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

  1. 1 ,
  2. 1 ,
  3. 1 and
  4. 2
1School of Chemistry and Life Science, Guangdong University of Petrochemical Technology, Maoming 525000, China
2College of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
  1. Corresponding author email
Associate Editor: B. Stoltz
Beilstein J. Org. Chem. 2012, 8, 344–348. https://doi.org/10.3762/bjoc.8.38
Received 18 Jan 2012, Accepted 14 Feb 2012, Published 07 Mar 2012
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Abstract

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.

Keywords: cleavage of carbon–carbon bond; (diacetoxyiodo)benzene; difunctionalized acetamides; novel oxidation; 3-oxo-N-phenylbutanamides

Introduction

Hypervalent iodine(III) reagents [1-18] have received much attention, as reflected by the plethora of publications and reviews [19-23]. This is due to their low toxicity, ready availability, easy handling, clean transformation, and reactivity, which is similar to heavy-metal-based oxidants, including harmful elements, such as Pb(IV), Hg(II), and Tl(III), as well as transition metal-catalyzed processes [24-30]. Recently, we reported an efficient acetoxylation approach to synthesize 1-carbamoyl-2-oxopropyl acetate derivatives by using (diacetoxyiodo)benzene (DIB) (Scheme 1) [31].

[1860-5397-8-38-i1]

Scheme 1: Synthesis of 1-carbamoyl-2-oxopropyl acetates.

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 FeCl3, ZnCl2 and CuCl2 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 [32-34]. Also, there are several reports on the synthesis of difunctionalized acetamide derivatives [35-38], 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.

[1860-5397-8-38-i2]

Scheme 2: Synthesis of 2,2-dihalo-N-phenylacetamides.

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 (Table 1, entry 11). For this transformation, FeCl3 and ZnCl2 were suitable Lewis acids (Table 1, entry 2 and entry 3), and dioxane and DMF were practical solvents among the various solvents examined (Table 1, entry 3 and entry 8). It is noteworthy that no product 2a was obtained when the reaction was carried out without the addition of Lewis acids (Table 1, entry 1) or without DIB (Table 1, entry 5).

Table 1: Optimization of reaction conditions.a

[Graphic 1]
entry solvent additive (1.5 equiv) time (h) yield (%)b
1 dioxane none 1 –
2 dioxane FeCl3 1 78
3 dioxane ZnCl2 1 81
4c dioxane ZnCl2 1 75
5d dioxane ZnCl2 1 –
6 cyclohexane ZnCl2 1 26
7 DCE ZnCl2 1 42
8 DMF ZnCl2 1 80
9 DMSO ZnCl2 1 46
10e dioxane ZnCl2 1 31
11f dioxane ZnCl2 1 89
12g dioxane ZnCl2 1 84
13f dioxane ZnCl2 0.5 53
14f dioxane ZnCl2 1.5 89
15f dioxane ZnCl2 2 89

a1a (0.25 mmol), solvent (2 mL), DIB (1.0 equiv); bGC yield; cZnCl2 (1.0 equiv); dwithout DIB; eDIB (0.5 equiv); fDIB (1.3 equiv); gDIB (2.0 equiv).

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-N-phenylbutanamide (1a), 3-oxo-N-o-tolylbutanamide (1b), N-(2,4-dimethoxyphenyl)-3-oxobutanamide (1j) and N-(4-chloro-2,5-dimethoxyphenyl)-3-oxobutanamide (1k) all led to their corresponding N-phenyl dichloroacetamides (Scheme 3, 2a, 2b, 2j, and 2k) in good isolated yields. In addition, the position of the substituents on the benzene ring also has little effect on this transformation, such that N-(2-chlorophenyl)-3-oxobutanamide (1c), N-(4-chlorophenyl)-3-oxobutanamide (1d), N-(4-methoxyphenyl)-3-oxobutanamide (1e) and N-(2-methoxyphenyl)-3-oxobutanamide (1f) could also serve as good substrates in this protocol (Scheme 3, 2c, 2d, 2e, and 2f).

[1860-5397-8-38-i3]

Scheme 3: Synthesis of dichloroacetamides. Reagents and conditions: 1 (1.0 mmol), dioxane (2 mL), DIB (1.3 equiv), ZnCl2(1.5 equiv); yields % are isolated yields.

Next, in order to expand the scope of this protocol, we employed ZnBr2 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.

[1860-5397-8-38-i4]

Scheme 4: Synthesis of dibromoacetamides. Reagents and conditions: 1 (1.0 mmol), dioxane (2 mL), DIB (1.3 equiv), ZnBr2 (1.5 equiv); yields % are isolated yields.

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).

[1860-5397-8-38-i5]

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 (PhICl2) [39], followed by dichlorination of the β-keto amide of 3-oxo-N-phenylbutanamide (1a) to give intermediate 4. It is well known that Lewis acids can activate 1,3-diketones [40] to produce intermediate 5 and 6. This complexation not only increases the nucleophilicity of the methylene carbon atom, but also simultaneously increases the electrophilicity of the carbonyl carbon atom. Consequently, nucleophilic attack of the acetate ion on the carbonyl carbon atom affords intermediate 7. A subsequent carbon–carbon bond cleavage of the labile α,α-dichloro β-keto amide through a retro-Claisen condensation reaction [41] generates intermediate 8. Finally, the electrophilic attack of a proton on the carbon–carbon double bond resulted in the final product 2,2-dichloro-N-phenylacetamide (2a).

[1860-5397-8-38-i6]

Scheme 6: Tentative mechanism for the synthesis of 2,2-dihalo-N-phenylacetamides.

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 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.
Format: PDF Size: 191.1 KB Download

Acknowledgements

The authors are grateful to the Guangdong University of Petrochemical Technology of China for financial support of this work.

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