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\DOI{10.5802/crchim.428}
\datereceived{2025-10-08}
\daterevised{2025-10-15}
\dateaccepted{2025-10-20}
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\begin{document}

\begin{noXML}

\CDRsetmeta{articletype}{clarification}

\title{High-pressure-driven cycloadditions: dearomatization of
electron-deficient arenes}

\alttitle{Cycloadditions sous haute pression : d\'{e}saromatisation
des aromatiques \'{e}lectro-appauvris}

\author{\firstname{Nathan} \lastname{No\"{e}l}}
\address{Univ Rouen Normandie, CNRS, INSA Rouen Normandie, Univ Caen 
Normandie, ENSICAEN, Institut CARMeN UMR 6064, F-76000 Rouen, France}

\author{\firstname{Rayhane} \lastname{Hammami}\CDRorcid{0009-0009-7214-7961}}
\addressSameAs{1}{Univ Rouen Normandie, CNRS, INSA Rouen Normandie, Univ Caen 
Normandie, ENSICAEN, Institut CARMeN UMR 6064, F-76000 Rouen, France}

\author{\firstname{La\"{e}titia} \lastname{Chausset-Boissarie}\CDRorcid{0009-0001-0530-704X}}
\addressSameAs{1}{Univ Rouen Normandie, CNRS, INSA Rouen Normandie, Univ Caen 
Normandie, ENSICAEN, Institut CARMeN UMR 6064, F-76000 Rouen, France}

\author{\firstname{Isabelle}\nobreakauthor\lastname{Chataigner}\CDRorcid{0000-0001-6302-7831}\IsCorresp}
\addressSameAs{1}{Univ Rouen Normandie, CNRS, INSA Rouen Normandie, Univ Caen 
Normandie, ENSICAEN, Institut CARMeN UMR 6064, F-76000 Rouen, France}
\address{Sorbonne Universit\'{e}, LCT, UMR 7616 CNRS, F-75005, Paris, France}
\email[I. Chataigner]{isabelle.chataigner@univ-rouen.fr}

\shortrunauthors

\keywords{\kwd{High pressure}\kwd{Cycloadditions}\kwd{Electron-poor
arenes}\kwd{Dearomatization}}

\altkeywords{\kwd{Haute pression}\kwd{Cycloadditions}\kwd{Aromatiques
\'{e}lectro-appauvris}\kwd{D\'{e}saromatisation}}

\begin{abstract}
Dearomative cycloadditions transform planar structures into intricate 
three-dimensional polycyclic compounds. The scope of these reactions is 
limited however due to steric or electronic limitations. High-pressure 
conditions provide an effective way to overcome these challenges, often 
minimizing the formation of side products and eliminating the need for 
chemical catalysts. This article showcases recent advances from our group, 
revealing that high-pressure-induced cycloadditions facilitate the efficient 
transformation of electron-deficient arenes into complex molecules under 
conditions that promote sustainable chemistry.
%\vspace*{2pt}
\end{abstract}

\begin{altabstract}
Les cycloadditions d\'{e}saromatisantes permettent la transformation de 
compos\'{e}s aromatiques plans en compos\'{e}s polycycliques 
tridimensionnels fonctionnalis\'{e}s complexes. Toutefois, le potentiel 
synth\'{e}tique de ces r\'{e}actions reste souvent limit\'{e} en raison de 
contraintes st\'{e}riques ou \'{e}lectroniques inh\'{e}rentes \`{a} ces 
r\'{e}actions. Les conditions de haute pression se r\'{e}v\`{e}lent 
particuli\`{e}rement efficaces dans ce contexte, en acc\'{e}l\'{e}rant les 
transformations, tout en r\'{e}duisant la formation de produits secondaires 
et en \'{e}vitant, dans la plupart des cas, le recours \`{a} des additifs 
chimiques. Cet article pr\'{e}sente des exemples de notre groupe dans ce 
domaine, montrant que les cycloadditions r\'{e}alis\'{e}es sous haute 
pression permettent de transformer efficacement les aromatiques 
\'{e}lectroniquement appauvris en mol\'{e}cules complexes, dans des 
conditions de chimie durable.
\end{altabstract}

%\input{CR-pagedemetas} 

\editornote{Article submitted by invitation}
\alteditornote{Article soumis sur invitation}

\maketitle

\vspace*{2pt}

\twocolumngrid

\end{noXML}

\section{Introduction}

Pressure is a parameter frequently overlooked by the community of organic 
synthetic chemists, except in cases involving gases, such as hydrogenation 
or carbonylation, where it typically reaches values between 1 and 50 bars. 
In organic chemistry, reaction media are most often liquids, and compressing 
a liquid is generally considered challenging, if not impossible, especially 
when aiming to attain pressures above 1~kbar, such as those needed to 
significantly affect the reaction outcomes. For clarity, the term ``high 
pressure'' (HP) used in the following refers specifically to the 1--20 kbar 
range (i.e., 2000--20\,000~atm or 0.2--2.0~GPa).

