Practical Synthesis and Application of Halogen-Doped Pyrrole Building Blocks

Abstract

A practical access to four new halogen-substituted pyrrole building blocks was realized in two to five synthetic steps from commercially available starting materials. The target compounds were prepared on a 50 mg to 1 g scale, and their conversion to nanomolar inhibitors of bacterial DNA gyrase B was demonstrated for three of the prepared building blocks to showcase the usefulness of such chemical motifs in medicinal chemistry.

Discovery and Hit-to-Lead Optimization of Benzothiazole Scaffold-Based DNA Gyrase Inhibitors with Potent Activity against Acinetobacter baumannii and Pseudomonas aeruginosa

“…4 6-carboxylate (22s19). A suspension of 3,4-dichloro-5-(phthalimidomethyl)-1H-pyrrole-2-carboxylic acid 36 (63 mg, 0.186 mmol) in SOCl 2 (1 mL) was refluxed for 1 h; then, the reaction mixture was concentrated under reduced pressure to get a red tinted white solid. To this, crude acyl chloride 20s18 (81 mg, 0.186 mmol) and toluene (64 mL) were added and the resulting suspension was refluxed overnight.…”

“…Prepared according to the typical procedure D from 2-aminobenzothiazole 32s36 (250 mg, 0.605 mmol); light pink solid (150 mg, 42% yield). 1 H NMR (400 MHz, DMSO-d 6 ): δ 12.27 (s, 2H), 8.18 (s,1H),3H),7.35 (app t,J = 7.5 Hz,2H),7.26 (t,J = 7.4 Hz,1H),5.86 (dd,J = 7.9,3.8 Hz,1H),3.81 (s,3H),4H) thiazole-6-carboxylic Acid (36). Prepared according to the typical procedure E from methyl ester 33s36 (75 mg, 0.127 mmol); light pink solid (60 mg, 82% yield).…”

“…Prepared according to the typical procedure C from aniline 4s48 (1.06 g, 4.50 mmol); light yellow powder (724 mg, 55% yield). 1 36,166.13,147.78,147.17,132.15,122.21,115.73,112.75,78.23,51.93,19.53,16.76,3.82,thiazole -6-carboxylate (6s48). Prepared according to the typical procedure D from 2aminobenzothiazole 5s48 (250 mg, 0.854 mmol); white solid (40 mg, 10% yield).…”

New Halogen-Containing Drugs Approved by FDA in 2021: An Overview on Their Syntheses and Pharmaceutical Use

“…Synthetically, given the high electronegativity of fluorine, the design of electrophilic fluorine source (F + ) has been more challenging over the years with respect to bromine and chlorine sources. In this sense, Selectfluor ® [ 18 ] ( Figure 2 ) has been groundbreaking, allowing several transformations on alkanes [ 19 ] and aromatic scaffolds [ 20 ]. In regard to the aromatic substrates, electron-donating substituents are known to increase the rate of the formation and yield of fluorinated compounds, obviously [ 21 ].…”

Visible-Light-Induced Catalytic Selective Halogenation with Photocatalyst

“…Halogenation is one of the most important modifications in organic synthesis because of its extremely wide applications. Halogen derivatives are useful building blocks in organic synthesis for the construction of complicated, high-activity molecules [ 1 , 2 , 3 ]. Moreover, as halogenation can be applied to a wide variety of organic compounds without altering their basic structures, halogen-substituted compounds have become popular intermediates for transformation to create different functional groups [ 4 , 5 , 6 ].…”