Lithiated Amine Additions to Nitroalkenes
A R T I C L E S
7.27 (m, 3H, PhH), 7.35 (m, 2H, PhH); 13C NMR (CDCl3, 125.6 MHz)
δ 12.7 (CH), 18.0 (CH3), 18.0 (CH3), 32.8 (CH2), 46.0 (CH), 51.7 (CH3),
73.1 (CH), 77.7 (CH2), 127.6 (CH), 128.2 (CH), 128.8 (CH), 137.7
(C), 172.1 (C). Anal. Calcd for C21H35NO5Si: C, 61.58; H, 8.61; N,
3.42. Found: C, 61.72; H, 8.54; N, 3.52.
Representative Procedure for Benzyl Protection of Piperi-
dones: 1-Benzyl-4-phenylpiperidin-2-one (73). To a solution of 58
(0.400 g, 2.28 mmol) in THF (5 mL) under an N2 atmosphere at room
temperature was added NaH (0.164 g, 6.84 mmol), followed by benzyl
bromide (1.36 mL, 11.4 mmol). The mixture was stirred overnight and
carefully quenched with H2O (10 mL). The aqueous layer was extracted
with ether (3 × 15 mL), dried over MgSO4, and concentrated.
Purification by column chromatography (1:1 pet ether/EtOAc) gave
73 (0.514 g, 85%) as a white solid: mp 88-90 °C; 1H NMR (CDCl3,
500 MHz) δ 1.94 (m, 1 H, CH2CHPh), 2.08 (m, 1 H, CH2CHPh), 2.60
(dd, J ) 17.6, 10.9 Hz, 1H, CHCH2CO), 2.68 (ddd, J ) 17.4, 5.1, 1.9
Hz, 1H, CHCH2CO), 3.11 (tdd, J ) 11.2, 5.2, 3.0 Hz, 1H, CHPh),
3.29 (m, 2H, CHCH2N), 4.58 (d, J ) 14.5 Hz, 1H, PhCH2N), 4.75 (d,
J ) 14.5 Hz, 1H, PhCH2N), 7.19-7.37 (m, 10 H, PhH); 13C NMR
(CDCl3, 125.6 MHz) δ 30.0 (CH2), 38.5 (CH), 39.3 (CH2), 46.2 (CH2),
49.8 (CH2), 126.4 (CH), 126.7 (CH), 127.3 (CH), 128.1 (CH), 128.5
(CH), 128.6 (CH), 137.0 (C), 143.3 (C), 169.1 (C). Anal. Calcd for
C18H19NO: C, 81.47; H, 7.22; N, 5.28. Found: C, 81.36; H, 7.24; N,
5.42. [R]D20: -35.9° (c ) 1.1, CHCl3), >97:3 er lit.23 [R]D20: +35.0°
(c ) 1.1, CHCl3), 96:4 er.
Representative Procedure for Enolization and Substitution of
2-Piperidones with t-BuLi. Conversion of 73 to 77, Part 1: 1,3-
Dibenzyl-4-phenylpiperidin-2-one. To a solution of 73 (0.250 g, 0.942
mmol) in THF (19 mL) at -78 °C was added t-BuLi (0.606 mL of a
1.7 M solution in pentane, 1.03 mmol). After stirring 20 min, BnBr
(0.224 mL, 1.88 mmol) was added, and the solution was stirred at -78
°C for 1.5 h and slowly warmed to room temperature. H2O (20 mL)
was added, and the aqueous was extracted with ether (3 × 20 mL).
The combined ether extracts were dried over MgSO4 and concentrated.
Purification of the residue by column chromatography (7:3 pet ether/
EtOAc) gave the title compound (0.285 g, 85%, >97:3 dr) as a colorless
oil. Major diastereomer: 1H NMR (CDCl3, 500 MHz) δ 1.89 (m, 2H,
CH2CHPh), 2.73 (dd, J ) 13.9, 4.9 Hz, 1H, CHCH2Ph), 2.84 (td, J )
9.6, 6.6 Hz, 1H, CHPh), 3.09 (m, 2H, CH2N, CHCH2Ph), 3.48 (dd, J
) 13.8, 4.9 Hz, 1H, CHCH2Ph), 4.48 (d, J ) 14.6 Hz, 1H, NCH2Ph),
4.89 (d, J ) 14.4 Hz, 1H, NCH2Ph), 7.13-7.38 (m, 15H, PhH); 13C
NMR (CDCl3, 125.6 MHz) δ 30.7 (CH2), 34.8 (CH2), 41.8 (CH), 46.2
(CH2), 48.4 (CH), 50.7 (CH2), 126.1 (CH), 126.8 (CH), 127.3 (CH),
127.3 (CH), 128.1 (CH), 128.5 (CH), 128.7 (CH), 130.0 (CH), 136.9
(C), 139.1 (C), 143.4 (C), 171.3 (C). HRMS-FAB (M + 1). Calcd for
C25H26NO: 356.2014. Found: 356.2016.
