The Journal of Organic Chemistry
Article
1A, EtOH, flow rate 0.5 mL/min, tR = 10.45 min (minor) and 13.41
min (major).
HPLC using CHIRALPAK 1A, EtOH, flow rate 0.5 mL/min, tR =
8.27 (minor) and 9.44 min (major).
(R)-3-((R)-2-Nitro-1-phenyl-ethyl)-tetrahydro-pyran-4-one
(S)-2-[(R)-1-(3,5-Dichloro-phenyl)-2-nitro-ethyl]-cyclohexanone
(31f).22 Purified by flash chromatography on silica gel (eluted with
hexane/EtOAc, 4/1). Colorless liquid (264 mg, 84% yield); [α]D25
(33a).22 White solid (161 mg, 65% yield); [α]D25 −29 (c 1.0, CHCl3)
[lit. [α]2D5 −34 (c 1.0, CHCl3)]; H NMR (400 MHz, CDCl3): δ
1
−26.2 (c 0.42, CHCl3), [lit. [α]2D5 −25.4 (c 0.36, CHCl3)]; H NMR
1
7.35−7.28 (m, 3H), 7.18−7.16 (m, 2H), 4.92 (dd, J = 12.68 and 4.44
Hz, 1H), 4.62 (dd, J = 12.52 and 10.12 Hz, 1H), 4.14−4.12 (m, 1H),
3.82−3.67 (m, 3H), 3.26 (dd, J = 11.32 and 8.92 Hz, 1H), 2.88−2.87
(m, 1H), 2.58−2.54 (m, 2H); HPLC analysis: 98% ee, Chiral HPLC
using CHIRALPAK 1A, EtOH, flow rate 1.0 mL/min, tR = 14.06
(minor) and 23.66 min (major).
(400 MHz, CDCl3): δH 7.27 (brs, 1H), 7.07 (brs, 2H), 4.92 (dd, J =
12.92 and 4.32 Hz, 1H), 4.62−4.56 (m, 1H), 3.75−3.71 (m, 1H),
2.65−2.60 (m, 1H), 2.49−2.46 (m, 1H), 2.39−2.35 (m, 1H), 2.10
(brs, 1H), 1.85−1.81 (m, 1H), 1.75−1.62 (m, 3H), 1.27−1.24 (m,
1H); HPLC analysis: 92% ee, Chiral HPLC using CHIRALPAK IF-3,
EtOH, flow rate 0.3 mL/min, tR = 13.04 min (minor) and 13.94 min
(major).
(S)-3-((R)-2-Nitro-1-phenyl-ethyl)-tetrahydro-thiopyran-4-one
(33b).22 Purified by flash chromatography on silica gel (eluted with
hexane/EtOAc, 3/2). White solid (159 mg, 60% yield); [α]2D5 −22.6
(c 0.52, CHCl3) [lit. [α]2D5 −26.9 (c 1.0, CHCl3)]; 7.36−7.25 (m,
3H), 7.19−7.18 (m, 2H),4.73 (dd, J = 12.56 and 4.52 Hz, 1H), 4.62
(dd, J = 12.64 and 9.84 Hz, 1H), 4.0−3.94 (m, 1H), 3.07−2.96 (m,
3H), 2.93−2.75 (m, 2H), 2.63−2.58 (m, 1H), 2.48−2.44 (m, 1H);
HPLC analysis: 91% ee, Chiral HPLC using CHIRALPAK 1A, EtOH,
flow rate: 0.5 mL/min, tR = 11.0 (minor) and 28.22 min (major).
(R)-tert-Butyl 3-((R)-2-Nitro-1-phenylethyl)-4-oxopiperidine-1-
carboxylate (33c). White solid (222 mg, 64% yield); [α]2D5 +11.46
(S)-2-((R)-1-(4-Morpholinophenyl)-2-nitroethyl)cyclohexanone
(31g). White solid (278 mg, 84% yield); [α]2D5 −24.19 (c 0.5, CHCl3);
1H NMR (400 MHz, CDCl3): δH 7.05 (d, J = 8.56 Hz, 2H), 6.83 (d, J
= 8.56 Hz, 2H), 4.88 (dd, J = 12.24 and 4.56 Hz, 1H), 4.60−4.55 (m,
1H), 3.84−3.82 (m, 4H), 3.70−3.65 (m, 1H), 3.14−3.12 (m, 4H),
2.66−2.60 (m, 1H), 2.48−2.43 (m, 1H), 2.40−2.33 (m, 1H), 2.07−
2.03 (m, 1H), 1.76−1.56 (m, 4H), 1.28−1.26 (m, 1H); 13C{1H}
NMR (100 MHz, CDCl3): δC 212.1, 150.5, 128.9, 128.5, 115.6, 79.0,
66.8, 52.6, 48.9, 43.1, 42.6, 33.1, 28.5, 24.9; HPLC analysis: 98% ee,
Chiral HPLC using CHIRALPAK IA, EtOH, flow rate 0.5 mL/min, tR
= 14.49 min (minor) and 17.60 min (major); HRMS (ESI-TOF) m/
z: [M + H]+ calcd for C18H25N2O4, 333.1815; found, 333.1845.
