Yun-Long Wei

Guillaume Dauvergne

Jean Rodriguez

Yoann Coquerel

Enantiospecific Generation and Trapping Reactions of Aryne Atropisomers

Enantioenriched aryne atropisomers having a biaryl stereogenic axis vicinal to the reactive triple bond are demonstrated to exist. These reaction intermediates are easily produced in situ and can undergo the standard aryne cycloaddition chemistry in an enantiospecific manner. Notably, the aryne atropisomers herein have allowed the practical syntheses of a small nanographene as well as some triptycene and anthracene derivatives that embed stereogenic axes of controlled absolute configurations.

ortho-Arynes have a rich chemistry with plenty of applications for the synthesis of partially or fully aromatic molecules, from complex natural products to large polycyclic aromatic hydrocarbons. [START_REF] Garcia-Lopez | Synthesis of Biaryls Using Aryne Intermediates[END_REF][2][START_REF] Takikawa | Aryne-Based Strategy in the Total Synthesis of Naturally Occurring Polycyclic Compounds[END_REF][START_REF] Pozo | Synthesis of Nanographenes, Starphenes, and Sterically Congested Polyarenes by Aryne Cyclotrimerization[END_REF] They are reactive electrophilic species that must be generated in situ, most often through the ortho-elimination of suitable aromatic precursors. While the synthetic chemistry of aromatic molecules is traditionally not associated with stereochemistry, chirality may result from the inherently chiral shapes of crowded polycyclic aromatic compounds as in the helicenes [5][START_REF] Rickhaus | Chirality in curved polyaromatic systems[END_REF][START_REF] Majewski | Synthetic Approaches to Curved Aromatic Molecules[END_REF] or from the presence of stereogenic axes in biaryl systems [START_REF] Wencel-Delord | Recent advances and new concepts for the synthesis of axially stereoenriched biaryls[END_REF][START_REF] Nguyen | The Use of Chiral ortho-Auxiliaries/Substituents and Remote Stereogenic Centers in Atropselective Biaryl Synthesis[END_REF] (Figure 1a). Chirality at the molecular scale is a property of growing importance in chemical and physical sciences, as well as in medicine and technology. [START_REF] Brandt | The added value of small-molecule chirality in technological applications[END_REF] Various additions to the electrophilic triple bond of ortho-arynes have largely been employed for the synthesis of chiral biaryls through the formation of the biaryl C(sp 2 )-C(sp 2 ) single bond, [START_REF] Garcia-Lopez | Synthesis of Biaryls Using Aryne Intermediates[END_REF][START_REF] Wencel-Delord | Recent advances and new concepts for the synthesis of axially stereoenriched biaryls[END_REF][START_REF] Nguyen | The Use of Chiral ortho-Auxiliaries/Substituents and Remote Stereogenic Centers in Atropselective Biaryl Synthesis[END_REF][START_REF] Panossian | Lithium/Element Exchange as an Efficient Tool for Accessing Atropo-enriched Biaryls via Arynes[END_REF] and some helicenes have also been derived from arynes. [START_REF] Peŕez | Aryne Cycloaddition Reactions in the Synthesis of Large Polycyclic Aromatic Compounds[END_REF][START_REF] Wu | Arynes in the synthesis of polycyclic aromatic hydrocarbons[END_REF] Recently, the palladium-catalyzed cyclotrimeriza-tion of rac-7,8- [5]helicyne (1, Figure 1b) was reported for the stereoselective syntheses of chiral nanographenes embedding up to six [5]helicene units. [START_REF] Hosokawa | Structures, and Properties of Hexapole Helicenes: Assembling Six[END_REF][START_REF] Zuzak | Building a 22-ring nanographene by combining in-solution and on-surface syntheses[END_REF][START_REF] Yubuta | Enantioselective Synthesis of Triple Helicenes by Cross-Cyclotrimerization of a Helicenyl Aryne and Alkynes via Dynamic Kinetic Resolution[END_REF] rac-7,8- [5]Helicyne (1) is an inherently chiral ortho-aryne, the first of its kind, [START_REF]The formation 13,14-dibenzo[f,j]picyne through a hexadehydro-Diels-Alder (HDDA) reaction was evidenced with no mention to its chirality[END_REF] and no enantioenriched inherently chiral aryne is known. Herein, we propose to extend the synthetic chemistry of arynes to chiral and enantioenriched aryne atropisomers 2 bearing a biaryl stereogenic axis vicinal to the reactive aryne triple bond (Figure 1b).

The aryne atropisomer 2a was selected as the molecular prototype to evaluate this idea (Scheme 1). It was devised that enantioenriched aryne 2a could be generated from its so-called Kobayashi (X = SiMe 3 ) [START_REF] Himeshima | Fluoride-induced 1,2-elimination of o-trimethylsilylphenyl triflate to benzyne under mild conditions[END_REF] or Suzuki (X = I) [START_REF] Matsumoto | New Efficient Protocol for Aryne Generation. Selective Synthesis of Differentially Protected 1,4,5-Naphthalenetriols[END_REF] aryltriflate precursors, themselves derived from an atroposelective transesterification of some Bringmann lactones. [START_REF] Bringmann | The Lactone Concept: An Efficient Pathway to Axially Chiral Natural Products and Useful Reagents[END_REF] The configurational stability of aryne atropisomer 2a (R = Me) was evaluated computationally using DFT methods (see the Supporting Information for details). Its barrier to enantiomerization was calculated at ΔG ‡ enant = 106.0 kJ/mol, corresponding to a racemization half-life of 58 h at 25 °C, or 132 days at 0 °C. The barrier to enantiomerization of the aryne atropisomer 2a is very significantly lower than the barrier to enantiomerization of the corresponding biaryl derivative having two C(sp 2 )-H bonds in place of the aryne triple bond, which was computed at ΔG ‡ enant = 151.6 kJ/mol. In addition to the obvious absence of steric effect from the ortho-H atom, the observed greater distortion toward linearity of the alkyne terminus ortho to the stereogenic axis in aryne 2a (129.8°vs 127.5°, Scheme 1) may contribute to this large difference in barriers to enantiomerization. This stresses the crucial contribution to configurational stability of the ortho-C(sp 2 )-H bond in tris(ortho-substituted) chiral biaryl systems. Because the half-life of the reactive aryne triple bond in 2a is likely lower than its racemization half-life by several orders of magnitude, the racemization of 2a itself should not be an issue under standard reaction conditions. Thus, providing that both the generation and the trapping reactions of the aryne atropisomer 2a are enantiospecific, some new options for the synthesis of a large array of biaryl atropisomers with controlled absolute configurations would be available.

In practice, repeating the work of Wang on the organocatalytic atroposelective opening of some Bringmann lactones [START_REF] Yu | Dynamic Kinetic Resolution of Biaryl Lactones via a Chiral Bifunctional Amine Thiourea-Catalyzed Highly Atropo-enantioselective Transesterification[END_REF] allowed us to obtain the bromo-naphthol 3a on a multigram scale in 82% yield and 92% ee, and the original iodosubstituted analog 3b was prepared by the same method in 81% yield and 90% ee (Scheme 2; all molecules in schemes are represented with their correct absolute configuration). Bromonaphthol 3a was then converted into the Kobayashi-type trimethylsilyl aryltriflate precursor 4a using the procedure developed by Peŕez and Guiti án, [START_REF] Penã | An Efficient Procedure for the Synthesis of ortho-Trialkylsilylaryl Triflates: Easy Access to Precursors of Functionalized Arynes[END_REF] and the Suzuki-type iodo aryltriflate precursor 5b was obtained directly by sulfonylation of naphthol 3b, both transformations occurring without detectable erosion of the enantiopurity.

The Diels-Alder cycloaddition between furan and the aryne atropisomer 2a, derived from either 4a or 5b, was selected as the benchmark reaction (Scheme 3). In an early trial, the reaction between the enantioenriched precursor 4a (92% ee) and excess furan in the presence of cesium fluoride afforded the expected functionalized biaryl atropisomeric cycloadduct 6a in 42% yield as a 1:1 mixture of diastereomers (Scheme 3a). Remarkably, both diastereomers of 6a showed 91% ee, demonstrating that the intermediate aryne atropisomer 2a was indeed generated and that it retained most if not all the stereochemical information in an enantiospecific reaction, validating our initial hypothesis. However, these conditions from the Kobayashi precursor 4a were impeded by the migration of the sulfonyl group onto the anionic carbon atom generated upon elimination of trimethylsilyl fluoride, leading to the formation of the thia-Fries rearrangement product 7a in 43% yield. Variations of the reaction conditions, as well as the use of precursors with alternative sulfonate leaving groups or functional groups, did not solve the problem (see the Supporting Information for details). From this part of the work, it was concluded not only that the enantioenriched aryne atropisomer 2a can be generated and reacted in an enantiospecific manner but also that its Kobayashi-type precursor is not suitable because of a propensity to undergo a competitive thia-Fries rearrangement instead of the expected 1,2-elimination. The formation of the undesired thia-Fries rearrangement side-product 7a under conditions that usually do not promote this rearrangement was attributed to steric effects from the proximal stereogenic axes in 4a and the corresponding anionic reactive intermediate that facilitate the O → C migration of the sulfonyl group for conformational reasons (see the Supporting Information for a DFT modeling study). In order to temper the thia-Fries process, the generation of the aryne atropisomer 2a was attempted from the Suzuki-type precursor 5b through ortho-magnesiated aryltriflate intermediates (Scheme 3b). [START_REF] Sapountzis | Preparation of Polyfunctional Arynes via 2-Magnesiated Diaryl Sulfonates[END_REF][START_REF] Yoshida | Generation of Arynes Using Trimethylsilylmethyl Grignard Reagent for Activation of ortho-Iodoaryl or ortho-Sulfinylaryl Triflates[END_REF] After optimization (see the Supporting Information), it was ultimately found that an excess of an ethereal trimethylsilylmethyl magnesium chloride solution [START_REF] Yoshida | Generation of Arynes Using Trimethylsilylmethyl Grignard Reagent for Activation of ortho-Iodoaryl or ortho-Sulfinylaryl Triflates[END_REF] at 0 °C promoted efficient and reproducible reactions, allowing the isolation of 6a in 83% yield (1:1 dr) with no detectable amount of the thia-Fries product 7a. Most importantly, both diastereomers of 6a were obtained with 90% ee indicating virtually no erosion of enantiomeric purity from the precursor 5b under the optimized conditions.

In order to evaluate the enantiospecific synthetic options available with the enantioenriched aryne atropisomer 2a, a set of representative cycloadditions was tested, first addressing diastereoselectivity and regioselectivity issues (Scheme 4). Diels-Alder cycloadditions proved possible with two substituted furans and N-phenylsulfonyl pyrrole affording products 6b, 6c, and 6d with homogeneous retention of the enantiomeric purity. In all three cases, the two possible diastereomers were obtained in a 1:1 ratio, indicating no substrate control of the diastereoselectivity from the aryne Scheme 2. Preparation of Enantioenriched Aryne Atropisomer Precursors Scheme 3. Diels-Alder Cycloaddition between Furan and the Aryne Atropisomer 2a: (a) Early Experiment; (b) Optimized Conditions atropisomer 2a. Regioselectivity in the reactions of aryne atropisomer 2a was evaluated through some 1,3-dipolar cycloadditions with two azides and a diazo compound to afford cycloadducts 6e, 6f, and 6g, and also a [2 + 2] cycloaddition with dimethyl ketene acetal to give the benzocyclobutane 6h. The regioselectivity in 6e was ascertained through the single-crystal X-ray diffraction analysis of a derivative (see the Supporting Information, CCDC 1997613). Overall, only moderate regiocontrol was observed, but counterintuitively favoring the regioisomer involving bond formation between the nucleophilic part of the polarized reaction partner and the alkyne terminus ortho to the stereogenic axis in aryne 2a, which is the most hindered reactive position. This selectivity is in agreement with the aryne distortion model proposed by Garg and Houk in which the nucleophile adds preferentially to the alkyne terminus with the greater distortion toward linearity (see angles in 2a, Scheme 1). [START_REF] Medina | The Role of Aryne Distortions, Steric Effects, and Charges in Regioselectivities of Aryne Reactions[END_REF] Some small but tangible variations in the stereoretention around the stereogenic axis were observed in the cases of the two diastereomers of 6c and the two regioisomers of 6h (Scheme 4). From the results in Schemes 3 and 4, it seems that the generation of the aryne atropisomer 2a, from either 4a or 5b, occurs with full enantiospecificity, and it can be reasonably hypothesized that the barriers to enantiomerization in products 6c and 6h are high enough to avoid their racemization at a significant rate under the reaction and analyses conditions. The variations in stereoretention in diastereomers 6c and regioisomers 6h could thus be attributed to the existence of some kinetically competing cycloaddition pathways in these cases that would allow for the rotation around the stereogenic axes.

