# Intramolecular carbolithiation of alkynes: observation, mechanism, applications

Jacques Maddaluno, Catherine Fressigné, Muriel Durandetti

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Jacques Maddaluno, Catherine Fressigné, Muriel Durandetti. Intramolecular carbolithiation of alkynes: observation, mechanism, applications. SYNLETT, In press. hal-05370036

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# Intramolecular carbolithiation of alkynes: observation, mechanism, applications

Jacques Maddaluno*<sup>a,b</sup>

Catherine Fressigné<sup>a</sup>

Muriel Durandetti*<sup>a</sup>

Muriel.durandetti@univ-rouen.fr

Click here to insert a dedication.

<figure><img src="image_2.png" /></figure>

Received:

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DOI:

**Abstract** The intramolecular carbolithiation of alkynes is a useful cyclisation reaction that gives stereoselectively access to functionalized alkenes. This reaction is supposed to proceed through a *syn*-addition mechanism. We show in this account that the interaction between the lithium cation and the substituent on the propargylic position (or directly on the triple bond) can derail this process and afford selectively the *anti*-addition product. The set of results presented in this account, both experimental and theoretical, suggests that the stereochemical outcome of the addition can be predicted with success.

<figure><img src="image_3.png" /></figure>

1. Introduction

2. Intramolecular carbolithiation of alkynes: coordination effect

3. Modulation of the coordination

4. Conclusion

**Key words** Alkynes – Carbolithiation – Cyclisation – Heterocycles – Lithium coordination – Stereoselectivity

## 1 Introduction

In 1927, Ziegler and Bähr described the first carbometallation reaction consisting of the addition of an alkyl potassium on stilbene.¹ª This pioneering result revolutionized not only organic chemistry itself, but also, subsequently, the daily lives of millions then billions of people on this planet, by indirectly opening up the gigantic field of Ziegler-Natta catalysis, whose success in oligo and polymerization is well known.¹ᵇ⁻ᶜ

The first step of this reaction consists in the catalytic or stoichiometric addition of a nucleophilic organometallic species on a C–C π bond, leading to a new C–C σ bond

simultaneously with a C–M σ bond, which can further add onto another olefin or alkyne, entering the iterative process that finally provides high to extremely high molecular weight polymers. However, this progression can be stopped, provided that the organometallic trigger is more reactive than the intermediate product, which can then be trapped by an electrophile. Under these conditions, this family of reactions becomes a simple and general means of functionalizing multiple C–C bonds, either inter- or intramolecularly (Figure 1), which explains its importance as a synthetic tool.²

<figure><img src="image_4.png" /><figcaption>Figure 1 Regio- and stereoselectivity for carbometallation of alkynes in inter- or intramolecular pathway.</figcaption></figure>

In the intramolecular case, this reaction has been extended in large to the chemo- and stereo-selective synthesis

<footnote><sup>a</sup> Univ Rouen Normandie, INSA Rouen Normandie, Univ Caen Normandie, ENSICAEN, CNRS, Institut CARMEN UMR 6064, F-76000 Rouen, France</footnote>

<footnote><sup>b</sup> Sorbonne Université, CNRS, Laboratoire d'Archéologie Moléculaire et Structurale UMR 8220, F-75005 Paris, France</footnote>

<footnote>* indicates the main/corresponding author. Use another symbol to indicate equal contributions.</footnote>
of functionalized cyclic systems. If alkaline metals, particularly lithium derivatives, have proven very effective in triggering a carbometallation reaction, several other elements including alkaline-earth, transition metals or metalloids (Mg, Pd, Zn, Ni, Pt, B, Al ...) have also been successfully employed in this family of reaction.³

The work published by our group in this field has focused mainly on the intramolecular carbometallation of alkynes using three metals: Pd,⁴ Ni⁵ and Li. In this account, we will concentrate on the results obtained on the intramolecular carbolithiation of internal alkynes.