On the basis of the Evans--Polanyi transition state theory, it has been 
established that the influence of pressure on the activation energy of 
chemical \mbox{reactions} $(\Delta G^{\ddagger })$, and thus on their 
kinetic constants, is a function of the sign and absolute value of the 
activation volume $(\Delta V^{{\ddagger }})$, which corresponds to the 
volume of the transition state $(V_{\mathrm{TS}})$ minus the volume of the 
substrate(s) $(V_{\mathrm{SM}})\ (\Delta V^{{\ddagger }}  = 
V_{\mathrm{TS}} - V_{\mathrm{SM}})$. A chemical reaction characterized by 
a negative $\Delta V^{{\ddagger  }}$ is accelerated when 
pressure increases, while in contrast it is decelerated when $\Delta 
V^{{\ddagger}}$ is positive~\cite{1,2,3}.      

Cycloadditions are among the most useful reactions in synthesis, giving
rapid access to functionalized (poly)cyclic compounds from simple
starting  materials such as, for example, alkenes, dienes, or dipoles.
As the  cycloadducts incorporate the entire starting materials, the
process  generates no waste and exhibits high atom economy. However,
the application  of these reactions is often hampered by the
unfavorable steric or electronic  characteristics of the reagents. The
typical activation methods used for  promoting cycloadditions are
thermal, microwave, or chemically catalyzed  ones (acid, base, metal,
or organo-catalyst). Because cycloadditions are  characterized by
highly compact transition states, they are generally  associated to
negative activation volumes, comprised between ${-}$10 and
${-}$50~cm$^{{3}}{\cdot} \mathrm{mol}^{{-1}}$, and are thus significantly 
accelerated when the pressure increases~\cite{4}. 

Under HP, deactivated and/or sterically hindered substrates can become good 
partners in cycloadditions, making HP a valuable alternative to conventional 
heating or chemical catalysis~\cite{5}. An 
increase in selectivity comes as an extra bonus since this activation mode 
disfavors uncontrolled side reactions, especially when they are 
characterized by a positive activation volume. For instance, HP tends to 
prevent retrocycloadditions or eliminations that are difficult to control 
under more classical conditions. Energy is required to compress the reaction 
medium, but HP remains constant once established, and the overall energy 
input remains low. Consequently, HP represents a sustainable and effective 
strategy to enhance the yields of sluggish or inefficient 
cycloadditions~\cite{6}.\looseness=1

Electron-deficient aromatic compounds are easily accessible, through 
S$_{E}$Ar reactions (electrophilic aromatic substitution) for example. Their 
involvement in dearomatizations is particularly attractive, facilitating a 
straightforward increase in the complexity of the molecular structure. In 
general, when electron-deficient aromatics interact with nucleophilic 
species, they undergo nucleophilic aromatic substitutions (S$_{N}$Ar), which 
involve an addition/elimination sequence restoring the aromaticity of the 
original ring~\cite{7}. In some cases, the dearomatized 
Meisenheimer intermediate resulting from the nucleophilic addition step can 
be trapped intramolecularly, in a formal cycloaddition process, affording a 
dearomatized cycloadduct~\cite{8}. Complementarily, 
concerted cycloadditions between electron-poor aromatics and electron-rich 
dienes or dipoles can also deliver the dearomatized cycloadducts. Because 
the latter processes involve transition states that are more compact than 
the starting materials, they are efficiently accelerated under HP. At the 
same time, HP helps to prevent potentially competitive retroadditions or 
rearomatizations, which are typically associated with positive activation 
volumes. \looseness=-1

Over the past two decades, our laboratory has explored dearomatizations
of  electron-deficient (hetero)arenes in different cycloaddition
processes.  While the involvement of the aromatics as electron-poor
dipolarophiles in  the presence of electron-rich 1,3-dipoles is
typically performed at  atmospheric pressure~\cite{9,10,11,12,13,14},
HP activation has proven very useful to promote ($4{+}2$) dearomative 
cycloadditions. Two different types of reactions have been developed:
the  first one involves one double bond of the aromatic compound acting
as an  electron-poor dienophile, while the second exploits the
C${=}$C--N${=}$O system  of nitroarenes acting as an electron-poor
heterodiene. Both approaches are  described below.