Next, the reactions of the aryne atropisomer 2a with symmetric small polycyclic aromatic hydrocarbons, as well as those of the structurally distinct aryne atropisomers derived from 5c and 5d, were assessed (Scheme 5). Notably, these reactions are free from diastereoselectivity and regioselectivity matters and proceeded with uniform retention of the stereochemical information. For instance, the annulative πextension (APEX) [START_REF] Ito | Annulative π-Extension (APEX): Rapid Access to Fused Arenes, Heteroarenes, and Nanographenes[END_REF] at the bay region of perylene with aryne atropisomer 2a afforded the small chiral nanographene 6i. Scheme 4. Representative Cycloadditions with the Aryne Atropisomer 2a Focusing on Diastereoselectivity and Regioselectivity Outcomes a a All reactions were performed with 3-5 equiv of the arynophile and 10 equiv of Me 3 SiCH 2 MgCl in Et 2 O at 0 °C. Yields were determined for isolated material. Diastereomer and regioisomer ratios (dr and rr, respectively) derived from 1 H NMR analyses of the crude reaction mixtures and were confirmed on isolation, and the enantiomer ratio was determined by analytical HPLC on chiral stationary phases of the isolated material.

Scheme 5. Examples of Cycloadditions of Aryne

Atropisomers with Small Polycyclic Aromatic Hydrocarbons a a All reactions were performed with 3-5 equiv of the arynophile and 10 equiv of Me 3 SiCH 2 MgCl in Et 2 O and/or toluene at 0 °C. The enantioenriched phenol precursor of 5c and 5d (3c, not depicted) was obtained by semi-preparative HPLC on a chiral stationary phase. Yields were determined for isolated material, and the enantiomer ratio was determined by analytical HPLC on chiral stationary phases. Also, the [4 + 2] cycloaddition of aryne atropisomer 2a with anthracene afforded the atropisomeric triptycene [START_REF] Preda | Chiral Triptycenes in Supramolecular and Materials Chemistry[END_REF] derivative 6j, and its structural analogues 6k and 6l were derived from the aryne atropisomer precursors 5c and 5d, respectively. The structure and absolute configuration in 6k were confirmed by X-ray diffraction techniques (see the Supporting Information, CCDC 2019279). Finally, the possibility for enantiospecific deoxygenative aromatization reactions with the oxa-bridged cycloadducts 28 obtained from the reaction between the aryne atropisomer derived from 5c and isobenzofuran was demonstrated through the synthesis of the enantioenriched anthracene atropisomer 8 (Scheme 6).

In summary, enantioenriched aryne atropisomers having a biaryl stereogenic axis vicinal to the reactive triple bond are demonstrated to exist. They can be generated in an enantiospecific manner from the corresponding ortho-iodo aryltriflates and trimethylsilylmethyl magnesium chloride, conditions mild enough to tolerate the presence of esters, some silyl ether, and bromine atoms for what was studied at this stage. Their trapping cycloaddition reactions with archetypal representative arynophiles occurred in an enantiospecific manner, unlocking new options for the stereocontrolled synthesis of nonracemic atropisomers in a broad meaning. Particularly appealing are their reactions with anthracene for the synthesis of triptycene atropisomers, and their APEX reactions with perylene and isobenzofuran, involving a complementary deoxygenative aromatization step in the latter case, for the synthesis of nonracemic large polycyclic aromatic hydrocarbon atropisomers. Studies in this direction are ongoing in our laboratory.

Figure 1 .

 1 Figure 1. (a) Examples of chiral aromatic hydrocarbons; (b) some corresponding racemic and enantioenriched ortho-arynes.

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■ ASSOCIATED CONTENT

* sı Supporting Information

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/jacs.0c08218.

X-ray diffraction structural analyses of a derivative of 6e (CIF) X-ray diffraction structural analyses of triptycene 6k (CIF) Synthetic procedures, characterization data, and details of the computational studies (PDF)


Salomé Granai

transgression, marking periods of climate deterioration [START_REF] Magny | Holocene climate variability as reflected by mid-European lake-level fluctuations and its probable impact on prehistoric human settlements[END_REF]. High temporal resolution records of Holocene climate fluctuations have been collected in lacustrine varve formations (e.g. [START_REF] Feeser | A Mid-Holocene annually laminated sediment sequence from Lake Woserin: The role of climate and environmental change for cultural development during the Neolithic in Northern Germany[END_REF][START_REF] Lücke | A Late-glacial and Holocene organic carbon isotope record of lacustrine palaeoproductivity and climatic change derived from varved lake sediments of Lake Holzmaar, Germany[END_REF] and speleothems (e.g. [START_REF] Mcdermott | Centennial-scale Holocene climate variability revealed by a high-resolution speleothem δ 18 O record from SW Ireland[END_REF][START_REF] Mischel | Holocene climate variability in Central Germany and a potential link to the polar North Atlantic: A replicated record from three coeval speleothems[END_REF]. In open-air conditions, tufas are one of the most suitable sedimentary archives to trace the evolution of climate conditions. These freshwater carbonate deposits provide valuable sediment sequences from which stable isotopes record changes in temperatures and humidity [START_REF] Andrews | Palaeoclimatic records from stable isotopes in riverine tufas: Synthesis and review[END_REF]. Shells of molluscs are often well-preserved in tufas whereas other biomarkers, such as pollen and seeds, are usually lacking [START_REF] Dabkowski | High potential of calcareous tufas for integrative multidisciplinary studies and prospects for archaeology in Europe[END_REF]. The snail communities lived and died more-or-less where they were found and were weakly affected by transport or diagenetic processes. Various studies demonstrated the increasing contribution of malacological data from tufa to the reconstruction of Holocene palaeoenvironmental developments in Europe (e.g. [START_REF] Alexandrowicz | Molluscan assemblages from Holocene calcareous tufa and their significance for palaeoenvironmental reconstructions. A study in the Pieniny Mountains (Carpathians, Southern Poland)[END_REF][START_REF] Gedda | Environmental and climatic aspects of the early and Mid-Holocene calcareous tufa and land mollusc fauna in southern Sweden[END_REF][START_REF] Kerney | Molluscan and plant biostratigraphy of some Late Devensian and Flandrian deposits in Kent[END_REF][START_REF] Limondin-Lozouet | Molluscan successions from the Holocene tufa of St Germain-le-Vasson, Normandy (France) and their biogeographical significance[END_REF][START_REF] Meyrick | Molluscan successions from two Holocene tufas near Northampton, English Midlands[END_REF][START_REF] Preece | Mollusca[END_REF]. Discussion between geochemical and malacological data provided an insight into local environmental changes directly correlated with climate variability [START_REF] Dabkowski | A complete Holocene climate and environment record for the Western Carpathians (Slovakia) derived from a tufa deposit[END_REF][START_REF] Garnett | Climatic change recorded by stable isotopes and trace elements in a British Holocene tufa[END_REF][START_REF] Žák | Climate-induced changes in Holocene calcareous tufa formations, Bohemian Karst, Czech Republic[END_REF], as tufas are often found in small valleys that were little affected by past human activities. During the second part of the Holocene, a reduction of European tufa deposits, both in deposition rate and occurrence, was suggested and referred as 'the Late-Holocene tufa decline' [START_REF] Goudie | The Late-Holocene tufa decline in Europe[END_REF]. At Direndall, in Luxembourg, a thick tufa sequence spanned almost the entire Holocene. [START_REF] Meyrick | Holocene molluscan faunal history and environmental change from a tufa at Direndall, Luxembourg[END_REF][START_REF] Meyrick | The development of terrestrial mollusc faunas in the 'Rheinland region' (western Germany and Luxembourg) during the Late-glacial and Holocene[END_REF] analysed the molluscan succession, which showed a broad outline of the sequence, but his counts were extremely low and much of the finer biostratigraphical detail was lost. Consequently, new molluscan analyses have been undertaken through the sequence in order to improve the record from this important site. These new malacological analyses were undertaken in parallel with a study of the stable isotopes from the same profile [START_REF] Dabkowski | New stratigraphic and geochemical data on the Holocene environment and climate from a tufa deposit at Direndall (Mamer Valley, Luxembourg)[END_REF], allowing the two datasets to be critically compared and put in perspective with regional vegetation change and climate trends.

Material and method

The Direndall tufa sequence is located at Lorentzweiler (Luxembourg), on the eastern valley slope of the Mamer River, flowing in a steep-side valley, ~ 100 m deep and ~ 300 m large (Figure 1). This valley was incised in the Luxembourg plateau comprised by Early Jurassic deposits. Our studies focused on the western side of a protruding crescent-shape mound of tufa ~ 95 m long and ~ 25 m wide [START_REF] Dabkowski | New stratigraphic and geochemical data on the Holocene environment and climate from a tufa deposit at Direndall (Mamer Valley, Luxembourg)[END_REF].

Stratigraphy and sampling strategy

The upper 3.7 m of the deposits were observed on an open stratigraphic section at the same place as that investigated by [START_REF] Meyrick | Holocene molluscan faunal history and environmental change from a tufa at Direndall, Luxembourg[END_REF]. The lower 7 m were drilled by coring ~6 m northward (Figure 2). First, a T6 corer was used but the injection of water into the corer caused the sediment liquefaction. A percussion corer with plastic sheathes was then used. Since the plastic sheathes were shorter than the corer, gaps of 22 cm were observed between cores (Figure 2). The use of the T6 corer for the deepest core, which was driven by technical reasons, resulted in the loss of sediment but allowed the geological bedrock, the Keuper marls (Triassic Period), to be reached. The comprehensive description of the stratigraphy can be found in [START_REF] Dabkowski | New stratigraphic and geochemical data on the Holocene environment and climate from a tufa deposit at Direndall (Mamer Valley, Luxembourg)[END_REF]. The whole succession of tufa facies is typical of a perched springline deposit [START_REF] Pedley | Classification and environmental models of cool freshwater tufas[END_REF]. Three main sedimentation phases were observed in the cores (Figure 2): (1) sands and sandy silts mixed with sandstone gravels interpreted as fluvial deposits mixed with colluvial inputs (units 15-10), (2) organic-rich clay interpreted as formed in hydromorphic conditions (unit 9) and (3) friable sandy tufa (unit 8). In the upper open section, seven units of tufa were described (Figure 2). The indurated Unit 6, with encrusted mosses and algae, was considered as characteristic of a traverse tufa barrier in a barrage system as described by [START_REF] Casanova | Morphologie et biolithogénèse des barrages de travertins[END_REF] and [START_REF] Pedley | Classification and environmental models of cool freshwater tufas[END_REF]. The overlying Unit 5, with fine and friable sediment, was regarded as typical of deposits developed upstream of such barrier [START_REF] Pedley | Does climate control the morphological fabric of freshwater carbonates? A comparative study of Holocene barrage tufas from Spain and Britain[END_REF]. The interstratified dark grey layer (e) observed within this unit suggested the development of a humic horizon. Unit 4 was then characterised by a succession of light brownish tufa with oncolites, interpreted as formed in wandering channels, and dark grey tufa with evidence of bioturbations attesting to the development of paleosols. The deposition of indurated tufa with encrusted mosses and algae in Unit 3 suggested the new development of a small barrage. The fine and friable tufa from Unit 2 might be deposited in the upstream of such a dam (as observed in Unit 5). The upper tufa (Unit 1), with encrusted vegetation fragments developed in thin horizontal layers, was considered as formed under paludal conditions [START_REF] Pedley | Tufas and travertines of the Mediterranean region: A testing ground for freshwater carbonate concepts and developments[END_REF][START_REF] Pedley | Sedimentology of Quaternary perched springline and paludal tufas: Criteria for recognition, with examples from Guadalajara Province, Spain[END_REF].

Twenty-eight malacological samples ranging in thickness from 5 to 30 cm were extracted from the cores (Figure 2). The weight of samples before sieving was between 0.4 and 2.9 kg. These thickness variations were guided by sedimentary boundaries, clear in sands and clay, but less easy to discern in the tufa (Figure 2). In the upper profile, 42 malacological samples were extracted every 10 cm between samples 0 and + 9 and every 5 cm between +11 and +41 (Figure 2). The weight of raw sediment before sieving was comprised between 4.2 and 7.9 kg for a standard volume of 5 L of sampled sediment.

Radiocarbon dating and age-depth model

Four radiocarbon dates on charcoal were reported by [START_REF] Meyrick | Holocene molluscan faunal history and environmental change from a tufa at Direndall, Luxembourg[END_REF], two in the part of the sequence corresponding to that investigated by drilling in 2013 and two at the top of the upper profile [START_REF] Dabkowski | New stratigraphic and geochemical data on the Holocene environment and climate from a tufa deposit at Direndall (Mamer Valley, Luxembourg)[END_REF]. The exact correlation between our cores and the profile studied by Meyrick was unclear since they were not made exactly at the same place. The two dates from the upper profile came from levels heavily intruded by roots, raising concerns about contamination. As a result, we have chosen to make a significant effort in providing new dating on our succession.

