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# Vinylogous and stereoselective domino synthesis of pyrano[2,3-c]pyrroles from alkylidene meldrum's acids

Mariia Savchuk, Giang Vo-Thanh, Sylvain Oudeyer, Hélène Beucher, Jean-François Brière

► To cite this version:

Mariia Savchuk, Giang Vo-Thanh, Sylvain Oudeyer, Hélène Beucher, Jean-François Brière. Vinylogous and stereoselective domino synthesis of pyrano[2,3-c]pyrroles from alkylidene meldrum's acids. Organic & Biomolecular Chemistry, 2024, 10.1039/D4OB00233D. hal-04511633

HAL Id: hal-04511633

https://normandie-univ.hal.science/hal-04511633v1

Submitted on 19 Mar 2024

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# Vinylogous and Stereoselective Domino Synthesis of Pyrano[2,3-c]pyrroles from Alkylidene Meldrum's acids

Mariia Savchuk,ª Giang Vo-Thanh,ᵇ Sylvain Oudeyer,ª Hélène Beucherª and Jean-François Brière*ª

A domino Vinylogous aza-Michael-Aldol-Cyclocondensation (aza-VMAC) reaction was achieved with a series of alkylidene Meldrum's acid derivatives under simple operational conditions paving the way to novel pyrano[2,3-c]pyrroles in an excellent diastereoselectivity (> 96:4), encompassing the relative control of three contiguous stereocenters.

Pyrrolidine is a privileged heterocycle, which is the core-
structure of several biologically active molecules. ¹ The hydroxy-
pyrrolidine motif, particularly embedded into a fused bicyclic
architecture (e.g. pyrano[2,3-c]pyrrole derivatives), has spurred
some interest in synthetic methodology to explore the chemical
diversity in this series of azaarenes,² but also to adopt the
“conformation restriction” approach appreciated in medicinal
chemistry, as a better target binding is thereby expected
(Scheme 1A).²b The development of strategies leading
efficiently to original pyrano[2,3-c]pyrrole derivatives is
therefore a valuable endeavor in organic synthesis, addressing
the “escape from the flatland” principle, which increases Fsp³
towards better druggable molecules.³

The vinylogous alkylidene Meldrum's acids **1** (MA, Scheme 1B) proved to be versatile platform molecules involved in various 1,6-conjugate additions or annulation sequences taking place at the terminal alkene moiety through C-C bond forming processes. 4,5 We recently challenged the C-heteroatom bond forming event through a 1,6-sulfa-Michael addition to vinylogous alkylidene MA **1**. 6 In order to prevent the expected equilibrated C-S bond formation, we took advantage of a subsequent domino aldol-cyclocondensation reaction, as a formal (4+2) annulation, highlighting an emerging vinylogous reactivity of ketone-derived alkylidene MA architectures. 7,8

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

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

<figure><img src="image_4.png" /></figure>

• Facile C-N,C-C,C-O construction • Relative control of three C* • 1 tetrasubstituted C*

<caption>**Scheme 1** Vinylogous alkylidene MA towards pyrrolidine derivatives.</caption>

This strategy opens a new avenue to the synthesis of original
chiral heterocycles triggered by a C-heteroatom bond formation
at C6 of vinylogous alkylidene MA, a platform molecule
behaving thereby as a C5 synthon. Subject to the use of suited
bifunctional nucleophiles like 2<sup>8a,9,10</sup> we questioned whether a
domino Vinylogous aza-Michael-Aldol-Cyclocondensation (aza-
VMAC) reaction could be achieved with the aim of opening a
new and expeditious route to original pyrrolidinones 3
embedded into a fused-bicyclic backbone (Scheme 1C). We are
delighted to report on our endeavours towards the
development of an original domino aza-VMAC reaction,
encompassing a C-N/C-C/C-O bond forming process to build a
three-dimensional shape architecture of type pyrano[2,3-
c]pyrrole and having three contiguous stereogenic centers
among which a valuable tetrasubstituted carbon atom.