\section{Electron-deficient arenes as dienophiles in HP-promoted
Diels--Alder cycloadditions}

We have developed ($4{+}2$) dearomative cycloadditions in which the
double  bond of the aromatic bearing an electron-withdrawing
substituent reacts as  dienophile, through its lowest unoccupied
molecular orbital (LUMO), with an  electron-rich 1,3-diene involved
through its highest occupied molecular  orbital (HOMO). This typically
leads to a polycyclic adduct bearing a  tetrasubstituted carbon atom at
the ring junction, with a relative \textit{cis}  stereochemistry of the
junction due to the pericyclic character of the  reaction
(Scheme~\ref{sch1}). 


\begin{scheme*}
\vspace*{-3pt}
\includegraphics{sc01}
\vspace*{3pt}
\caption{\label{sch1}Electron-deficient arenes as dienophiles in
Diels--Alder cycloadditions.}
\vspace*{-7pt}
\end{scheme*}

Different electron-poor (hetero)aromatics have been involved in these 
reactions with electron-rich dienes, and the cycloaddition conditions depend 
on the nature of the aromatic (indole, pyrrole, naphthalene, quinoline, or 
benzene), the electron-withdrawing group(s) (nitro, cyano, (alkoxy)carbonyl, 
or ketoamide) and the electron-rich diene. The following classification is 
based on the nature of the aromatic.\looseness=-1

\subsection{Electron-depleted indoles as dienophiles in Diels--Alder 
cycloadditions}

Indoles are crucial structural frameworks present in a wide range of
natural  products, many of which display notable biological activities.
From a  reactivity perspective, indoles are widely recognized as
moderate  nucleophiles~\cite{15}, and their reactivity with various 
electrophiles has been extensively studied in organic synthesis.
Recently,  in a complementary approach, the electrophilic reactivity of
electron-deficient indoles has been largely  \mbox{investigated}~\cite{16,17}.
Intramolecular reactions have been developed some time ago, to generate
interesting  scaffolds~\cite{18,19}.  In the case of the intermolecular
version of the cycloadditions, it has been  demonstrated that
introducing a nitro group at the C3 position of this  heterocycle
decreases its aromaticity, thereby facilitating the addition of 
electron-rich species~\cite{20}. In this  context, different research
groups have contributed to exploit the  ``\textit{umpolung}''
reactivity of electron-depleted indoles and demonstrated that 
3-nitroindoles can react as C2${=}$C3 electron-poor dienophiles with 
electron-rich dienes in Diels--Alder cycloadditions
(Scheme~\ref{sch2})~\cite{21}. Note that thermally activated  processes
generally lead to partial or complete rearomatization of the 
cycloadducts by nitrous acid elimination, a thermodynamically favored 
process~\cite{21,22,23,24,25,26,27}. \looseness=-1

\begin{scheme*}
\includegraphics{sc02}
{\vspace*{5pt}}
\caption{\label{sch2}3-Nitroindoles as dienophiles in Diels--Alder 
cycloadditions.} 
{\vspace*{-7pt}}
\end{scheme*}


Thanks to the relatively high electrophilic character of 3-nitroindoles
bearing an electron-withdrawing group at the nitrogen 
position~\cite{20}, the presence of the Danishefsky's
diene \textbf{2a}, doubly activated by two  oxy groups at positions N1
and C3, renders the cycloaddition possible at  room temperature (r.t.)
in the absence of any promoter. Under these smooth  conditions,
rearomatization is prevented and the indoline cycloadduct  isolated in
good yields~\cite{20}.  Diastereoselectivities are low, probably
because of the conflicting  influences of the stabilizing secondary
orbital interactions \mbox{favoring} the  \textit{endo} approach, and of the
steric hindrance favoring the \textit{exo} one. The reaction can  also
occur with thiourea- or squaramide-based organocatalysts, including 
chiral ones. However, the stereoselectivities observed with these
catalysts  are generally low, likely due to the competing non-catalyzed
process~\cite{28}.

With less reactive dienes such as 2-trimethylsilyloxycyclohexadiene 
\textbf{2b}, the reaction is not possible at atmospheric pressure. In
such  cases, HP activation proves efficient, and the reaction proceeds
under 16~kbar at r.t.~\cite{29}. These smooth thermal and chemical 
conditions lead to the preservation of the three-dimensional nature of
the  dearomatized cycloadduct, which is isolated in good yields
(Scheme~\ref{sch3}).  Notably, the diastereoselectivity of the
cycloaddition is complete with this  diene, leading to the exquisite
formation of the \textit{exo} cycloadduct. The  corresponding
approach is characterized by lower distortion of the  substrates in a
late transition state and by more favorable orbital  interactions,
presumably between the nitro group and the dienic part,  explaining the
stereoselectivity~\cite{29}. Under these  conditions,
7-aza-3-nitroindoles also react well, leading to azaindolines in  a
similar \mbox{manner.}\looseness=1

\begin{scheme*}
\includegraphics{sc03}
{\vspace*{5pt}}
\caption{\label{sch3}HP-promoted Diels--Alder reaction of 3-nitro(aza)indoles 
with diene \textbf{2b}.}
{\vspace*{-5pt}}
\end{scheme*}

