# Convenient synthesis of substituted thiazolo [4,5-b] quinolines

Elodie Cortelazzo-Polisini, Michel Boisbrun, Axel Gansmuller, Corinne Comoy

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Elodie Cortelazzo-Polisini, Michel Boisbrun, Axel Gansmuller, Corinne Comoy. Convenient synthesis of substituted thiazolo [4,5-b] quinolines. BOSS XVII 17th Belgian Organic Synthesis Symposium, Jul 2022, Namur, Belgium. . hal-03975258

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Submitted on 6 Feb 2023

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<figure><img src="image_1.png" /></figure>

Distributed under a Creative Commons Attribution 4.0 International License
# CONVENIENT SYNTHESIS OF SUBSTITUTED THIAZOLO[4,5-b]QUINOLINES

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

Cortelazzo-Polisini, E.;<sup>a</sup> Boisbrun, M.;<sup>a</sup> Gansmüller, A. H.;<sup>b</sup> Comoy, C.<sup>a</sup>

## Introduction

Quinoline structure are interesting as they are present in a large variety of biologically active compounds,¹ thus their synthesis have received a large attention. Many methods are employed to prepare these moieties but they often need hard conditions.²,³,⁴ In this work, we focused our attention on a short and efficient synthesis of fused quinolines. We envisioned two strategies:

* one with classical conditions,

* a more original one, based on photo-induction.

<figure><img src="image_3.png" /><figcaption>Strategies for the preparation of fused quinolines.</figcaption></figure>

## Preparation of o-aminobenzylidene scaffold

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

<figure><img src="image_5.png" /><figcaption>DRX structure of 1
CCDC: 2151344.</figcaption></figure>

* Easy and fast synthesis.

* Good overall yield (59%).

* Only pure isomer (Z) is obtained.

## Extension of the sequence to various aminobenzylidenes

<figure><img src="image_6.png" /></figure>

*Obtained from 1 by Wittig condensation with Ph₃P in MeOH for 2h then reduction.

## Classical way

The preparation of quinoline 4 depends on the isomerization of the double bond.

<figure><img src="image_7.png" /><figcaption>Conditions for preparation of quinoline 4.</figcaption></figure>

<table><thead><tr><th>Starting material</th><th>Solvent</th><th>T (°C)</th><th>time</th><th>Reagents</th><th>Results</th></tr></thead><tbody><tr><td rowspan="2">(Z)-3</td><td>Acetone</td><td>r.t.</td><td>2 h to 48 h</td><td>none</td><td>Traces of 4</td></tr><tr><td>Acetone</td><td>r.t.</td><td>2 months</td><td>none</td><td>80% of 4</td></tr><tr><td rowspan="4"></td><td>Acetone</td><td>reflux</td><td>2 h to 24 h</td><td>none</td><td>degradation</td></tr><tr><td>Toluene</td><td>reflux</td><td>3 h to 24 h</td><td>APTS (0.1 eq)</td><td>s.m.<sup>c</sup></td></tr><tr><td>EtOH</td><td>180°C<sup>a</sup></td><td>3 h</td><td>none</td><td>degradation</td></tr><tr><td>EtOH</td><td>150°C<sup>a</sup></td><td>3 h</td><td>none</td><td>degradation</td></tr><tr><td rowspan="3"></td><td>EtOH</td><td>120°C<sup>a</sup></td><td>3 h</td><td>none</td><td>degradation</td></tr><tr><td>EtOH</td><td>reflux<sup>b</sup></td><td>8 h</td><td>SnCl<sub>2</sub> (5.0 eq)</td><td>3 (90%), 4 (10%)<sup>d</sup></td></tr><tr><td>EtOH</td><td>reflux</td><td>8 h</td><td>SnCl<sub>2</sub> (20.0 eq)</td><td>3 (90%), 4 (10%)<sup>d</sup></td></tr><tr><td></td><td>EtOH</td><td>120°C<sup>a</sup></td><td>3 h</td><td>SnCl<sub>2</sub> (5.0 eq)</td><td>degradation</td></tr></tbody></table>

<sup>a</sup>Thermal reactions were run in sealed vessel. <sup>b</sup>Under microwaves. <sup>c</sup>s.m. Starting material. <sup>d</sup>Yield estimated by ¹H NMR.

