Palladium Catalyzed Domino Sonogashira Coupling of 2-Chloro-3-(Chloromethyl)Quinolines with Terminal Acetylenes Followed by Dimerization

Abstract A domino Sonogashira coupling of 2-chloro-3-(chloromethyl)quinolines and terminal acetylenes and then dimerization is described. This palladium-catalyzed reaction gave novel dimer quinolinium salts in good to high yield. Based on empirical evidence, a plausible mechanism was provided. The produced quinolinium salt are amenable to further synthetic elaborations such as reactions with phenoxide and thiophenoxide to yield the corresponding ether and thioether.

Choosing a versatile starting material can provide access for the synthesis of various useful molecules. During the past two decades 2-chloroquinoline-3-carboxaldehydes have gained more attraction as starting material to synthetic chemists to construct the diverse quinoline-based molecules. 14 In our further research on quinolines chemistry, 15 herein we wish to report palladium catalyzed Sonogashira reaction followed by a subsequent dimerization of 2-chloro-3-(chloromethyl)quinolines 1.

Results and discussion
We prepared 2-chloro-3-(chloromethyl)-quinolines 1 as starting material from acetanilides with different substituents as outlined in Scheme 1. 16 A series of experiments were performed with 2-chloro-3-(chloromethyl)-8-methylquinoline 1a and phenylacetylene 2a as the model reaction. Pleasingly, this reaction in the presence of PdCl 2 , PPh 3 and TEA in toluene, gave 3a instead of the expected simple Sonogashira coupling product 3'a (Scheme 2).
The proposed mechanism for the reaction is shown in Scheme 4. The general mechanism starts from the in-situ generation of the Pd(0) complex with PPh 3, followed by the oxidative addition of the Ar-Cl bond of the quinoline heterocycle to form I. Addition of terminal acetylene to intermediate I assisted by Et 3 N generated the complex II which, by reductive elimination, led to compound III. Finally, dimerization of III via nucleophilic substitution of nitrogen of one molecule to Csp 3 -Cl of another one formed the salt 3 (Scheme 4).
With regards to investigating the mechanism described above, reactions in Scheme 5 were performed. Treatment of 2-chloro-3-chloromethylquinoline with Et 3 N in refluxing CH 3 CN did not yield product even after 24 h (Scheme 5). This may be due to the existence of an electron withdrawing Cl in the 2 position of quinoline which reduced activation of nitrogen toward nucleophilic substitution. In addition, 3-(chloromethyl)-2-(phenylethynyl)quinoline (B), which has alkyne as electron releasing group, in the presence of Et 3 N tended to dimerize to 4d. Notably increasing the temperature to reflux converted B to unidentified polymer.

Conclusions
In summary, because of the importance of quinoline core and the ability of 2-chloro-3-(chloromethyl)quinolines to expand into more complex compounds, the primary materials of 1 were subject of reaction with terminal alkynes in a Sonogashira reaction. Surprisingly, in addition to the Sonogashira coupling, the corresponding adducts were dimerized in-situ to afford novel attractive molecules 3. Interestingly, the product 3b reacted efficiently with phenoxide and thiophenoxide to yield the corresponding ether and thioether respectively.

Funding
We are thankful to Alzahra University and the Iran National Science Foundation (INSF) for the financial support.