Other possible indolic dienophiles include 3-carbonylated substrates.
In  this case, the Diels--Alder (DA) reaction involving the C2${=}$C3
double bond  of the heteroaromatic competes with the
hetero-Diels--Alder (HAD) reaction,  where the carbonyl C${=}$O bond
acts as a competing dienophile. The reaction  outcome depends on the
carbonyl substituent, with tertiary ketoamide  favoring the DA process,
while formyl, ketoester, and secondary ketoamide  favor the HDA one,
all using Danishefsky's diene \textbf{2a} (Scheme~\ref{sch4})~\cite{30}. 


\begin{scheme*}
\includegraphics{sc04}
{\vspace*{5pt}}
\caption{\label{sch4}HP-promoted Diels--Alder reaction of 3-carbonylated 
indoles with \textbf{2a}.}
{\vspace*{-7pt}}
\end{scheme*}

When less polarized, all-carbon dienes \textbf{2c} and \textbf{2d} are 
involved in the process with 
3-formylindole \textbf{1c}, chemoselectivity favors the DA cycloadduct. 
Owing to the lower reactivity of these dienes, Lewis acid activation, such 
as zinc chloride catalysis, can be beneficial. However, this acidic catalyst 
also promotes competitive polymerization of the diene used in excess under 
HP, and this can sometimes complicate the isolation of the desired 
cycloadduct. Under thermal conditions (195~\textdegree C), cycloadduct 
\textbf{6c} is obtained in a good yield. However, when diene \textbf{2c} is 
used, HP activation triggers a subsequent reaction, leading to the formation 
of bis-cycloadduct \textbf{8} (Scheme~\ref{sch5})~\cite{30,31}.

\begin{scheme*}
\includegraphics{sc05}
{\vspace*{5pt}}
\caption{\label{sch5}Thermal versus HP-promoted Diels--Alder reaction of 
3-formylindole with \textbf{2c}.}
{\vspace*{-7pt}}
\end{scheme*}

In contrast, when cyclohexa-1,3-diene \textbf{2d} is involved, the reaction 
leads to cycloadduct \textbf{6d} regardless of the reaction conditions 
(Scheme~\ref{sch6})~\cite{31}. The conversion, yield and 
diastereoselectivity of the reaction under HP conditions are greater than 
under thermal activation.

\begin{scheme*}
\includegraphics{sc06}
{\vspace*{5pt}}
\caption{\label{sch6}Thermal versus HP-promoted Diels--Alder reaction of 
3-formylindole with \textbf{2d}.}
{\vspace*{-3pt}}
\end{scheme*}

\begin{scheme*}
\includegraphics{sc07}
{\vspace*{6pt}}
\caption{\label{sch7}Influence of the nitrogen atom substituent on the 
cycloaddition.}
{\vspace*{-3pt}}
\end{scheme*}

The type of electron-withdrawing substituent on the nitrogen atom of
the  indolic dienophile plays a crucial role in the cycloaddition.
Although  sulfonyl groups are known to be stronger electron-withdrawing
groups than  (alkoxy)carbonyl groups, the cycloaddition of 3-ketoamidic
indoles with  diene \textbf{2a} occurs more readily when the nitrogen
atom is activated as  an amide or carbamate rather than as a
sulfonamide (Scheme~\ref{sch7})~\cite{32}. This fact is ascribed to a
greater ability  of the carbon-centered groups to achieve
delocalization of the nitrogen's  lone pair, resulting in stronger
global withdrawing effects. The  sulfur-centered functional group is
less efficacious in decreasing electron  density on the nitrogen atom,
even when inductive effects are considered.  This results in a lower
aromaticity of the (alkoxy)carbonyl indoles and a  higher reactivity at
C2${=}$C3 electron-poor  dienophile~\cite{32}.

