# Iron-catalyzed synthesis of substituted 3-arylquinolin-2(1 H )-ones via an intramolecular dehydrogenative coupling of amido-alcohols

Léo Bettoni, Nicolas Joly, Inès Mendas, Matteo Maria Moscogiuri, Jean-François Lohier, Sylvain Gaillard, Albert Poater, Jean-Luc Renaud

► To cite this version:

Léo Bettoni, Nicolas Joly, Inès Mendas, Matteo Maria Moscogiuri, Jean-François Lohier, et al. Iron-catalyzed synthesis of substituted 3-arylquinolin-2(1 H )-ones via an intramolecular dehydrogenative coupling of amido-alcohols. Organic & Biomolecular Chemistry, 2024, 22 (34), pp.6933-6940. 10.1039/d4ob00649f. hal-05426358

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# Iron-Catalyzed Synthesis of Substituted 3-Arylquinolin-2(1H)-ones *via* an Intramolecular Dehydrogenative Coupling of Amido-Alcohols.

Léo Bettoni,ª Nicolas Joly,ª,b Inès Mendas,ª Matteo Maria Moscogiuri,ª Jean-François Lohier,ª Sylvain Gaillard,ª Albert Poaterb* and Jean-Luc Renaudª,a,c*

In this work, we report an iron complex-catalyzed the synthesis of various mono- and di-substituted quinolin-2(1H)-ones *via* the intramolecular acceptorless dehydrogenative cyclization of amido-alcohols. This approach for the synthesis of *N*-heterocycles opens an access to underdescribed disubstituted quinolinones and represents an alternative to the well-known palladium-catalyzed coupling reactions.

## INTRODUCTION

*N*-heterocycle structures are often present not only in natural products but also in pharmaceutical relevant derivatives,¹ or material science. As examples, bioactivities, such as antibiotics,² antitumor³ or antiplatelet⁴ activities, have been reported in the literature. Therefore, their synthesis has been the subject of intense researches. Among the nitrogen containing heterocycles belonging to these relevant family of compounds, 2-quinolinones have a pivotal role.⁵ Thus, as examples, (3)-*O*-Methylviridicatin is an anti-inflammatory and HIV inhibiting agent,⁶ª Brexipiprazole⁶b is employed as antidepressant drug (Figure 1A). Some other representative members of this family of biologically quinolinone based compounds are showed in Figure 1. Finally, six members in this class of 2-quinolinones have been also commercialized (Figure 1B). Besides biological relevant structures, pharmaceutical applications, the 2-quinolinone motive can also be found in functional organic materials, such as metal-sensors,⁷⁻⁸ luminescent materials,⁹ fluorescent pH probes,⁷ª and p-acceptor subunit in dye-sensitized solar cells,¹⁰ or even photosensitizers for application in visible light catalysis (Figure 1C).¹⁰

Various procedures have been already reported for the synthesis of quinolin-2(1H)-one derivatives and were originally based on (i) Vilsmeier-Haack or Friedlander type reactions,¹¹⁻¹² (ii) Knorr type reactions or (iv) Friedel-Craft reactions.¹³⁻¹⁵ More recently, Heck reactions, cross-coupling followed by a cyclization or Larock carbonylative cyclizations of alkynes,¹⁶ C-H functionalization and visible-light catalysis have opened new perspectives for the preparation of these important structures (Scheme 1). To highlight these recent methodologies, Manley and Ding developed a synthesis of 4-substituted and 3,4-disubstituted quinolinones from 2-halo-benzocarbonyl compounds and 2-arylacetamides through either palladium¹⁷ª or copper-catalysis.¹⁷b Liu *et al*. reported a palladium-catalyzed C-H functionalization to access 2-quinolinones and 4-substituted 2-quinolinones from anilines derivatives and acrylates in acidic medium or in the presence a large excess of oxidant and acetic anhydride.¹⁸ A palladium-catalyzed an oxidative CH-functionalisation/cyclisation of acrylamides with benzyne precursors has been successfully developed by Xu and coll.,¹⁹ opening an access to some 3-substituted or 3,4-disubstituted quinolinones. A ruthenium-catalyzed C-H functionalization of anilides with substitutes acrylates or propiolates in the presence of silver salts, and copper acetate as oxidant or pivalic acid furnished 4 substituted-2-quinolinones (Scheme 1).²⁰