Representative Procedure for Catalytic Hydrogenation and
Cyclization to Lactams. Conversion of 22 to 57, Part 2: 4-Phenyl-
5-triisopropylsilanyloxypiperidin-2-one (57). To a solution of the
methyl ester (1.34 g, 3.27 mmol) in MeOH (50 mL) was added RaNi
(∼1.0 mL). The mixture was hydrogenated at 250 psi for 72 h. The
catalyst was filtered, and the filtrate was concentrated to an opaque
oil. Purification by column chromatography (3:2 pet ether/EtOAc) gave
1
the title compound (0.886 g, 78%, >99:1 dr) as a colorless oil. H
NMR (CDCl3, 500 MHz) δ 1.00 (m, 21 H, ((CH3)2CH)3Si), 2.59 (dd,
J ) 17.8, 4.7 Hz, 1H, CHCH2CON), 2.95 (dd, J ) 17.8, 6.4 Hz, 1H,
CHCH2CON), 3.24 (m, 3H, CHPh, NCH2), 4.16 (dt, J ) 5.6, 3.6 Hz,
1H, CHOTIPS), 7.21 (m, 3H, PhH), 7.30 (m, 2H, PhH), 7.37 (br s,
1H, NH); 13C NMR (CDCl3, 125.6 MHz) δ 12.2 (CH), 17.8 (CH3),
17.9 (CH3), 32.6 (CH2), 45.2 (CH), 46.3 (CH2), 69.3 (CH), 127.0 (CH),
127.3 (CH), 128.6 (CH), 140.9 (C), 172.2 (C). HRMS-FAB (M + 1).
Calcd for C20H34NO2Si: 348.2359. Found: 348.2359. [R]D20: +7.1°
(c ) 1.95, CHCl3).
Representative Procedure for Reduction to Piperidines: 3-(2-
Methoxyphenyl)-4-phenylpiperidine-1-carboxylic Acid tert-Butyl
Ester (61). To a solution of 55 (0.060 g, 0.213 mmol) in THF (1.5
mL) was added LAH (0.642 mL of a 1 M solution in THF, 0.642
mmol), and the solution was stirred at reflux for 4 h. The reaction was
cooled to room temperature, quenched carefully with saturated Na2-
SO4, filtered, and concentrated. The crude residue was redissolved in
CH2Cl2 (4 mL), and Boc2O (0.073 mL, 0.319 mmol) was added. The
solution was stirred for 1 h and concentrated. Purification by column
chromatography (8:1 pet ether/EtOAc) 61 (0.064 g, 82%) as a colorless
1
oil. H NMR (CDCl3, 500 MHz) δ 1.51 (s, 9H, Ot-Bu), 1.81 (td, J )
12.6, 3.9 Hz, 1H, CHCH2CH), 1.92 (m, 1H, CHCH2CH), 2.90 (m, 2H,
NCH2), 3.06 (m, 1H, CHPh), 3.47 (m 1H, CHPh), 3.72 (s, 3H, CH3-
OPh), 4.29 (m 2H, NCH2), 6.71 (d, J ) 8.4 Hz, 1H, PhH), 6.77 (t, J
) 7.3 Hz, 1H, PhH), 7.01-7.14 (m, 7H, PhH); 13C NMR (CDCl3, 125.6
MHz) δ 28.4 (CH3), 34.7 (CH2), 47.2 (CH), 55.3 (CH3), 56.2 (CH2),
60.3 (CH2), 79.3 (C), 110.5 (CH), 120.3 (CH), 125.9 (CH), 127.2 (CH),
127.4 (CH), 127.9 (CH), 141.7 (C), 129.5 (C), 144.1 (C), 154.8 (C),
157.2 (C). HRMS-FAB (M + 1). Calcd for C23H30NO3: 368.2226.
Found: 368.2225. [R]D20: -5.6° (c ) 0.25, CHCl3).
