Asymmetric Synthesis of 4-Aryl-2-piperidinones
J . Org. Chem., Vol. 66, No. 21, 2001 6855
1.8 Hz, 1H), 6.55 (dt, J ) 9.9, 4.2 Hz, 1H), 7.24-7.35 (m, 5H);
13C NMR (CDCl3) δ 24.18, 44.58, 49.68, 125.41, 127.38, 128.01,
128.59, 137.46, 139.41, 164.52. Anal. Calcd for C12H13NO: C,
76.98; H, 7.00. Found: C, 77.24; H, 7.15.
J ) 8.2, 6.2 Hz, 6H); 13C NMR (CDCl3) δ 115.30 (d, J CF ) 20.7
Hz), 138.02 (d, J CF ) 8.2 Hz), 166.13 (d, J CF ) 252.2 Hz). Anal.
Calcd for C18H12B3F3O3: C, 59.12; H, 3.31. Found: C, 58.83;
H, 3.39. 4-Ch lor op h en ylbor oxin e (4c): 1H NMR (CDCl3) δ
7.49 (d, J ) 8.3 Hz, 6H), 8.14 (d, J ) 8.3 Hz, 6H); 13C NMR
(CDCl3) δ 128.46, 136.99, 139.40. Anal. Calcd for C18H12B3-
Cl3O3: C, 52.08; H, 2.91. Found: C, 51.80; H, 3.12.
P r ep a r a tion of (R)-2,2′-Bis[bis(3,5-d im eth yl-4-m eth -
oxyp h en yl)p h osp h in o]-1,1′-bin a p h th yl ((R)-bin a p *). Bis-
(3,5-d im eth yl-4-m eth oxyp h en yl)p h osp h in e Oxid e. Finely
divided sodium (18.6 g 80.8 mmol) was placed in a flask under
nitrogen with dry THF (600 mL). To this was added (EtO)2POH
(110 g, 80.0 mmol) by means of syringe, and then the mixture
was refluxed until evolution of hydrogen gas was ceased. The
solution was cooled with ice-water, and to this was added a
THF solution of (3,5-Me-4-MeO-C6H2)MgBr (ca. 180 mmol),
which was prepared from 1-Br-3,5-Me-4-MeO-C6H2 and Mg,
at this temperature by means of cannula transfer. After
refluxing the mixture for 1 h, the remaining excess Grignard
reagent was quenched with dil HCl, and then most of THF
was removed using a rotary evaporator. The residue was
dissolved in a mixture of chloroform-H2O and separated. The
aquaous layer was extracted with chloroform twice, and the
combined organic phase was dried over MgSO4. Evaporation
of the solvent gave the crude material. The crude material was
purified by silica gel chromatography (with acetone/hexane )
1/1). The product was highly viscous colorless oil and not all
the solvent could be eliminated. This material is sufficiently
pure for the next step and used without further purification.
Rh od iu m -Ca ta lyzed Asym m etr ic 1,4-Ad d ition of Ar yl-
bor oxin es to 5,6-Dih yd r o-2(1H)-p yr id in on es. The results
are summarized in Tables 1 and 2. A typical procedure is given
for the preparation of N-benzyl-4-(4-fluorophenyl)-2-piperidi-
none (3a ) with 4-fluorophenylboroxine (4a ) (Table 1, entry 8):
To a mixture of Rh(acac)(C2H4)2 (1.6 mg, 6.0 µmol), (R)-binap*
(5.6 mg, 6.6 µmol), and 4-fluorophenylboroxine (122 mg, 0.33
mmol; 4a ) was added 1,4-dioxane (1.0 mL), and the mixture
was stirred at room temperature for 3 min. N-Benzyl-5,6-
dihydro-2(1H)-pyridinone (37.4 mg, 0.20 mmol; 1) and water
(18 µL) were added, and the whole mixture was stirred at 40
°C for 12 h. After evaporation of the solvent, the residue was
dissolved in ethyl acetate. The solution was washed with