## 2 Intramolecular carbolithiation of alkynes: coordination effect

Our preliminary reaction in this field began with the intramolecular cascade reaction, involving a 5-*exo-dig* cyclization followed by a *β*-elimination of lithium ethoxide, witnessed when treating propargylic arylether **1** with an excess of *n*-BuLi (Scheme 1).⁶ We first concluded that a regioselective carbolithiation of the internal alkyne had occurred, affording a vinyllithium that in turn prompted a *β*-elimination of lithium ethoxide. This unexpected observation made full sense with respect to an original investigation we dedicated to the conjugated elimination applied to propargylic acetals.⁷ Because it is both efficient and stereoselective, this uncommon reaction caught our attention. It indeed opens a handy access to 3-vinylheterocycles in medium to good yields and fine *E*-selectivity, starting from easily accessible aromatic substrates.

An extra bonus came when we discovered that these vinylbenzofuranes can be regarded as dienic skeletons, reactive in [4+2] fully regioselective cycloaddition under thermal or high-pressure conditions, affording functionalized tri- and tetracyclic heterocycles, of interest in the synthesis of complex, natural or unnatural structures.⁸ It is worth noting that these cycloadditions involve one heteroaromatic double bond, and lead to stable exocyclic alkylidene dihydro-indoles or -benzofurans. These processes are therefore to be regarded as dearomatisation reactions.⁹

<figure><img src="image_5.png" /><figcaption>**Scheme 1** Anionic heterocyclisation by carbolithiation/β-elimination cascade and reactivity of 3-vinylbenzofuran in [4+2] cycloadditions</figcaption></figure>

In order to better understand the mechanism of each step of the organometallic cascade reaction, as well as its regio- and stereochemical outcomes, experimental and theoretical investigations were launched. Since the use of three equivalent of BuLi were required to reach completion, we decided to evaluate the specific effect of each BuLi equivalent. When only one equivalent is used, and the reaction directly trapped at -78 °C, the dihydrobenzufran **5** bearing an exocyclic double bond in the three position was isolated as a sole *E*-isomer (established by nOesy experiments) in 88% yields (Scheme 2).¹⁰ It is worth noting that such a structure lies on the edge of the aromatization gap, and we observed that the primary addition products easily isomerize into the corresponding benzofurans. The presence of the vinyllithium intermediate **4** could be confirmed by deuteration experiments, which lead to 5-D with 34% labelling. What this result suggests is that i) the rapid lithium halogene/exchange initiated by *n*-butyllithium is immediately followed by a stereo-controlled intramolecular addition of the aryl lithium on the alkyne; ii) the cyclisation takes place in agreement with Baldwin's rules (5-*exo-dig* addition); iii) it unexpectedly leads to the *E* and not to the *Z*-isomer, which is supposed to result from a *syn* addition; iv) the lithium ethoxide elimination is not the driving force of this reaction.

<figure><img src="image_6.png" /><figcaption>**Scheme 2** Step by step addition of *n*-BuLi for carbolithiation of **1**.</figcaption></figure>

If the addition of a second equivalent of *n*-BuLi is performed at -78 °C, the elimination is ineffective, and **5** is obtained after quenching. It takes either an increase of the temperature at -40 °C or the addition of a third equivalent of *n*-BuLi at -78 °C to finally trigger the lithium ethoxide elimination.¹⁰b It therefore seems that the second BuLi equivalent is trapped, probably as an inert (at -78 °C) mixed aggregate,¹¹ and that the third equivalent is required to initiate the deprotonation of the allylic position, leading to a putative dilithiated intermediate.
In order to shed light on the unexpected configuration of the double bond in compound 4, as well as on the second elimination step, we carried out an extensive DFT study on the mechanism of this reaction.¹⁰ At the B3P86/6-31G** level conducted on an explicit THF di-solvated model of 3, our results suggest that the reaction starts with a coordination of the lithium bound to the aryl by the C–C triple bond and ends-up in a 5-exo-dig addition, in fine agreement with the experimental results. The origin of the *E* configuration of the resulting double bond is also explained, and the calculation shows that it is directly related to a strong and persisting interaction between one of the oxygens of the acetal and the lithium cation (Figure 2). Snapshots along the reaction route suggest that Li⁺ first acts as a classical Lewis acid to activate the triple bond and promote the C–C bond formation. The cation is then “carried” from one side of the newly created exocyclic double bond to the other, as if it were hooked on a crane that would rotate around its axis before delivering its cargo on the opposite site of the olefin.

