1139, 1094, 1058, 1021, 984, 796, 753, 704. EA: calculated
C: 60.50, H: 6.77, N: 4.70, Cl: 11.91, found: C: 60.02,
H: 6.94, N: 4.71, Cl: 11.81. MS (ISP): 262 (100%, [M +
H]+).
3.22-3.11 (m, CH, 1H), 2.96-2.81 (m, CH2, 1H), 2.41-
2.32 (m, CH2, 1H), 2.07-1.85 (m, CH2, 2H). IR (Nujol)
selected cm-1: 2925, 2854, 2459, 2361, 1720, 1454, 1342,
1074, 971, 921, 755, 727, 700. EA: calculated C: 72.25,
H: 7.02, N: 4.43, Cl: 11.23, found: C: 72.01, H: 6.83,
N: 4.53, Cl: 11.27. MS (ISP): 280 (100%, [M + H]+),
262 (9). Mp 202-203 °C.
1,4-Dibenzyl-3-oxo-piperidine-4-carboxylic Acid Ethyl
Ester 3. A mixture of 38.3 g (341.0 mmol) of potassium
tert-butoxide and 625 mL of absolute tetrahydrofuran was
stirred at room temperature for 0.5 h. The resulting milky
solution was cooled to 0 °C, and then 50.0 g (168.0 mmol)
of N-benzyl-3-oxo-4-piperidine carboxylate hydrochloride (2)
was added via a powder dropping funnel whereby the
temperature was kept below 5 °C. The mixture was then
warmed to room temperature and further stirred for 1 h,
resulting in a yellow solution. After cooling to 0 °C, a
solution of 30.2 g (176.0 mmol) of benzyl bromide in 20.0
mL of absolute tetrahydrofuran was added dropwise within
0.5 h. A maximum temperature of 2 °C was observed. The
reaction mixture was warmed to room temperature and stirred
for 4 h. The reaction solution was cooled to 0 °C, and 200
mL of saturated NH4Cl solution was added. After extraction
and phase separation, the aqueous phase was extracted twice
with 100 mL of ethyl acetate. The combined organic phases
were washed twice with 100 mL of saturated NaCl solution
and dried over Na2SO4; the solvent was evaporated under
reduced pressure and the residue dried to yield 58.3 g (99%)
(3S, 4S)-1,4-Dibenzyl-piperidin-3-ol (S,S)-5. In a glove-
box (O2 content e 2 ppm) 16.9 mg of [RuCl2((S)-3,5-iPr-
MeOBIPHEP)((R,R)-DPEN)] 11e (0.013 mmol) were dis-
solved in 20.0 mL of 2-propanol. The clear, yellow catalyst
solution was stirred for 20 min at room temperature. In the
glovebox a glass flask was charged with 41.0 g of 4*HCl
(128.8 mmol), 205.0 mL of 2-propanol, and 17.5 g (156.0
mmol) of potassium tert-butylate. The resulting suspension
was stirred for 10 min (exothermic up to 30 °C) and
transferred into a 380-mL stainless steel, glass-lined autoclave
and treated with 4.0 mL of catalyst solution (2.6 µmol f
S/C 50,000). The autoclave was then sealed and connected
to a hydrogenation line. The hydrogenation was carried out
under stirring at room temperature and at a pressure of 40
bar. After 2 h the reaction was completed as determined by
hydrogen absorption. The reaction mixture (yellow suspen-
sion) was removed from the autoclave with the aid 50 mL
of 2-propanol and treated under vigorous stirring with 300
mL of ethyl acetate, 170 mL of water, 50 mL of aqueous
NH4Cl 5% solution, and 50 g of solid NaCl. After phase
separation, the aqueous phase was extracted twice with 100
mL of ethyl acetate, and the combined organic phases were
washed with 150 mL of brine. The combined organic phase
was dried over Na2SO4, the solvent was evaporated under
reduced pressure to yield 35.6 g of crude (S,S)-5 as light-
yellow crystals (ee ) 96%). 1H NMR (250 MHz, CDCl3) δ
) 7.37-7.13 (m, ArH, 10H), 3.59 (s, CHOH, 1H), 3.50 (s,
CH2ArH, 2H), 3.00-2.90 (m, CH2, 1H), 2.89-2.71 (m, OH,
CH2, 3H), 2.61-2.49 (m, CH2, 1H), 2.13-2.04 (m, CH2,
1H), 2.00-1.86 (m, CH2, 1H), 1.68-1.38 (m, CH, CH2, 3H).