<figure><img src="image_5.png" /><figcaption>**Table 1** Optimization of the domino aza-VMAC reaction<sup>a</sup></figcaption></figure>
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<table><thead><tr><th>Entry</th><th>Base and additive (equiv.)</th><th>Solvent</th><th>Time (h)</th><th>Conversion (%)<sup>b</sup></th></tr></thead><tbody><tr><td>1</td><td>Na<sub>2</sub>CO<sub>3</sub> (2)</td><td>CH<sub>2</sub>Cl<sub>2</sub></td><td>16</td><td>0</td></tr><tr><td>2</td><td>K<sub>2</sub>CO<sub>3</sub> (2)</td><td>CH<sub>2</sub>Cl<sub>2</sub></td><td>16</td><td>0</td></tr><tr><td>3</td><td>K<sub>3</sub>PO<sub>4</sub> (2)</td><td>CH<sub>2</sub>Cl<sub>2</sub></td><td>16</td><td>0</td></tr><tr><td>4</td><td>K<sub>3</sub>PO<sub>4</sub> (2) + PPh<sub>3</sub> (0.2)</td><td>CH<sub>2</sub>Cl<sub>2</sub></td><td>16</td><td>0</td></tr><tr><td>5</td><td>K<sub>3</sub>PO<sub>4</sub> (2) + Et<sub>3</sub>N (0.2)</td><td>CH<sub>2</sub>Cl<sub>2</sub></td><td>16</td><td>0</td></tr><tr><td>6</td><td>K<sub>3</sub>PO<sub>4</sub> (2) + BnEt<sub>3</sub>NCl (0.2)</td><td>CH<sub>2</sub>Cl<sub>2</sub></td><td>16</td><td>67</td></tr><tr><td>7</td><td>Cs<sub>2</sub>CO<sub>3</sub> (2)</td><td>CH<sub>2</sub>Cl<sub>2</sub></td><td>5</td><td>>99</td></tr><tr><td>8</td><td>Cs<sub>2</sub>CO<sub>3</sub> (1)</td><td>CH<sub>2</sub>Cl<sub>2</sub></td><td>5</td><td>36</td></tr><tr><td>9</td><td>Cs<sub>2</sub>CO<sub>3</sub> (0.2)</td><td>CH<sub>2</sub>Cl<sub>2</sub></td><td>5</td><td>traces</td></tr><tr><td>10</td><td>Cs<sub>2</sub>CO<sub>3</sub> (1)</td><td>toluene</td><td>5</td><td>30</td></tr><tr><td>11</td><td>Cs<sub>2</sub>CO<sub>3</sub> (1)</td><td>THF</td><td>5</td><td>45</td></tr><tr><td>12</td><td>Cs<sub>2</sub>CO<sub>3</sub> (1)</td><td>AcOEt</td><td>5</td><td>54</td></tr><tr><td>13</td><td>Cs<sub>2</sub>CO<sub>3</sub> (1)</td><td>MeCN</td><td>5</td><td>89</td></tr><tr><td>14</td><td>Cs<sub>2</sub>CO<sub>3</sub> (1.2)</td><td>MeCN</td><td>4</td><td>>99</td></tr><tr><td>15</td><td>Cs<sub>2</sub>CO<sub>3</sub> (1.2)</td><td>MeCN</td><td>1</td><td>>99</td></tr></tbody></table>

We first investigated the possibility of performing a domino aza-VMAC reaction by means of the model vinylogous alkylidene MA 1a in the presence of various bifunctional aza-nucleophiles like 2 (Table 1, see Supplementary Information -SI for details). Nevertheless, only the α-ketoamide 2a afforded promising results, providing that the suited basic conditions were used.⁸,⁹,¹⁰ At first, the addition of 2 equivalents of sodium or potassium carbonate (entries 1-2), as well as potassium phosphate (entry 3) in dichloromethane as solvent led to the recovery of starting materials. Then, we wondered whether an organocatalytic process could occur using a phosphorus Lewis base (0.2 equiv. of PPh₃, entry 4) or an amino Lewis or Brønsted base (0.2 equiv. of Et₃N, entry 5) in the presence of K₃PO₄, as an “innocent” co-base. We did not get any reactivity in these cases. However, the Phase-Transfer Catalysis (PTC) conditions (0.2 equiv. of BnEt₃NCl, entry 6), allowed 67% of conversion of 1a into 3aa after 16 hours. The product was isolated after an acidic work-up in order to restore the carboxylic acid functional group from the *in situ* formed carboxylate under basic conditions and the loss of acetone. This outcome shows that the nature of the lipophilic cation, and the ion pairs derived thereof, is an important parameter for getting a successful reactivity for this domino sequence. Eventually, it was found that the simple addition of cesium carbonate as a base promoted a complete transformation of 1a into the corresponding pyrano[2,3-c]pyrrole derivative 3aa (entry 7). Worthy of note, a single diastereoisomer was observed on the ¹H NMR of the crude reaction mixture (> 96:4 dr), showing an excellent stereocontrol throughout the domino sequence. A screening of reaction conditions was carried out by decreasing the amount of the mineral base Cs₂CO₃ to 1 equivalent (entry 8, 36% of conversion in CH₂Cl₂). While the transformation was slowed down in a less polar solvent like toluene (30%, entry 10), better conversions were observed in THF and AcOEt (45% and 54%, entries 11-12). Eventually, the use of acetonitrile as solvent displayed a much faster reaction rate (entry 13), and a complete conversion was measured in only 1 hour using 1.2 equivalent of Cs₂CO₃ (entries 13-14). This constitutes an expeditious construction of a novel pyrano[2,3-c]pyrrole 3aa,