saturated sodium bicarbonate and dried over anhydrous
magnesium sulfate. Chromatography on silica gel (hexane/
ethyl acetate ) 1/1) gave (41.9 mg, 74% yield) of N-benzyl-4-
(4-fluorophenyl)-2-piperidinone (3a ). N-Ben zyl-4-(4-flu o-
r op h en yl)-2-p ip er id in on e (3a ):2 1H NMR (CDCl3) δ 1.90
(dddd, J ) 13.4, 11.2, 10.5, 5.8 Hz, 1H), 2.06 (br d, J ) 13.4
Hz, 1H), 2.55 (dd, J ) 17.5, 11.0 Hz, 1H), 2.80 (ddd, J ) 17.5,
5.3, 2.1 Hz, 1H), 3.09 (tdd, J ) 11.2, 5.3, 3.1 Hz, 1H), 3.23-
3.33 (m, 2H), 4.55 (d, J ) 14.6 Hz, 1H), 4.74 (d, J ) 14.6 Hz,
1H), 7.01 (t, J ) 8.6 Hz, 2H), 7.15 (dd, J ) 8.6 Hz, 2H), 7.26-
7.30 (m, 3H), 7.32-7.36 (m, 2H); 13C NMR (CDCl3) δ 30.31,
37.97, 39.60, 46.20, 50.00, 115.51 (d, J CF ) 21.8 Hz), 127.45,
127.91 (d, J CF ) 7.3 Hz), 128.16, 128.61, 137.02, 139.06 (d,
1
Yield: 22.4 g (88%). H NMR (CDCl3) δ 2.31 (s, 12H), 3.75 (s,
6H), 7.34 (d, J PH ) 13.7 Hz, 4H), 7.91 (d, J PH ) 477 Hz, 1H);
13C NMR (CDCl3) δ 16.11, 59.62, 131.26 (d, J PC ) 11.9 Hz),
131.93 (d, J PC ) 14.5 Hz), 133.02 (d, J PC ) 8.8 Hz), 160.54 (d,
J PC ) 3.6 Hz); 31P NMR (CDCl3) δ 22.0. Bis(3,5-d im eth yl-4-
m eth oxyp h en yl)p h osp h in e. To a solution of bis(3,5-dim-
ethyl-4-methoxyphenyl)phosphine oxide (20.2 g, 63.5 mmol)
in dry Et2O (ca. 150 mL) was added LiAlH4 (2.5 g, 65.9 mmol)
in a small portion under nitrogen. The mixture was stirred at
room temperature for 3 h and then quenched with degassed
water with external cooling. The mixture was filtered, and the
precipitate was washed with ether. The combined ether
solution was evaporated under reduced pressure, and the
residual yellow oil was purified by column chromatography
over SiO2 with Et2O under nitrogen. The title compound was
obtained as a colorless oil, and this material was sufficiently
pure for the next step without further purification. Yield: 13.9
g (72%). 1H NMR (CDCl3) δ 2.25 (s, 12H), 3.70 (s, 6H), 5.07 (d,
J PH ) 19.0 Hz, 1H), 7.12 (d, J PH ) 7.4 Hz, 4H); 13C NMR
(CDCl3) δ 16.07, 59.66, 129.47 (d, J PC ) 8.8 Hz), 131.16 (d,
J PC ) 7.2 Hz), 134.61 (d, J PC ) 18.1 Hz), 157.57; 31P NMR
(CDCl3) δ -41.6. (R)-2,2′-Bis[bis(3,5-d im eth yl-4-m eth ox-
yp h en yl)p h osp h in o]-1,1′-bin a p h th yl ((R)-bin a p *). A DMF
(20 mL) solution of NiCl2(dppe) (530 mg, 1.00 mmol) and bis-
(3,5-dimethyl-4-methoxyphenyl)phosphine (1.74 g, 5.75 mmol)
was stirred at 100 °C for 30 min under nitrogen. To this was
added a solution of (R)-2,2′-bis[(trifluoromethanesulfonyl)oxy]-
1,1′-binaphthyl (5.50 g, 10.0 mmol) and DABCO (4.5 g, 40
mmol) in DMF (30 mL) by means of cannula transfer and the
solution was stirred at 100 °C. Three additional portions of
the diarylphosphine (1.74 g × 3) were added at 1, 3, and 7 h
later. The solution was stirred at 100 °C for 5 days, however,
complete consumption of the ditriflate could not be achieved.