Another approach toward the synthesis of heterocycle compounds is the acceptorless dehydrogenative coupling (ADC) methodology catalyzed by transition metal-based complexes (including Earth-abundant ones).²¹ This emerging area allowed the synthesis of a variety of nitrogen containing cycles, such as pyrroles, pyrimidines, quinolines, quinazolines, or quinoxalines...²¹ Compared to more classical protocols, which involve typically protection/deprotection steps, the ADC reactions appear more attractive, more effective and greener. The one-pot multistep sequence begins with a metal-based catalyzed dehydrogenation of an alcohol, the pro-electrophile, and generates a carbonyl intermediate and a metal-hydride compound. Then, the condensation of a *N*-nucleophile followed by a cyclization delivers the targeted *N*-heterocycle and liberate hydrogen and water as side-products. Its simple implementation and the environmentally acceptable side-products make this methodology attractive in organic synthesis. Recently, Cabrero-Antonino has reported a
heterogeneous silver-catalyzed the synthesis of a few numbers of 3-aryl quinolinone derivatives.²¹f However, to date, no Earth-abundant metal based-complexes catalyzed ADC approach has been developed for the synthesis of quinoline-2(1H)-one products.

<figure><img src="image_2.png" /><figcaption>Figure 1B: Drug Market</figcaption></figure>

<figure><img src="image_3.png" /><figcaption>Figure 1C: Functional Organic Material</figcaption></figure>

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

**Figure 1:** Some representative molecules containing quinolinone motif.
<figure><img src="image_5.png" /><figcaption>**Scheme 1.** Recent metal-catalyzed syntheses of quinolin-2(1H)-ones.</figcaption></figure>

Our group initiated a research program in the area of the borrowing hydrogen strategy catalyzed by cyclopentadienone iron- or ruthenium-tricarbonyl complexes, including the alkylation of ketones,²² indoles,²³ alcohols,²⁴ nitrogen derivatives,²⁵ tandem or cascade multicomponent reactions.²⁶ Based on these previous results, we hypothesized that these complexes could be applied in the synthesis of quinolinones and open new routes to functionalized heterocycles. In this work, we report the first phosphine-free iron catalyzed quinolinone derivatives synthesis *via* an ADC methodology in mild reaction conditions (Scheme 2).

<figure><img src="image_6.png" /><figcaption>**Scheme 2.** Outline of the Ru- or Fe-catalyzed synthesis of quinolin-2(1H)-ones.</figcaption></figure>

## RESULTS AND DISCUSSION

### Optimisation of the ADC reaction conditions

To initiate this study and validate our approach, compound **1a** was chosen as a model substrate. Following our work on the mono-, dialkylation and tandem multicomponent alkylation of acyl hydrazide derivatives using alcohols as pro-electrophiles,²⁵,²⁶ the preliminary catalytic reactions were attempted in the presence of the cyclopentadienone ruthenium tricarbonyl complex **Ru1**, initially developed by Haak (Table 1).²⁷ In basic conditions (2 equiv. of *t*-BuONa), the ADC reaction was tested in different solvent. **2a** was only obtained in MeOH and DMF (28 %, and 38 %
conversion, respectively, see S.I.), while a complex mixture was obtained in toluene and only 2-methyl quinoline and 2-aminobenzyl alcohol were isolated in 56 and 44 % yield, respectively, in acetone. Then various bases were also evaluated in DMF and, while alkoxide bases led to **2a** along with C-N amide bond cleavage compounds, carbonate bases provided the highest conversions (see S.I.).

