2-Halobenzamides

Introduction

2-Halobenzamides are important precursors in organic synthesis to construct various heterocyclic compounds. They exhibit strong intermolecular N–H···O=C hydrogen bonding[1a] and therefore, most of them are crystalline solids in nature and can be stored for a long period of time. Most of the 2-halobenzamides are soluble in organic solvents, for example, in dichloromethane, chloroform, acetone, methanol, etc.

Preparation

2-Halobenzamide can be easily prepared from the corresponding 2-halobenzoyl chloride and freshly distilled ­primary amine in the presence of triethylamine.[1a] [b] [c] [d] [e] ­Dichloromethane, chloroform, tetrahydrofuran, etc. are suitable solvents for this reaction.

Scheme 1 Synthesis of 2-halobenzamides

Abstracts

(A) Synthesis of Isoquinolones: Cheng and colleagues described an efficient nickel-catalyzed method for the synthesis of substituted 1(2H)-isoquinolones via annulation of variously substituted 2-halobenzamides with alkynes. The reaction worked well with both internal and terminal alkynes. Here, Ni(II) is reduced to Ni(0) by zinc powder, followed by oxidative addition of 2-halobenzamide to Ni(0) to form a five-membered nickelacycle. The insertion of alkyne gave a seven-membered nickelacycle which upon reductive elimination yielded the isoquinolone.[2]
(B) Synthesis of Isocoumarins: Isocoumarins are well-known heterocyclic scaffolds for the construction of various natural products possessing a wide range of ­biological activities. Yao and co-workers described an efficient synthesis of isocoumarins by a copper-catalyzed tandem C–C/C–O coupling strategy by utilizing various 2-iodo-N-phenylbenzamides and acyclic 1,3-diketones as starting materials.[3] By using a cyclic ketone as starting material the isoquinolinone is produced.
(C) Synthesis of Chalcogen–N Heterocycles: Kumar and colleagues described a copper-catalyzed methodology for the construction of heterocyclic compounds bearing a Se–N or S–N bond.[4] 2-Halobenzamides are treated with elemental selenium or sulfur in the presence of CuI catalyst and K2CO3 as base.
(D) Synthesis of 2-Hydroxybenzamides: The 2-hydroxybenzamide motif has a wide range of biological activities. Kumar and co-worker described an efficient methodology for the synthesis of 2-hydroxybenzamides from the corresponding 2-chlorobenzamides by using CuI/1,10-phenanthroline.[5] This is the first report of a copper-catalyzed hydroxylation in neat water.
(E) Synthesis of Phenanthridinones: Synthesis of phenanthridinones is described from 2-halobenzamides in the presence of KOt-Bu by using a catalytic amount of 1,10-phenanthroline or AIBN. The reaction proceeds through a radical mechanism as it is progressing smoothly in the presence of the radical initiator AIBN. Moreover, the presence of the radical was confirmed by EPR spectroscopy.[6] Larock and co-workers described the synthesis from 2-halobenzamides and ortho-(trimethylsilyl)aryl triflate in the presence of a palladium catalyst.[7] CsF is used as fluoride source to generate benzyne. A toluene–acetonitrile solvent ratio of 4:1 is important to get high yields of the desired products.
(F) Synthesis of 3-Methylisoindolin-1-ones: Ma and co-workers reported a CuI/l-proline-catalyzed coupling of 2-bromobenzamides with terminal alkynes to cyclize into 3-methylisoindolin-1-ones. The reaction works equally well in DMF/DMSO solvents.[8]
(G) Synthesis of Dibenzoxazepinones: A copper-catalyzed domino reaction between 2-iodobenzamides and 2-bromophenols by using K3PO4 as base resulted in dibenzoxazi­pinones. The reaction sequence started with a copper-catalyzed ­Ullmann coupling followed by a base-mediated Smiles rearrangement and a final ring-closing process to give the desired product.[9]

• References

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