The solution was evaporated to dryness at 80 °C, and a dark
brown residue was chromatographed over SiO2 under nitrogen
with benzene as an eluent to give the title compound as a
colorless solid. An analytically pure sample was obtained by
recrystallization from DMF as colorless crystals. Yield: 2.23
J CF ) 3.1 Hz), 161.62 (d, J CF ) 244.9 Hz), 169.00. [R]20 +33
D
(c 1.07, CHCl3) for 3a of 95.9% ee. Chiral HPLC conditions:
Daicel Chiralpak AD (hexane/2-propanol ) 9/1). N-Ben zyl-
4-p h en yl-2-p ip er id in on e (3b): 1H NMR (CDCl3) δ 1.93
(dddd, J ) 13.2, 11.1, 10.7, 5.7 Hz, 1H), 2.04-2.11 (m, 1H),
2.60 (dd, J ) 17.5, 11.1 Hz, 1H), 2.81 (ddd, J ) 17.5, 5.2, 2.1
Hz, 1H), 3.10 (tdd, J ) 11.1, 5.2, 3.2 Hz, 1H), 3.23-3.34 (m,
2H), 4.57 (d, J ) 14.6 Hz, 1H), 4.73 (d, J ) 14.6 Hz, 1H), 7.19
(d, J ) 7.4 Hz, 2H), 7.24 (t, J ) 7.4 Hz, 1H), 7.27-7.36 (m,
7H); 13C NMR (CDCl3) δ 30.24, 38.68, 39.47, 46.34, 50.02,
126.51, 126.80, 127.42, 128.17, 128.61, 128.73, 137.13, 143.41,
169.26. Anal. Calcd for C18H19NO: C, 81.47; H, 7.22. Found:
C, 81.65; H, 7.30. [R]20 +35 (c 1.10, CHCl3) for 3b of 92.5%
D
ee. Chiral HPLC conditions: Daicel Chiralpak AD (hexane/2-
propanol ) 9/1). N-Ben zyl-4-(4-ch lor op h en yl)-2-p ip er id i-
n on e (3c): 1H NMR (CDCl3) δ 1.90 (dtd, J ) 13.4, 11.0, 5.6
Hz, 1H), 2.05 (br d, J ) 13.4 Hz, 1H), 2.54 (dd, J ) 17.5, 11.0
Hz, 1H), 2.79 (ddd, J ) 17.5, 4.8, 1.6 Hz, 1H), 3.08 (tdd, J )
11.0, 4.8, 3.2 Hz, 1H), 3.22-3.33 (m, 2H), 4.55 (d, J ) 14.6
Hz, 1H), 4.73 (d, J ) 14.6 Hz, 1H), 7.11 (d, J ) 8.4 Hz, 2H),
7.26-7.31 (m, 5H), 7.31-7.36 (m, 2H); 13C NMR (CDCl3) δ
30.08, 38.09, 39.35, 46.12, 49.99, 127.45, 127.84, 128.14,
128.61, 128.83, 132.50. 136.98, 141.79, 168.84. Anal. Calcd for
C18H18ClNO: C, 72.11; H, 6.05. Found: C, 72.17; H, 6.09. [R]20
D
+41 (c 1.28, CHCl3) for 3c of 95.2% ee. Chiral HPLC condi-
tions: Daicel Chiralpak AD (hexane/2-propanol ) 9/1). 4-(4-
F lu or op h en yl)-2-p ip er id in on e (6a ): 1H NMR (CDCl3) δ
1.84-1.96 (m, 1H), 2.06 (br d, J ) 13.0 Hz, 1H), 2.44 (dd, J )
17.6, 11.1 Hz, 1H), 2.67 (dd, J ) 17.6, 4.2 Hz, 1H), 3.09 (tdd,
J ) 11.1, 4.9, 3.2 Hz, 1H), 3.38-3.44 (m, 2H), 7.03 (t, J ) 8.5
Hz, 2H), 7.07 (br s, 1H), 7.18 (dd, J ) 8.5, 5.4 Hz, 2H); 13C
1
g (26%). H NMR (CDCl3) δ 2.06 (s, 12H), 2.07 (s, 12H), 3.63
NMR (CDCl3) δ 29.56, 37.64, 38.81, 41.16, 115.50 (d, J CF
)
(s, 6H), 3.65 (s, 6H), 6.68-6.70 (m, 4H), 6.80-6.81 (m, 6H),
6.95 (ddd, J ) 8.4, 6.7, 1.3 Hz, 2H), 7.35 (ddd, J ) 8.2, 6.7, 1.2
Hz, 2H), 7.50-7.52 (m, 2H), 7.83 (br d, J ) 8.2 Hz, 2H), 7.86
22.0 Hz), 127.93 (d, J CF ) 7.3 Hz), 139.20 (d, J CF ) 3.1 Hz),
161.56 (d, J CF ) 244.9 Hz), 172.00. Anal. Calcd for C11H12
-
(br d, J ) 8.2 Hz, 2H); 31P NMR (CDCl3) δ -15.1. [R]20 +93
FNO: C, 68.38; H, 6.26; N, 7.25. Found: C, 68.31; H, 6.29; N,
D
7.19. [R]20 +19 (c 1.02, CHCl3) for 6a of 98.3% ee. Chiral
(c 1.01, CHCl3). Anal. Calcd for C56H56O4P2: C, 78.67; H, 6.60.
Found: C, 78.54; H, 6.73.
D
HPLC conditions: Daicel Chiralpak AD (hexane/2-propanol )
9/1). 4-(4-Ch lor op h en yl)-2-p ip er id in on e (6c): 1H NMR
(CDCl3) δ 1.86-1.97 (m, 1H), 2.04-2.11 (m, 1H), 2.45 (dd, J
) 17.6, 11.0 Hz, 1H), 2.67 (ddd, J ) 17.6, 5.3, 1.7 Hz, 1H),
3.09 (tdd, J ) 11.0, 5.3, 3.2 Hz, 1H), 3.38-3.45 (m, 2H), 6.58
P r ep a r a tion of Ar ylbor oxin es 4. They were prepared
from the corresponding arylboronic acids by azeotropic removal
of water from benzene solution. 4-F lu or op h en ylb or oxin e
(4a ): 1H NMR (CDCl3) δ 7.19 (t, J ) 8.7 Hz, 6H), 8.22 (dd,