through a highly diastereoselective domino aza-VMAC reaction performed under very simple operational conditions (only a slight excess of Cs₂CO₃ was used). Then, the investigation of the scope of this original sequence was undertaken.

Thanks to the readily accessibility of α-ketoamides 2, we were able to probe the influence of its nature on the reaction in the presence of alkylidene MA 1a and Cs₂CO₃ (1.2 equivalent) in MeCN as solvent for 1 hour (Scheme 2A). The esterification of the crude acid 3 was carried out using Me₃SiCHN₂ to facilitate the purification by column chromatography and thus giving the corresponding methyl ester compound 4. The model α-ketoamide 2a furnished the corresponding pyrrolidinone methyl ester 4aa in an excellent 92% isolated yield, validating thereby the previously measured conversion into 3aa (see Table 1). Uneventfully, the reaction could be scaled up to 1 mmol while maintaining a high yield of 94%. The structure of compound 4aa and its relative configuration was unequivocally proven by X-ray analyses. The reaction rate was much slower with the α-ketoamide 2b having an N-Et group, and hence a less acidic N-H bond, albeit a descent 73% yield was obtained for product 4ab in 16 hours of reaction and an excess of base (2 equiv. of Cs₂CO₃). The precursors 2c-d with a N-alkoxyamide moiety proved to be competent nucleophiles for the domino aza-VMAC reaction, affording the corresponding products 4ac (R³ = OCH₂CH=CH₂) and 4ad (R³ = OBn) in 81% and 74% yields, respectively. However, the starting material 2e with a primary amide functional group showed no reactivity towards the Michael acceptor 1a. Nonetheless, a facile and chemoselective molybdenum N-O bond cleavage was carried out to transform compound 4ad into the N-H product 4ae in 76% yield. Interestingly, the ketone part of the α-ketoamides 2f-h could also be varied and we were delighted to observe that an aryl moiety with an electron-donating (4af, R = OMe, 93%) or electron-withdrawing group (4ag-4ah, R = CF₃, Cl, 88-93%) at the *para*-position did not impact the reactivity. Moreover, other nucleophiles 2i-j, with a thiophene or a 2-naphthyl pendant, also furnished the corresponding products 4ai-4aj in excellent yields (75 and 89%, respectively, Scheme 2B).

<footnote><sup>a</sup>Reaction performed at 0.04 M on 0.07 mmol scale (versus 1) with 1.2 equiv. of acetamide 2 and a base, followed by an acidic work-up before extraction and analysis of the crude reaction mixture. <sup>b</sup>Conversion (1 versus 3) determined on the crude product by an ¹H NMR after an acidic work-up.</footnote>
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<figure><img src="image_6.png" /><figcaption>**Scheme 2** Scope and limitations. <sup>a</sup>Reaction conditions: reaction performed at 0.04-0.09 M on 0.06-0.08 mmol scale (versus 1) with 1.2 equiv. of α-ketoamides 2 and 1.2 equiv. of Cs₂CO₃, followed by an acidic work-up; the isolated product after extraction was treated with Me₃CHN₂ in PhMe/MeOH mixture. Isolated yield after purification by column chromatography. Note: the first letter of compounds 4 corresponds to the letter of alkylidene Meldrum's acids 1 and the second letter corresponds to the letter of α-ketoamides 2. <sup>b</sup>Outcome with Cs₂CO₃ (1.2 equiv.) gave respectively 14% conversion in 1 hour and 60% conversion in 16 hours, but an improved 73% yield was obtained using Cs₂CO₃ (2 equiv.) in 16 hours. <sup>c</sup>Structure 4aa (CCDC2328277) was ascertained by X-ray analyses.</figcaption></figure>