Regarding the elimination step, the calculations suggest that the direct lithium methoxide elimination on intermediate 4' is unlikely at low temperature. It takes indeed more than 15 kcal.mol⁻¹ to transform 4' in the exocyclic allene 7', while a mechanism going through a sigmatropic rearrangement involving one of the alkoxy group of the acetal and one allylic proton of 4' lies more than 22 kcal.mol⁻¹ higher (Scheme 3). In contrast, starting the computation from the dilithiated intermediate 6' leads to a *gem*-diLi intermediate 8' without any activation barrier, and this same 8' undergoes spontaneous β-elimination of lithium methoxide. It therefore seems that a dilithiated intermediate, already evoked above (scheme 2), is required to complete the cascade. This

hypothesis was further buttressed by a complementary experiment consisting of deprotonating dihydro-benzofuran 5', taken as an substitute for 4', and recovering vinylbenzofurane 2' in good experimental yields and without DFT activation barrier.

<figure><img src="image_7.png" /><figcaption>Figure 2 Energy characteristics of the cyclisation route</figcaption></figure>
<figure><img src="image_8.png" /></figure>

### 3 Modulation of the coordination

Since the elimination of lithium ethoxide appeared not to be the driving force of the carbometallation, we investigated the influence of the acetylenic appendages on the reactivity and the selectivity (Scheme 4).¹² We first selected the simple terminal propyne (X = H) **9** and butyne ethers (X = Me) **10**. In these cases, no cyclisation was observed, the sole product recovered being the deiodinated aromatic **11**. Thus, if the iodine/lithium exchange is efficient the carbolithiation does not proceed this time. In the case of X = H, a series of experiments led us to the conclusion that the kinetic of the iodine/lithium exchange was superior to that of the abstraction of the acetylenic acidic proton. Comparable observations of exchange/deprotonation competitions have been noted previously.¹³ In no cases, a transfer of the iodine from the aromatic nucleus to the triple bond was observed.

<figure><img src="image_9.png" /><figcaption>Scheme 4 Inefficient carbolithiation of 9, 10, 17-19</figcaption></figure>

With the presence of a coordinating oxygen atom apparently playing an essential role, we considered the three easily accessible ethral substrates **12** (X = CH₂OMe), **13** (X = CHMeOMe) and **14** (X = CMe₂OMe).¹²a Interestingly, while **12** did not undergo cyclization and afforded the sole reduction product **11** (I → Li → H), 37 % of anti-addition cyclized olefin **15** was obtained with **13**, suggesting that the O-Li coordination is necessary but not sufficient (Scheme 5). Finally, quaternary ether **14** undergoes cyclization provided 3 equivalents of n-butyl-lithium are used. However, the excess of base triggers an uncontrolled elimination of lithium methoxide, providing 46% of iso-butene-3-benzofuran **16**.

At this stage, we undertook a series of DFT calculations to probe the O-Li interaction in these different
situations.¹²b For **12-Li**, it remains insufficient, in THF, and its reactive (folded) conformer is sterically hampered. The barrier for the unobserved intramolecular addition step itself is estimated at > 12 kcal.mol⁻¹ (vs. 8.3 kcal.mol⁻¹ for acetal **1-Li**).¹²b For **13-Li**, the MeO–Li interaction remains weak, and the energy barrier is higher (> 13 kcal.mol⁻¹), even though a low yields cyclisation has been observed. The unexplained pro-E conformation in the transition state is in agreement with the stereochemical outcome of the cyclization.

