2}$. The organic phase was dried over MgSO$_{4}$, and 
CH$_{2}$Cl$_{2}$ was removed under reduced pressure. Subsequently,
products \textbf{3} were purified by column chromatographic silica gel,
using CH$_{2}$Cl$_{2}$/Et$_{2}$O (40:60) as the eluent. The resulting
products \textbf{3a--m} were obtained as solid compounds with excellent
purity.\vspace*{.4pc}

\inlinefig{fx27}

{\vspace*{4pt}}

\subsubsection{2-((Diphenylphosphoryl)methyl)cyclohex-2-enone (3a)}

mp: 106--107~{\textdegree}C; Yield: 93\% (465~mg on 1.62~mmol reaction
scale); ${}^{1}$H NMR (300~MHz, CDCl$_{3}$): ${\updelta}$: 1.79 (m, 2H),
2.22 (t, $J = 6.0$~Hz, 2H), 2.31 (m, 2H), 3.37 (d,
$J_{\mathrm{P}\ndash \mathrm{H}} = 12.0$~Hz, 2H), 7.31 (t, $J =
6.0$~Hz, 1H), 7.44--7.77 (m, 10H); ${}^{13}$C NMR (75~MHz, CDCl$_{3}$):
${\updelta}$: 22.6, 26.2, 27.8 (d, $J = 68.8$~Hz), 37.6, 128.2--131.6
(aromatics), 133.1 (d, $J_{\mathrm{C}\ndash \mathrm{P}} = 3$~Hz),
150.2 (d, $J_{\mathrm{C}\ndash \mathrm{P}} = 7.5$~Hz), 197.2 (d,
$J_{\mathrm{C}\ndash \mathrm{P}} = 4.5$~Hz); ${}^{31}$P NMR (121~MHz,
CDCl$_{3}$): ${\updelta}$: 30.4; HRMS (ESI-TOF): [M${+}$H]$^{+}$ calcd
for C$_{19}$H$_{20}$O$_{2}$P: 311.1195. Found: 311.1206.
\vspace*{.4pc}

\inlinefig{fx28}

{\vspace*{4pt}}

\subsubsection{2-(1-(Diphenylphosphoryl)ethyl)cyclohex-2-en-1-one (3b)}

mp: 112--113~{\textdegree}C; Yield: 97\% (485~mg on 1.543 mmol reaction
scale); ${}^{1}$H NMR (300~MHz, CDCl$_{3}$): ${\updelta}$: 1.29 (dd, $J
= 15.9$, 7.4~Hz, 3H), 1.66 (m, 1H), 1.86 (m, 1H), 2.26 (m, 2H), 2.35
(m, 2H), 4.15 (dd, $J = 7.3$~Hz, 1H), 7.28--7.94 (m, 11H); ${}^{13}$C
NMR (75~MHz, CDCl$_{3}$): ${\updelta}$: 14.4 (d,
$J_{\mathrm{C}\ndash \mathrm{P}} = 3$~Hz), 22.5, 26.3 (d,
$J_{\mathrm{C}\ndash \text{P}} = 2.5$~Hz), 28.4 (d,
$J_{\mathrm{C}\ndash \text{P}} = 69$~Hz), 37.7, 128--133.3
(aromatics), 136.9 (d, $J_{\mathrm{C}\ndash \text{P}} = 4.5$~Hz),
149.4 (d, $J_{\mathrm{C}\ndash \text{P}} =
6.75$~Hz), 197.3 (d, $J_{\mathrm{C}\ndash \text{P}} = 4.5$~Hz);
${}^{31}$P NMR (121~MHz, CDCl$_{3}$): ${\updelta}$: 34.19; HRMS
(ESI-TOF): [M$^{+}$] calcd for C$_{20}$H$_{21}$O$_{2}$P: 324.1279.
Found: 324.1264.