Then, we studied the substitution pattern of the alkylidene MA **1** using the *N*-Ph α-ketoamide **2a** as the model nucleophile (Scheme 2C, R³,⁴ = Ph). Various *para*-substituted aryl groups were tolerated as a R¹ substituent, affording the corresponding products **4ba-4ea** with yields ranging from 53 to 85%. The strong electron-withdrawing NO₂ group might have a slight impact on the reactivity considering the partial conversion of 82% into intermediate **3ea** after one hour of reaction (*vide infra*), although the lower yield of 53% after esterification to **4ea** is essentially explained by purification issues. Interestingly, the more hindered *ortho*-substituted tolyl moiety afforded product **4fa** in a lower 69% yield. Worth to point out that all the reactions thus far gave products **4** in high diastereoselectivities (>96:4), with respect to the ¹H NMR of the crude product. Only compound **4fa** appeared with two sets of signals in a ratio of 80:20 after esterification (50:50 before esterification). We believe that the rotation around the C4-R¹ bond of **4fa** is hindered enough to reveal a chiral axis, which gave a diastereoisomeric ratio at room temperature. As long as R² pendants on the alkylidene MA **1g-k** are concerned, *para*-substituted aryl moieties with electron-donating or electron-withdrawing functional groups led to the corresponding pyrazolidiones **4ga-4ia** with 62-75% yields (Scheme 2D). *Meta*- (from **1j**) and *ortho*-substituted aryl (from **1k**) groups were also nicely tolerated, affording products **4ja** and **4ka** in 84 and 77% yields, respectively. Interestingly, no clear stereoisomers were observed in the latter case with an *ortho*-substituted aryl group at this position but broad signal might account for the existence of rotamers with a rather rapid interconversion. Eventually, a product mixing an electron-rich aryl group like R¹ and a furan

heterocycle like R² was easily synthesized in 75% yield (4la, Scheme 2E). At that stage, under these Cs₂CO₃ promoted conditions, alkylidenes MA **1m** and **1n**, having an alkyl group like R¹ (Me, *iso*-propyl), led to extensive decompositions in our hands (Scheme 2F). Although we cannot rule out a competitive deprotonation of the methyl group by the carbonate base,⁷ this outcome tends to show the required stabilization by an aromatic group at this position (R¹). This was reinforced by a similar decomposition event observed by means of the unsubstituted derivative **4oa** (R¹ = H), which might lead also to a competitive 1,4-addition event.

Taking into account the stereoselective outcome of the domino aza-VMAC reaction, we propose the mechanistic pathway depicted in Scheme 3. After deprotonation of α-ketoamide **2** by Cs₂CO₃, the corresponding cesium amide ions pair **5** would add, in a vinylogous fashion, to the presumed more stable *s-trans* to alkylidene MA **1**. The resulting aza-Michael adduct **6** would undergo a vinylogous aldol reaction giving rise to the formation of alkoxide **7** and triggering a cyclocondensation to the proximal carbonyl group to furnish the cesium carboxylate **8** after releasing a molecule of acetone. The corresponding acid product **3** is then isolated after a simple acidic work-up. Two important features were noteworthy during the achievement of the domino aza-VMAC reaction. First of all, the key role of cesium carbonate, which might generate a more soluble and nucleophilic amide ion pair **5**, facilitating the initial C-N bond forming process. This enhanced reactivity could also favour the subsequent C-C and C-O bonds formation (**6** to **7** to **8**) through less tight ion pairing events. Next, the excellent diastereoselective outcome obtained throughout the scope of
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this domino sequence is remarkable. One can imagine that the R¹ substituent of the ketone moiety of 6 is located at the less hindered position, a conformation favored by a chelation with cesium cation and which prevents a clash with R². But we assume that, after the vinylogous aldol reaction, this conformation ideally orientates the alkoxide group of intermediate 7 in order to allow the addition to the proximal carbonyl function. Then, the loss of acetone (fragmentation) prevents the potential equilibration of compound 7 back to starting materials 1 and 2.