Coming back to the effect of the propargylic acetal appendage, we tried to enlarge the scope of this reaction by resorting to 5- or 7-membered cyclic acetals, prepared by simple trans-acetalization of dimethylacetal. Indeed, we expected that the elimination reaction would lead to a lithium alkoxide, which could be trapped by an externally added electrophile, thus extending the cascade by one step.¹⁴ Unfortunately, the reaction remained unsuccessful, regardless of the conditions used.¹²a

<figure><img src="image_10.png" /><figcaption>Scheme 5 Tentative of carbolithiation of ether 12-14</figcaption></figure>

We also evaluated the ability of propargylic amines to assist the cyclisation through a N–Li coordination, synthesizing and testing dibenzylamine **17**, pyrrolidine **18** and piperidine **19** (Scheme 4).¹²a All these substrates, as well as their homopropargylic homologues, did not undergo cyclization, whatever the experimental conditions, and the reduction products ArH **11** were recovered systematically (Scheme 4). DFT calculations run on a model dimethyl propargylic amine concluded that no N–Li interaction is computed, while the activation barrier remains slightly superior to 12 kcal.mol⁻¹, which appears as the threshold values for these reactions.¹²b

We next moved to the phenyl substituted triple bond **20**, possibly coordinating Li through an extra π-cation interaction.¹⁵ In this case, the carbolithiation reaction proceeds in decent (65%) yield, affording a mixture of *E* and *Z* isomers of which proportion depends on the temperature of the reaction. This ratio evolves from 10/1 at -100 °C, to 2/1 at -40 °C, suggesting a progressive isomerization between the kinetic *E* isomer and its thermodynamic *Z* counterpart (Scheme 6).¹²a

<figure><img src="image_11.png" /><figcaption>Scheme 6 Carbolithiation of phenyl-substituted alkyne 20</figcaption></figure>

In a subsequent step, we chose to replace the propargylic C by the next elements in the crystallogen family (group 14) family, expecting a possible influence of the metalloid character of Si and Ge.¹⁵⁻¹⁶ The two new derivatives **22** (Si) and **23** (Ge) were prepared adapting the known procedures. With these substrates, we retained phenyllithium to trigger a clean iodine/lithium exchange and to avoid the butylation (Wurtz-Fittig) side reaction observed with *n*-BuLi.

<figure><img src="image_12.png" /><figcaption>Scheme 7 Syn-Carbolithiation of alkynes 22 and 23</figcaption></figure>

In the two cases (**22-23**), the heteroelements do not alter the course of the reaction and the cyclisation leads selectively to the expected vinyl benzofuran, as the sole *Z*-isomer in 59 and 56% yields, respectively (Scheme 7).¹²a DFT calculations run on solvated **22-Li** are in agreement with the experimental results, since a pro-Z conformation is obtained in the transition state in the absence of any Si–Li interaction¹²b and a relatively low barrier of 10.8 kcal.mol⁻¹ is computed.

As the transient O–Li interactions seem to exert a strong influence on the stereochemistry of the carbometallation reaction, we decided to investigate its outcome when the heteroatom was placed directly on the acetylenic position, i.e. when an ynol ether substrate was employed. The original work of Funk in 1993,¹⁷ and others after him,¹⁸ described the organometallic annelation of ynol and thioynol ethers, allowing us to consider chalcogenes as terminal substituents.¹⁹ We thus selected the ynol ether **26**, easily prepared by Mitsunobu condensation between iodophenol and 1-methoxypropyn-3-ol.²⁰ Using the phenyllithium I/Li exchange protocol mentioned above, the cyclisation of **26** occurred smoothly, affording the enol ether **27**-*(*E*)* in 51%, resulting from a total anti-addition (Scheme 8). Parallel DFT calculations revealed a transition state in which the lithium triple bond and lithium-oxygen interactions are pronounced, favouring the pro-*E* configuration of the double bond being formed.