\subsection{Electron-depleted benzofurans as\newline dienophiles in
Diels--Alder  cycloadditions}

Other possible heteroarenic dienophiles include benzofuranic compounds,
bearing an electron-withdrawing substituent at position C3. Here again,
while 3-nitrobenzofurans react as C2${=}$C3 dienophile at r.t.\ and
ambient  pressure with Danishefsky's diene \textbf{2a} to yield the
corresponding  cycloadduct~\cite{20}, reactions with  the less depleted
3-carbonylated substrates require a stronger activation.  With
2,3-dimethylbuta-1,3-diene \textbf{2c} or cyclohexa-1,3-diene 
\textbf{2d}, the cycloadditions can be thermally activated. However,
this  activation mode is less efficient when more sensitive
silyloxydienes are  involved and HP conditions are then to be preferred
(Scheme~\ref{sch8})~\cite{33}. Here again, competitive HDA processes,
involving  the carbonyl substituent at position C3 as heterodienophile,
are observed  with benzofurans bearing a ketoester group in the
presence of Danishefsky's  diene \textbf{2a}~\cite{33}. 

\begin{scheme*}
\includegraphics{sc08}
{\vspace*{5pt}}
\caption{\label{sch8}3-Carbonylated benzofurans as C2${=}$C3
dienophiles under  HP activation.}
{\vspace*{-4pt}}
\end{scheme*}

\subsection{Electron-depleted pyrroles as dienophiles in Diels--Alder 
cycloadditions}

When reacted under thermal conditions or Lewis acid activation, 
3-nitro-$N$-tosylpyrrole \textbf{11} remains inert toward Danishesfky's
diene  \textbf{2a} and this sensitive diene is generally destroyed. In
contrast, it  reacts efficiently as an electron-poor dienophile with
\textbf{2a} under HP  activation~\cite{34}. The cycloadduct generated
is  unstable after decompression and leads to the corresponding
carbazole  \textbf{12}, resulting from a complete rearomatization
(Scheme~\ref{sch9}). 

\begin{scheme*}
\includegraphics{sc09}
{\vspace*{5pt}}
\caption{\label{sch9}3-Nitropyrrole as C2${=}$C3 dienophile under HP activation.}
{\vspace*{-4pt}}
\end{scheme*}

Cycloadditions with the less electron-depleted 3-acylpyrroles are also 
feasible under HP conditions, although Lewis acid catalysis is required
alongside HP activation in this case. For example, cycloadditions
between  electron-poor pyrroles \textbf{13}, which contain
electron-withdrawing  groups at least at the N1 and C3 positions and a
series of electron-rich  dienes, result in the formation of
cycloadducts \textbf{14}
(Scheme~\ref{sch10})~\cite{35,36}. These products are 
obtained in very low yields under thermal activation in the presence of
ZnCl$_{{2}}$. Similarly, under HP and without a catalyst, this 
dienophile reacts poorly and enters a competitive polymerization
process.  However, combining HP and Lewis acid (ZnCl$_{{2}}$)
activations  significantly improves the efficiency of the cycloaddition
and the expected  \textit{syn}-tetrahydroindole \textbf{14} is
recovered in good to excellent yields.

\begin{scheme*}
{\vspace*{-2pt}}
\includegraphics{sc10}
{\vspace*{4pt}}
\caption{\label{sch10}3-Acylpyrrole \textbf{13} as C2${=}$C3 dienophile
under HP  activation combined with Lewis acid catalysis.}
{\vspace*{-10pt}}
\end{scheme*}

\subsection{Other electron-depleted five-membered-ring heteroaromatics as 
dienophiles in Diels--Alder cycloadditions}

Other nitrated five-membered-ring heteroaromatics can be dearomatized under 
HP in the presence of Danishefsky's diene \textbf{2a}, among which 
benzothiophene, pyrazole, or furan. The reaction does not require any 
additional chemical activation and smooth hydrolysis of the pressurized 
mixture leads to preservation of the three-dimensional structure of the 
dearomatized cycloadduct in these cases (Scheme~\ref{sch11})~\cite{34}. 

\begin{scheme*}
\includegraphics{sc11}
{\vspace*{3pt}}
\caption{\label{sch11}Nitrated five-membered-ring heteroaromatics as 
dienophiles under HP activation.}
{\vspace*{-7pt}}
\end{scheme*}

\subsection{Six-membered-ring (hetero)aromatics as dienophiles in 
Diels--Alder cycloadditions}

HP--promoted DA reactions may also involve highly aromatic six-membered
rings, such as nitroquinolines or nitronaphthalenes and nitrobenzenes
in the  presence of Danishefsky's diene \textbf{2a}
(Scheme~\ref{sch12})~\cite{34}. The reaction proceeds at r.t.\ in the 
absence of any chemical promoter and affords in good yields the
hydrolyzed  cycloadducts with their three-dimensional structures
intact. Here again, the  \textit{endo}/\textit{exo}
diastereoselectivities are low with this diene, because of compensation
between the stabilizing secondary orbital interactions favoring the
\textit{endo}  approach and steric hindrance favoring the \textit{exo}
one. The diastereoselectivity is  slightly enhanced with structurally
similar but sterically more hindered  dienes, especially those bearing
bulky groups at position C1 or C3, but this  comes at the expense of
reactivity~\cite{34}. Notably,  when two nitro groups are positioned on
the same ring of the original  aromatic substrate, two cycloadditions
occur, resulting in the formation of  polycyclic bis-cycloadducts
\textbf{19 }from 1,3-dinitronaphthalene or  1,3-dinitrobenzene. 

