An Acetal Acylation Methodology for Producing Diversity of Trihalomethyl- 1,3‑dielectrophiles and 1,2-Azole Derivatives

Valéria Bareño,Juliana Malavolta,Rogerio Blanco,Daiane Santos,Darlene Flores,Alex Flores,Debora De Mello,Lucas Pizzuti,Leandro Frigo

doi:10.21577/0103-5053.20190160

Abstract

A series of functionalized 1,1,1-trihalo-4-methoxy-3-alken-2-ones [CX3C(O)CR1=CROMe, where X = F or Cl; R = n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-tridecyl, (CH2)2CH=C(Me)2, (CH2)2Ph, (CH2)2-(4-HOC6H4), (CH2)2-(4-MeOC6H4), (CH2)2CO2Me, (CH2)3CO2Me, CH(SMe)CH3, CH2(2-MeOC6H4), and R1 = H, and R = H and R1 = n-decyl] were synthesized from respective alkyl methyl ketones or aldehyde via acetal acylation using trifluoroacetic anhydride and trichloroacetyl chloride. 1,1,1-Trihalo-4-methoxy-3-alken-2-ones with acid-compatible substituents were easily hydrolyzed to respective trihalomethyl-1,3-diketones. The 1,1,1-trihalo-4-methoxy-3-alken-2-ones and/or respective trihalomethyl-1,3-diketones were reacted regiospecifically with hydroxylamine hydrochloride, leading to isoxazole derivatives, and with hydrazines, leading to respective 1H-pyrazole derivatives. The structures of all compounds were assigned based on nuclear magnetic resonance (NMR) and mass spectrometric data. This method represents an efficient pathway for the regioselective trihaloacetylation of asymmetrically substituted alkyl methyl ketones and highly self-condensing aldehydes. Moreover, this approach allows the introduction of biologically recognizable moieties, such as those from levulinic acid, sulcatone (prenyl), benzylacetone, anisylacetone, and raspberry ketone, as synthetic molecular targets.

Highlights

1,1,1-Trihalo-4-alkoxy-3-alken-2-ones have been used as important regioselective heterocycle precursors.1,2 These compounds can be used to prepare a wide variety of trihalomethyl-substituted heterocyclic systems and other useful compounds.3,4 Perfluoroacylation, including trifluoroacetylation reactions, of the acetone and asymmetrically substituted, one-enolizable-site ketones with esters is of fundamental importance in organic synthesis.5-7 1,3-Diketones products have long been widely employed as effective chelating reagents and heterocyclic precursors.8-11 Fluorinated 1,3-diketones are currently
This is important in the context that two independent groups have provided evidence that another cyanobacterium, the symbiotic Oscillatoria spongeliae, which lives in association with D. herbacea, is the source of chlorinated metabolites extracted from D. herbacea
Ketones 1a-j were reacted with one mol-equivalent of trimethyl orthoformate under p-toluenesulfonic acid catalysis; after 8 to 24 h, the acid was neutralized with K2CO3

Summary

Introduction

1,1,1-Trihalo-4-alkoxy-3-alken-2-ones have been used as important regioselective heterocycle precursors. These compounds can be used to prepare a wide variety of trihalomethyl-substituted heterocyclic systems and other useful compounds. Perfluoroacylation, including trifluoroacetylation reactions, of the acetone and asymmetrically substituted, one-enolizable-site ketones with esters is of fundamental importance in organic synthesis.5-7 1,3-Diketones products have long been widely employed as effective chelating reagents and heterocyclic precursors. Fluorinated 1,3-diketones are currently. Interest in natural products that contain the trichloromethyl group found in sponges has been stimulated by biosynthetic observations that the pro-S methyl group of leucine, or an unidentified leucine derivative, is the origin of the trichloromethyl group in a compound produced by the marine cyanobacterium Lyngbya majuscule. This is important in the context that two independent groups have provided evidence that another cyanobacterium, the symbiotic Oscillatoria spongeliae, which lives in association with D. herbacea, is the source of chlorinated metabolites extracted from D. herbacea.. To the best of our knowledge, acylation of acetals is the only method to date that has been useful to systematically obtain trichloromethyl-substituted 1,3-dielectrophiles.

Results and Discussion

Methodology

Conclusions