Extending this work to ynol thioethers **28**, prepared by adding thiosulfonates to lithium alkyne, did not pose any problems. The two corresponding ynol thioethers could be cyclized, in similar conditions and in medium to good yields,
into products **29** and **30**. The substituent **bound to** the sulfur atom exerts its own influence, since a thiophenyl appendage leads to the rearomatized benzofuran **29**, even when the lithiated intermediate is trapped with an electrophile such as benzyl bromide. On the contrary the thiomethyl group **bound to** **28b** affords dihydrobenzofuran **30** under its pure *E*-configuration (Scheme 9). Note that **30** undergoes a facile rearomatization during purification or over time. This complete *E*-selectivity suggests that a S–Li coordination occurs during the reaction course, a phenomenon often overlooked although pointed out by Hilmersson and colleagues,²¹ and supported by our own DFT computation leading to a very low activation barrier (≈ 4.0 kcal.mol⁻¹) and pro-*E*-configuration at the TS.¹²b Going from sulfur to selenium proved impossible, leading to an unidentified mixture of products. The possible formation of a lithium selenate complex, in competition with the iodine-lithium exchange, probably explains this disappointing result.

<figure><img src="image_13.png" /><figcaption>Scheme 8 Anti-carbolithiation of ynol-ether 26</figcaption></figure>

<figure><img src="image_14.png" /><figcaption>Scheme 9 Intramolecular anti-carbolithiation of thioethers 28</figcaption></figure>

Further extending our study prompted us to consider the pnictogen family of substituent and synthesize protected ynamides **31**. The copper catalyzed methodology described by Hsung²² revealed extremely convenient to prepare these new substrates. Three derivatives of benzylamine were thus synthetized and submitted to our cyclisation protocol (Scheme 10).¹⁹

As above, the N-Ts **31a** and N-Boc **31b** substrates led to the expected 5-*exo-dig* cyclized dihydrobenzofurans in medium yields (46 and 42% respectively) and full *E*-selectivity. The benzylamine can by replaced by a chiral imidazolidinone, as in **31d**, derived from (-)ephedrine,²³ without altering the efficiency nor the *anti*-selectivity of this addition. In sharp contrast, when the phosphonamide **31c** was employed, we obtained for the first time a 6-*endo-dig* addition product, i.e. the benzochromene **32c**, in 72% yield. The origin of this unexpected regioselectivity derailing remains unknown; we could nevertheless establish, based on DFT calculations, that this phenomenon is not directly related to an inversion of polarization between the two carbons of the triple bond.

<figure><img src="image_15.png" /><figcaption>Scheme 10 Intramolecular carbolithiation of ynamides 31</figcaption></figure>

Going further down column 15 from nitrogen to phosphorus led us to consider the case of diphenyl alkyne phosphine **33**. Phosphorus is known to poorly coordinate the lithium cation, and a *Z*-selectivity was rather expected this time. The first attempt following our usual experimental protocol could not confirm this hypothesis since the primary product rearomatized very fast leading to the benzofuran **34** (Scheme 11). However, when the reaction medium was quenched with BH₃THF right after the hydrolysis at -78 °C, we were able to isolate the phosphine borane complex **35**, exhibiting an exocyclic double bond, with the expected *Z*-configuration as demonstrated by nOesy experiments and X-ray analysis of a monocrystal.¹⁹ DFT results are in good agreement with the above results: no P–Li interaction is computed (d(P–Li) = 3.40 Å at the TS), resulting in a pro-*Z* transition state, associated to a
cyclisation barrier of only 6.5 kcal.mol⁻¹ that justifies the reactivity.