Fifteen new AMS radiocarbon dates were obtained (Table 1). In the deepest cores, with sand and clay, radiocarbon dates were measured on charcoal, wood and organic sediments (Table 1). In the tufa, charcoal was virtually absent. One date on charcoal in the malacological sample -9 gave an age far too young (Table 1). The other dates were measured on minute shells of gastropods as recommended by [START_REF] Pigati | Radiocarbon dating of small terrestrial gastropod shells in North America[END_REF]. Each date was measured on about 15 shells of the same species. The shells were broken to facilitate the removal of the tufa filling the shells and ultrasonically cleaned. No inversion was observed along the sequence even though some dates were obtained on different species (Table 1) at an interval of smaller than 20 cm in stratigraphy (Figure 2). The only archaeological evidence recovered within the sequence was a piece of pottery with a paste characteristic of Terra Belgica [START_REF] Reinert | Les débuts de la céramique gallo-belge en pays trévire: l'exemple des sépultures dites 'aristocratiques[END_REF] that was found at the level of the malacological sample +31 (Figure 2). The date of 2626 ± 29 BP obtained from shells in the malacological sample +30 (Table 1) was about a thousand years too old compared with this pottery fragment. However, this small piece of pottery was found under a bed of oncolite and could have been moved by rough water, as suggested by the damaged surface and blunt edges of the ceramic (Figure 2).

Table 1. Radiocarbon dating. Calibrations were performed with

IntCal13 curve [START_REF] Reimer | IntCal13 and Marine13 Radiocarbon Age Calibration Curves 0-50,000 years cal BP[END_REF]) in OxCal 4.3.2 (Bronk Ramsey, 2017).

The dates were calibrated using the IntCal13 calibration curve [START_REF] Reimer | IntCal13 and Marine13 Radiocarbon Age Calibration Curves 0-50,000 years cal BP[END_REF] in OxCal 4. 3.2 (Bronk Ramsey, 2017). An age-depth model was built using the median values of calibrated 2 σ range BP (Figure 3). In the intervals between dated samples, ages were calculated using the model with a resolution between 1 and 0.5 cm. The command 'Boundary' was applied to incorporate sediment transitions into the model. An agreement value of 97% between measured and modelled values was reached. The model stopped at the level of the malacological sample + 39 since we had no radiocarbon dating for the upper samples. For sedimentary description see Figure 2; for dating, see Table 1.

Malacological data

All the samples from cores were fully sorted, except -16, which was lost, and -19, for which only a half has been sorted (Table 2). Samples -28 to -23 were completely free of any shell. In the upper profile, 36 of the 42 samples collected were sorted (Table 3). Between samples +10 and +41, each taken over a thickness of 5 cm, only one sample out of two was first sorted. The resolution was tightened according to variations in the malacological assemblages. Samples that have not been sorted are in portions of the sequence where the assemblages were not subject to significant changes both in their species and ecological composition. For some samples, the volume and weight of sediment to be sorted were so large that an exhaustive sorting was not carried out, as the number of shells collected from one-half or one-quarter of the sample was sufficient to ensure the statistical representativeness of the studied portion. According to the method described by [START_REF] Evans | Land Snails in Archaeology[END_REF], the sieve sediments with a grain size component between 0.5 and 2 mm were placed flat, ensuring a good mixture of the different fractions and then divided into eight portions, at least two of which were studied. Land snails were represented by at least 55 taxa and freshwater molluscs by only 3 (Tables 1 and2). Determination and ecological requirements of species were based on literature [START_REF] Horsák | Molluscs of the Czech and Slovak Republics[END_REF][START_REF] Welter-Schultes | European Non-Marine Molluscs: A Guide for Species Identification[END_REF][START_REF] Wiese | Die Landschnecken Deutschlands: Finden -Erkennen -Bestimmen[END_REF]. The genera Cepaea, Arianta and Bradybaena were mixed because it was often difficult to differentiate these taxa based on broken shells. For Nesovitrea, the presence of Nesovitrea hammonis and Nesovitrea petronella was suspected in some samples. To mark this uncertainty, the mention 'agg.' was added to Nesovitrea hammonis, the most common species of the genus Nesovitrea at Direndall. The mention 'agg.' was also added to the species Euconulus fulvus, which could have been mixed with Euconulus alderi in some samples. Other genera were followed by the mention 'sp.' because the recovered shells were too fragmented for species determination. For Clausilia and Macrogastra, fragmentation and encrustation of shells had often precluded species determination. Limacidae and Milacidae were mixed as 'slugs'.

Most of the samples taken from the cores yielded counts below the threshold of representativeness of a fossil sample set at 150 individuals by [START_REF] Evans | Land Snails in Archaeology[END_REF]. A presence/absence diagram of species allowed the development of biodiversity between samples -22 and -1 to be tracked (Figure 4). All the samples from the upper profile provided enough shells to draw a diagram showing the proportions of each taxon (Figure 5). For the sake of readability of this diagram, some species with comparable environmental requirements have been combined. For the coring section, samples with small numbers of individuals were merged.

Results

Unfavourable conditions for mollusc development and shell preservation

The samples 28 to 24, from cores C5 and C4bis, are sterile. These samples were extracted from sandy sedimentary units (Figure 2). The absence of shells suggests unfavourable conditions for the development of molluscs or the preservation of shells. The radiocarbon dates allow these samples to be assigned to the late glacial and the beginning of the early Holocene (Table 1). The two periods are separated by a sedimentary hiatus spanning about 1000 years (Figure 3).

Phase DIR.1, between 10.7 and 10.1/9.7 cal. kyr BP: Mesophile species and first shade-demanding species

In the organic-rich clay from the base of the core C4, the sample -23 is sterile. The first sample with shells (-22) comes from the upper part of this clayey unit (Figure 2).

The faunal list, composed of 45 specimens divided into 8 taxa, is dominated by slugs (Table 2). These molluscs without external shell are found with species characterised by thin shells (Nesovitrea hammonis agg., Vitrea crystallina, Vitrinobrachium breve).

This assemblage is the initial phase of the malacological succession at Direndall and indicates the onset of plant colonisation. In samples -22 to -17, mesophile taxa are predominant (Figure 4). Within the group of the shade-demanding species, Aegopinella nitidula and Carychium tridentatum appeared in c. 10.5 cal. kyr BP (sample -21) and Acanthinula aculeata, Merdigera obscura and Vertigo pusilla c. 10.2 cal. kyr BP (sample -18). Such an increase in the biodiversity of shadedemanding species is a sign of an expansion of forest habitats.

Phase DIR.2, between 10.1/9.7 and 7.5 cal. kyr BP: Marshland species and new shade-demanding species

The base of the environmental phase DIR.2 is defined by the expansion of marshland species (mainly from the Succineidae family) in -14, which is a persistent feature until -1 (Table 2). Thirteen new taxa are recovered within this phase and most of them are forest species (Figure 4). Within this ecological group, Discus rotundatus appeared in c. 9.5 cal. kyr BP, Pomatias elegans and Aegopinella pura c. 9.2 cal. kyr BP, Cochlodina laminata c. 8.9 cal. kyr BP, Helicodonta obvoluta, Macrogastra sp. and Azeca goodalli c. 8.8 cal. kyr BP, and Sphyradium doliolum and Monachoides incarnatus c. 7.8 cal. kyr BP. The timing of these appearances should be considered with caution, as the samples provide assemblages with low abundances (Table 2). Such an increase in biodiversity indicates the development of a forest with deep shade.

Phase DIR.3, between 7.5 and 7.3 cal. kyr BP: Expansion of Vallonia costata and appearance of Platyla polita This environmental phase is based on the composition of the malacological fauna recovered in sample 0. A sharp increase in Vallonia costata proportions is observed together with a sharp decrease in proportions of marshland species (Figure 5). All the open-ground species and some of the forest species found in the preceding phase are lacking. This simultaneous decline in biodiversity in these two groups of species can be explained by drier conditions. Platyla polita, inhabiting today moderately humid forests, occurs during this phase.

DIR.4, between 7.3 and 7.1 cal. kyr BP: Shade-demanding species with Carychium tridentatum and Discus rotundatus as main species Samples +1 to +3 are characterised by increasing proportions of shade-demanding species that develop at the expense of Vallonia costata (Figure 5). Carychium tridentatum shows the highest proportions. Its association with Discus rotundatus and Vitrea crystallina suggests the development of a moist forest litter that could be related to the expansion of a deciduous forest. The appearance of Ena montana in sample +2 (Table 2) is consistent with this assumption since this species mainly inhabits today broadleaf forests. DIR.5, between 7.1 and 6.5 cal. kyr BP: Decrease in Carychium tridentatum, increase in Vallonia costata

In samples +4 to +11, the proportions of Carychium tridentatum decline while those of Vallonia costata increase (Figure 5). The decline of the hygrophilous C. tridentatum and the expansion of V. costata, living in drier conditions, might suggest a moisture reduction of the floor litter. DIR.6, between 6.5 and 3.5 cal. kyr BP: Shade-demanding species with Discus rotundatus and Aegopinella pura as main species

The proportions and diversity of forest species increase significantly in samples +11 to +26 (Figure 5). In this ecological group, Discus rotundatus and Aegopinella pura are the main taxa. Aegopinella pura is found today in moist forest. Such a palaeoenvironmental reconstruction hypothesis would be consistent with the increase in the proportions of slugs that, devoid of an external shell, have high moisture requirements. In samples +25 and +26, the decrease in proportions of shade-demanding species marks the transitional phase between DIR.6 and DIR.7.

DIR.7, between 3.5 and 2.4 cal. kyr BP: Expansion of Vallonia costata and Pupilla muscorum

This phase is characterised by a decrease in the proportions of shade-demanding species, mainly in favour of Vallonia costata and the open-ground species Pupilla muscorum (Figure 5). These malacological developments reflect a phase of forest clearing. In samples +31 and +32, the proportions of open-ground species decrease while those of shade-demanding species increase. These two samples initiate a new phase of forest expansion. DIR.8, after 2.4 cal. kyr BP: Shade-demanding species with Carychium tridentatum and Aegopinella pura as main species A new development of shade-demanding species is observed in samples +34 to +41 (Figure 5). Carychium tridentatum and Aegopinella pura are the main species. These two species live today in moist habitats. Vallonia costata, which prefers drier locations, and the open-ground species are virtually absent.

Discussion

Discussion with local stable isotope records

The new malacological data recovered at Direndall provide detailed environmental information that can be discussed with much higher confidence to climatic records than the Meyrick's malacological data originally used in [START_REF] Dabkowski | New stratigraphic and geochemical data on the Holocene environment and climate from a tufa deposit at Direndall (Mamer Valley, Luxembourg)[END_REF]. As observed in [START_REF] Dabkowski | New stratigraphic and geochemical data on the Holocene environment and climate from a tufa deposit at Direndall (Mamer Valley, Luxembourg)[END_REF], correlations between the δ 18 O profile and the malacological records are sparse. The main correlation found is the increase in the number of forest species as a consequence of the early Holocene warming (Figure 6). However, this connection was evident since tree vegetation could not grow until postglacial conditions were established. The dashed lines illustrate areas of convergence between the δ 13 C profile and changes in the number of forest species. The accumulation curve of forest species tracks the timing of the appearance of these species within the sequence.

There is much more to be said about the connection between molluscan record and δ 13 C profile. A strong correlation is observed between the number of shadedemanding species and the δ 13 C profile. Increased diversity of forest species is observed during periods of increased humidity. In the coring section, the abundance of shells is too low to accurately discuss changes in fauna and in δ 13 C profile, except for samples -19, -18 and -2. Increased humidity and biodiversity are observed in samples -18 and -2, respectively, dating from 10.2 and 7.8 cal. kyr BP. One might think that this increase in biodiversity would be caused by the higher counts in these samples. However, the recurrence of this biodiversity/humidity relationship throughout the sequence suggests that the observations made in the core section are valid. In the upper profile, in addition to providing assemblages with more shells, the malacological samples were also taken in the same (or almost the same) sampling interval as the geochemical samples (Figure 2). Between 7.1 and 6.5 cal.

kyr BP (zone DIR.5), a decline of the number of shade-demanding species is coincident with a reduction of moisture (Figure 6). Between 6.5 and 3.5 kyr cal. BP (zone DIR.6), there is first an increase in biodiversity and humidity, and then both are stabilised. During the late-Holocene, the number of shade-demanding species became more uneven, while humidity increased but the three most biodiverse periods correspond to moisture peaks (3.7, 3.1 and 2.3 cal. kyr BP).

