Organic synthesis using (diacetoxyiodo)benzene (DIB): Unexpected and novel oxidation of 3-oxo-butanamides to 2,2-dihalo-N-phenylacetamides

A novel and reliable method for the direct preparation of 2,2-dihalo-N-phenylacetamides is reported. The key transformation involves the cleavage of a carbon–carbon bond in the presence of DIB and a Lewis acid as the halogen source, and thus this method significantly expands the value of DIB as a unique and powerful tool in chemical synthesis. This protocol not only adds a new aspect to reactions that use other hypervalent iodine reagents but also provides a wide space for the synthesis of disubstituted acetamides.

During the course of conditional optimization to synthesize 1-carbamoyl-2-oxopropyl acetate derivatives, we surprisingly found that almost none of the desired acetoxylation product was obtained, but 2,2-dichloro-N-phenylacetamide was provided as the major product, upon addition of Lewis acids such as FeCl 3 , Scheme 1: Synthesis of 1-carbamoyl-2-oxopropyl acetates.
ZnCl 2 and CuCl 2 in the reaction system. Based on this result, we developed a simple and efficient approach to the synthesis of 2,2-dihalo-N-phenylacetamides, on which we report herein (Scheme 2). To the best of our knowledge, there are several reports on chlorination and bromination reactions with PhI(OAc) 2 and a halogen source such as TMSBr, lithium halide or pyridinium halide [32][33][34]. Also, there are several reports on the synthesis of difunctionalized acetamide derivatives [35][36][37][38], but this report is the first to describe the synthesis of 2,2-dihalo-N-phenylacetamides through an oxidative process with PhI(OAc) 2 and Lewis acids as the halogen source.

Results and Discussion
Initially, we used 3-oxo-N-phenylbutanamide (1a) as the model substrate to optimize the reaction conditions in different solvents, temperatures and amounts of DIB ( Table 1). The best result was obtained in dioxane in the presence of 1.3 equiv of DIB and 1.5 equiv of zinc(II) chloride at room temperature for one hour ( After optimizing the reaction conditions, we used a range of 3-oxo-N-phenylbutanamides to explore the substrate scope and limitations of this reaction. As shown in Scheme 3, all the reactions proceeded smoothly and gave the corresponding N-phenyl dichloroacetamides 2a-2k exclusively and in good to excellent isolated yields. It was also found that the number and the electronic properties of the substituents on the benzene ring had little effect on the reaction. For example, the reactions of 3-oxo-
Next, in order to expand the scope of this protocol, we employed ZnBr 2 as a reagent under the same reaction conditions, and we were pleased to find that the corresponding dibromo derivatives were obtained as the products. As shown in Scheme 4, all tested substrates provided the corresponding dibromoacetamides 3a-3l in good to excellent isolated yields, which not only greatly expanded the application scope of this protocol but also provided a wide space for the synthesis of 2,2-dihalo-N-phenylacetamides.
In spite of the widespread use of DIB, there is no direct precedent for DIB-mediated cleavage of C-C bonds. In particular, the application of this protocol to synthesize difunctionalized acetamides from 3-oxo-butanamides is reported here for the first time. In order to probe the mechanism of this transformation, we employed 2,2-dichloro-3-oxo-N-phenylbutanamide (1m) and 2,2-dibromo-3-oxo-N-phenylbutanamide (1n) as reactants under acidic conditions in the presence of Zn(OAc) 2 (Scheme 5), and we found that the reaction can also give the corresponding product 2,2-dichloro-N-phenylacetamide (2a) and 2,2-dibromo-N-phenylacetamide (3a).

Scheme 5: Probe the mechanism.
On the basis of these preliminary results, a mechanistic proposal for this transformation, exemplified by the formation of 2a, is depicted in Scheme 6. Initially, the reaction involved generation of the known chlorinating agent (dichloroiodo)benzene (PhICl 2 ) [39], followed by dichlorination of the β-keto amide of 3-oxo-N-phenylbutanamide (1a) to give intermediate 4.

Conclusion
In summary, we have shown an efficient and operationally simple method to synthesize 2,2-dihalo-N-phenylacetamides. The mild reaction conditions, good substrate scope and good to excellent yields make the present protocol potentially useful in organic synthesis. Moreover, it should be pointed out that this transformation includes an oxidative process involving the Scheme 6: Tentative mechanism for the synthesis of 2,2-dihalo-N-phenylacetamides.
cleavage of a carbon-carbon bond, which significantly expands the value of DIB as a unique and powerful tool in chemical synthesis. Future studies on the application of this protocol to the synthesis of other difunctionalized acetamides and detailed investigations of the reaction mechanism are in progress.

Supporting Information
Supporting Information File 1 Experimental details and characterization of compounds.