We next move to column 17, and examine the reactivity of halogenoalkynes **36**, **37** and **38**. Fluorine was dodged since the possibly explosive fluoroalkyne **36** revealed extremely difficult to obtain by classical methodologies.²⁴ On the contrary, chloroalkynes are easily synthesized by electrophilic chloration of the lithium acetylide.²⁵ Treated by one equivalent of phenyllithium, chloroalkyne **37** gave the expected *exo*-cyclic chloroalkene **39** in excellent yield (92%) and pure *E* configuration, suggesting as before that an *anti*-addition occurred on the triple bond (Scheme 12).²⁶

We were particularly satisfied by these results, which implied a vinyl intermediate **40** (Scheme 13) juxtaposing a chlorine and a lithium on the same terminal carbon. The stability and reactivity of such a carbenoidic²⁷ intermediate raised interesting questions. We first checked if the *E* selectivity was controlled by Cl–Li interactions as evoked above, launching DFT calculations on **37-Li**.

<figure><img src="image_16.png" /><figcaption>Scheme 11 Carbolithiation of alkynyl phosphine 33</figcaption></figure>

The result suggested that, as in the case of oxygen, a strong Cl–Li coordination occurred ($d(\text{Li}–\text{Cl}) = 2.76$ Å) and a low activation barrier (7.8 kcal.mol⁻¹) was associated to a pro-*E* TS, affording the *E*-carbenoid **39** following a strongly exothermic process (–61.3 kcal.mol⁻¹). The process was extended to six different chloroalkynes, bearing different substituents at the (hetero)aromatic ring or various tethers between the alkyne and the aryl.

<figure><img src="image_17.png" /><figcaption>Scheme 12 Carbolithiation of chloroalkyne 37</figcaption></figure>

The carbenoic character of intermediate **40** was corroborated by involving it in a classic test reaction with (*E*)-pentenylchloro-zirconocene prepared using the Schwartz reagent. The expected coupling took place efficiently, affording exocyclic diene ((Z)-3-((*E*)-hex-2-enylidene)-2,3-dihydrobenzofuran) **41** in 62% yield. The nucleophilic character of **40** could also be well established, trapping this intermediate with a series of electrophiles, showing the ability of **40** to be protonated, alkylated, hydroxyalkylated, or transmetallated (Scheme 13).

<figure><img src="image_18.png" /><figcaption>Scheme 13 Trapping of carbenoid intermediate 40</figcaption></figure>

The electrophilic character was proven in a second time by involving the residual chlorine atom in Suzuki cross-couplings with three different boronic acids (scheme 14). The stannic and boronic transmetallated derivatives **45** and **42g** could also be **utilized** in a further Stille or Suzuki reaction,
adding a supplementary aromatic substituent on the exocyclic
olefin. Overall, the dual nature of carbenoid **40** opens the door
to a wide variety of possible reactions. The efficient and
selective carbolithation of chloroalkyne **37** should therefore be
considered one of the most promising results of all those
studied by our team.

Concerning bromoalkyne 38, the lithium/halogen exchange is not selective and both iodine and bromine react in a competitive manner, leading to a mixture of iodo and bromoaryl propyne ether.

4 Conclusion

In conclusion, the intramolecular carbolithiation
reaction of alkynes that we have undertaken to develop in our
laboratory has yielded a number of interesting results. Starting
from the conditions established for cyclization of acetal 1, we
extended to eight new types of propargyl precursors. Thus,
propargyl alkoxy, phenyl, silicon, oxygen, sulfur, nitrogen,
phosphorus and chlorine substituents allowed the addition of
aryllithium to the triple bond, and afforded a series of
dihydrobenzofurans or analogs, bearing an exocyclic double
bond. We have clearly established on both theoretical and
experimental grounds, that the syn- or anti- character of the
addition depends on the substituent **bound to** the original triple
bond, and rely on the possible coordination between these
substituents and the lithium **intermediately bound to** the
aromatic nucleus. The various activation barriers determined
enabled us to "predict" the outcome of cyclization, while
establishing a "threshold" value of ≈12 kcal.mol⁻¹ above which
addition no longer took place. Regarding the stereoselectivity of
the approach, all substrates featuring a lithium-heteroatom
interaction lead without exception to a selective *anti*-carbolithiation.

