CDRI Synthesis of TCMDC Aryl Pyrrole Analogues

Synthesis of 1-(3-fluorophenyl)-2,5-dimethyl-1H-pyrrole-3-carbaldehyde (SBBH-1-5) via oxidation of (1-(3-fluorophenyl)-2,5-dimethyl-1H-pyrrol-3-yl)methanol (SBBH-1-4)

Experimental Procedure: To a stirred solution of (1-(3-fluorophenyl)-2,5-dimethyl-1H-pyrrol-3-yl)methanol (SBBH-1-4) (0.262 g, 1.19 mmol, 1 equiv) in dry CH₂Cl₂ (5 mL) in a 50 mL round bottom flask fitted with guard tube was added quickly weighed activated MnO₂ (0.512 g, 5.95 mmol, 5 equiv) at room temperature. The reaction mixture which turned black on addition was allowed to continue for 1.5 h. The TLC analysis (20% ethyl acetate - hexane) at this stage indicated the formation of a new spot. The reaction was monitored again after 3.5 h but as no progress was observed more activated MnO₂ (5 equiv) was added to the reaction mixture. Thereafter TLC analysis after 2 h showed that the completion of the reaction. The reaction mixture was filtered through a Celite bed and washed with CH₂Cl₂(20 mL), and the filtrate evaporated under reduced pressure to yield a blackish gummy crude product. The crude product was purified via column chromatography over silica gel (100-200 mesh) using 3-4: 97-96 % ethyl acetate and hexane as eluent. The pure fractions were pooled and evaporated to obtain the required compound (0.172 g). However it was observed that minor amount of impurities were present in desired compound.

TLC after 3.5 hour (20% ethyl acetate in hexane) visualised using UV and I₂:

¹H NMR:

Synthesis of (1-(3-fluorophenyl)-2,5-dimethyl-1H-pyrrol-3-yl)methanol (SBBH-1-4) via reduction of ethyl 1-(3-fluorophenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate (SBBH-1-3)

Reaction Time: 14-01-12 12:15 PM (IST)

Experimental Procedure: To a stirred ice-cool solution of ethyl 1-(3-fluorophenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate (SBBH-1-3) (0.640 g, 2.45 mmol, 1 equiv) in THF (20 mL) in a 100 mL flask fitted with guard tube was added LiAlH₄ (0.112 g, 2.94 mmol, 1.2 equiv) portion wise. After addition of LiAlH₄ the color of the reaction mixture is changed from yellow to steel black. After 20 min the TLC analysis indicated the presence of a highly polar new spot. The reaction mixture was brought to room temperature and the reaction continued for another 2 h. During checking of the TLC reaction mixture spot on the TLC plate turned blue without the use of any indicator. After 3 h, as there was no progress in the reaction the reaction mixture was heated at 70 ⁰C under stirring in an oil bath. After 30 minutes the TLC showed completion of reaction. The reaction was removed from heating and cooled to room temperature, then 2 mL saturated solution of sodium tartrate was added to the reaction mixture to quench excess LiAlH₄. The reaction mixture become colloidal solution which was filtered through celite bed and washed with THF (40 mL). The filtrate which was collected displayed the presence of two more spots on TLC. The filtrate was concentrated under pressure to give crude 0.421 g in yields. The compound was purified through column chromatography over silica gel using 6-15:94-85 EtoAc:hexane as eluent. During column chromtography a blue color appears on silica. Purification via column chromtography furnsihed 0.182 g of the desired product. However multiple impurities are confirmed by both TLC and 1H NMR spectrum. Therefore it is concluded that the alcohol (SBBH-1-4) is not stable.

TLC after 20 minutes(20% ethyl acetate in hexane) visualised using UV and I₂:

From left to right in TLC plate: starting material (SBBH-1-3), co spot, reaction mixture.

TLC after 4 hours (20% ethyl acetate in hexane) visualised using UV and vanillin:

From left to right in TLC plate: starting material (SBBH-1-3), co spot, reaction mixture.

¹H NMR:

Raw Data: