Trimethylsilyldiazomethane → HCID 59648543, compound

HRID 1363269Notes

Reaction equation

HRID 1363269 reaction equation
[F:1][C:2]1[C:3]2[S:20][CH:19]=[CH:18][C:4]=2[N:5]([CH2:10][O:11][CH2:12][CH2:13][Si:14]([CH3:17])([CH3:16])[CH3:15])[C:6]=1[C:7]([OH:9])=[O:8].[CH3:21][Si](C=[N+]=[N-])(C)C>>[F:1][C:2]1[C:3]2[S:20][CH:19]=[CH:18][C:4]=2[N:5]([CH2:10][O:11][CH2:12][CH2:13][Si:14]([CH3:16])([CH3:15])[CH3:17])[C:6]=1[C:7]([O:9][CH3:21])=[O:8]

Participants

3

Reactant 2

HCID 167693TrimethylsilyldiazomethaneHCID 69322974HCID 69322974, compound

Product 1

HCID 59648543HCID 59648543, compoundYield 0.8%

Procedure

4-(2-Trimethylsilanyl-ethoxymethyl)-4H-thieno[3,2-b]pyrrole-5-carboxylic acid (1.9 g, 6.4 mmol) was dissolved in anhydrous THF (250 mL) and cooled to −78° C. n-BuLi (1.6 M in hexanes, 12 mL, 19.2 mmol, 3 equiv) was added over 5 min and stirred at −78° C. for 60 min. A solution of NFSI (3.1 g, 9.6 mmol, 1.5 equiv) in 15 mL anhydrous THF was added over 15 min and the reaction was stirred at −78° C. for 5 h and then allowed to warm to rt overnight. The reaction was cooled in an ice bath, quenched with 6N HCl, and then extracted with EtOAc and evaporated in vacuo to give 5.5 g of dark residue. The residue was chromatographed over silica gel (DCM in EtOAc) to give a more pure residue. This residue was further purified via prep reverse phase HPLC (RP-HPLC) to give 360 mg of the 2-fluoro isomer (2-fluoro-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-thieno[3,2-b]pyrrole-5-carboxylic acid) and a separate mixture of starting material and 6-fluoro isomer (6-fluoro-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-thieno[3,2-b]pyrrole-5-carboxylic acid). This latter mixture was converted to the corresponding methyl ester via TMSCH2N2. The mixture of esters was chromatographed over silica gel (EtOAc in heptane, 5%-20%) to give methyl 6-fluoro-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-thieno[3,2-b]pyrrole-5-carboxylate (16 mg, 0.0485 mmol, 0.8% yield). 1H NMR (400 MHz, (CD3)2CO) δ ppm −0.08 (s, 9H) 0.80-0.87 (m, 2H) 3.49-3.57 (m, 2H) 3.87 (s, 3H) 5.88 (s, 2H) 7.29 (dd, J=5.32, 2.20 Hz, 1H) 7.66 (d, J=5.32 Hz, 1H).

Workup

  1. customThe residue was chromatographed over silica gel (DCM in EtOAc)
  2. customto give a more pure residue
  3. customThis residue was further purified via prep reverse phase HPLC (RP-HPLC)
  4. customto give 360 mg of the 2-fluoro isomer (2-fluoro-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-thieno[3,2-b]pyrrole-5-carboxylic acid)
  5. customwas chromatographed over silica gel (EtOAc in heptane, 5%-20%)

Sources & evidence

ORD record
ord-bf973307fc984cd2a77867270c32e865
Source dataset
uspto-grants-2011_02
Patent number
US07884124B2

Reaction notes

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