<table><caption>**Table 1.** Optimization of the reaction conditions.ª</caption><thead><tr><th>entry</th><th>Ru or Fe</th><th>base (equiv.)</th><th>solvent</th><th>Temp</th><th>1a/2a<sup>b</sup></th></tr></thead><tbody><tr><td>1</td><td><b>Ru1</b></td><td>Na<sub>2</sub>CO<sub>3</sub> (1)</td><td>DMF</td><td>90</td><td>-/96</td></tr><tr><td>2</td><td><b>Fe1</b></td><td>Na<sub>2</sub>CO<sub>3</sub> (1)</td><td>DMF</td><td>90</td><td>65/35</td></tr><tr><td>3</td><td><b>Fe2</b></td><td>Na<sub>2</sub>CO<sub>3</sub> (1)</td><td>DMF</td><td>90</td><td>72/28</td></tr><tr><td>4</td><td><b>Fe3</b></td><td>Na<sub>2</sub>CO<sub>3</sub> (1)</td><td>DMF</td><td>90</td><td>22/78</td></tr><tr><td>5</td><td><b>Fe4</b></td><td>Na<sub>2</sub>CO<sub>3</sub> (1)</td><td>DMF</td><td>90</td><td>41/59</td></tr><tr><td>6</td><td><b>Fe3</b></td><td>Na<sub>2</sub>CO<sub>3</sub> (1)</td><td>DMF</td><td>100</td><td>14/86</td></tr><tr><td>7</td><td><b>Fe3</b></td><td>Na<sub>2</sub>CO<sub>3</sub> (1)</td><td>DMF</td><td>110</td><td>-/77 (48)<sup>c</sup></td></tr><tr><td><b>8</b></td><td><b>Fe3</b></td><td><b>Na<sub>2</sub>CO<sub>3</sub> (2)</b></td><td><b>DMF</b></td><td><b>100</b></td><td><b>8/92 (78)<sup>c</sup></b></td></tr><tr><td>9</td><td><b>Fe3</b></td><td>Na<sub>2</sub>CO<sub>3</sub> (2)</td><td>DMF</td><td>100</td><td>83/17</td></tr><tr><td>10</td><td><b>Fe3</b></td><td>K<sub>2</sub>CO<sub>3</sub> (2)</td><td>DMF</td><td>100</td><td>26/74</td></tr><tr><td>11</td><td><b>Fe3</b></td><td>Cs<sub>2</sub>CO<sub>3</sub> (2)</td><td>DMF</td><td>100</td><td>28/72</td></tr><tr><td>12</td><td><b>Fe3</b></td><td>NaHCO<sub>3</sub> (2)</td><td>DMF</td><td>100</td><td>63/37</td></tr><tr><td>13</td><td><b>Fe3</b></td><td>NaOH (2)</td><td>DMF</td><td>100</td><td>-/25</td></tr></tbody><tfoot><tr><td colspan="6"><sup>a</sup>General Conditions: Amido-alcohol **1a** (0.5 mmol), **Ru** or **Fe** (2 mol %), **Me<sub>3</sub>NO** (4 mol %), base (x equiv.), solvent (1 M) for 24 h (**Ru**) or 40 h (**Fe**). <sup>b</sup>Conversions and selectivities **1a/2a** were determined by <sup>1</sup>H-NMR analysis of the crude mixture. <sup>c</sup>Isolated yield in brackets.</td></tr></tfoot></table>

Finally, a combination of 1 mol % of **Ru1**, 2 mol % of **Me<sub>3</sub>NO**, 2 equiv. of **Na<sub>2</sub>CO<sub>3</sub>** and 1 equiv. of **1a** in DMF at 100 °C provided the 3-phenylquinolin-2(1H)-one **2a** with the highest NMR conversion (96 %, entry 1, Table 1). While these preliminary results were encouraging for the synthesis of substituted quinolinones *via* an ADC methodology, we thought to develop a more competitive and attractive procedure. Toward this objective, we introduced the iron congener **Fe1-Fe4** in this reaction. Gratifyingly, **Fe1** catalyzed the synthesis of **2a** from **1a**, albeit with a moderate conversion at 90 °C in DMF in the presence of 1 equivalent of sodium carbonate (35 %). Previous works from our group emphasized that the nature of the cyclopentadienone ligand could play an important role in the catalytic activities.²⁸ Consequently, complexes **Fe3** and **Fe4** were evaluated in the same conditions and, to our delight, the quinolinone **2a** was obtained in 78 and 59 % conversion, respectively (Table 1). The higher activity might be explained by a better ability to release hydrogen with **Fe3** than with **Fe1**. This conversion was increased by using 2 equivalent of sodium carbonate at 100 °C in DMF. In these conditions, **2a** was isolated in 78 % yield and 92 % conversion. Other solvents and other bases led to no or lower conversions, as observed also with **Ru1**. These results highlighted again that the cyclopentadienone iron complexes can now compete with platinum-type complexes.