\begin{scheme*}
{\vspace*{-2pt}}
\includegraphics{sc12}
{\vspace*{6pt}}
\caption{\label{sch12}Cycloadditions of nitrated six-membered-ring 
(hetero)aromatics as dienophiles with Danishefsky's diene \textbf{2a} under 
HP activation.}
{\vspace*{-2pt}}
\end{scheme*}

As suggested by DFT computations performed on a model reaction between 
1-nitronaphthalene and Danishefsky's diene \textbf{2a}, the cycloaddition 
occurs in a stepwise fashion, the silylenol ether first adding at position 
C2 of the aromatic. The formation of an elusive zwitterionic primary adduct 
(\textbf{PA}) is quickly followed by cyclization via a Michael addition to 
furnish the cycloadduct (\textbf{CA}), prior to hydrolysis of the silyl enol 
ether moiety (Scheme~\ref{sch13}). The initial dearomatization addition is associated 
with a significantly higher energy barrier than that of the subsequent 
cyclization step (${\sim} 27$ versus 
${\sim} 4~\mathrm{kcal}{\cdot}\mathrm{mol}^{-1}$), making it the
rate-determining step.  Assuming that the \textbf{PA} undergoes no
conformational change before  cyclization, the diastereoselectivity of
the overall cycloaddition is  governed by the stereochemical outcome of
the initial addition. Consistent  with the experimental data, the small
energy difference between the \textit{endo} and  \textit{exo}
transition states ($\Delta \Delta G^{{\ddagger }}  = 
0.4~\mathrm{kcal}{\cdot}\mathrm{mol}^{-1}$) accounts for the low 
diastereoselectivity observed in the resulting cycloadducts.

\begin{scheme*}
{\vspace*{-1.5pt}}
\includegraphics{sc13}
{\vspace*{6pt}}
\caption{\label{sch13}Energy profiles for the cycloadditions between 
1-nitronaphthalene and diene \textbf{2a}~; \textit{trans}
(\textit{endo}) approach (red); \textit{cis} (\textit{exo}) approach 
(blue), computed at the (SMD:CH$_{{2}}$Cl$_{{2}})$  M062X/6-31${+}$G(d,p)
level of theory.}
{\vspace*{-8pt}}
\end{scheme*}

With the less reactive 2-trimethylsilyloxycyclo-hexadiene \textbf{2b},
the  reaction is still possible at r.t.\ under 16 kbar in the absence of
a  catalyst (Scheme~\ref{sch14})~\cite{29}. As observed with 
3-nitroindoles, diastereoselectivity with this cyclic diene is now
totally  controlled and the exquisite formation of the sole
\textit{exo}-cycloadduct is observed.  As suggested by DFT
computations, the \textit{exo} approach is associated with reduced 
substrate distortion in a late transition state, along with more
favorable  orbital interactions, likely between the nitro group and the
diene moiety.  The propensity for the cycloadducts to rearomatize by
loss of nitrous acid  is higher here, causing a slight lowering of the
\mbox{isolated} yields. Here  again, when two nitro groups are positioned on
the same ring of the initial  aromatic compound, two cycloadditions
occur, resulting in the formation of  the \textit{bis}-cycloadduct
\textbf{21} from 1,3-dinitro-naphthalene in a completely 
diastereoselective way. \looseness=1

\begin{scheme*}
\includegraphics{sc14}
{\vspace*{3pt}}
\caption{\label{sch14}Cycloadditions of nitrated six-membered-ring 
(hetero)aromatics as dienophiles with \textbf{2b} under HP activation.}
{\vspace*{-3pt}}
\end{scheme*}



\section{Nitroarenes as heterodienes in HP-{\ubreak}promoted domino
(4+2)-/(3+2)-{\ubreak}cycloadditions}