Acid activation X High pressure X Microwaves X Long time agitation ✓

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

Light
activation ?

<figure><img src="image_9.png" /></figure>

## Photochemistry way

The nucleophilic attack of the amine moiety on a carbonyl group depends on the double bond configuration: an inversion is necessary to obtain the fused quinoline. As a consequence of the latter results (acetone, r.t., 2 months), we investigated the photo-induced isomerization of the double bond with light.⁵,⁶,⁷

<figure><img src="image_10.png" /></figure>

<figure><img src="image_11.png" /></figure>

<figure><img src="image_12.png" /></figure>

<figure><img src="image_13.png" /></figure>

<figure><img src="image_14.png" /><figcaption>Solutions of amine 3 and quinoline 4 in EtOH</figcaption></figure>

<figure><img src="image_15.png" /><figcaption>DRX structure of quinoline 4'
CCDC: 2151345.</figcaption></figure>

<figure><img src="image_16.png" /><figcaption>a) UV-visible spectra of amine 3 and quinoline 4 in EtOH; b) kinetic study of amine 3 consumption under irradiation at 405 nm.</figcaption></figure>

→ Product 4 was prepared after a 48h irradiation at 405 nm in an excellent 84% yield (overall yield 49%).

→ Extension of the photoinduced cyclization sequence afforded various fused azaheterocycles in 48 to 77% yields.

## Exemplification

Various fused azaheterocycles were obtained by photoinduction.

<figure><img src="image_17.png" /></figure>

Overall yield : 33%*

<figure><img src="image_18.png" /></figure>

Overall yield : 39%*

<figure><img src="image_19.png" /></figure>

Overall yield : 18%*

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

Overall yield : 30%*

*Overall yield calculated for 3 steps.

## Conclusion

We succeed in preparing various fused quinolines with a 3-steps synthesis in **18 to 49 %** overall yields. The first two steps were fast and effective as we obtained amines **3** as pure products in very good yields (**23 to 62 %**). The third step consisted in a photo-induced isomerization followed by a subsequent cyclization. This method is convenient, clean and really effective compared to classical ways.⁸

## References

[1] Weyesa, A.; Mulugeta, E., RSC Adv. **2010**, *10*, 20784–20793. [2] Mekheimer, R.A.; Al-Sheikh, M. A.; Medrasi, H. Y.; Sadek, K. U., RSC Adv. **2020**, *10*, 19867-19935. [3] Ramann, G. A.; Cowen, B. J., Molecules, **2016**, *21*, 986. [4] Kouznetsov, V. V.; Vargas Méndez, L. Y.; MeléndezGómez, C. M., Curr. Org. Chem. **2005**, *9*, 141-161. [5] Momose, Y.; Meguro, K.; Ikeda, H.; Hatanaka, C.; Oi, S.; Sohda, T., Chem. Pharm. Bull. **1991**, *39*, 1440–1445. [6] Murata, M.; Zheng, H.; Chen, L.; Li, R.; He, C.; Yang, S.; Ye, X.; Chen, Z.; Li, Z.; Gao, Y.; Han J.; He, G.; Yang, L.; Wei, Y., J. Med. Chem. **1999**, *34*, 1061-1070. [7] Chen, X.; Qiu, S.; Wang, S.; Wang, H.; Zhai, H., Org. Biomol. Chem. **2017**, *15*, 6349-6352. [8] Cortelazzo-Polisini, E.; Boisbrun, M.; Gansmüller, A. H.; Comoy, C. J. Org. Chem, **2022**, submitted.

<footnote><sup>a</sup>Université de Lorraine, CNRS, L2CM, F-54000 Nancy, France</footnote>

<footnote><sup>b</sup>Université de Lorraine, CNRS, CRM2, F-54000 Nancy, France</footnote>