4-Methylbenzaldehyde → Ethyl 3-(4-methylphenyl)-2-propenoate

HRID 493164Notes

Reaction equation

HRID 493164 reaction equation
[C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.[CH2:10]([O:12][C:13](=[O:18])[CH2:14]C(O)=O)[CH3:11].N1CCCCC1>N1C=CC=CC=1>[CH2:10]([O:12][C:13](=[O:18])[CH:14]=[CH:7][C:4]1[CH:5]=[CH:6][C:1]([CH3:9])=[CH:2][CH:3]=1)[CH3:11]

Participants

5

Reactant 3

HCID 77254-MethylbenzaldehydeHCID 8082PiperidineHCID 70615Monoethyl malonate

Product 1

HCID 334099Ethyl 3-(4-methylphenyl)-2-propenoateYield 79%

Reagents, catalysts & solvents 1

HCID 1049PyridineSolvent

Procedure

Application of the previously unused Knoevenagel condensation (Silva, N. M. et al., Eur. J. Med. Chem. 2002, 37, 163-170; Diaz, J. L. et al., Chem. Mater. 2002, 14, 2240-2251; Ren, X. et al., Tetrahedron: Asymmetry 2002, 13, 1799-1804) of p-tolualdehyde with malonic acid monoethyl ester (Breslow, D. S. et al., J. Am. Chem. Soc. 1944, 66, 1286-1288) in pyridine containing a catalytic amount of piperidine gave the known α,β-unsaturated ethyl cinnamate 5 (Tsuge, O. et al., J. Org. Chem. 1982, 47, 5171-5177; Colas, C.; Goeldner, M. Eur. J. Org. Chem. 1999, 1357-1366; Chuzel, O.; Piva, O. Synth. Commun. 2003, 33, 393-402) in 79% yield. Reaction of 5 with (p-tolylsulfonyl)methyl isocyanide (TosMIC) afforded β-substituted pyrrole 6 (a known compound with incomplete data (Di Santo, R. et al., Med. Chem. Res. 1997, 7, 98-108)) in 74% yield. Removal of the ethoxycarbonyl group of pyrrole 6 by treatment with NaOH in ethylene glycol at 160° C. gave the known β-substituted pyrrole 7 (Sakai, K. et al., Chem. Pharm. Bull. 1980, 28, 2384-2393; Campi, E. M. et al., Aust. J. Chem. 1992, 45, 1167-1178; Pavri, N, P.; Trudell, M. L. J. Org. Chem. 1997, 62, 2649-2651) in 71% yield. Vilsmeier-Haack formylation of 7 yielded a mixture of regioisomers owing to substitution at the 2- or 5-position. After column chromatography, the two regioisomers were determined to be present in ˜13:1 ratio by 1H NMR integration of the methyl unit of the p-tolyl group. Selective precipitation readily afforded the major regioisomer 8 in 64% yield (Scheme 3).

Sources & evidence

ORD record
ord-3688ac6c24f243ccb086d456c7be89bf
Source dataset
uspto-grants-2009_05
Patent number
US07534807B2

Reaction notes

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