<figure><img src="image_7.png" /><figcaption>Scheme 3 Proposed mechanism of the domino aza-VMAC reaction.</figcaption></figure>

In summary, we reported a novel exploitation of vinylogous alkylidene Meldrum's acids **1** as platform molecules to be engaged into a domino aza-VMAC reaction affording a new entry to pyrano[2,3-c]pyrrole derivatives, encompassing the control of three contiguous stereocenters in an excellent diastereoselectivity. The extension of this expeditious domino strategy with two vinylogous steps to the construction of other medicinally important heterocycles, especially in an asymmetric version, is currently under investigation in our laboratory.<sup>11,12</sup>

## Acknowledgement

This work was partially supported by University of Rouen Normandy, INSA Rouen Normandy, the Centre National de la Recherche Scientifique (CNRS), European Regional Development Fund (ERDF), Labex SynOrg (ANR-11-LABX-0029), Carnot Institute I2C, the graduate school for research XL-Chem (ANR-18-EURE-0020 XL CHEM) and by region Normandie. We warmly thank Morgane Sanselme for X-ray analyses.

## Conflicts of interest

There are no conflicts to declare.

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3. (a) F. Lovering, J. Bikker and C. Humblet, *J. Med. Chem.*, **2009**, *52*, 6752-6756; (b) F. Lovering, *MedChemComm*, **2013**, *4*, 515-519.

4. (a) S. Chen, L. Wu, Q. Shao, G. Yang and W. Zhang, *Chem. Commun.*, **2018**, *54*, 2522-2525; (b) X.-Y. Chen, Q. Liu, P. Chauhan, S. Li, A. Peuronen, K. Rissanen, E. Jafari and D. Enders, *Angew. Chem. Int. Ed.*, **2017**, *56*, 6241-6245; (c) E. Fillion, A. Wilsily and E. T. Liao, *Tetrahedron: Asymmetry*, **2006**, *17*, 2957-2959; (d) C. Ma, Z.-J. Jia, J.-X. Liu, Q.-Q. Zhou, L. Dong and Y.-C. Chen, *Angew. Chem. Int. Ed.*, **2013**, *52*, 948-951.

5. (a) For reviews on Meldrum's acid chemistry, see: A. M. Dumas and E. Fillion, *Acc. Chem. Res.*, **2010**, *43*, 440-454; (b) E. Pair, T. Cadart, V. Levacher and J. F. Brière, *ChemCatChem*, **2016**, *8*, 1882-1890; (c) F. Brosge, P. Singh, F. Almqvist and C. Bolm, *Org. Biomol. Chem.*, **2021**, *19*, 5014-5027.

6. P. Milbeo, A. Lebrêne, M. Savchuk, G. Vo-Thanh, S. Oudeyer, H. Beucher and J.-F. Brière, *Chem. Eur. J.*, **2023**, *29*, e202301311.

7. (a) M. Toffano, R. Guillot, C. Bournaud, J. F. Brière and G. Vo-Thanh, *Adv. Synth. Catal.*, **2021**, *363*, 4452-4458; (b) S. Wittmann, T. Martzel, C.-T. Pham truong, M. Toffano, S. Oudeyer, R. Guillot, C. Bournaud, V. Gandon, J.-F. Brière and G. Vo-Thanh, *Angew. Chem. Int. Ed.*, **2021**, *60*, 11110-11114.

8. (a) Y. Hussain, Tamanna, M. Sharma, A. Kumar and P. Chauhan, *Org. Chem. Front.*, **2022**, *9*, 572-592; (b) P. Chauhan, U. Kaya and D. Enders, *Adv. Synth. Catal.*, **2017**, *359*, 888-912; (c) A. T. Biju, *ChemCatChem*, **2011**, *3*, 1847-1849; (d) M. J. Lear and Y. Hayashi, *ChemCatChem*, **2013**, *5*, 3499-3501; (e) A. G. Csákÿ, G. d. I. Herrán and M. C. Murcia, *Chem. Soc. Rev.*, **2010**, *39*, 4080-4102.

9. Y.-X. Song and D.-M. Du, *Adv. Synth. Catal.*, **2021**, *363*, 4667-4694.

10. (a) Representative examples making use of α-ketoamides involved into an aza-Michael-aldol sequence towards hydroxy-pyrrolidinones, see: Y.-f. Zhu and C. Cai, *New J. Chem.*, **2015**, *39*, 5104-5107; (b) C. Joie, K. Deckers and D. Enders, *Synthesis*, **2014**, *46*, 799-808.

11. A preliminary screening of chiral ammonium salts (CH₂Cl₂, Cs₂CO₃) in PTC conditions with compounds Meldrum's acid derivative **1a** and ketoamides **2a** or **2c**, led to the corresponding product in 16% ee with the Waser's catalyst (see reference 12).

12. J. Novacek and M. Waser, *Eur. J. Org. Chem.*, **2014**, 802-809.
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