A Wittig-olefination–Claisen-rearrangement approach to the 3-methylquinoline-4-carbaldehyde synthesis

Efficient syntheses are described for the synthetically important 3-methylquinoline-4-carbaldehydes 6a–h from o-nitrobenzaldehydes 1a–h employing a Wittig-olefination–Claisen-rearrangement protocol. The Wittig reaction of o-nitrobenzaldehydes with crotyloxymethylene triphenylphosphorane afforded crotyl vinyl ethers 2a–h, which on heating under reflux in xylene underwent Claisen rearrangement to give 4-pentenals 3a–h. Protection of the aldehyde group of the 4-pentenals as acetals 4a–h and subsequent oxidative cleavage of the terminal olefin furnished nitroaldehydes 5a–h. Reductive cyclization of these nitroaldehydes yielded the required 3-methylquinoline-4-carbaldehydes 6a–h in excellent yields. Therefore, an efficient method was developed for the preparation of 3-methylquinoline-4-carbaldehydes from o-nitrobenzaldehydes in a simple five-step procedure.


Results and Discussion
Reaction of the o-nitrobenzaldehydes 1a-h with crotyloxymethylene triphenylphosphorane under optimized reaction conditions (Scheme 1) gave crotyl vinyl ethers in good yields ( Table 1). The geometrical isomers of the crotyl vinyl ethers 2a-d were well separated on TLC, and it was possible to separate them by column chromatography. In the case of other crotyl vinyl ethers 2e-h, all attempts to separate these (E)-or (Z)-isomers were unsuccessful.
Claisen rearrangement on either (E)-or (Z)-isomers 2a-d also led to a diastereomeric mixture of 4-pentenals. However, these diastereomers remained inseparable. The crotyl vinyl ethers 2e-h, on heating under reflux in anhydrous xylene, underwent the Claisen rearrangement smoothly to give the diastereomeric mixture of the corresponding 4-pentenals 3e-h in good yields ( Table 1).
Treatment of the 4-pentenals 3a-h with ethylene glycol furnished the corresponding acetals 4a-h in good yields ( Table 1). From the NMR spectra of these acetals, it was clear that they were also a mixture of diastereomers, although they appeared to be homogeneous on TLC. All attempts to separate the diastereomers at this stage were also unsuccessful. Subjecting these acetals to oxidative cleavage in aq THF furnished the aldehydes 5a-h in good yields ( Table 1). The  [6,9].
NMR of these aldehydes revealed them again to be a mixture of diastereomers, although they appeared to be homogeneous on TLC. Reductive cyclization of these nitroaldehydes furnished the required 3-methylquinoline-4-carbaldehydes 6a-h.

Conclusion
A new and efficient methodology for the construction of a 3-methylquinoline-4-carbaldehyde framework, with 50-55% overall yield, through a Wittig-olefination-Claisen-rearrangement protocol has been developed.

Experimental General
Silica gel (100-200 mesh) was used for column chromatography. IR spectra were recorded on a Perkin Elmer model 1600 series FTIR instrument. 1  General procedure for the protection of aldehyde Aldehydes 3a-h obtained from Claisen rearrangement (15 mmol) were dissolved in anhydrous toluene (25 mL). To this solution, a catalytic amount of p-TSA (1.5 mmol, 0.1 equiv) and ethylene glycol (45 mmol, 3 equiv) were added. The reaction mixture was heated under reflux for 3-4 h by using a Dean-Stark condenser (TLC, ethyl acetate/petroleum ether 1:9). After removal of the solvent under reduced pressure, water (20 mL) was added to the reaction mixture, and then the aqueous layer was extracted with ethyl acetate (3 × 15 mL), the combined organic layer was dried over sodium sulfate, and ethyl acetate was evaporated under vacuum. Finally, the product was purified by silica-gel column chromatography (mobile phase 1-3% ethyl acetate in petroleum ether). The products 4a-h were obtained in 89-93% yield.
General procedure for the oxidative cleavage of alkene Alkenes 4a-h (13.5 mmol), obtained as described above, were dissolved in aq. THF (30 mL, THF/H 2 O 1:1). N-Methylmorpholine-N-oxide (NMO) (27 mmol, 2 equiv) and potassium osmate (0.027 mmol, 2 mol %) were added to this solution. The mixture was stirred at room temperature for 2-3 h until the starting compound disappeared (TLC, ethyl acetate/petroleum ether 1:9). Then, sodium metaperiodate was added (27 mmol, 2 equiv) and stirring was continued for 1 h (TLC, ethyl acetate/ petroleum ether 1:9). THF was removed under reduced pressure. Water (20 mL) was added to the reaction mixture, and then the aqueous layer was extracted with ethyl acetate (3 × 10 mL), the combined organic layer was dried over sodium sulfate, and ethyl acetate was evaporated under vacuum. The crude product was obtained after removal of the solvent under reduced pressure. The product was purified by using silica-gel column chromatography (mobile phase 4-7% ethyl acetate in petroleum ether). The products 5a-h were obtained in 89-95% yield.
General procedure for the reductive cyclization Aldehydes 5a-h (11 mmol) were dissolved in glacial acetic acid (20 mL) and heated under reflux with zinc dust (5 equiv) for 0.5 h (TLC, ethyl acetate/petroleum ether 1:9). Acetic acid was evaporated under vacuum, and chloroform was added to the residue. The solution was filtered through a celite bed. CHCl 3 was removed under reduced pressure. Water (25 mL) was added to the reaction mixture, and then the aqueous layer was extracted with ethyl acetate (3 × 15 mL), the combined organic layer was dried over sodium sulfate, and ethyl acetate was evap-orated under vacuum. The crude product was obtained and purified by silica-gel column chromatography (mobile phase 2-3% ethyl acetate in petroleum ether). The products 6a-h were obtained in 84-87% yield.

Supporting Information
Supporting Information File 1 IR, 1 H NMR, 13 C NMR and CHN analysis and spectral data of synthesized compounds. The geometric isomeric ratios for 2g and 2h and diastereomeric ratios for 3a-h, 4a-h and 5a-h were calculated from their NMR signals.