Over the years, domino processes have proven to be powerful and
efficient  strategies for the rapid construction of complex molecules
in a minimal  number of synthetic steps. Notably, Denmark et~al.\ 
described a series of  ($4{+}2$)-/($3{+}2$)-cycloadditions~involving
nitroalkenes, and these processes  have proven highly valuable for the
synthesis of a wide range of \mbox{nitrogen-containing} compounds~\cite{37}.
In these domino  transformations, the nitroalkene partner \textbf{22}
initially acts as a  heterodiene in an inverse electron-demand
($4{+}2$)-cycloaddition, forming the  intermediate nitronate
\textbf{23}. This species then undergoes a subsequent 
($3{+}2$)-cycloaddition to afford a nitroso-ketal derivative
\textbf{24} (Scheme~\ref{sch15}). Such compounds provide useful
synthetic intermediates, giving  an easy access to nitrogenated motifs,
after selective cleavage of the  N--O bonds for instance. 

\begin{scheme*}
\includegraphics{sc15}
{\vspace*{4pt}}
\caption{\label{sch15}($4{+}2$)-/(3${+}$2)-Domino cycloadditions involving 
nitroalkenes.}
{\vspace*{-8pt}}
\end{scheme*}

\begin{scheme*}
\includegraphics{sc16}
{\vspace*{2pt}}
\caption{\label{sch16}($4{+}2$)/(3${+}$2)-Domino cycloadditions
involving  3-nitroindole \textbf{1a}, ethyl vinyl ether \textbf{25},
and methylacrylate  \textbf{26}.}
{\vspace*{-8pt}}
\end{scheme*}

It turns out that both ($4{+}2$)- and (3${+}$2)-cycloaddition processes are 
promoted under HP~\cite{4}. Hence, Scheeren et~al.\ have 
demonstrated that such 
($4{+}2$)-/($3{+}2$)-reactions using nitrostyrenes as heterodienes can be 
efficiently promoted under HP~\cite{38}. Given the 
comparable electrophilic character of \mbox{nitrostyrenes} and 
3-nitroindoles~\cite{20}, we sought to 
explore the participation of these nitro heteroarenes in similar domino 
processes. If such a synthetic endeavor could be impeded by the aromaticity 
of the substrate, it would offer the advantage of relying on readily 
accessible starting materials to generate partially dearomatized polycyclic 
structures bearing a tetrasubstituted center at the ring junction, a feature 
generally difficult to control. In the first ($4{+}2$)-cycloaddition,
the  nitroalkene moiety is \mbox{expected} to react via its LUMO as an 
{electron-deficient} {heterodiene,} favoring interaction with
an electron-rich  dienophile in an inverse electron-demand
($4{+}2$)-cycloaddition. Ethyl vinyl  ether was selected as a model
electron-rich dienophile. In contrast, the  nitronate dipole
intermediate is expected to react more effectively via its  HOMO with
an electron-deficient dipolarophile, such as an acrylate. The 
complementary reactivities of these two alkene species make them
excellent  candidates for the design of a multicomponent domino process
enabling the  efficient synthesis of nitroso  ketals.\looseness=-1

Indeed, the reaction of indole \textbf{1a} with ethyl vinyl ether 
\textbf{25} and methyl acrylate \textbf{26} in dichloromethane at r.t.\ 
successfully affords the expected nitroso ketal 
\textbf{27}~\cite{39}. Comparing different activation 
modes shows that HP is the most efficient one, leading to the expected 
tetracyclic adduct in good yield and with superior diastereoselectivities 
(Scheme~\ref{sch16}). The \mbox{reaction} can also occur with thiourea- or squaramide-based 
organocatalysts, including chiral ones. However, the enantioselectivities 
observed with these catalysts are low, likely due to the competing 
non-catalyzed process~\cite{28}.

\begin{scheme*}
\includegraphics{sc17}
{\vspace*{5pt}}
\caption{\label{sch17}Proposed pathways for the
($4{+}2$)-/(3${+}$2)-sequence  accounting for the observed
diastereoselectivity.}
{\vspace*{-6pt}}
\end{scheme*}

\begin{scheme*}
\includegraphics{sc18}
{\vspace*{5pt}}
\caption{\label{sch18}Influence of the dipolarophile on the 
diastereoselectivity of the ($4{+}2$)-/(3${+}$2)-process.}
{\vspace*{-6pt}}
\end{scheme*}

In this process, two of the eight possible diastereomer couples are
formed  under HP. As shown by X-ray diffraction analyses on the two
separated  compounds resulting from the same reaction, but involving
$n$-butyl vinyl ether  instead of ethyl vinyl ether, the difference
stems from the relative  stereochemistry at the methoxycarbonyl alpha
position. This suggests that  the initial ($4{+}2$)-cycloaddition
proceeds in a purely \textit{endo} mode, determining the  relative
configurations of both C7$_{\mathrm{a}}$ at the ring junction and  C6
alpha to the alkoxy group. A complete facial differentiation for the 
subsequent (3${+}$2)-process, with an approach of the dipolarophile
from the  more {accessible} bottom face sets the relative \mbox{stereochemistry}
of \mbox{quaternary}  carbon C12$_{\mathrm{b}}$ at the ring {junction.}
This second \mbox{cycloaddition,}  however, shows little or no
\textit{endo}/\textit{exo} selectivity for the acrylate approach
(Scheme~\ref{sch17})~\cite{40}.

