A Two-Step Protocol for Umpolung Functionalization of Ketones Via Enolonium Species

Summary

A two step one-pot protocol for the umpolung of ketone enolates to enolonium species and addition of a nucleophile to the α-position is described. Nucleophiles include chloride, azide, azoles, allyl-silanes, and aromatic compounds.

Abstract

α-Functionalization of ketones via umpolung of enolates by hypervalent iodine reagents is an important concept in synthetic organic chemistry. Recently, we have developed a two-step strategy for ketone enolate umpolung that has enabled the development of methods for chlorination, azidation, and amination using azoles. In addition, we have developed C-C bond–forming arylation and allylation reactions. At the heart of these methods is the preparation of the intermediate and highly reactive enolonium species prior to addition of a reactive nucleophile. This strategy is thus reminiscent of the preparation and use of metal enolates in classical synthetic chemistry. This strategy allows the use of nucleophiles that would otherwise be incompatible with the strongly oxidizing hypervalent iodine reagents. In this paper we present a detailed protocol for chlorination, azidation, N-heteroarylation, arylation, and allylation. The products include motifs prevalent in medicinally active products. This article will greatly assist others in using these methods.

Introduction

Enolates are classical carbon nucleophiles in organic chemistry and among the most widely used. Umpolung of enolates to create electrophilic enolonium species allows valuable alternative ways to produce α-functionalized ketones as well as to enable novel reactions not possible via classical enolate chemistry. Enolonium species have been proposed as intermediates in numerous reactions, in particular reactions involving hypervalent iodine reagents. These reactions include α-halogenation, oxygenation, and amination¹ as well as other reactions^2,3,4

Protocol

1. Preparation of the Enolonium Species

Caution: Before carrying out the protocol, consult the MSDS for all reagents and solvents.

NOTE: All new reagents were used as received from the commercial source. If the boron trifluoride etherate has been stored, distill it before use.

1. In a dry round bottomed flask equipped with a septum and a magnet for magnetic stirring, add Koser's reagent (1.5 equiv.) and flush the flask with nitrogen or argon.
2. Add dry dichloromethane to give a suspension of 0.234 mol/L formal concentration.
3. Cool the suspension to -78 °C using a dry ice/ac....

Results

Representative results, achieved following the protocol, are given in Figure 1 and are discussed in the discussion section. Notably, a very large range of different ketones may be used successfully in the reaction to give the products in good yields as may be seen for the azidation¹¹. The scope of the reaction for introducing azoles in the α-position of ketones includes most of the common mono-cyclic and bicyclic nitrogen containing he.......

Discussion

The successful preparation of enolonium species from TMS-enolates is dependent on a number of factors. The major side reaction in the preparation step is the homo coupling of the starting material by reaction of a molecule of formed enolonium species with a molecule of TMS-enolate. Thus, the requirement of the reaction conditions is to avoid this dimerization by ensuring fast reaction of the Lewis acid activated hypervalent iodine reagent with added TMS-enolate relative to the rate of dimerization. This is achieved in th.......

Materials

List of materials used in this article

Name	Company	Catalog Number	Comments
Chlorotrimethylsilane, 98+%	Alfa Aesar	A13651	TMS-Cl
Boron trifluoride diethyl etherate, 98+%	Alfa Aesar	A15275	BF3*Et2O
2-Methylindole, 98+%	Alfa Aesar	A10764	2-Me-indole
Hydroxy(tosyloxy) iodobenzene, 97%	Alfa Aesar	L15701	Koser's reagent
Acetophenone, >98%	Merck	800028
n-Butyllithium solution 1.6M in hexanes	Aldrich	186171	nBuLi
BIS(ISOPROPYL)AMINE	Apollo	OR1090	DIPA
Trimethylsilyl azide, 94%	Alfa Aesar	L00173	TMS-N3