\inlinefig{fx29}

\subsubsection{2-(1-(Diphenylphosphoryl)propyl)cyclohex-2-en-1-one (3c)}

mp: 117--118~{\textdegree}C; Yield: 94\% (470~mg on 1.48~mmol reaction
scale); ${}^{1}$H NMR (300~MHz, CDCl$_{3}$): ${\updelta}$: 0.81 (t, $J
= 9$~Hz, 3H), 1.63 (m, 1H), 1.81 (m, 3H), 2.02 (m, 1H), 2.35 (m, 3H),
4.00 (td, $J = 6.0$, $J_{\mathrm{P}\ndash \mathrm{H}} = 9.0$~Hz, 1H),
7.28--7.95 (m, 11H); ${}^{13}$C NMR (75~MHz, CDCl$_{3}$): ${\updelta}$:
12.2 (d, $J_{\mathrm{C}\ndash \text{P}}= 13.5$~Hz), 22.6 (d,
$J_{\mathrm{C}\ndash \text{P}} = 1.5$~Hz), 26.4 (d,
$J_{\mathrm{C}\ndash \text{P}} = 2.25$~Hz), 30.8, 35.6 (d,
$J_{\mathrm{C}\ndash \mathrm{P}} = 69$~Hz), 37.7, 127.9--133.6
(aromatics), 135.1 (d, $J_{\mathrm{C}\ndash \mathrm{P}} = 5.25$~Hz),
149.1 (d, $J_{\mathrm{C}\ndash \text{P}} = 6.75$~Hz), 197.9 (d,
$J_{\mathrm{C}\ndash \text{P}} = 5.25$~Hz); ${}^{31}$P NMR (121~MHz,
CDCl$_{3}$): ${\updelta}$: 33.30; HRMS (ESI-TOF): [M$^{+}$] calcd for
C$_{21}$H$_{23}$O$_{2}$P: 338.1436. Found (M${+}$H): 339.1502.

\inlinefig{fx30}

\subsubsection{2-(1-(Diphenylphosphoryl)butyl)cyclohex-2-en-1-one (3d)}

mp: 124--125~{\textdegree}C; Yield: 96\% (480~mg on 1.42~mmol reaction
scale); ${}^{1}$H NMR (300~MHz, CDCl$_{3}$): ${\updelta}$: 0.80 (t, $J
= 6.0$~Hz, 3H), 1.60--2.04 (m, 6H), 2.24--2.38 (m, 4H), 4.09 (ddd, $J =
3.0$, $J_{\mathrm{P}\ndash \mathrm{H}} = 12.0$~Hz, 1H), 7.27--7.95 (m,
11H); ${}^{13}$C NMR (75~MHz, CDCl$_{3}$): ${\updelta}$: 13.7, 20.7 (d,
$J_{\mathrm{C}\ndash \text{P}} = 12.75$~Hz), 22.6, 26.4, 31.3 (d,
$J_{\mathrm{C}\ndash \mathrm{P}} = 1.5$~Hz), 33.6 (d,
$J_{\mathrm{C}\ndash \text{P}} = 69$~Hz), 37.7, 127.9--133.6
(aromatics), 135.4 (d, $J_{\mathrm{C}\ndash \text{P}} = 4.5$~Hz),
149.1 (d, $J_{\mathrm{C}\ndash \text{P}} = 6.75$~Hz), 197.97 (d,
$J_{\mathrm{C}\ndash \text{P}} = 4.5$~Hz); ${}^{31}$P NMR (121~MHz,
CDCl$_{3}$): ${\updelta}$: 33.55; HRMS (ESI-TOF): [M$^{+}$] calcd for
C$_{22}$H$_{25}$O$_{2}$P: 352.1592. Found (M${+}$H): 352.1639.

