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Racemic 2-Aminomethyl-4-oxo-piperidine Intermediates
1793
(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-acetaldehyde
isolated:
63.20 g
(88%). M.p. ¼ 112–114ꢁC (lit. value: 114ꢁC; Ref.[4]); 1H NMR
(400 MHz, CDCl3) ꢀ: 9.64 (s, 1H), 7.87 (dd, J ¼ 5.6, 2.4, 2H), 7.75 (dd,
J ¼ 5.2, 2.8, 2H), 4.56 (s, 2H); 13C NMR (100 MHz, CDCl3) ꢀ: 47.6, 123.9,
132.1, 134.5, 167.7, 193.7; Anal. calcd for C10H7NO3 (%): C, 63.49;
H, 3.73; N, 7.40; found: C, 63.09; H, 3.73; N, 7.15; MS (APCI) m/z
190.0 (M þ 1).
(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-acetaldehyde (17.3 g, 0.092
moles), 150 mL of dry dichloromethane, molecular sieves (15 g, 4 A),
and 4-methoxybenzylamine (11.9 mL, 0.092 moles) were stirred at rt,
under nitrogen for 1 h. The reaction mixture was filtered and the solution
(imine in dichloromethane) added to an addition funnel containing 2-
trimethylsilyloxy-1,3-butadiene (20.9 mL, 0.12 moles). The resultant mix-
turewas added slowly to a solution of aluminum chloride(14.64 g, 0.11
moles) in dichloromethane (100 mL) previously cooled to ꢂ78ꢁC. Once
theaddition was completethemixturewas allowed to stir for 18 h, slowly
warming to rt. The reaction mixture was cooled to 0ꢁC and 1 N HCl
(100 mL) was added slowly. Once the addition completed, the reaction
mixture was stirred for 2 h. Water was added (0.5 L) and the product
extracted with dichloromethane (Keep aqueous layer). The aqueous
layer was basified with sodium carbonate and extracted with dichloro-
methane. The organic fractions were combined, washed with brine (2ꢃ)
and dried over anhydrous magnesium sulfate. The solvent was removed
in-vacuo to yield a brown solid (35 g). The solid was subjected to
flash chromatography (60:40 hexanes/ethyl acetate) to produce 11.8 g
of 2-[1-(4-methoxy-benzyl)-4-oxo-piperidin-2-yl methyl]-isoindole-1,3-
dione( 1 (Rf ¼ 0.4)) as a yellow solid. Also obtained was 4.6 g of crude
TMS enol ether product (Rf ¼ 0.87, 60 hexanes/40 ethyl acetate). The
crude enol ether was subjected to 1 N HCl for 2 h. The solution was
basified with sodium carbonate and extracted with dichloromethane.
The organic layer was washed with brine and subjected to flash chroma-
tography to yield 1.0 g of additional 1. Total amount of compound 1
isolated: 12.8 g (37%). M.p. ¼ 97–99ꢁC; H NMR (400 MHz, CDCl3) ꢀ
1
7.77 (dd, J ¼ 4.8, 2.8, 2H), 7.69 (dd, J ¼ 5.6, 2.8, 2H), 6.97 (d, J ¼ 8.8,
2H), 6.54 (d, J ¼ 8.8, 2H), 3.88 (q, J ¼ 4.4, 1H), 3.76 (q, J ¼ 19.2, 2H),
3.68 (s, 3H), 3.52ꢂ3.44 (m, 2H), 3.38 (ddd, J ¼ 14, 10, 3.6, 1H), 2.89 (dt,
J ¼ 10, 4.8, 1H), 2.61 (ddd, J ¼ 15, 6, 1.2, 1H), 2.47 (dddd, J ¼ 15, 14, 10,
6, 1H), 2.26 (m, 1H), 2.22 (m, 1H); 13C NMR (100 MHz, CDCl3) ꢀ:
39.0, 39.5, 41.6, 47.7, 55.3, 56.7, 58.2, 113.8, 123.4, 129.7, 130.9, 132.2,
134.1, 158.9, 168.2, 208.7; Anal. calcd for C22H22N2O4 (%): C, 69.77; H,
5.86; N, 7.26; found: C, 69.83; H, 5.86; N, 7.40; MS (APCI) m/z
379.3 (M þ 1).