Development of forest between 10.7 and 7.5 cal. kyr BP At Direndall, the absence of botanical remains in the tufa prevented a direct insight into the precise composition of the vegetation cover. However, a discussion of local malacological and geochemical results with regional palaeobotanical data is of relevance. At Waldbillig, 20 km northeast of Direndall, open woodland dominated by Pinus sylvestris was reconstructed from a charcoal sequence dating from the first part of the early Holocene [START_REF] Pernaud | Postglacial vegetation history in Luxembourg: New charcoal data from the cave of la Karelslé (Waldbillig, eastern Gutland)[END_REF]. At Direndall, the occurrence of Vertigo substriata in samples -21 to -17 might suggest a plant cover dominated by Pinus. In Poland, Vertigo substriata was a frequent component of the molluscan assemblages from the early Holocene boreal forest [START_REF] Alexandrowicz | Malacostratigraphy of vistulian and Holocene in Poland[END_REF]. At Direndall, this species completely disappeared shortly after 10.2 cal. kyr BP (Figure 4), and its disappearance may be indicative of changes in the composition of the vegetation cover. Between 10.2 and 7.5 cal. kyr BP, a gradual increase in shade-demanding species diversity is observed. This development is coincident with the establishment of deciduous forests reconstructed in regional pollen records through the decline of Pinus and the expansion of Corylus after 10.2 cal. kyr BP [START_REF] Slotboom | Pollen records of mardel deposits: The effects of climatic oscillations and land management on soil erosion in Gutland, Luxembourg[END_REF].

The progressive development of forest environments was extensively observed in numerous malacological successions over Central and Western Europe [START_REF] Alexandrowicz | Malacostratigraphy of vistulian and Holocene in Poland[END_REF][START_REF] Horác̆ek | Palaeozoology and the mid-European Quaternary past: Scope of the approach and selected results[END_REF][START_REF] Limondin-Lozouet | Molluscan successions from the Holocene tufa of St Germain-le-Vasson, Normandy (France) and their biogeographical significance[END_REF][START_REF] Preece | Mollusca[END_REF]. In these two large areas, there was a pool of species in common, but several shade-demanding species showed a smaller geographical distribution. At Direndall, we recovered some species with a western distribution, such as Azeca goodalli and Pomatias elegans. These two species were absent from the Holocene successions from the Czech and Slovak Republics (Juřic̆ková et al., 2014a) whereas they were recovered in Northern France (Limondin-Lozouet and Preece, 2004) and in Southern England [START_REF] Evans | Land Snails in Archaeology[END_REF]. A reverse pattern was observed for the eastern species Platyla polita and Monachoides incarnatus.

Direndall thus appears as a succession at the crossroads of Atlantic and Continental climate influence. This sequence has recently been integrated into a synthesis of Holocene malacological data comparing the ecological and specific compositions of European assemblages. Luxembourg and eastern France have emerged as key territories for the assessment of colonisation pathways of shade-demanding species during the Holocene across temperate Europe [START_REF] Horsák | Holocene succession patterns of land snails across temperate Europe: East to west variation related to glacial refugia, climate and human impact[END_REF].

Changing environmental conditions between 7.5 and 3.5 cal. kyr BP During the phase DIR.4, dated between c. 7.4 and 7.1 cal. kyr BP, the association of Carychium tridentatum and Discus rotundatus suggested the development of a moist forest litter. During the next phase (DIR.5), the decline of the hygrophilous species Carychium tridentatum and the expansion of Vallonia costata, preferring drier conditions, suggested a period of relative reduction of the soil moisture. This assertion was strengthened by the reduction of moisture expressed in the δ 13 C profile. The reconstruction of drier conditions between c. 7.1 and 6.5 cal. kyr BP is consistent with the estimate of a significant decrease in both winter and summer precipitation derived from pollen data at Echternach, 25 km northwest of Direndall [START_REF] Guiot | Quantitative climate reconstruction from pollen data in the Grand Duchy of Luxembourg since 15000 yr BP[END_REF]. At Waldbillig, 20 km northeast of Direndall, a recent review of pollen data collected by Heim in 1992 [START_REF] Gaudin | État de l'art à propos des données archéobotaniques luxembourgeoises holocènes[END_REF] found 90% of arboreal pollen with a strong dominance of Corylus, which is characteristic of light woodland areas and tolerant to drought. Such a prevalence of Corylus had already been observed in the pollen data from Berdof [START_REF] Schwenninger | Pollen analysis and community structure of Holecene forests: A regional palynological study of the Middle and Upper Postglacial from semi-subhydric alder carr sediments at Berdorf (Luxembourg)[END_REF] and Echternach [START_REF] Couteaux | Etude palynologique des dépôts quaternaires de la Vallée de la Sûre à Echternarch et à Berdorf, et de la Moselle à Mertert[END_REF] dating from the same period. This dry excursion observed in Luxembourg is contemporaneous with a long low lake-level phase in the Jura, northern French pre-Alps and Swiss Plateau [START_REF] Magny | Holocene climate variability as reflected by mid-European lake-level fluctuations and its probable impact on prehistoric human settlements[END_REF]. After c. 6.5 cal. kyr BP (phase DIR.6), the development of Aegopinella pura refers to moister forest habitats.

Up to 6.0 cal. kyr BP, the proportions of shade-demanding species increase in strict correspondence with moisture conditions reconstructed from the δ 13 C profile. This shift in moisture conditions is coincident with the local development of the Quercetum mixtum inferred from the pollen data from the Gutland region [START_REF] Slotboom | Pollen records of mardel deposits: The effects of climatic oscillations and land management on soil erosion in Gutland, Luxembourg[END_REF]. After 6.0 cal. kyr BP, which is the end of the middle-Holocene thermal optimum in Central-Western Europe [START_REF] Davis | The temperature of Europe during the Holocene reconstructed from pollen data[END_REF], malacological data and δ 13 C profile are broadly stabilised up to c. 4.0 cal. kyr BP. This date broadly corresponds with a shift towards colder conditions in the δ 18 O profile. In Luxembourg, Fagus expansion is observed during the same period in regional pollen data [START_REF] Couteaux | Etude palynologique des dépôts quaternaires de la Vallée de la Sûre à Echternarch et à Berdorf, et de la Moselle à Mertert[END_REF][START_REF] Slotboom | Pollen records of mardel deposits: The effects of climatic oscillations and land management on soil erosion in Gutland, Luxembourg[END_REF]. In southern Germany and lowland Switzerland, pulses in the expansion of Fagus were precisely observed during cold and wet episodes of the first part of the late-Holocene [START_REF] Tinner | Holocene expansions of Fagus silvatica and Abies alba in Central Europe: Where are we after eight decades of debate?[END_REF].

A place under a low anthropogenic influence during the late-Holocene?

In [START_REF] Meyrick | Holocene molluscan faunal history and environmental change from a tufa at Direndall, Luxembourg[END_REF], the mollusc zone Dir4, which spanned both the middle and the late-Holocene, was divided into three subzones: Dir4a and Dir4c, marking forest optimum phases, were interspersed with an episode of forest clearance (Dir4b). In our new study, three phases of forest expansion interspersed with two phases of forest clearing were reconstructed. The higher counts recovered in our new samples made this more accurate zonation scheme possible. The clearing episode suggested by [START_REF] Meyrick | Holocene molluscan faunal history and environmental change from a tufa at Direndall, Luxembourg[END_REF], corresponding to the phase DIR.7, is better defined from a malacological and chronological perspective. This phase was originally assumed to be of Roman origin [START_REF] Meyrick | Holocene molluscan faunal history and environmental change from a tufa at Direndall, Luxembourg[END_REF]. In our new study, this phase is dated between 3.5 and 2.4 cal. kyr BP, that is, between the middle of the Bronze Age and the middle of the Iron Age. One could hypothesise an anthropogenic phase of forest clearance, especially since a human-induced expansion of grasslands was widely observed in north-western Europe during this period [START_REF] Granai | The Holocene expansion of grassland in northern Europe reconstructed from molluscan assemblages[END_REF].

However, there is no evidence of human settlement in the vicinity of the sequence or of landscape opening at the same time in Waldbillig's charcoal data [START_REF] Pernaud | Postglacial vegetation history in Luxembourg: New charcoal data from the cave of la Karelslé (Waldbillig, eastern Gutland)[END_REF] and Echternach's pollen data [START_REF] Couteaux | Etude palynologique des dépôts quaternaires de la Vallée de la Sûre à Echternarch et à Berdorf, et de la Moselle à Mertert[END_REF], both located around 20 km away. At Direndall, the phase of landscape openness seems to be rather related to local geomorphological parameters. The phase DIR.7 was reconstructed within the sedimentary unit 4, which was characterised by alternating dark grey tufa levels and light brownish tufa levels with oncolites deposited in wandering channels. It can be hypothesised that the phase of forest clearance inferred from the molluscan assemblages was the result of a local phenomenon, which was related to the

Conclusion

The molluscan succession of Direndall is the longest and best-dated Holocene succession at a regional scale. This reference series can be used as a basis for comparison with the molluscan successions studied further west (the United Kingdom and France) and further east (Poland, Czech and Slovak Republics).

Species with a western European distribution and species with an eastern European distribution were found. This peculiarity highlighted the key position of the Luxembourg and neighbouring regions for tracking the colonisation pathways of forest species during the Holocene across temperate Europe. Regarding the second part of the Holocene, forest environments were mainly observed so far in mountainous regions under a low anthropogenic influence such as in the Carpathians [START_REF] Alexandrowicz | Molluscan assemblages from Holocene calcareous tufa and their significance for palaeoenvironmental reconstructions. A study in the Pieniny Mountains (Carpathians, Southern Poland)[END_REF][START_REF] Juřičková | Early postglacial recolonisation, refugial dynamics and the origin of a major biodiversity hotspot. A case study from the Malá Fatra Mountains, Western Carpathians, Slovakia[END_REF] and the Sudetes (Juřičková et al., 2014b). Conversely, open environments were reconstructed in places under stronger human influence, particularly in floodplains (e.g. [START_REF] Scholar Alexandrowicz | Molluscan communities in Late-Holocene fluvial deposits as an indicator of human activity: A study in Podhale basin in South Poland[END_REF][START_REF] Granai | Contribution of two malacological successions from the Seine floodplain (France) in the reconstruction of the Holocene palaeoenvironmental history of northwest and central Europe: Vegetation cover and human impact[END_REF][START_REF] Juřic̆ková | Impoverishment of recent floodplain forest mollusc fauna in the lower Ohře River (Czech Republic) as a result of prehistoric human impact[END_REF]. At Direndall, forest environments persisted during the second part of the Holocene. However, almost no new forest species colonise the site after the middle-Holocene climate optimum. Most species appear during the Early Holocene warming phase.

The combination of malacological and geochemical investigations highlighted the positive correlation between variations of δ 13 C and those of shade-demanding molluscs. Phases of expansion of proportions of forest species were correlated to increasing moisture conditions in the δ 13 C profile. Conversely, the first phase of regression of these taxa was correlated to decreasing moisture conditions between 7.1 and 6.5 cal. kyr BP. The second phase of decline of shade-demanding taxa, between 3.5 and 2.4 cal. kyr BP, was interpreted as resulting from a local exposure of the soil in connection with a wandering channel. Influences of local environmental conditions and regional climatic trends were thus emphasised. Changes in vegetation composition were hypothesised based on variations in malacological assemblages and then discussed with Holocene climate dynamics. However, at the regional scale, we still lack a reference series with both botanical and malacological records.

Figure 1 .

 1 Figure 1. Location maps of Direndall in Luxembourg (top left), in the Mamer valley (top right) and in the local topography (bottom).

Figure 2 .

 2 Figure 2. Schematic map of the location of the samples in the tufa mound, stratigraphy with the position of malacological and geochemical samples, radiocarbon dating and photograph of the pottery fragment found in unit 4.

Figure 3 .

 3 Figure3. Age-depth model and schematic stratigraphic log of Direndall. For sedimentary description see Figure2; for dating, see Table1.

Figure 4 .

 4 Figure 4. Presence/absence diagram of species recovered in the samples from the coring section.

Figure 5 .

 5 Figure 5. Variations in proportions of some key species and group of species.

Figure 6 .

 6 Figure 6. Variations in oxygen and carbon stable isotopes from tufa calcite with regard to variations of forest species biodiversity and main environmental phases.

  exposure of the soil by erosion in the vicinity of the channels. The new development of shade-demanding species during the phase DIR.8 reflects the small spatial coverage of the vegetation openness. All forest species present in the previous phases return to the sampling location, indicating the unaltered nature of the surrounding forest cover. Shade-demanding species diversity remains broadly unchanged until at least 1.8 cal. kyr BP. The site is still located today in a forest environment. The Direndall molluscan succession has thus shed light on the late-Holocene palaeoenvironmental developments observed in contexts under low anthropogenic influence.

Table 2 .

 2 List of fauna and modelled ages of samples from the coring section.

Table 3 .

 3 List of fauna and modelled ages of samples from the upper profile.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship and/or publication of this article: This research was supported by the Service d'archéologie préhistorique of the CNRA (National Centre for Archaeological Research) of the Grand-Duchy of Luxembourg that funded fieldwork, malacological and geochemical analyses as well as nine radiocarbon dates. Five additional dates were funded by the Czech Science Foundation (P504/17-05696 S) and one last by the project EscarGO supported by the Panthéon-Sorbonne University (Paris, France). PH was partially supported by a long-term developmental project of the Czech Academy of Sciences (RVO 67985939).