\inlinefig{fx31}

\subsubsection{2-(1-(Diphenylphosphoryl)-2-{\ubreak}methylpropyl)cyclohex-2-en-1-one (3e)}

mp: 125--126~{\textdegree}C; Yield: 92\% (456~mg on 1.42~mmol reaction
scale); ${}^{1}$H NMR (300~MHz, CDCl$_{3}$): ${\updelta}$: 0.81 (d, $J =
6.0$~Hz, 3H), 0.98 (d, $J = 6.0$~Hz, 3H), 1.49 (m, 1H), 1.86 (m, 2H),
2.28 (m, 4H), 4.05 (t, $J = 6.0$, $J_{\mathrm{P}\ndash \mathrm{H}} =
15.0$~Hz, 1H), 7.33--7.96 (m, 11H); ${}^{13}$C NMR (75~MHz, CDCl$_{3}$):
${\updelta}$: 20.3 (d, $J_{\mathrm{C}\ndash \mathrm{P}} = 6.75$~Hz),
22.4, 22.9 (d, $J_{\mathrm{C}\ndash \mathrm{P}} = 9$~Hz), 26.2, 29.4,
37.6, 39.6 (d, $J_{\mathrm{C}\ndash \mathrm{P}} = 69$~Hz),
127.9--134 (aromatics), 134.6 (d, $J_{\mathrm{C}\ndash \mathrm{P}} =
8.7$~Hz), 150.1 (d, $J_{\mathrm{C}\ndash \text{P}} = 6.75$~Hz), 197.9
(d, $J_{\mathrm{C}\ndash \text{P}} = 6$~Hz); ${}^{31}$P NMR (121~MHz,
CDCl$_{3}$): ${\updelta}$: 33.20; HRMS (ESI-TOF): [M$^{+}$] calcd for
C$_{22}$H$_{25}$O$_{2}$P: 352.1592. Found [M${+}$H]$^{+}$: 352.9818.

\inlinefig{fx32}

\subsubsection{2-((Diphenylphosphoryl)(phenyl)methyl){\ubreak}cyclohex-2-en-1-one (3f)}

mp:\ 157--158~{\textdegree}C; Yield: 90\% (450~mg on 1.295 mmol reaction
scale); ${}^{1}$H NMR (300~MHz, CDCl$_{3}$): ${\updelta}$: 1.64--1.89
(m, 2H), 2.18--2.34 (m, 4H), 5.30 (d,
$J_{\mathrm{P}\ndash \mathrm{H}} = 6.0$~Hz, 1H), 7.16--7.92 (m, 16H);
${}^{13}$C NMR (75~MHz, CDCl$_{3}$): ${\updelta}$: 22.4, 26.4 (d,
$J_{\mathrm{C}\ndash \mathrm{P}} = 0.75$~Hz), 37.8, 41.2 (d,
$J_{\mathrm{C}\ndash \mathrm{P}} = 68.25$~Hz), 126.9--133.3
(aromatics), 136.3 (d, $J_{\mathrm{C}\ndash \mathrm{P}} = 6$~Hz),
150.5 (d, $J_{\mathrm{C}\ndash \mathrm{P}} = 6.75$~Hz), 197.0 (d,
$J_{\mathrm{C}\ndash \mathrm{P}} = 6.75$~Hz); ${}^{31}$P NMR
(121~MHz, CDCl$_{3}$): ${\updelta}$: 32.51; HRMS (ESI-TOF): [M$^{+}$]
calcd for C$_{25}$H$_{2}$3O$_{2}$P: 386.1436. Found [M${+}$H]$^{+}$:
386.1434. \vspace*{.5pc}

\inlinefig{fx33}

\subsubsection{2-((4-Chlorophenyl)(diphenylphosphoryl){\ubreak}methyl)cyclohex-2-en-1-one (3g)}

