Stereoselective Synthesis of 2-Thio-3-Chloroacrylamides and Investigation of their Reactivity

Abstract

The stereoselective transformation of 2-thioamides to 2-thio-3-chloroacrylamides and the investigation of the scope of this transformation, including extension to ester and nitrile derivatives, is described. These highly functionalised acrylamide derivatives are synthetically versatile, and their reactivity has been investigated in a wide range of transformations, including chemoselective oxidation to the racemic sulfoxide or sulfone, and enantioselective and ­diastereoselective oxidation to the sulfoxides. The 2-thio-3-chloroacrylamides were found to be very effective Michael acceptors in nucleophilic addition/substitution reactions, dienophiles in Diels-Alder cycloadditions, and dipolarophiles in 1,3-dipolar cycloadditions. The level of oxidation at sulfur was found to strongly influence the reactivity. This account summarises synthetic and mechanistic aspects of the research programme focussed on the synthesis and reactivity of 2-thio-3-chloroacrylamides in our research group over the past decade.

1 Introduction - Discovery of 2-Thio-2-chloroacrylamides and Initial Observations

2 Synthesis of the β-Chloroacrylamides and Investigation of their Mechanistic Pathway

3 Extension of the Methodology to β-Haloacrylamides, β-Acrylates, and β-Acrylonitriles

4 Oxidation of the β-Chloroacrylamides

4.1 Chemoselective Sulfur Oxidation

4.2 Enantioselective Sulfur Oxidation

4.3 Diastereoselective Sulfur Oxidation

5 Nucleophilic Addition/Substitution Reactions of the β-­Chloroacrylamides

5.1 Addition of Carbon Nucleophiles

5.2 Addition of Nitrogen Nucleophiles

5.3 Addition of Oxygen Nucleophiles

5.4 Addition of Sulfur and Selenium Nucleophiles

5.5 Summary of Nucleophilic Additions

6 Reactivity of the β-Chloroacrylamides in Diels-Alder ­Cycloaddition Reactions

6.1 Cycloadditions with Cyclopentadiene

6.2 Cycloadditions with 2,3-Dimethyl-1,3-butadiene

6.3 Summary of Diels-Alder Cycloadditions

7 Reactivity of the β-Chloroacrylamides in 1,3-Dipolar ­Cycloaddition Reactions

7.1 Cycloadditions with Diazoalkanes

7.2 Cycloadditions with Nitrile Oxides and Nitrones

8 Conclusion

Key words

stereoselective synthesis - organosulfur compounds - oxidation - nucleophilic addition - cycloaddition

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Foley, D. A.; Doecke, C. W.; Buser, J. Y.; Koerner, A.; Merrit, J. M.; Murphy, L.; Kissane, M.; Collins, S. G.; Maguire, A. R. manuscript in preparation.

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