Juan-Carlos Castillo

Brian Castro Agudelo

Jaime Gaĺvez

Yannick Carissan

Jean Rodriguez
email: jean.rodriguez@univ-amu.fr

Yoann Coquerel
email: yoann.coquerel@univ-amu.fr

Brian Castro

Dr Michel Giorgi

Periselectivity in the aza-Diels-Alder Cycloaddition between α-Oxoketenes and N-(5-Pyrazolyl)imines: A Combined Experimental and Theoretical Study

The thermal 6π aza-Diels-Alder cycloadditions between α-oxoketenes, in situ derived from a thermally induced Wolff rearrangement of 2-diazo-1,3-diketones, and N-(5-pyrazolyl)imines as prototypical electron-rich 2-azadienes lead to two distinct sets of products, essentially as a function of the nature of the α-oxoketenes involved. For instance, cyclic five-membered α-oxoketenes lead preferentially to spiro hydropyridin-4-ones, which involves the α-oxoketenes as the 2π partners at their CC double bond and the N-(5-pyrazolyl)imines as the 4π partners at their 2-azadiene moiety. In contrast, other cyclic and acyclic α-oxoketenes lead preferentially to 1,3-oxazin-4-ones, which now involves the α-oxoketenes as the 4π partners at their 1-oxadiene moiety and the N-(5pyrazolyl)imines as the 2π partners at their CN double bond. A computational modeling study using DFT methods allowed rationalizing this change of periselectivity: the formation of spiro hydropyridin-4-ones is under thermodynamic control while the formation of 1,3-oxazin-4-ones is kinetically controlled, and slightly thermodynamically disfavored in the five-membered ring series. The competing cyclodimerization of the α-oxoketenes is also studied in detail.

■ INTRODUCTION

α-Oxoketenes are short-lived chemical species with a long history, 1 and with few exceptions, they cannot be isolated and must be generated in situ. 2 They are routinely obtained either from the thermal decomposition of dioxinones with concomitant extrusion of acetone 3 or from the thermal or photochemical Wolff rearrangement of 2-diazo-1,3-dicarbonyl compounds extruding nitrogen gas. 1,4 α-Oxoketenes are electrophilic species with widespread applications in organic synthesis, from the preparation of simple β-oxocarbonyl derivatives 5a to the total synthesis of natural products 2d,e and complex heterocycles. 5b As to their annulation and cycloaddition reactions, they most commonly react with unsaturated substrates as 4π partners, i.e. 1-oxadienes, in inverse electrondemand formal Diels-Alder processes. 2 However, in a few occasions, α-oxoketenes were found to react preferentially as 2π partners in normal electron-demand formal aza-Diels-Alder and 1,3-dipolar cycloadditions with 4π electron-rich substrates including 1-azadienes, [START_REF] Presset | Periselectivity Switch of Acylketenes in Cycloadditions with 1-Azadienes: Microwave-Assisted Diastereoselective Domino Three-Component Synthesis of α-Spiro-δlactams[END_REF] 2-azadienes, [START_REF] Galvez | Divergent Chemo-, Regio-, and Diastereoselective Normal Electron-Demand Povarov-Type Reactions with α-Oxoketene Dienophiles[END_REF] and azomethine imines. [START_REF] Presset | 1,3-Dipolar Cycloaddition of Hydrazones with α-Oxoketenes: A Three-Component Stereoselective Entry to Pyrazolidinones and an Original Class of Spirooxindoles[END_REF] For instance, we previously reported that electron-rich 2-azadienes such as N-hetaryl imines 2 generated from 5-amino-pyrazoles could react with five-membered cyclic α-oxoketenes as a chemo-, regio-, and diastereoselective entry to spiro hydropyridin-4-ones of type 3 (Scheme 1, left). [START_REF] Galvez | Divergent Chemo-, Regio-, and Diastereoselective Normal Electron-Demand Povarov-Type Reactions with α-Oxoketene Dienophiles[END_REF] More recently, re-examination of this reaction with larger cyclic and acyclic α-oxoketenes has unexpectedly led to the formation of 1,3-oxazin-4-ones of type 4 instead of the awaited hydropyridin-4-one products 3 (Scheme 1, right). The reasons responsible for this change of periselectivity, the selectivity in formation of the pericyclic products, [START_REF] Mcleod | Expanding the Frontiers of Higher-Order Cycloadditions[END_REF] within a relatively homogeneous class of substrates have been identified by a combination of experimental and computational studies as detailed hereafter.

■ RESULTS AND DISCUSSION

The new experimental observations are summarized in Table 1 (entries 4-14), together with a few results from our previous study [START_REF] Galvez | Divergent Chemo-, Regio-, and Diastereoselective Normal Electron-Demand Povarov-Type Reactions with α-Oxoketene Dienophiles[END_REF] for the sake of comparison (entries 1-3). It was previously found that the five-membered cyclic α-oxoketene 1a derived from 2-diazo-1,3-cyclohexanedione reacted with the N-(5-pyrazolyl)aldimine 2a to give diastereoselectively the spiro hydropyridin-4-one 3a product after 4 min at 150 °C (entry 1). A similar reaction with the five-membered cyclic α-oxoketene 1b derived from diazodimedone and aldimine 2b gave the spiro hydropyridin-4-one 3b in comparable yield and stereoselectivity after 4 min at 180 °C (entry 2), and the sixmembered cyclic α-oxoketene 1c derived from 2-diazo-1,3cycloheptanedione reacted with the same aldimine 2b to give the corresponding spiro hydropyridin-4-one 3c, albeit in reduced yield and after 45 min at 250 °C (entry 3). In contrast, we observed more recently that the reactions between the six-membered cyclic α-oxoketene 1c and aldimines 2b-e afforded the corresponding 1,3-oxazin-4-ones 4a-d, respectively, in good yields (entries 4-7). Complementarily, αoxoketene 1c reacted with ketimine 2f derived from cyclopentanone to afford the spiro oxazinone 4e in good yield (entry 8), and with the ketimines 2g and 2h obtained from Nbenzyl isatin to give the spirooxindoles 4f and 4g also in good yields (entries 9 and 10). Interestingly, in the latter two cases, the products were obtained as mixtures of two rotamers in a 1.6:1 ratio at 25 °C due to the presence of both a stereogenic center at the spiro carbon atom and a stereogenic axis along the C-N bond linking the pyrazolyl substituent to the oxazinone core. [START_REF] Bonne | A Bird's Eye View of Atropisomers Featuring a Five-Membered Ring[END_REF] The free Gibbs energies of the optimized conformations of both rotamers 4f and 4g were computed (see details in the Supporting Information), which showed a slight preference for the (aS,R)-configured rotamer for 4f [Δ(ΔG) = -4.3 kJ mol -1 ] and for the (aR,R)-configured rotamer for 4g [Δ(ΔG) = -5.8 kJ mol -1 ] at 25 °C. The barriers to epimerization along the C-N stereogenic axes were computed at 91.7 and 82.9 kJ mol -1 , respectively, corresponding to halflives in the magnitude of seconds to minutes at 25 °C in agreement with the experimental observations. The reaction of the seven-membered cyclic α-oxoketene 1d with aldimine 2c afforded the 1,3-oxazin-4-one 4h in 36% isolated yield (entry 11). Finally, a series of reactions with the acyclic α-oxoketene 1e derived from the Wolff rearrangement of 2-diazoacetylacetone combined with the N-(5-pyrazolyl)aldimines 2c, 2i, and 2j afforded the 1,3-oxazin-4-ones 4i, 4j, and 4k in 64%, 49%, and 62% yield, respectively (entries 12-14). The reaction between the α-oxoketene derived from methyl 2-diazoacetylacetate (involving the migration of the methyl group during the Wolff rearrangement) and imine 2a afforded a complex mixture of unidentified products.

From the results in Table 1, the following can be noted: (i) five-membered cyclic α-oxoketenes led exclusively to spiro hydropyridin-4-one of type 3; (ii) other cyclic or acyclic α-oxoketenes led very preferentially to 1,3-oxazin-4-ones of type 4 pointing out the importance of the ring size in these reactions; (iii) thermodynamic versus kinetic control of the reaction is seemingly operative in the reactions between the six-membered α-oxoketene 1c and N-(5-pyrazolyl)aldimine 2b (compare entries 3 and 4); and (iv) some unreacted aldimine substrate could be recovered in many cases after the reaction despite the use of excess α-oxoketene diazo precursor (2 × 1.2 equiv, 2.4 equiv in total). With the intention to rationalize these experimental observations, the formal aza-Diels-Alder cycloadditions between the α-oxoketene 1a, 1c, or 1e and the model N-(5-pyrazolyl)aldimine 2k were analyzed by computational DFT methods. Because subtle differences were anticipated, the calculations were performed using B3LYP-D3/6-311++G (d,p), a relatively robust level of theory that includes polarization and diffuse functions on all atoms and the Grimme's D3 London dispersion correction, with the iefpcm solvation model for toluene (see details in the Supporting Information). The reactions of the five-membered α-oxoketene 1a with the model aldimine 2k were first considered. Paralleling our early investigations, [START_REF] Galvez | Divergent Chemo-, Regio-, and Diastereoselective Normal Electron-Demand Povarov-Type Reactions with α-Oxoketene Dienophiles[END_REF] it was found that the diastereoselective formation of the model spiro hydropyridin-4-one 3d is exergonic [Δ(ΔG) = -48.2 kJ mol -1 ] and results from a Friedel-Crafts/Mannich sequence operating in three steps through intermediates Int1 (fleeting) and Int2 as depicted in Figure 1a with an overall activation barrier computed at +78.1 kJ mol -1 . The conversion of intermediate Int2 into product 3d is a concerted asynchronous proton transfer/6-enol-exo-endo-trig cyclization that controls the relative stereochemistry in the product. Examination of the concurrent reaction leading to the model 1,3-oxazin-4-one 4l revealed a slightly endergonic [Δ(ΔG) = +6.7 kJ mol -1 ] concerted very asynchronous process, formation of the N-C bond being largely in advance of the formation of the O-C bond, with a barrier computed at +71.2 kJ mol -1 (Figure 1b). [START_REF] Li | Annuloselectivity in Reactions of Diacyl Dichlorides and Imines: Combined Experimental and Theoretical Studies[END_REF] In line with the experimental observations, this shows that the formation of the spiro hydropyridin-4-one 3d is thermodynamically favored over the formation of the 1,3-oxazin-4-one 4l, whatever the reaction temperature and time. The requirement for excess α-oxoketenes 1a,b in their aza-Diels-Alder reaction with aldimines of type 2 indicates that some competing process consumes the α-oxoketenes under the optimized reaction conditions. Some α-oxoketenes have previously been shown to cyclodimerize through [4 + 2] cycloadditions 2,12 as illustrated in Figure 1c with the computed cyclodimerization energy profile of α-oxoketene 1a into cyclodimer 5a. However, alternative cyclodimerization processes are possible. 13 The formation of the cyclodimer 5a was Scheme 1. Periselectivity in the Formal aza-Diels-Alder Cycloadditions of α-Oxoketenes with 2-Azadienes Derived from 5-Aminopyrazoles

The Journal of Organic Chemistry computed as a concerted asynchronous exergonic process [Δ(ΔG) = -47.7 kJ mol -1 ] requiring only +72.7 kJ mol -1 of activation energy (Figure 1c), and it is thus in competition with the formation of the spiro hydropyridin-4-one 3d. Experimentally, the dimer 5a could indeed be detected in the crude reaction mixture leading to 3a as a minor byproduct while the major byproduct was the rearranged dimer 6a (6a/5a ≈ 2:1 as determined by NMR analyses). The formation of 6a can be explained by a thermodynamically favored [Δ(ΔG) = -7.1 kJ mol -1 ] Lewis base-catalyzed ring rearrangement of 5a via the zwitterionic intermediate Int3 as depicted in Figure 1c, [START_REF] Galvez | Divergent Chemo-, Regio-, and Diastereoselective Normal Electron-Demand Povarov-Type Reactions with α-Oxoketene Dienophiles[END_REF][START_REF] Wei | An Organocatalytic Two-atom Ring Expansion Approach to Optically Active Glutarimides[END_REF] with the Lewis base catalyst being in this case the imine 2a and/or the product 3a itself. In control experiments, the dielectric heating of a toluene solution of 2-diazo-1,3cyclohexanedione at 160 °C for 5 min produced the dimer 5a quantitatively (Scheme 2), while the same reaction conducted in the presence of N,N-dimethylallyl amine as the Lewis base promoter afforded essentially the rearranged dimer 6a, the structure of which could be confirmed by single-crystal X-ray diffraction analysis. 15 Interestingly, the structure of the rearranged cyclodimer 6a was initially proposed in 1963 as the product of the reaction of adipyl dichloride with triethylamine, and its formation is postulated to occur through the intermediate α-oxoketene 5a [START_REF] Li | Annuloselectivity in Reactions of Diacyl Dichlorides and Imines: Combined Experimental and Theoretical Studies[END_REF] and a subsequent rearrangement, a spectacular cascade reaction not rationalized at the time. 16 The present work offers a satisfactory explanation for these early observations on the dimerization of five-membered cyclic α-oxoketenes, and for their preferred periselectivity as 2π partners in normal electron-demand formal aza-Diels-Alder processes involving N-hetaryl imines as 2-azadienes.