\looseness=-1
mp: 181--182~{\textdegree}C; Yield: 91\% (455~mg on 1.19~mmol reaction
scale); ${}^{1}$H NMR (300~MHz, CDCl$_{3}$): ${\updelta}$: {1.64--1.87}
(m, 2H), 2.10--2.37 (m, 4H), 5.26 (d,
$J_{\mathrm{P}\ndash \mathrm{H}} = 9.0$~Hz, 1H),
7.13--7.87 (m, 15H); ${}^{13}$C NMR (75~MHz,
CDCl$_{3}$): ${\updelta}$: 22.4, 26.4 (d,
$J_{\mathrm{C}\ndash \mathrm{P}} = 0.75$~Hz), 37.6, 40.7 (d,
$J_{\mathrm{C}\ndash \mathrm{P}} = 148.5$~Hz), 128.2--134.9
(aromatics), 136.3 (d, $J_{\mathrm{C}\ndash \mathrm{P}} = 17.25$~Hz),
150.7 (d, $J_{\mathrm{C}\ndash \mathrm{P}} = 18.75$~Hz), 196.9 (d,
$J_{\mathrm{C}\ndash \mathrm{P}} = 12$~Hz); ${}^{31}$P NMR (121~MHz,
CDCl$_{3}$): ${\updelta}$: 32.15; HRMS (ESI-TOF): [M$^{+}$] calcd for
C$_{25}$H$_{22}$ClO$_{2}$P: 420.1046. Found [M${+}$H]$^{+}$: 420.1109.
\vspace*{.4pc}

\inlinefig{fx34}

\subsubsection{2-((Diphenylphosphoryl)(4-nitrophenyl){\ubreak}methyl)cyclohex-2-enone (3h)}

mp: 214--215~{\textdegree}C; Yield: 97\% (485~mg on 1.16~mmol reaction
scale); ${}^{1}$H NMR (300~MHz, CDCl$_{3}$): ${\updelta}$: 1.74 (m, 2H),
2.27 (m, 4H), 5.42 (d, $J_{\mathrm{P}\ndash \mathrm{H}} = 6.0$~Hz,
1H), 7.96 (t, $J = 6.0$~Hz, 1H), 7.30--8.04 (m, 14H); ${}^{13}$C NMR
(75~MHz, CDCl$_{3}$): ${\updelta}$: 22.3, 26.4, 37.7, 41.3 (d,
$J_{\mathrm{C}\ndash \mathrm{P}} = 66$~Hz), 123.7--135.3 (aromatics),
143.9 (d, $J_{\mathrm{C}\ndash \mathrm{P}} = 4.5$~Hz), 151.3 (d,
$J_{\mathrm{C}\ndash \mathrm{P}} = 6$~Hz), 196.4 (d,
$J_{\mathrm{C}\ndash \mathrm{P}} = 6$~Hz); ${}^{31}$P NMR (121~MHz,
CDCl$_{3}$): ${\updelta}$: 31.7; HRMS (ESI-TOF): [M$^{+}$] calcd for
C$_{25}$H$_{23}$NO$_{4}$P: 431.1286. Found: 431.1288.
\vspace*{.4pc}

\inlinefig{fx35}

\subsubsection{2-((Diphenylphosphoryl)(2-nitrophenyl){\ubreak}methyl)cyclohex-2-enone (3i)}

mp: 213--212~{\textdegree}C; Yield: 92\% (460~mg on 1.16~mmol reaction
scale); ${}^{1}$H NMR (300~MHz, CDCl$_{3}$): ${\updelta}$: 1.77 (m,
2H), 2.21 (m, 2H), 2.34 (m, 2H), 6.14 (d,
$J_{\mathrm{P}\ndash \mathrm{H}} = 12.0$~Hz, 1H), 7.23--8.33 (m,
15H); ${}^{13}$C NMR (75~MHz, CDCl$_{3}$): ${\updelta}$: 22.3, 26.4 (d,
$J_{\mathrm{C}\ndash \mathrm{P}} = 0.75$~Hz), 35.4 (d,
$J_{\mathrm{C}\ndash \mathrm{P}} = 66.75$~Hz), 37.6, 124.4--132.3
(aromatics), 135.7 (d, $J_{\mathrm{C}\ndash \mathrm{P}} = 3$~Hz),
151.1 (d, $J_{\mathrm{C}\ndash \mathrm{P}} = 6$~Hz), 196.1 (d,
$J_{\mathrm{C}\ndash \mathrm{P}} = 6$~Hz); ${}^{31}$P NMR (121~MHz,
CDCl$_{3}$): ${\updelta}$: 32.52; HRMS (ESI-TOF):
[M$^{+}$] calcd for C$_{25}$H$_{22}$NO$_{4}$P: 431.1286. Found:
431.8281.