Representative Procedure for Reduction of Benzyl Lactams to
Benzyl Piperidines. Conversion of 73 to 77, Part 2: 1,3-Dibenzyl-
4-phenylpiperidine (77). To a solution of 1,3-dibenzyl-4-phenyl-
piperidin-2-one (0.160 g, 0.450 mmol) in THF (9 mL) was added LAH
(1.35 mL of a 1 M solution in THF, 0.1.35 mmol), and the solution
was stirred at reflux for 4 h. The reaction was cooled to room
temperature, quenched carefully with saturated Na2SO4, filtered, and
concentrated. Purification by column chromatography (7:3 pet ether/
EtOAc) gave 77 (0.137 g, 90%) as a colorless oil. Major diastere-
omer: 1H NMR (CDCl3, 500 MHz) δ 1.85 (m, 3H, CH2CHPh,
CHCH2Ph), 1.97 (td, J ) 10.9, 4.1 Hz, 1H, CH2N), 2.11 (m, 1H,
CHCH2Ph), 2.27 (m, 2H, CHPh, CHCH2Ph), 2.62 (d, J ) 12.8 Hz,
1H, NCH2), 2.94 (d, J ) 11.2 Hz, 1H, NCH2), 2.99 (d, J ) 11.1 Hz,
1H, NCH2), 3.35 (d, J ) 13.1 Hz, 1H, NCH2Ph), 3.68 (d, J ) 13.1 Hz,
1H, NCH2Ph), 7.03 (m, 2H, PhH), 7.14-7.40 (m, 13H, PhH); 13C NMR
(CDCl3, 125.6 MHz) δ 35.0 (CH2), 38.3 (CH2), 43.0 (CH), 49.3 (CH),
53.3 (CH2), 59.8 (CH2), 63.3 (CH2), 125.7 (CH), 126.3 (CH), 126.9
(CH), 127.8 (CH), 128.0 (CH), 128.1 (CH), 128.6 (CH), 128.9 (CH),
129.2 (CH), 138.1 (C), 140.4 (C), 145.1 (C). HRMS-FAB (M + 1).
Calcd for C25H28N: 342.2222. Found: 342.2223. [R]D20: +26.7° (c )
1.25, CHCl3).
Representative Procedure for Conversion of Enecarbamates to
4-Nitrobutyric Acid Methyl Esters. Conversion of 17 to 62, Part 1:
4-Nitro-2,3-diphenylbutyric Acid Methyl Ester. A solution of 17
(3.15 g, 6.44 mmol) in CH2Cl2 (90 mL) was cooled to -78 °C. O3
was bubbled through the solution until a purple solution persisted (∼30
min). O2 was then bubbled through the solution for 15 min at -78 °C
followed by the addition of dimethyl sulfide (5 mL). The solution was
slowly warmed to room temperature, stirred overnight, and concentrated.
The residue was dissolved in t-BuOH (140 mL) and 2-methyl-2-butene
(32.6 mL). A solution of NaClO2 (5.43 g, 59.4 mmol) and NaH2PO4
(5.43 g, 45.0 mmol) in H2O (54.0 mL) was added, and the resulting
yellow solution was stirred for 10 min. The solution was poured into
CH2Cl2 (220 mL) and acidified with 2.5% HCl (220 mL). The organic
layer was separated and the aqueous layer extracted with CH2Cl2 (3 ×
180 mL). The combined organics were dried over MgSO4 and
concentrated. Chromatography of the residue with 7:3 pet ether/EtOAc
and then 5% AcOH gave the crude acid, which was redissolved in
MeOH (90 mL) and treated with HCl (16.3 mL of a 2 N solution in
Et2O, 32.6 mmol). The solution was stirred for 72 h and concentrated.
Purification of the residue by column chromatography (6:1 pet ether/
EtOAc) gave the title compound (1.39 g, 72%, >99:1 dr) as a white
solid: mp 84-86 °C (lit.22 100-136 °C; mixture of diastereomers)
The 1H NMR spectrum was consistent with reported literature values.22
(22) Mahboobi, S.; Eibler, E.; Koller, M.; KC, S. K.; Popp, A.; Schollmeyer,
D. J. Org. Chem. 1999, 64, 4697.
(23) Senda, T.; Ogasawana, M.; Hayashi, T. J. Org. Chem. 2001, 66, 6852.
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J. AM. CHEM. SOC. VOL. 124, NO. 39, 2002 11697