[Hydroxy(tosyloxy)iodo]benzene Mediated α-Azidation of Ketones

Abstract

Reaction of various ketones with [hydroxy(tosyloxy)iodo]benzene (HTIB) followed by treatment of the α-tosyloxy ketones thus generated in situ with NaN₃ offers a one-pot procedure for the synthesis of α-azido ketones. The HTIB used in this conversion may also be generated in situ by using iodosobenzene in combination with p-toluene-sulphonic acid.

Introduction

The application of organohypervalent iodine reagents is a fertile and attractive field in organic synthesis [1]. Of the various hypervalent iodine reagents, iodobenzene diacetate (IBD) [2] and [hydroxy(tosyloxy)iodo]benzene (HTIB) (Koser’s reagent) [3] have been found to be more versatile than other reagents such as iodosobenzene (IOB), etc. The relatively lesser utility of IOB is due to its polymeric nature [4], which makes it insoluble in common solvents. To overcome such difficulties, combination reagents were developed. For example, the utility of IOB is greatly enhanced when it is combined with acids [5], bases [6] or salts [7]. These reactions are thought to proceed via generation in situ of the I(III) species 4 (Scheme 1). Continuing our investigations on the use of I(III) reagents, we now report a one pot α-azidation of ketones using HTIB or the combination reagent [(PhIO)_n + p‑TsOH] [8] and NaN₃.

Scheme 1.

Scheme 1.

Results and Discussion

Based on previous reports on the use of [ydroxyl(tosyloxy)iodo]benzene (HTIB) [9] in one-pot syntheses of α-functionalized ketones, we first attempted the azidation of 1a using HTIB. Accordingly, acetophenone (1a) was oxidized with one equivalent of HTIB in acetonitrile and subsequently the α‑tosyloxy ketone 2a generated in situ was treated with sodium azide. The reaction resulted in the formation of the corresponding α-azido acetophenone 3a in 80% yield (Method A, Scheme 2). In order to study the scope of this approach, various ketones 1b-1g were subjected to α−azidation using one equivalent of HTIB and NaN₃ to afford the corresponding α−azido ketones 3b-3g in yields ranging from 69% to 81% (Table 1).

Scheme 2.

Scheme 2.

Method A: (i) HTIB/ CH₃CN, reflux 2 h; (ii) NaN₃, rt, 2-3 h

Method B: (i) (PhIO)_n + p-TsOH/CH₃CN, reflux 2 h; (ii) NaN₃, rt, 2-3 h

In another important development, we established that it is possible to use a combination of iodosobenzene and p-toluenesulphonic acid [(PhIO)n + p-TsOH] in place of HTIB. This combination reagent generates HTIB in situ, which then reacts with ketones 1 to give the intermediary α-tosyloxy ketones 2 (Method B).

It is evident from the results summarized in Table 1 that Method A and Method B work equally well, although Method B is more convenient than Method A as the former avoids the preparation of HTIB. It is to be mentioned that the reported preparation of HTIB consists of two steps starting from iodosobenzene [10,11] (Scheme 3).

Scheme 3.

Scheme 3.

Table 1. α-Azido ketones 2 prepared according to Scheme 2.

Compound	R1	R2	Yield (%)a
			Method A	Method B
2a	H	H	80	76
2b	4-CH3C6H4	H	69	74
2c	4-CH3OC6H4	H	72	70
2d	4-BrC6H4	H	78	71
2e	4-ClC6H4	H	70	69
2f	H	CH3	81	71
2g	-(CH2)4-		81	83

^aYields of isolated pure product based on the amount of ketones 1 used.

Table 1. α-Azido ketones 2 prepared according to Scheme 2.

Compound	R1	R2	Yield (%)a
			Method A	Method B
2a	H	H	80	76
2b	4-CH3C6H4	H	69	74
2c	4-CH3OC6H4	H	72	70
2d	4-BrC6H4	H	78	71
2e	4-ClC6H4	H	70	69
2f	H	CH3	81	71
2g	-(CH2)4-		81	83

^aYields of isolated pure product based on the amount of ketones 1 used.

Conclusions

In summary, the present study offers a better alternative to the existing methods for the synthesis of α-azido ketones, which are valuable intermediates for various transformations [12] and are generally prepared by the reaction of α-halo ketones [12] or α-nosyloxy ketones [13] with sodium azide.