## Synthesis of the 2-amido-benzylalcohols 1

To delineate the scope of the ADC reaction, we have aimed to prepare three libraries of 2-amido-benzyl alcohols having either substituents on the aromatic ring A, on the aromatic C or a secondary benzylic alcohol (Schemes 2-3).
Regarding the first library (variation of the substituent on the C ring), amido-alcohols **1a-l** were synthesized in two steps from 2-arylacetic acids (Scheme 3A). Addition of 2-aminobenzyl alcohol or 2-(methylamino)benzyl alcohol to the acyl chloride led to the corresponding amido-alcohols **1a-l** in 37-91 % yield (Scheme 3A).²⁹

The second small library is based on the introduction of substituent on the ring A, corresponding to the initial 2-amino benzyl alcohol moiety. Protection of a substituted aniline with pivaloyl chloride, followed by an ortho-formylation, provided the corresponding 2-amido benzaldehydes.³⁰ A reduction and a saponification reaction furnished the substituted 2-amino-benzyl alcohols. Finally, compounds **1m-o** were isolated after an amidation reaction in 26 to 35 % overall yields (Scheme 3B). Compound **1p** was synthesized in two steps from commercially available anthranilic acid in 77 % yield (Scheme 3B).

The third portfolio focussed on the synthesis of secondary 2-acetamido benzylic alcohols (Scheme 3C). Addition of a substituted aryl Grignard reagent to the 2-nitrobenzaldehyde, followed by the reduction of the nitro function by an excess of NaBH₄ in the presence of NiCl₂ in ethanol and the amide formation, furnished the amide **1q-s** in 47 to 55 % overall yields (Scheme 3C). Compound **1t** was prepared in 71 % from the commercially available 2-amino-acetophenone in two steps (Scheme 3C).
### 3A: modification of the ring C

<figure><img src="image_7.png" /></figure>

### 3B: modification of the ring A

<figure><img src="image_8.png" /></figure>

### 3C: synthesis of secondary alcohols

<figure><img src="image_9.png" /><figcaption>**Scheme 3:** Preparation of compounds 1a-1t</figcaption></figure>
<figure><img src="image_10.png" /><figcaption>**Scheme 4:** Scope and Limitation of the iron-catalyzed synthesis of substituted quinoline-2(1H)-ones.</figcaption></figure>
## Scope and Limitation of the ADC cyclization

Having in hands this library of differentially substituted amido-alcohols **1a-t**, the scope of this unprecedented iron-catalyzed dehydrogenative coupling was investigated (Scheme 4). Substituted 3-arylquinolin-2(1H)-ones **2a-1** were isolated in moderate to good yields (48-89 %, Scheme 4). Not surprisingly, electron-donating or electron-withdrawing substituent on the C ring (Scheme 2) did not modify the reactivity, whatever the ortho/para-position (Scheme 4). Free amine or *N*-methylated quinolinone **2a** and **2b** were prepared in quite similar yields in these conditions (78 vs. 89 %, Scheme 4), demonstrating that an amide anion may not be involved as key intermediate in such an acceptorless dehydrogenation cyclization. Introduction of a heterocycle as C-ring was feasible and the thiophene containing derivative **2l** was synthesized in 48 % yield (Scheme 4). To unambiguously establish the atom connectivity, single crystals were grown by slow evaporation of methanol. Suitable single crystals were obtained for **2a** and **2j** and subjected to X-ray diffraction. Thermal ellipsoid representation is shown in Scheme 4 and confirmed unambiguously the quinolinone structure. Worth to note, the phenyl substituent in position 3 of the quinolinone is not coplanar to the heterocycle. This non-coplanarity could be due to the presence of the oxygen in position 2 which blocks the free rotation of the phenyl ring. The same trend was observed with the modification of the A-ring (Scheme 2). Namely, whatever the nature of the substituent (electron-donating or withdrawing group) and its position on the ring, the chemical yields were not hampered and the 3-phenylquinolin-2(1H)-ones **2m-p** were prepared in 56-71 % yields (Scheme 4). In a last stage, the synthesis of some less reported 3,4-disubstituted quinolinone derivatives was assessed, starting from secondary amido-alcohols **1q-t** (Scheme 4). Gratifyingly, compounds **2q-t** were afforded in good yields (58-79 %, Scheme 6). The yield decreases with an aliphatic substituent in position 4 (**2t**, 58 %, Scheme 4). Aromatic or aliphatic substituent were introduced on position 4 without any dramatic change in the chemical yield, demonstrating the robustness of this methodology.