(3S, 4S)-4-Benzyl-piperidin-3-ol (S,S)-6. A solution of
35.6 g of crude (S,S)-5 (126.6 mmol) in 400.0 mL of ethanol
was treated at room temperature with 6.7 g of Pd/C 10%
(6.3 mmol). The black suspension was stirred under H2 for
2 h at 55 °C. Subsequent filtration and evaporation of the
solvent yielded 25.3 g of the crude product (S,S)-6 as
amorphous material. This material was dissolved at 100 °C
in 100 mL of toluene, cooled to 65 °C, and treated with 125
mL of hexane. The so-formed suspension was cooled to 35
°C and treated again with 125 mL of hexane. The suspension
was stirred for 48 h at 0 °C and filtered to yield 10.0 g of
product (S,S)-6 as white crystals. The mother liquor was
dissolved at 90 °C in 45 mL of toluene, treated at 55 °C
with 55 mL of hexane, cooled to 45 °C, and 55 mL of hexane
was again added. The suspension was stirred for 16 h at room
temperature and for 3 h at 0 °C and filtered to yield 9.7 g of
product (S,S)-6 as white crystals. Yield: 81% over two steps.
1H NMR (400 MHz, CDCl3) δ ) 7.31-7.14 (2m, ArH, 5H),
3.58 (s, CHOH, 1H), 3.09-2.98 (m, CH2, 2H), 2.79-2.71
(m, CH2, 1H), 2.65-2.49 (m, OH, NH, CH2 (1H), CH2, 5H),
1.71-1.61 (m, CH, 1H), 1.61-1.48 (m, CH2, 1H), 1.46-
1
of crude ester 3. H NMR (400 MHz, CDCl3) δ ) 7.31-
7.09 (m, 2 × ArH, 10H), 4.06 (q, COOCH2, 2 H, J ) 7.2),
3.53 (d, CH2ArH, 1H, J ) 13.2), 3.48 (d, CH2ArH, 1H, J )
13.2), 3.25 (d, NCH2CO, 1H, J ) 14.0), 3.14 (d, CH2ArH,
1H, J ) 15.6), 3.02 (d, CH2ArH, 1H, J ) 16.0), 2.91 (d,
NCH2CO, 1H, J ) 13.6), 2.74-2.65 (m, CH2, 1H), 2.60-
2.44 (m, CH2, 2H), 1.69-1.60 (m, CH2, 1H), 1.10 (t, CH3,
3H, J ) 7.2). IR (film) selected cm-1: 3029, 2931, 2801,
1722, 1604, 1584, 1495, 1454, 1367, 1297, 1237, 1194, 1095,
1028, 917, 860, 776, 743, 702. MS (ISP): 352 (100%, [M
+ H]+), 174 (15).
1,4-Dibenzyl-3-oxo-piperidine Hydrochloride 4*HCl.
A solution of 118.0 g (0.34 mol) of crude 1,4-dibenzyl-3-
oxo-piperidine-4-carboxylic acid ethyl ester (3) in 118.0 mL
of absolute ethanol was cooled to 0 °C, and subsequently
405 mL (4.9 mol) of 37% hydrochloric acid was cautiously
added. The reaction temperature was kept below 7 °C. Finally
the mixture was heated under reflux for 19 h. To the dark-
brown solution was added some crystals of 1,4-dibenzyl-3-
oxo-piperidine hydrochloride, and then the mixture was
allowed to cooled to room temperature and was further stirred
for 2 h. The resulting crystals were isolated on a Buchner
funnel, washed twice with 60 mL of deionized water, and
dried to yield 102.2 g of crude product 4*HCl. Then 400
mL of ethyl acetate was added to the crude product, and the
mixture refluxed for 2 h and cooled to room temperature.
The resulting beige suspension was filtered, and the crystals
were washed twice with 50 mL of ethyl acetate and dried to
yield 82.2 g (78% over two steps) of 4*HCl. 1H NMR (400
MHz, CDCl3) E/Z isomers of the salt, very broad peaks δ
) 11.48, 11.75 (2s, HCl, 1H), 7.65-7.40 (m, ArH, 5H),
7.32-7.11 (m, ArH, 5H), 4.49-4.28 (m, CH2ArH, 2H),
3.97-3.75 (m, CH2, 2H), 3.60-3.45 (m, CH2ArH, 2H),
Vol. 7, No. 3, 2003 / Organic Process Research & Development
•
423