Synthesis of Amino‐ and Hydroxymethyl Benzoxaboroles: Prominent Scaffolds for Further Functionalization

Abstract

Herein, we describe the development of a short, simple, and efficient synthesis of amino‐ and hydroxymethyl‐substituted benzoxaboroles. The key step in our strategy was the early stage incorporation of the boron by the borylation of an aniline. The formed boronates were then elaborated to the final products in two additional steps, usually in good yields. The synthetic sequence was amenable to be performed on a preparative scale and 4‐amino benzoxaborole 4b and 6‐hydroxymethyl benzoxaborole 10c have been prepared, without any significant decrease in the overall yield. The amino and hydroxymethyl present at the molecules are useful for further elaboration and/or conjugation to bioactive molecules and therefore we believe that this method should be useful in the development of new compounds for Medicinal Chemistry.

Emerging Building Blocks for Medicinal Chemistry: Recent Synthetic Advances

“…[49] Figure 3 shows some approved boron-containing drugs; so far, they all fall into one of two chemotypes, namely, aminoboronic acids or their derivatives, [50][51][52] as well as benzoxaboroles. [53] Alternatively, (hetero)aliphatic boronates and trifluoroborates are widely used to create the C(sp 3 )À C or C-(sp 3 )À heteroatom bonds in early drug discovery. Evidently, their leading role originated from application in the palladiumcatalyzed SuzukiÀ Miyaura reaction, [54][55][56][57] which is a top transformation for structure-activity relationship (SAR) exploration in drug discovery.…”

Practical Synthesis of 6-Amino-1-hydroxy-2,1-benzoxaborolane: A Key Intermediate of DNDI-6148

“…Attempts to decrease the catalyst loading in the synthesis of 9a resulted in considerably lower conversion, challenging the use of this method as part of an overall cost-effective process. As a result, this route was abandoned in favor of the more cost-effective deaminative borylation of arylamines (see below). − …”

“…The synthesis of compound 9a has been described in the literature from the corresponding diazonium salt of commercially available 2-methyl-5-nitroaniline ( 13 , Table ), with an excess of B 2 Pin 2 , but only on a small scale and requiring chromatographic purification. − We focused on the optimization of this transformation for the synthesis of the intermediates 9a or 9b , by addressing three major issues: (1) minimize the amount of expensive diboron compound needed, thus reducing the raw material cost; (2) remove column purification to minimize the processing cost and enable scalability; and (3) diminish the process mass intensity (PMI) with a low-molecular-weight diboron source, such as B 2 (OH) 4 . As shown in Table , our first attempt was to utilize costly B 2 pin 2 as the limiting reagent.…”

“…As a result, this route was abandoned in favor of the more cost-effective deaminative borylation of arylamines (see below). 40 − 42 …”