Based on these results and on previous works on the acceptorless dehydrogenative coupling and the borrowing hydrogen methodology, the following simplified mechanism, which has been initially studied by Density Functional Theory (DFT) calculations, could be proposed (Scheme 5). After a preliminary removal of a CO ligand in the presence of Me3NO, the unsaturated intermediate **I** could coordinate the *in-situ* generated amido-alkoxide to furnish the intermediate **II**, overcoming an energy barrier of 20.0 kcal/mol. Subsequently, in basic conditions, the dehydrogenation step was facilitated to yield the corresponding amido-benzaldehyde and liberate the hydrido-iron complex **III**, this step becoming nearly barrierless. The latter could react with sodium bicarbonate to release hydrogen and regenerate the 16-electron-deficient intermediate **I**. The regeneration of **I** from **IV** proceeds via two transition states, namely the deprotonation of the hydroxyl group of the cyclopentadienyl ring, followed by the molecular hydrogen release. These transition states required to overcome energy barriers of 25.2 and 11.5 kcal/mol, respectively, and are the first rate determining step (rds) of the whole reaction pathway,³² since it has an overall kinetic cost of 33.1 kcal/mol. A non-metal catalysed two-steps sequence, namely a barrierless aldolization followed by a dehydration releasing NaOH, led to the targeted 3-arylquinolin-2(1H)-one. However, the latter step incurs a relatively kinetic cost of 30.2 kcal/mol,³² becoming the rate determining step of the non-metal catalyzed reaction pathway. Indeed, the base exhibits a catalytic behaviour and significantly reduces the kinetic cost of these two steps by at least half.
<figure><img src="image_11.png" /><figcaption>**Scheme 5:** Proposed reaction mechanism with DFT calculations (relative Gibbs energies in kcal/mol for substrate 2a).</figcaption></figure>

## Conclusions

In conclusion, we have reported an original way to access quinolin-2(1H)-one derivatives using iron catalysis. This procedure relies on an intramolecular dehydrogenative coupling of amido-alcohols. Various amido-alcohols have been synthesized and applied in the acceptorless reaction conditions. The role of the base is revealed, emerging as the primary driving force behind the reaction. The corresponding 3- or 3,4-substituted quinolinones have been isolated in moderate to excellent yields (48-89 %). Compared to some others coupling reactions, this methodology allows the formation of a wide range of substituted 3-arylquinolin-2(1H)-ones bearing a variety of substituent in any position of the heterocycle. This work opens consequently an alternative route to the synthesis of substituted 3-arylquinolin-2(1H)-ones, a family of heterocycles which can be difficult to obtain.

## Experimental

### General Procedure Synthesis of 3-Arylquinolin-2(1H)-ones

In a 15 mL flame-dried Schlenk tube equipped with a stirring bar, the desired amido-alcohol (0.5 mmol, 1 equiv.), Me₃NO (2.22 mg, 0.02 mmol, 4 mol%), iron complex Fe3 (4.21 mg, 0.01 mmol, 2 mol %), and Na₂CO₃ (106 mg, 1 mmol, 2 equiv.) were added to a solution of dry DMF (0.5 mL) under an argon atmosphere. The mixture was then placed into a pre-heated oil bath and stirred at 100 °C for 40 h. The mixture was cooled down to room temperature, filtered over a pad of Celite with diethyl ether, and concentrated under reduced pressure. The conversion was determined by ¹H NMR spectroscopy and the residue was purified by flash chromatography on silica gel using dichloromethane/diethyl ether as the eluent to afford the desired product.

## Author Contributions

The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.

## Conflicts of interest

There are no conflicts to declare.

## Acknowledgements
We gratefully acknowledge financial support from the "Ministère de la Recherche et des Nouvelles Technologies", Normandie Université, University of Caen Normandie, CNRS, "Région Normandie", the LABEX SynOrg (ANR-11-LABEX-0029), and European Union (HORIZON-MSCA-2022-DN-01 Project: 101119574). A.P. is a Serra Húnter Fellow and thanks ICREA Academia prize 2019, the Spanish Ministerio de Ciencia e Innovación for project PID2021-127423NB-I00 and the Generalitat de Catalunya for project 2021SGR623.

## Notes and references

‡ Footnotes relating to the main text should appear here. These might include comments relevant not central to the matter under discussion, limited experimental and spectral data, and crystallographic data.

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