Piperidine-4-methanol 10.0g (86.8 mmol) was dissolved in mixture of THF 160mL and water 160mL and K2CO3 18.0g (130mmol) was added. The mixture was stirred until complete dissolution of the solids (10 min), the resulting bi-phasic mixture was cooled to 0C. After 20 min at 0C, neat allyl chloroformate 11.0mL (103.5 mmol, 1.2 eq,) was added dropwise with vigorous stirring over a 5 min period. The mixture was stirred on ice bath for 1 hour, then the bath was allowed to melt and reach ambient temperature over 3 hour period. The reaction mixture was extracted with ether (2x200mL). The organic extracts were washed with sat. aqueous NaHCO3 200mL, combined, dried with MgSO4 and evaporated. The residue was dried on highvac (0.5 Torr, 60C).
Y=16.85g (97.5%) of the Alloc-protected piperidinemethanol intermediate as a pale yellow oil 1H(d6-DMSO, 400MHz): 5.920(m, 1H), 5.280(dq, d:17.2Hz, q:1.7Hz, 1H), 5.174(dq, d:10.5Hz, q:1.6Hz, 1H), 4.503(dt, d:5.2Hz, t:1.6Hz, 2H), 4.477(t, 5.3Hz, 1H), 3.985(br m, 2H), 3.239(t, 5.8Hz, 2H), 2.752(very br s, 1H), 1.643(m, 2H), 1.532(m, 1H), 0.994(m, 2H)
16.85g (84.56mmol) of 1-Alloc-4-piperidinemethanol from the previous step was combined with anhydrous N-methylmorpholine-N-oxide 23.8g (203mmol, 2.4 eq.) and activated powdered 4A sieves 38g. The mixture was suspended in anh. dichloromethane 210mL with added anh. MeCN 40mL (40 min stirring). The slurry was cooled to 0C, TPAP 306mg (0.87mmol, 1mol%) solid was added in one portion and the mixture was vigorously stirred at 0-5 C for 90 min under Ar. The cooling bath was allowed to melt and reach the ambient temperature over 2 hour period. The stirring was then continued at RT for additional 9 hours (overnight). The reaction mixture was diluted with EtOAc (250mL), filtered through a pad of silica (100g), the silica was washed with EtOAc 0.5L. The combined filtrates were evaporated and the residue dried on highvac to remove N-methyl morpholine. The obtained crude aldehyde (14.0g) was purified on a column of silica (250g) in hexane-EtOAc 1:1 mixture (3L).
Y=9.18g of a pure aldehyde as a colorless oil, with a faint mowed-grass odor (55% th, 53.5% overall Y).
LC/MS (+ESI): 198 (M+1); the 1H-NMR spectra of the purified product was quite awfull because the product was a mixture of aldehyde hydrate with the parent aldehyde
TPAP review: Synthesis 1994, 639-666.
[The typical catalyst loading in TPAP oxidations is 5 mol%. In this large-scale experiment I used less catalyst and stopped the reaction before complete conversion of the alcohol because some sideproducts started appearing on the baseline.]