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DMSO AS A C1 BUILDING BLOCK IN THE CO(III)-CATALYZED SYNTHESIS OF QUINOLINES

Quinolines are common structural units in pharmaceuticals and other biologically-active compounds.

Therefore, there are numerous named reactions to construct this motif (e.g., Skraup, Pfitzinger, etc.). As many of these reactions require harsh conditions and/or unusual starting materials, efforts have been made to develop milder methods using readily available starting materials with broader substrate scope. Recently Yi, et al., reported a Co(III)-catalyzed procedure in DMSO to synthesize functionalized quinolines.1 This method advantageously uses the earth-abundant and inexpensive first row transition metal cobalt as a catalyst instead of the more commonly used second row transition metals. It also uses readily available starting materials and reagents.
The conditions for this synthesis were optimized using aniline and phenylacetylene. Once the optimized conditions were determined (equation in Table 1), the substrate scope was tested relative to substituents on the aniline (entries 1–19, Table 1), to substituents on the phenylacetylene (entries 20–35, Table 1), and to various terminal and internal alkynes (entries 36–46). As can be seen, all yields were good to excellent, and the method tolerated electron-withdrawing and electron-drawing substituents on both substrates as well as groups that could be sensitive to pH (i.e., amines and esters, entries 18, 19, 35, 44, and 71). The reaction also performed well when the acetylenic substrate contained various heterocycles (entries 36-43).

Table 1: Optimized Conditions and Substrate Scope

Mechanistic studies showed that DMSO serves as a one carbon synthon in the reaction as the use of DMSO-d6 results in a deuterium atom being located at the 2-position of the quinoline ring. With this knowledge, along with information from other mechanistic experiments, the authors proposed the mechanism shown in Scheme 1.

Scheme 1: Proposed Mechanism showing the role of DMSO as a C1 component

In this mechanism, the active catalyst is formed in situ by reaction of Cp*Co(CO)I2 with AgNTf2. Aniline then undergoes ortho metalation by the catalyst to form intermediate A, which then undergoes an insertion reaction with phenylacetylene to form intermediate B. Meanwhile, DMSO reacts with potassium persulfate to generate cation C, which undergoes nucleophilic attack by the amine to form intermediate D. Oxidation of intermediate D leads to the imine species E. Cobalt-carbon migratory insertion then results in intermediate F. Following protonolysis the product quinoline is formed, and the active cobalt catalyst is released.

This method by the Yi group shows the first example of a Co(III)/DMSO reaction using anilines and alkynes to form a variety of substituted quinolines. The method affords high yields with inexpensive and easily available starting materials. It also is mild, tolerating a wide array of functional groups. These attributes make this an attractive method to synthesize quinolines.

Debra D. Dolliver, Ph.D.

 

References

1 Xu, X.; Yang, Y.; Zhang, X.; Yi, W. Organic Letters 2018, 20, 566.

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