The results of the DFT calculations in the six-membered ring series are summarized in Figure 2. Modeling the aza-Diels-Alder reaction between the six-membered cyclic αoxoketene 1c and the aldimine 2k showed that the model spiro hydropyridin-4-one 3e is the thermodynamic product with Δ(ΔG) = -20.6 kJ mol -1 , and that the model 1,3-oxazinone product 4m is the kinetic product with Δ(ΔG ‡ ) = -10.2 kJ mol -1 (Figure 2a,b). The major difference between the fiveand six-membered ring series resides in the relative stability of the 1,3-oxazin-4-one products: in the five-membered ring series, the formation of 4l is slightly endergonic as shown in Figure 1b, while in the six-membered ring series the formation of 4m is exergonic. This difference was attributed to the greater ring strain induced by the double bond at the ring junction in the five-membered ring series. Complementarily, the plausible formation of cyclodimer 5c from α-oxoketene 1c 12a was computed with a barrier at 87.5 kJ mol -1 and a stabilization energy of -61.2 kJ mol -1 , and the Lewis base-catalyzed rearrangement of cyclodimer 5c involving the formation of an eight-membered ring in 6c was unsurprisingly found to be thermodynamically disfavored, though by only a few kJ mol -1 (Figure 2c). It was concluded that six-membered cyclic αoxoketenes preferentially react as 4π partners, i.e. 1-oxadienes, in inverse electron-demand formal aza-Diels-Alder processes in their reactions with N-hetaryl imines to afford 1,3-oxazin-4ones of type 4 for kinetic reasons. The calculations also indicated that this reaction is in competition with the cyclodimerization of the α-oxoketene, justifying the introduction of the diazo precursor in excess. However, providing that enough energy is brought to the reaction mixture to allow for the retro-cyclodimerization of 5c at a significant rate (t 1/2 ≈ 46 s at 250 °C for an activation energy of 148.7 kJ mol -1 ; see 5c → 1c in Figure 2c), thermodynamic control becomes operative The Journal of Organic Chemistry resulting in a switch of periselectivity in this series allowing for the formation of a spiro hydropyridin-4-one of type 3 (see entry 3, Table 1).

The situation is more complex for the reactions with the acyclic α-oxoketene 1e because of the coexistence of both conformers s-cis-1e and s-trans-1e in a ca. 1:20 ratio at 180 °C according to the computational model [Δ(ΔG) = 11.3 kJ mol -1 , ΔG ‡ = 53.9 kJ mol -1 ] illustrated in Figure 3. Paralleling the previous calculations, formation of the model hydropyridin-4-one 3f was found under thermodynamic control [Δ(ΔG) = -26.8 kJ mol -1 , Figure 3a,b]. Notably, the calculations indicated that only the s-cis conformer of αoxoketene 1e is amenable to the Friedel-Crafts acylation, highlighting the crucial assistance of the ketone carbonyl group of the α-oxoketene in the Friedel-Crafts dearomatization/ rearomatization process. [START_REF] Mohanan | Catalyst-and Halogen-Free Regioselective Friedel-Crafts α-Ketoacylations[END_REF] Conversely, the model 1,3-oxazin-4- The Journal of Organic Chemistry one 4n was computed as the kinetic product with Δ(ΔG ‡ ) = -10.8 kJ mol -1 (Figure 3a,b). This is in good agreement with the experimental results that have shown the preferential formation of the 1,3-oxazin-4-ones 4i-k after short reaction times at 180 °C (Table 1, entries 12-14). Some plausible [2 + 2] cycloadditions between α-oxoketene s-trans-1e and the model aldimine 2k leading to the corresponding β-lactams were also investigated computationally and found largely kinetically disfavored when compared to the aza-Diels-Alder processes discussed herein (see the Supporting Information). As above, significant amounts of unreacted aldimines were recovered after the reactions, indicating some competing dimerization of the acyclic α-oxoketene 1e. 12c Computational modeling of the plausible reaction paths leading to the cyclodimer 5e from s-cis-1e and s-trans-1e led to the identification of two distinct processes with nearly identical activation barriers (Figure 3c): (i) the direct concerted asynchronous [4 + 2] cycloaddition between the 1-oxadiene in s-cis-1e and the ketene double bond in s-trans-1e with a barrier computed at 115.3 kJ mol -1 , and (ii) a two-step process with a barrier computed at 115.2 kJ mol -1 initiated by the concerted asynchronous [4 + 2] cycloaddition between the 1oxadiene in s-cis-1e and the ketone carbonyl group in s-trans-1e to give the ketene intermediate 7e, 13 the Cope-like rearrangement of which can provide the cyclodimer 5e via TS23. Alternative [4 + 2], [2 + 2], and [4 + 4] cyclodimerization processes of s-cis-1e and/or s-trans-1e were also computed and found kinetically and/or thermodynamically disfavored (see the Supporting Information). In a control experiment, heating a toluene solution of 2-diazoacetylacetone with microwaves at 180 °C for 2 min afforded a somehow complex mixture of products (Scheme 3), which contrasts with the very clean α- The Journal of Organic Chemistry oxoketene cyclodimerization observed for the reaction of 2diazo-1,3-cyclohexanedione (Scheme 2). The structure of the major component of this mixture was tentatively attributed to the cyclodimer 5e by 1 H NMR analysis of the crude reaction mixture because we failed at isolating this product by silica gel chromatography or crystallization. Instead, crystallization from the crude mixture (slow evaporation of the solvent) allowed the isolation of the 4-hydroxy-2H-pyran-2-one 8e (ca. 30%), the structure of which was ascertained by X-ray diffraction analysis. 15 It can reasonably be surmised that cyclodimer 5e is the actual major product of the cyclodimerization of α-oxoketene 1e, and that in the presence of atmospheric water it can hydrolyze into the deacetylated product 8e, a known pyran-2-one previously employed for applications in the total syntheses of naturally occurring pyrones. 18 For all model reactions above, the computed activation barriers at 298 K correspond to significant reaction rates at temperatures below 150 °C, and the same holds for calculations at 150 °C (see the Supporting Information). Thus, it is very likely that some chemistry is still going on during the experimental cooling cycles, blurring the image. Examination of the frontier orbitals in the α-oxoketenes 1a, 1c, and cis-1e revealed that their LUMO are essentially located over the two atoms of the ketene CO bonds with the π* system parallel to the mean plane of the molecule (Figure 4). In contrast, their LUMO+1 are principally distributed over the ketene CC bonds and ketone CO bonds with the π* system now perpendicular to the mean plane of the molecule. Thus, in all their reactions with the model 2-azadiene 2k, the transformations are initiated by an overlap between the HOMO of 2k (through its 4-C or 2-N atom depending on The Journal of Organic Chemistry the periselectivity) and the LUMO of the α-oxoketenes located in the mean plane of the molecules, not perpendicular to it as in standard Diels-Alder cycloadditions. More generally, the localization of the LUMO of the α-oxoketenes on their ketene carbonyl groups accounts for the stepwise or highly asynchronous nature of the [4 + 2] processes described herein.

■ CONCLUSIONS

The reactions between α-oxoketenes generated by a thermally induced Wolff rearrangement of 2-diazo-1,3-diketones and some N-(5-pyrazolyl)imines were studied in detail. Among the many possibilities of formal or true cycloadditions in principle allowed with these polyunsaturated substrates, two 6π formal aza-Diels-Alder cycloadditions were observed experimentally: cyclic five-membered α-oxoketenes were found to react preferentially as 2π partners through their CC double bond with N-hetaryl imines reacting as 4π 2-azadienes to produce spiro hydropyridin-4-ones of type 3 , while other cyclic or acyclic α-oxoketenes predominantly reacted as 4π partners, i.e. 1-oxadienes, with the CN bond of the N-hetaryl imines as the 2π partners to produce 1,3-oxazin-4-ones of type 4. Both reactions are synthetically relevant to the preparation of chiral N-heterocycles and alkaloids, which called for a rationale for the observed periselectivity in these formal aza-Diels-Alder cycloadditions. A computational modeling study using DFT allowed understanding the fundamental reasons at the origin of the observed change in periselectivity. It was generally found that the formation of spiro hydropyridin-4-ones of type 3 is under thermodynamic control while 1,3-oxazin-4-ones of type 4 are produced under kinetic control. However, it does not seem practical to control efficiently the reaction outcomes by adjusting their temperature and time. One reason for this is the existence of competing decomposition pathways of the αoxoketenes, for instance, the formation of cyclodimers of type 5 and/or their rearranged derivatives of type 6 . These findings are expected to have a significant impact on the development of applications of α-oxoketenes in organic synthesis.

■ EXPERIMENTAL SECTION

General Information. All reagents were purchased from commercial sources and used without further purification unless otherwise noted. All compounds were weighed and handled in air at room temperature. Microwave-assisted heating was performed using a professional Anton-Paar Monowave 300 system in specific sealed tubular reaction vessels. The reactions were monitored by TLC (60 F 254 ) visualized by UV lamp (254 or 365 nm). Flash chromatography was performed on silica gel (particle size 40-63 μm). Petroleum ether refers to the fraction with bp = 40-60 °C. NMR spectra were recorded at 300 MHz ( 1 H) and 75 MHz ( 13 C) at 298 K in CDCl 3 using as internal standards the residual nondeuterated signal for 1 H NMR (δ = 7.26 ppm) and the deuterated solvent signal for 13 C NMR spectroscopy (δ = 77.16 ppm). DEPT-135 experiments were used to determine the multiplicity of the 13 C resonances. Chemical shifts (δ) are given in ppm, coupling constants (J) are given in Hz, and the classical abbreviations are used to describe the multiplicity of the 1 H resonances. High-resolution mass spectra were recorded in triplicate at the Spectropole (https://fr-chimie.univ-amu.fr/spectropole/). 2-Diazo-1,3-diketones, [START_REF] Presset | Diazo-Transfer Reactions to 1,3-Dicarbonyl Compounds with Tosyl Azide[END_REF] aldimines 2a-e and 2i, [START_REF] Galvez | Divergent Chemo-, Regio-, and Diastereoselective Normal Electron-Demand Povarov-Type Reactions with α-Oxoketene Dienophiles[END_REF] and ketimines 2f-h 20 were prepared as previously reported in similar yields and purity.

Aldimine 2j. A 10 mL sealable (with screw cap) tubular reaction vessel containing a Teflon-coated magnetic stirring bar was charged with 1-benzyl-3-phenyl-1H-pyrazol-5-amine (270 mg, 1.08 mmol), panisaldehyde (160 mg, 1.18 mmol), 2 pellets of solid KOH, and 4.0 mL of anhydrous toluene. The reaction vessel was sealed, and the mixture was heated at 90 °C for 5 h with stirring, cooled down to room temperature, and filtered over Celite. The filtrate was concentrated under vacuum, and the resulting solid material was triturated with petroleum ether/ethyl acetate 9:1 to afford, after filtration and drying in vacuo, aldimine 2j (380 mg, 95%) as a pale yellow solid. R f (EtOAc/petroleum ether 1:10) = 0.45. Mp = 62 °C (amorphous). 13 C{ 1 H} NMR (75 MHz, δ ppm/CDCl 3 ): 162. 7, 159.0, 150.9, 150.6, 137.8, 133.8, 130.7, 128.9, 128.5, 128.5, 127.7, 127.6, 127.4, 125.5, 114.3, 114.3, 88.5, 55.4, 51.6. 1 H NMR (300 MHz, δ ppm/CDCl 3 ): 8.60 (s, 1H), 7.92-7.80 (m, 4H), 7.43-7.23 (m, 8H), 7.04-6.96 (m, 2H), 6.54 (s, 1H), 5.58 (s, 2H), 3.88 (s, 3H). HRMS (ESI) m/z: [M + H] + calcd for C 24 H 22 N 3 O + 368.1757; found 368.1757.

General Procedure for the aza-Diels-Alder Reactions (Table 1, entries 4-14). A solution of the N-hetaryl imine 2 (ca. The Journal of Organic Chemistry 0.2 mmol) and the corresponding 2-diazo-1,3-dicarbonyl precursor of the α-oxoketene 1 (1.2 equiv) in 2.0 mL anhydrous toluene placed in a 10 mL sealed tube containing a Teflon-coated magnetic stirring bar was irradiated with microwaves at 150 or 180 °C for 2 min and cooled down to 55 °C by an air flow over 5-6 min. A second portion of the 2-diazo-1,3-dicarbonyl compound (1.2 equiv) was added to the reaction mixture that was irradiated at the same temperature for an additional 2 min, cooled down to 55 °C by an air flow over 5-6 min, concentrated, analyzed by 1 H NMR, and purified by flash chromatography on silica gel to afford product 4.