<figure><img src="image_19.png" /><figcaption>Scheme 14 Valorization of vinylchlorine 42 by Suzuki or Stille cross-coupling reactions</figcaption></figure>

Finally, we believe the intramolecular carbolithiation
of alkynes is a simple but powerful reaction to create C–C bond
in a regio- and (most of the time) stereoselective way, thereby
providing polycyclic skeletons bearing functionalized alkenes
that can be regarded as valuable templates in organic synthesis.
The results, both experimental and theoretical, we have
compiled and organized in this account highlight the
physicochemical parameters underlying the reaction and
provide a rational explanation for its characteristics. We hope it
will reinforce the legitimate position this reaction occupy in the
organic chemist’s toolbox.

Acknowledgment

We would like to sincerely thank all the (under)graduate students, with whom these intramolecular carbolithiation reactions were explored and developed. Thanks also to our colleagues from Université de Rouen Normandie and CNRS for stimulating discussions. This work was partially supported by Normandie Université, the Région Normandie, the Centre National de la Recherche Scientifique (CNRS), Université de Rouen Normandie, INSA Rouen Normandie, Université Caen Normandie, ENSICAEN, Labex SynOrg (ANR-11-LABX-0029), the graduate school for research XL-Chem (ANR-18-EURE-0020 XL CHEM) and Innovation Chimie Carnot (I2C). All computations were run at CRIANN (St Etienne-du-Rouvray), that we thanks for generous allocation of computer time.

Conflict of Interest

The authors declare no conflict of interest.

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Biosketches

<figure><img src="image_20.png" /></figure>

Muriel Durandetti, born in 1968 in Saint-Etienne, France, is a Professor at the Rouen Normandie University. She completed her PhD, under the supervision of Professor Jacques Périchon on nickel-catalyzed electrosynthesis, in 1994 at University of Paris VI. She then worked for 4 years as an assistant professor at the University of Paris XII. In 1998, she obtained an associate professorship and developed electro-catalyzed cross-coupling reactions using nickel, chromium or iron salts. She complemented this work with mechanistic studies using electroanalytical processes. In 2005, she joined Rouen University as Associate Professor, and was promoted full Professor in 2023. Her research interests focus on electrosynthesis, intramolecular cyclization reaction by carbo- or hetero-metallation, or the synthesis of silylated heterocycles, opening up new strategies for generating valuable scaffolds.
<figure><img src="image_21.png" /></figure>

Catherine Fressigné, born in 1964 in Vierzon, France, has been an associate professor of theoretical chemistry at the University of Rouen Normandy since September 1993. She obtained her PhD in Orsay (France) at the Laboratory of Physical Chemistry of Amorphous Materials (Paris XI) on 'the structural characterisation of a petroleum fluid by one-dimensional and two-dimensional nuclear magnetic resonance' (1992, thesis supervisor Alain Fuchs). Her research focuses on theoretical mechanistic studies of structure, reactivity in solution, association effects of aggregates involving organic and organometallic compounds (Ab Initio theory), topological analyses (ELF), applied to organic chemistry (intramolecular cyclisation reactions by carbometallation or heterometallation).

<figure><img src="image_22.png" /></figure>

Jacques Maddaluno, born in 1958 in Philippeville (Algeria), is a CNRS research fellow since 1989. He obtained is PhD in organic chemistry in ESPCI Paris in 1986, under the supervision of Dr Jean d'Angelo. He then joined Stanford University Medical School in Dr Kym Faull and Prof. Jack D. Barchas team to study ¹⁵O-labelled L-DOPA. Hired by CNRS, he returned to France in 1989 and joined Prof. Pierre and Dr Lucette Duhamel's laboratory in University of Rouen where he focused on chiral lithium amides in asymmetric synthesis. He also collaborated with Dr Claude Giessner then Prof. Hélène Gérard (Sorbonne Université) in theoretical chemistry, and with Prof. Hassan Oulyadi (University of Rouen) in NMR spectroscopy. After working at CNRS headquarters for 14 years, he moved in June 2025 to the Laboratoire d'Archéologie Moléculaire et Structurale in Paris.

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