\inlinefig{fx36}

\subsubsection{2-((2-Chlorophenyl)(diphenylphosphoryl){\ubreak}methyl)cyclohex-2-en-1-one (3j)}

mp: 106--107~{\textdegree}C; Yield: 96\% (1.19~mg on 480~mmol reaction
scale); ${}^{1}$H NMR (300~MHz, CDCl$_{3}$): ${\updelta}$: 1.69--1.91
(m, 2H), 2.22--2.39 (m, 4H), 5.94 (d,
$J_{\mathrm{P}\ndash \mathrm{H}} = 9.0$~Hz, 1H), 7.06--8.18 (m, 15H);
${}^{13}$C NMR (75~MHz, CDCl$_{3}$): ${\updelta}$: 22.4, 26.5 (d,
$J_{\mathrm{C}\ndash \mathrm{P}} = 1.50$~Hz), 37.1 (d,
$J_{\mathrm{C}\ndash \mathrm{P}} = 67.50$~Hz), 37.7, 126.8--134.7
(aromatics), 135.0 (d, $J_{\mathrm{C}\ndash \mathrm{P}} = 4.50$~Hz),
151.3 (d, $J_{\mathrm{C}\ndash \mathrm{P}} =6$~Hz), 195.9 (d,
$J_{\mathrm{C}\ndash \mathrm{P}} = 5.25$~Hz); ${}^{31}$P NMR
(121~MHz, CDCl$_{3}$): ${\updelta}$: 32.56; HRMS (ESI-TOF): [M$^{+}$]
calcd for C$_{25}$H$_{22}$ClO$_{2}$P: 420.1046. Found: 420.3382.
{\vspace*{.2pc}}

\inlinefig{fx37}

\subsubsection{Diethyl
((4-chlorophenyl)(6-oxocyclohex-1-{\ubreak}en-1-yl)methyl)phosphonate (3k)}

mp: 142--141~{\textdegree}C; Yield: 98\% (498.4~mg on 1.40 mmol
reaction scale); ${}^{1}$H NMR (300~MHz, CDCl$_3$):
${\updelta}$: 1.09 (t, $J = 6.0$~Hz, 3H), 1.26 (t, $J = 6.0$~Hz, 3H),
1.96 (m, 2H), 2.43 (m, 4H), 3.91 (q, $J = 6.0$~Hz, 2H), 4.04 (q, $J =
6.0$~Hz, 2H), 4.77 (d, $J_{\mathrm{P}\ndash \mathrm{H}} = 24.0$~Hz,
1H), 7.24--7.41 (AB, $J = 9.0$~Hz, 4H), 7.56 (t, $J = 3.0$~Hz, 1H).
${}^{13}$C NMR (75~MHz, CDCl$_{3}$): ${\updelta}$: 16.1, 16.4, 22.5,
26.3, 39.56 (d, $J_{\mathrm{C}\ndash \mathrm{P}} = 141$~Hz), 52.2,
62.3, 62.8, 117.5--134.6 (aromatics), 135.65 (d,
$J_{\mathrm{C}\ndash \mathrm{P}} = 2.25$~Hz), 149.1 (d,
$J_{\mathrm{C}\ndash \mathrm{P}} = 6.75$~Hz), 196.7 (d,
$J_{\mathrm{C}\ndash \mathrm{P}} = 9$~Hz). ${}^{31}$P NMR (121~MHz,
CDCl$_{3}$): ${\updelta}$: 25.09. HRMS (ESI-TOF): [M$^{+}$] calcd for
C$_{17}$H$_{22}$ClO$_{4}$P: 356.0944. Found: 356.5342.
{\vspace*{.2pc}}