1,3-Oxazin-4-one 4a. By following the general procedure at 150 °C with 2-diazocycloheptan-1,3-dione (2 × 40.5 mg, 0.53 mmol) and aldimine 2b (60 mg, 0.22 mmol) in 2.0 mL of anhydrous toluene, compound 4a was obtained as a white solid (81 mg, 93%). R f (EtOAc/petroleum ether 1:3) = 0.11. Mp = 109-110 °C (amorphous). 13 °C with 2-diazocycloheptan-1,3-dione (2 × 22 mg, 0.29 mmol) and aldimine 2c (40 mg, 0.12 mmol) in 2.0 mL of anhydrous toluene, compound 4b was obtained as a white solid (44 mg, 80%). R f (EtOAc/petroleum ether 1:7) = 0.12. Mp = 107 °C (amorphous). 1,3-Oxazin-4-one 4c. By following the general procedure at 150 °C with 2-diazocycloheptan-1,3-dione (2 × 24.5 mg, 0.32 mmol) and aldimine 2d (45 mg, 0.13 mmol) in 2.0 mL of anhydrous toluene, compound 4c was obtained as a white solid (36 mg, 59%). R f (EtOAc/petroleum ether 1:7) = 0.16. Mp = 150-151 °C (amorphous). 13 C{ 1 H} NMR (75 MHz, δ ppm/CDCl 3 ): 164. + 462.1943; found 462.1941. 1,3-Oxazin-4-one 4d. By following the general procedure at 180 °C with 2-diazocycloheptan-1,3-dione (2 × 56.5 mg, 0.74 mmol) and aldimine 2e (90 mg, 0.31 mmol) in 2.0 mL of anhydrous toluene, compound 4d was obtained as a white solid (90 mg, 70%). R f (EtOAc/petroleum ether 1:2) = 0.20. Mp = 104-105 °C (amorphous). 13 C{ 1 H} NMR (75 MHz, δ ppm/CDCl 3 ): 164.2 (C), 164.2 (C), 160.8 (C), 149.9 (C), 137.9 (C), 133.5 (C), 128.9 (2 × CH), 128.6 (2 × CH), 127.6 (CH), 127.1 (C), 125.4 (2 × CH), 114.1 (2 × CH), 107.8 (C), 100.0 (CH), 89.8 (CH), 55.4 (CH 3 ), 36.3 (CH 3 ), 27.7 (CH 2 ), 22.0 (CH 2 ), 22.0 (CH 2 ), 21.5 (CH 2 ). 1 H NMR (300 MHz, δ ppm/CDCl 3 ): 7.62 (d, J = 8.7 Hz, 2H), 7.34-7.29 (m, 4H), 7.23 (t, J = 7.5 Hz, 1H), 6.83 (d, J = 8.7 Hz, 2H), 6.28 (s, 1H), 6.11 (s, 1H), 3.76 (s, 3H), 3.73 (s, 3H), 2.38-2.16 (m, 4H), 1.80-1.65 (m, 4H). HRMS (ESI) m/z: + 416.1969; found 416.1969. 1,3-Oxazin-4-one 4e. By following the general procedure at 150 °C with 2-diazocycloheptan-1,3-dione (2 × 19.5 mg, 0.26 mmol) and ketimine 2f (30 mg, 0.11 mmol) in 2.0 mL of anhydrous toluene, compound 4e was obtained as a white solid (35 mg, 80%). R f (EtOAc/petroleum ether 1:10) = 0.27. Mp = 119 °C (amorphous). 13 C{ 1 H} NMR (75 MHz, δ ppm/CDCl 3 ): 164.7 (C), 162.3 (C), 162.2 (C), 139.2 (C), 135.8 (C), 129.0 (2 × CH), 127.4 (CH), 124.3 (2 × CH), 106.9 (C), 102.5 (C), 102.1 (CH), 35.7 (CH 2 ), 35.0 (CH 2 ), 32.6 (C), 30.5 (3 × CH 3 ), 27.9 (CH 2 ), 22.5 (CH 2 ), 22.4 (CH 2 ), 22.2 (CH 2 ), 22.1 (CH 2 ), 21.4 (CH 2 ). 1 H NMR (300 MHz, δ ppm/CDCl 3 ): 7.48 (d, J = 7.8 Hz, 2H), 7.36 (t, J = 7.5 Hz, 2H), 7.27 (t, J = 7.2 Hz, 1H), 6.13 (s, 1H), 2.35-2.30 (m, 3H), 2.10-2.09 (m, 2H), 1.75-1.52 (m, 11H), 1. 34 (s, 9H). HRMS (ESI) m/z: [M + H] + calcd for C 25 H 32 N 3 O 2 + 406.2489; found 406.2489. 1,3-Oxazin-4-one 4f. By following the general procedure at 150 °C with 2-diazocycloheptan-1,3-dione (2 × 29.5 mg, 0.39 mmol) and ketimine 2g (70 mg, 0.16 mmol) in 2.0 mL of anhydrous toluene, compound 4f was obtained as a yellow solid (74 mg, 83%, dr = 1:1.6). R f (EtOAc/petroleum ether 1:10) = 0.10. 13 ). 1 H NMR (300 MHz, δ ppm/ CDCl 3 ): major diastereomer: 7.43-7.24 (m, 10H), 7.12-7.07 (m, 1H), 6.67 (t, J = 7.5 Hz, 1H), 6.53 (d, J = 8.1 Hz, 1H), 6.45 (d, J = 7.0 Hz, 1H), 5.94 (s, 1H), 4.87 (d, J = 15.6 Hz, 1H), 4.70 (d, J = 15.6 Hz, 1H), 2.48-2.38 (m, 2H), 2.28-2.11 (m, 2H), 1.84-1.72 (m, 4H), 1.07 (s, 9H); minor diastereomer : 7.54-7.52 (m, 2H), 7.43-7.24 (m, 8H), 7.12-7.07 (m, 2H), 6.97 (t, J = 7.5 Hz, 1H), 6.59 (d, J = 8.1 Hz, 1H), 5.60 (s, 1H), 4.62 (d, J = 15.6 Hz, 1H), 4.20 (d, J = 15.6 Hz, 1H), 2.48-2.38 (m, 2H), 2.28-2.11 (m, 2H), 1.84-1.72 (m, 4H) 1,3-Oxazin-4-one 4g. By following the general procedure at 150 °C with 2-diazocycloheptan-1,3-dione (2 × 34.5 mg, 0.45 mmol) and ketimine 2h (70 mg, 0.19 mmol) in 2.0 mL of anhydrous toluene, compound 4g was obtained as a yellow solid (72 mg, 77%, dr = 1:1.6). R f (EtOAc/petroleum ether 1:5) = 0.10. 13 CH 2 ). 1 H NMR (300 MHz, δ ppm/CDCl 3 ): major diastereomer: 7.62 (d, J = 7.2 Hz, 1H), 7.33-7.24 (m, 5H), 7.10-7.02 (m, 2H), 6.67-6.64 (m, 1H), 5.01 (s, 1H), 4.76 (d, J = 15.6 Hz, 1H), 4.62 (d, J = 15.6 Hz, 1H), 3.75 (s, 3H), 2.42-2.17 (m, 4H), 1.84-1.56 (m, 4H), 1.06 (s, 9H); minor diastereomer : 7.33-7.24 (m, 4H), 7.18 (t, J = 7.8 Hz, 1H), 7.10-7.02 (m, 2H), 6.94 (t, J = 7.5 Hz, 1H), 6.67-6.64 (m, 1H), 5.48 (s, 1H), 5.00 (d, J = 15.3 Hz, 1H), 4.63 (d, J = 15.3 Hz, 1H), 3.57 (s, 3H), 2.42-2.17 (m, 4H), 1.84-1.56 (m, 4H), 0.93 (s, 9H). HRMS (ESI) m/z: [M + H] + calcd for C 30 H 33 N 4 O 3 + 497.2547; found 497.2536. 1,3-Oxazin-4-one 4h. By following the general procedure at 150 °C with 2-diazocyclooctan-1,3-dione (2 × 39 mg, 0.35 mmol) and aldimine 2c (49 mg, 0.15 mmol) in 2.0 mL of anhydrous toluene, compound 4h was obtained as a white solid (25 mg, 36%). R f (EtOAc/petroleum ether 1:7) = 0.18. Mp = 115 °C (amorphous). 1,3-Oxazin-4-one 4j. By following the general procedure at 180 °C with 2-diazoacetylacetone (2 × 32 mg, 0.51 mmol) and aldimine 2i (80 mg, 0.21 mmol) in 2.0 mL of anhydrous toluene, compound 4j was obtained as a white solid (49 mg, 49%). R f (EtOAc/petroleum ether 1:5) = 0.11. Mp = 46 °C (amorphous). 13 C{ 1 H} NMR (75 MHz, δ ppm/CDCl 3 ): 163.7 (C), 161.9 (C), 160.9 (C), 137.9 (C), 135.5 (C), 132.1 (2 × C, 2 J C-F = 33.7 Hz), 127.7 (2 × CH, 3 J C-F = 2.7 Hz), 123.7 (CH, 3 J C-F = 3.6 Hz), 122.9 (2 × C, 1 J C-F = 271.2 Hz), 106.9 (C), 99.4 (CH), 88.1 (CH), 35.5 (CH 3 ), 32.2 (C), 30.2 (3 × CH 3 ), 17.5 (CH 3 ), 10.5 (CH 3 ). 1 H NMR (300 MHz, δ ppm/ CDCl 3 ): 7.84 (s, 1H), 7.82 (s, 2H), 6.34 (s, 1H), 5.66 (s, 1H), 3.56 (s, 3H), 2.07 (s, 3H), 1.86 (s, 3H), 1.11 (s, 9H). HRMS (ESI) m/z: [M + H] + calcd for C 22 H 24 F 6 N 3 O 2 + 476.1767; found 476.1767. 1,3-Oxazin-4-one 4k. By following the general procedure at 180 °C with 2-diazoacetylacetone (2 × 26 mg, 0.41 mmol) and aldimine 2j (75 mg, 0.20 mmol) in 2.0 mL of anhydrous toluene, compound 4k was obtained as a white solid (59 mg, 62%). R f (EtOAc/petroleum ether 1:4) = 0.25. Mp = 81 °C (amorphous). 13 C{ 1 H} NMR (75 MHz, δ ppm/CDCl 3 ): 160.5 (C), 149.9 (C), 137.6 (C), 136.7 (C), 133.4 (C), 128.8 (2 × CH), 128.5 (2 × CH), 128.4 (2 × CH), 127.9 (2 × CH), 127.7 (CH), 127.6 (CH), 126.9 (C), 125.4 (2 × CH), 113.8 (2 × CH), 105.5 (C), 100.6 (CH), 89.1 (CH), 55.2 (CH), 53.5 (CH 2 ), 17.5 (CH 3 ), 10.4 (CH 3 ). 1 H NMR (300 MHz, δ ppm/ CDCl 3 ): 7.69-7.63 (m, 2H), 7.36-7.29 (m, 5H), 7.23 (m, 3H), 7.07 (d, 2H), 6.75 (d, 2H), 6.11 (s, 1H), 5.94 (s, 1H), 5.30 (d, J = 15.4 Hz, 1H), 5.21 (d, J = 15.4 Hz, 1H), 3.76 (s, 3H), 1.93 (s, 3H), 1.85 (s, 3H). HRMS (ESI) m/z: [M + H] + calcd for C 29 H 28 N 3 O 3 + 466.2125; found 466.2126. Cyclodimer 5a. A solution of 2-diazocyclohexan-1,3-dione (70 mg, 0.51 mmol) in 2.5 mL anhydrous toluene was irradiated with microwaves at 160 °C for 5 min, cooled down to 55 °C by an air flow and concentrated to afford cyclodimer 5a (57 mg, quant.) as a pale yellow oil. R f (EtOAc/petroleum ether 3:2) = 0.68. 13 C{ 1 H} NMR (75 MHz, δ ppm/CDCl 3 ): 204.0, 184.4, 172.3, 166.5, 115.6, 72.0, 38.1, 32.1, 30.4, 25.7, 20.3, 18.8. 1 H NMR (300 MHz, δ ppm/ CDCl 3 ): 2.90-2.56 (m, 4H), 2.57-2.47 (m, 2H), 2.43 (m, 2H), 2. 23-1.94 (m, 4H). HRMS (ESI) m/z: [M + H] + calcd for C 12 H 13 O 4 + 221.0808; found 221.0812. Cyclodimer 6a. A solution of 2-diazocyclohexan-1,3-dione (267 mg, 2.0 mmol) and N,N-dimethylallylamine (240 μL, 2.0 mmol) in 3.0 mL of anhydrous toluene was irradiated with microwaves at 160 °C for 10 min, cooled down to 55 °C by an air flow, and concentrated to afford cyclodimer 6a (195 mg, 88%) as a brown solid. Recrystallization of this material from toluene afforded colorless prisms suitable for X-ray diffraction structural analysis (CCDC 1975653). R f (EtOAc/petroleum ether 1:4) = 0.10. 13 C{ 1 H} NMR (75 MHz, δ ppm/CDCl 3 ): 168.8, 165.4, 164.3, 161.0, 111.5, 107.5, 32.7, 31.5, 26.5, 25.9, 21.5, 19.9. 1 H NMR (300 MHz, δ ppm/ CDCl 3 ): 2.81-2.73 (m, 2H), 2.74-2.62 (m, 4H), 2.58 (t, J = 7.2 Hz, 2H), 2. 19 (tt, J = 7.2, 7.3 Hz, 2H), 2.05 (tt, J = 7.3, 7.4 Hz, 2H). The structure of 6a was resolved by X-ray diffraction analysis (CCDC 1975653).