The diastereoselectivity is improved when other dipolarophiles are employed, 
notably when they bear an aromatic moiety (Scheme~\ref{sch18})~\cite{39}. 

\begin{scheme*}
\includegraphics{sc19}
{\vspace*{6pt}}
\caption{\label{sch19}Reduction of nitroso ketal \textbf{27}.}
{\vspace*{-6pt}}
\end{scheme*}

\begin{scheme*}
\includegraphics{sc20}
{\vspace*{6pt}}
\caption{\label{sch20}($4{+}2$)/(3${+}$2)-Domino cycloadditions involving 
3-nitropyrrole \textbf{11}, ethyl vinyl ether \textbf{25,} and methyl 
acrylate \textbf{26} and subsequent reduction of nitroso ketal~\textbf{29}.}
{\vspace*{-4pt}}
\end{scheme*}

One of the key strengths of this method is the straightforward and
efficient  conversion of the resulting nitroso ketals. Therefore, the
simple catalytic  reduction of \textbf{\textit{endo}-27} under 15 bar 
hydrogen using Raney nickel$^{\text{\textregistered}}$ for 48 h results
in the formation  of pyrrolizidone \textbf{28}, isolated in 98{\%}
yield, with the original  characteristics of the stereogenic centers
completely retained (Scheme~\ref{sch19}).  Most likely, this product
results from the sequential cleavage of two N--O  bonds, formation, and
subsequent reduction of an imine intermediate to  construct ring D,
followed by lactamization to complete ring C. 
\mbox{Similarly,}  \mbox{reduction} of
the diastereomer \textbf{\textit{exo}-27} led to the  formation of the
corresponding diastereomeric tetracyclic lactam.

Extension of this process to other ring systems has been achieved with 
3-nitropyrrole (Scheme~\ref{sch20}). As expected, this more aromatic substrate requires a
higher  pressure of 16 kbar and heating to 50~\textdegree C to react.
It leads to  the corresponding nitroso ketal obtained in a 25:75
\textit{endo}/\textit{exo} ratio and isolated in  an overall 81{\%}
yield. Note that this smaller heterocycle leads to a  stereoselectivity
different from that above. Here again, the nitroso ketal  can be
efficiently reduced into the corresponding tricyclic compound under 
similar hydrogenation conditions and the tricyclic amine is obtained in
68{\%} isolated yield.

Although these tetra- or tricyclic structures are not commonly found in 
natural products, they certainly exhibit functional and three-dimensional 
topological characteristics that could contribute to the development of 
novel pharmacological scaffolds.


\section{Conclusion}

\looseness=-1
In conclusion, dearomative cycloadditions involving electron-deficient 
(hetero)arenes are strongly favored by high-pressure conditions. These 
easily available aromatic compounds can act as dienophiles or heterodienes, 
in reaction with electron-rich dienes or dienophiles, providing an efficient 
access to the \mbox{corresponding} \mbox{three-dimensional} polycyclic adducts. 
High-pressure conditions primarily promote these reactions by overcoming the 
high energy barrier required to disrupt aromaticity, thereby enabling more 
efficient and selective transformations. High pressure favors forward 
cycloadditions over retroreactions, which is a key point since 
dearomatization is often endergonic and reversible under normal thermal 
conditions. High pressure can indeed shift equilibria toward product 
formation since cycloadditions are characterized by highly negative 
activation volumes, associated to a decrease in volume from reactants to the 
transition state and products. They also stabilize tightly packed transition 
states and intermediates. High pressure (HP) simultaneously disfavors the 
retrocycloadditions involving an elimination reaction, which are 
characterized by a positive activation volume. Because these dearomative 
cycloadditions proceed at lower temperatures under HP, the side reactions 
and decomposition processes are limited. In many cases, HP conditions also 
help improving selectivity and stereocontrol as the pressurized confined 
environment can favor specific diastereomers or regioisomers, thus improving 
the stereochemical outcome of cycloadditions. In summary, acting as a 
physical promoter, HP facilitates cycloadditions that disrupt aromaticity 
and enables the access to strained or unusual polycyclic structures. In 
doing so, HP helps in building complex three-dimensional polycyclic 
scaffolds with a high sp$^{{3}}$~character that are important in 
pharmaceutics and materials science.

\section*{Declaration of interests}

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

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