\inlinefig{fx38}

\subsubsection{Diethyl
((2-nitrophenyl)(6-oxocyclohex-1-en-{\ubreak}1-yl)methyl)phosphonate (3l)}

mp: 146--145~{\textdegree}C; Yield: 95\% (475~mg on 1.36~mmol reaction
scale); ${}^{1}$H NMR (300~MHz, CDCl$_{3}$): ${\updelta}$: 1.1 (t, $J
= 6.0$~Hz, 3H), 1.28 (t, $J = 6.0$~Hz, 3H), 1.98 (m, 2H), 2.45 (m,
4H), 3.87 (q, $J = 6.0$~Hz, 2H), 4.11 (q, $J = 6.0$~Hz, 2H), 5.39
(d, $J_{\mathrm{P}\ndash \mathrm{H}} = 27.0$~Hz, 1H), 7.14--7.81 (m,
5H). ${}^{13}$C NMR (75~MHz, CDCl$_{3}$): ${\updelta}$: 16.1, 16.2,
21.8, 25.4, 36.7 (d, $J_{\mathrm{C}\ndash \mathrm{P}} = 138.75$~Hz),
52.2, 62.7, 62.8, 117.5--134.1 (aromatics), 134.9 (d,
$J_{\mathrm{C}\ndash \mathrm{P}} = 8.25$~Hz), 147.6 (d,
$J_{\mathrm{C}\ndash \mathrm{P}} = 54.75$~Hz), 200.2 (d,
$J_{\mathrm{C}\ndash \mathrm{P}} = 12.75$~Hz). ${}^{31}$P NMR
(121~MHz, CDCl$_{3}$): ${\updelta}$: 26.74. HRMS (ESI-TOF): [M$^{+}$]
calcd for C$_{17}$H$_{22}$NO$_{6}$P: 367.1185. Found: 367.6969.
\looseness=-1\vspace*{.2pc}

\inlinefig{fx39}

\subsubsection{Diethyl
((2-chlorophenyl)(6-oxocyclohex-1-{\ubreak}en-1-yl)methyl)phosphonate (3m)}

mp: 144--143~{\textdegree}C; Yield: 95\% (485~mg on 1.40~mmol reaction
scale); ${}^{1}$H NMR (300~MHz, CDCl$_{3}$): ${\updelta}$: 1.1 (t, $J
= 6.0$~Hz, 3H), 1.28 (t, $J = 6.0$~Hz, 3H), 1.98 (m, 2H), 2.45 (m,
4H), 3.87 (q, $J = 6.0$~Hz, 2H), 4.11 (q, $J = 6.0$~Hz, 2H), 5.38
(d, $J_{\mathrm{P}\ndash \mathrm{H}} = 27.0$~Hz, 1H), 7.14--7.81 (m,
5H). ${}^{13}$C NMR (75~MHz, CDCl$_{3}$): ${\updelta}$: 16.1, 16.4,
22.5, 26.4, 36.6 (d, $J_{\mathrm{C}\ndash \mathrm{P}} = 141$~Hz),
53.4, 62.5, 62.8, 126--131 (aromatics), 135 (d,
$J_{\mathrm{C}\ndash \mathrm{P}} = 4.5$~Hz), 149.8 (d,
$J_{\mathrm{C}\ndash \mathrm{P}} = 6.75$~Hz), 296.9 (d,
$J_{\mathrm{C}\ndash \mathrm{P}} = 5.25$~Hz). ${}^{31}$P NMR
(121~MHz, CDCl$_{3}$): ${\updelta}$: 24.38. HRMS (ESI-TOF): [M$^{+}$]
calcd for C$_{17}$H$_{22}$ClO$_{4}$P: 356.0944. Found: 356.8127.

\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.

\section*{Funding}
The authors thank the DGRST and the Ministry of Higher Education,
Tunisia, for financial support of this work.

The authors extend their appreciation to the Deanship of Scientific
Research at Northern Border University, Arar, KSA for funding this
research work through the project number FFR-2024-2939-01.

\CDRGrant[NBU]{FFR-2024-2939-01}

{\vspace*{-.25pc}}

\back{}

\bibliographystyle{crchim}
\bibliography{crchim20240407}
\refinput{crchim20240407-reference.tex}

\end{document}