[M + H] + calcd for C 25 H 26 N 3 O 3
Pyran-2-one 8e. A solution of 2-diazoacetylacetone (65 mg, 0,52 mmol) in 2.0 mL of anhydrous toluene was irradiated with microwaves at 180 °C for 3 min, cooled down to 55 °C by an air flow, and concentrated in vacuum to afford a crude sticky solid, probably containing the cyclodimer 5e as analyzed from its crude 1 H NMR at 300 MHz in CDCl 3 showing predominantly four singlet resonances of equal area at 2.23, 2.18, 1.83, and 1.72 ppm (see spectrum in the Supporting Information). This material was dissolved in diethyl ether, and the slow evaporation of this solution over several days in a tubular vial open to air afforded monocrystalline needles, which were washed with petroleum ether to afford 8e (11 mg, 30%). R f (EtOAc/petroleum ether 1:2) = 0.15. Mp = 179 °C (recrystallized from diethyl ether). 13 C{ 1 H} NMR (75 MHz, δ ppm/CDCl 3 ): 165. 7, 164.3, 155.6, 106.4, 98.0, 77.2, 17.2, 9.8, 8.3. 1 H NMR (400 MHz, δ ppm/CDCl 3 ): 2.22 (s, 1H), 1.98 (s, 1H), 1.96 (s, 1H). The structure of 8e was resolved by X-ray diffraction analysis (CCDC 1985157).

Table 1 .

 1 Reactions of α-Oxoketenes with N-(5-Pyrazolyl)imines a a All reactions in toluene (ca. 0.1 M) in sealed reaction vessels under microwave irradiation with two heating/cooling cycles. Periselectivity ≥20:1 in all cases. brsm = based on recovered starting material 2. b Previously reported results from ref 7 included for direct comparison. c dr at 25 °C.

Figure 1 .

 1 Figure 1. Free Gibbs energy profiles computed at 298 K [DFT, B3LYP-D3/6-311++G(d,p)] of some Diels-Alder reactions involving α-oxoketene 1a. (a) Model reaction between α-oxoketene 1a and aldimine 2k leading to spiro hydropyridin-4-one 3d. (b) Model reaction between α-oxoketene 1a and aldimine 2k leading to 1,3-oxazin-4-one 4l. (c) Cyclodimerization of α-oxoketene 1a leading to dimer 5a and its rearranged product 6a; LB = Lewis base. Scheme 2. Control Experiments for the Synthesis of Dimer 5a and Its Lewis Base-Catalyzed Rearranged Product 6a

Figure 2 .

 2 Figure 2. Free Gibbs energy profiles computed at 298 K [DFT, B3LYP-D3/6-311++G(d,p)] of some Diels-Alder reactions with α-oxoketene 1c. (a) Model reaction between α-oxoketene 1c and aldimine 2k leading to spiro hydropyridin-4-one 3e. (b) Model reaction between α-oxoketene 1c and aldimine 2k leading to 1,3-oxazin-4-one 4m. (c) Plausible cyclodimerization of α-oxoketene 1c leading to dimer 5c and its rearranged product 6c; LB = Lewis base.

Figure 3 .

 3 Figure 3. Free Gibbs energy profiles computed at 298 K [DFT, B3LYP-D3/6-311++G(d,p)] of some Diels-Alder reactions with α-oxoketene 1e. (a) Model reaction between α-oxoketene 1e and aldimine 2k leading to hydropyridin-4-one 3f. (b) Model reaction between α-oxoketene 1e and aldimine 2k leading to 1,3-oxazin-4-one 4n. (c) Plausible cyclodimerization processes of α-oxoketene 1e leading to dimer 5e. Scheme 3. Control Experiments on the Cyclodimerization of α-Oxoketene 1e

Figure 4 .

 4 Figure 4. Contour plots and energies of the frontier orbitals in the α-oxoketenes 1a, 1c, and cis-1e and the model 2-azadiene 2k.

13C{ 1

 1 H} NMR (75 MHz, δ ppm/CDCl 3 ): 165.1 (C), 164.6 (C), 161.8 (C), 160.7 (C), 139.2 (C), 135.8 (C), 129.4 (2 × CH), 129.0 (2 × CH), 127.3 (CH), 126.0 (C), 124.2 (2 × CH), 113.4 (2 × CH), 107.9 (C), 103.3 (CH), 89.8 (CH), 55.4 (CH 3 ), 32.4 (C), 30.3 (3 × CH 3 ), 27.5 (CH 2 ), 22.0 (CH 2 ), 22.0 (CH 2 ), 21.6 (CH 2 ). 1 H NMR (300 MHz, δ ppm/CDCl 3 ): 7.41-7.27 (m, 5H), 6.94 (d, J = 8.7 Hz, 2H), 6.68 (d, J = 8.7 Hz, 2H), 6.00 (s, 1H), 5.96 (s, 1H), 3.75 (s, 3H), 2.39-2.19 (m, 4H), 1.80-1.54 (m, 4H), 1.20 (s, 9H). HRMS (ESI) m/z: [M + H] + calcd for C 28 H 32 N 3 O 3 + 458.2438; found 458.2442.

  7 (C), 164.4 (C), 162.0 (C), 139.0 (C), 135.8 (C), 135.5 (C), 132.6 (C), 129.2 (2 × CH), 129.1 (2 × CH), 128.3 (2 × CH), 127.4 (CH), 124.1 (2 × CH), 108.2 (C), 103.2 (CH), 89.2 (CH), 32.4 (C), 30.3(3 × CH 3 ), 27.5 (CH 2 ), 21.9 (CH 2 ), 21.9 (CH 2 ), 21.5 (CH 2 ). 1 H NMR (300 MHz, δ ppm/CDCl 3 ):7.42-7.28 (m, 5H), 7.15 (d, J = 8.4 Hz, 2H), 6.96 (d, J = 8.4 Hz, 2H), 6.01 (s, 1H), 6.00 (s, 1H), 2.38-2.18 (m, 4H), 1.77-1.58 (m, 4H), 1.21 (s, 9H). HRMS (ESI) m/z: [M + H] + calcd for C 27 H 29 ClN 3 O 2

  C{ 1 H} NMR (75 MHz, δ ppm/CDCl 3 ): major diastereomer: 169.1 (C), 163.0 (C), 162.6 (C), 160.2 (C), 142.6 (C), 134.5 (C), 133.6 (C), 132.2 (CH), 129.1 (CH), 128.0 (CH), 127.0 (CH), 126.2 (C), 124.4 (CH), 123.9 (CH), 110.5 (CH), 106.6 (C), 98.7 (CH), 89.5 (C), 44.4 (CH 2 ), 35.9 (CH 3 ), 32.1 (C), 30.4 (3 × CH 3 ), 27.7 (CH 2 ), 22.0 (CH 2 ), 22.0 (CH 2 ), 21.2 (CH 2 ); minor diastereomer: 170.7 (C), 163.2 (C), 162.1 (C), 160.6 (C), 143.0 (C), 134.9 (C), 134.6 (C), 131.9 (CH), 129.3 (CH), 128.2 (CH), 127.9 (CH), 124.6 (C), 124.5 (CH), 123.7 (CH), 109.8 (CH), 106.9 (C), 98.7 (CH), 89.3 (C), 44.3 (CH 2 ), 35.6 (CH 3 ), 32.0 (C), 30.2 (3 × CH 3 ), 27.5 (CH 2 ), 21.9 (CH 2 ), 21.8 (CH 2 ), 21.2 (

  By following the general procedure at 150

	C{ 1 H} NMR (75 MHz, δ ppm/CDCl 3 ): 163.9 (C), 163.8 (C), 160.6 (C), 160.3 (C), 136.5 (C), 128.8 (2 × CH), 127.3 (C), 113.8 (2 × CH), 108.0 (C), 99.3 (CH), 89.7 (CH), 55.4 (CH 3 ), 35.8 (CH 3 ), 32.1 (C), 30.4 (3 × CH 3 ), 27.6 (CH 2 ), 21.9 (CH 2 ), 21.9 (CH 2 ), 21.5 (CH 2 ). 1 H NMR (300 MHz, δ ppm/ CDCl 3 ): 7.24 (d, J = 8.7 Hz, 2H), 6.79 (d, J = 8.7 Hz, 2H), 6.18 (s, 1H), 5.58 (s, 1H), 3.74 (s, 3H), 3.58 (s, 3H), 2.32-2.14 (m, 4H), 1.74-1.55 (m, 4H), 1.10 (s, 9H). HRMS (ESI) m/z: [M + H] + calcd + 396.2282; found 396.2287. for C 23 H 30 N 3 O 3 1,3-Oxazin-4-one 4b.

  13 C{ 1 H} NMR (100 MHz, δ ppm/CDCl 3 ): 169.4 (C), 165.0 (C),

	The Journal of Organic Chemistry
	161.8 (C), 160.6 (C), 139.3 (C), 136.1 (C), 129.3 (2 × CH), 129.0 (2 × CH), 127.3 (CH), 126.3 (C), 124.2 (2 × CH), 113.5 (2 × CH),
	112.2 (C), 103.1 (CH), 89.8 (CH), 55.5 (CH 3 ), 33.6 (CH 2 ), 32.4 (C), 31.6 (CH 2 ), 30.3 (3 × CH 3 ), 26.9 (CH 2 ), 24.8 (CH 2 ), 23.6 (CH 2 ). 1 H NMR (400 MHz, δ ppm/CDCl 3 ): 7.40-7.28 (m, 5H), 7.00 (d, J = 8.4 Hz, 2H), 6.71 (d, J = 8.4 Hz, 2H), 5.98 (s, 1H), 5.97
	(s, 1H), 3.76 (s, 3H), 2.53-2.30 (m, 4H), 1.74-1.69 (m, 2H), 1.60-1.46 (m, 4H), 1.20 (s, 9H). HRMS (ESI) m/z: [M + H] + calcd for C 29 H 34 N 3 O 3 + 472.2595; found 472.2598. °C 1,3-Oxazin-4-one 4i. By following the general procedure at 180 with 2-diazoacetylacetone (2 × 27 mg, 0.43 mmol) and aldimine 2c
	(60 mg, 0.18 mmol) in 2.0 mL of anhydrous toluene, compound 4i
	was obtained as a pale yellow solid (50 mg, 64%). R f (EtOAc/ petroleum ether 1:8) = 0.19. Mp = 60 °C (amorphous). 13 C{ 1 H}
	NMR (75 MHz, δ ppm/CDCl 3 ): 165.5 (C), 162.4 (C), 161.8 (C), 160.6 (C), 139.2 (C), 135.8 (C), 129.3 (2 × CH), 129.0 (2 × CH), 127.3 (CH), 126.1 (C), 124.2 (2 × CH), 113.4 (2 × CH), 105.9 (C), 103.1 (CH), 89.5 (CH), 55.4 (CH 3 ), 32.4 (C), 30.3 (3 × CH 3 ), 17.5 (CH 3 ), 10.6 (CH 3 ). 1 H NMR (300 MHz, δ ppm/CDCl 3 ): 7.40-7.27 (m, 5H), 6.94 (d, J = 8.7 Hz, 2H), 6.68 (d, J = 8.7 Hz, 2H), 5.99 (s,
	1H), 5.94 (s, 1H), 3.75 (s, 3H), 1.96 (s, 3H), 1.85 (s, 3H), 1.20 (s, + 432.2282; 9H). HRMS (ESI) m/z: [M + H] + calcd for C 26 H 30 N 3 O 3 found 432.2283.

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https://dx.doi.org/10.1021/acs.joc.0c00767 J.Org. Chem. 2020, 85, 7368-7377

University) for preliminary calculations. Part of this work was supported by the computing facilities of the CRCMM, 'Centre Reǵional de Competences en Modeĺisation Molećulaire de Marseille'. Financial support from Aix-Marseille University, Centrale Marseille, the CNRS and Universidad del Valle is also gratefully acknowledged. B.C.A. thanks the French Reǵion PACA and the ProvePharm Life solutions company for a PhD studentship (EJD 2017/2020). J.-C.C. and J.G. thank COLCIENCIAS, 'Colombian Institute for Science and Research', for mobility fellowships (494/2009).