(S)-2-((R)-2-Nitro-1-pyridin-3-yl-ethyl)-cyclohexanone (31h).22
Purified by flash chromatography on silica gel (eluted with hexane/
EtOAc, 3/2). Light-brown solid (188 mg, 76% yield); [α]2D5 −9.6 (c
1.04, CHCl3); [lit. [α]D25 −22 (c 0.48, CHCl3)]; 1H NMR (400 MHz,
CDCl3): δH 8.53−8.47 (m, 2H), 7.53 (d, J = 7.72 Hz, 1H), 7.28 (brs,
1H), 4.94 (dd, J = 12.80 and 4.60 Hz, 1H), 4.71−4.66 (m, 1H),
3.84−3.78 (m, 1H), 2.75−2.69 (m, 1H), 2.50−2.34 (m, 2H), 2.11−
2.07 (m, 1H), 1.84−1.60 (m, 3H), 1.31−1.21 (m, 2H); HPLC
analysis: 100% ee, Chiral HPLC using CHIRALPAK 1A, (hexane/
EtOH/IPA: 80/20/0.1), flow rate 1.0 mL/min, tR = 18.08.
(S)-2-((R)-1-(1-Methyl-1H-indol-3-yl)-2-nitroethyl)cyclohexanone
(31i). Purified by flash chromatography on silica gel (eluted with
hexane/EtOAc, 4/1). Light-brown semisolid (258 mg, 86% yield);
[α]2D5 −11 (c 0.5, CHCl3); 1H NMR (400 MHz, CDCl3): δH 7.54 (d, J
= 7.88 Hz, 1H), 7.30−7.27 (m, 1H), 7.22−7.20 (m, 1H), 7.13−7.09
(m, 1H), 6.90 (brs, 1H), 4.90−4.79 (m, 2H), 4.12−4.02 (m, 1H),
3.73 (s, 3H), 2.94−2.90 (m, 1H), 2.49−2.38 (m, 2H), 2.03 (brs, 1H),
1.93−1.90 (m, 1H), 1.78−1.65 (m, 2H), 1.34−1.23 (m, 2H);
13C{1H} NMR (100 MHz, CDCl3): δC 212.4, 137.1, 127.8, 126.7,
1
(c 0.5, CHCl3); H NMR (400 MHz, CDCl3): δH 7.35−7.28 (m,
3H), 7.19−7.17 (m, 2H), 4.92 (dd, J = 12.44 and 4.64 Hz, 1H),
4.67−4.59 (m, 1H), 4.20−4.09 (m, 1H), 3.79 (brs, 2H), 3.25−3.19
(m, 1H), 2.77−2.67 (m, 2H), 2.55−2.38 (m, 2H), 1.38 (s, 9H);
13C{1H} NMR (100 MHz, CDCl3): δC 208.3, 154.0, 129.2, 129.0,
128.2, 128.1, 128.0, 80.7, 78.8, 44.2, 41.8, 41.7, 40.8, 28.2; HPLC
analysis: 76% ee, Chiral HPLC using CHIRALPAK 1G, (hexane/
DCM/EtOH: 80/10/10), flow rate: 1.0 mL/min, tR= 6.68 (major)
and 7.23 min (minor); Anal. Calcd. for C18H24N2O5: C, 62.05; H,
6.94; N, 8.04. Found: C, 62.01; H, 7.01; N, 8.01.
(R)-5-Nitro-4-phenyl-pentan-2-one (33d).22 Purified by flash
chromatography on silica gel (eluted with hexane/EtOAc, 4/1).
White solid (101 mg, 49% yield); [α]2D5 −4.4 (c 0.42, CHCl3) [lit.
[α]2D5 −0.70 (c 1.0, CHCl3)]; 1H NMR (400 MHz, CDCl3): δH 7.34−
7.30 (m, 2H), 7.28 (brs, 1H), 7.21−7.19 (m, 2H), 4.71−4.66 (m,
1H), 4.62−4.57 (m, 1H), 4.03−3.98 (m, 1H), 2.91 (d, J = 7.00 Hz,
2H), 2.11 (s, 3H); HPLC analysis: 55% ee, Chiral HPLC using
CHIRACEL OJ-H (hexane/EtOH/IPA: 60/40/0.1), flow rate 1.0
mL/min, tR= 12.69 (minor) and 17.33 min (major).
(3S,4R)-3-Methyl-5-nitro-4-phenylpentan-2-one (33e).22 White
solid (77 mg, 35% yield); [α]2D5 −13.6 (c 0.3, CHCl3) [lit. [α]2D5
−11.04 (c 0.2, CHCl3); 1H NMR (400 MHz, CDCl3): δH 7.34−7.24
(m, 3H), 7.15 (d, J = 7.48 Hz, 2H), 4.69−4.59 (m, 2H), 3.69−3.63
(m, 1H), 2.99−2.95 (m, 1H), 2.22 (s, 3H), 0.97 (d, J = 7.12 Hz, 3H);
HPLC analysis: 89% ee, Chiral HPLC using CHIRALPAK IG
(hexane/EtOH/IPA): 80/20/0.1, flow rate 1.0 mL/min, tR = 12.10
(minor) and 20.16 min (major).
121.8, 119.3, 118.6, 110.4, 109.6, 78.5, 52.3, 42.7, 35.9, 33.3, 32.7,
28.5, 25.1; HPLC analysis: 93% ee, Chiral HPLC using CHIRALPAK
IA, (hexane/EtOH/IP amine: 80/20/0.1), flow rate 1.0 mL/min, tR =
6.81 min (minor) and 10.75 min (major); Anal. Calcd. for
C17H20N2O3: C, 67.98; H, 6.71; N, 9.33. Found: C, 67.92; H, 6.77;
N, 9.27.
(S)-2,2-Dimethyl-4-nitro-3-phenylbutanal (33f).26,27 Purified by
flash chromatography on silica gel (eluted with hexane/EtOAc, 3/1).
Colorless liquid (59 mg, 27%); [α]2D5 +1.2 (c 1, CHCl3) [lit. [α]2D5
−4.9 (c 1.0, CHCl3)]; 1H NMR (400 MHz, CDCl3): δH 9.52 (s, 1H),
7.35−7.28 (m, 3H), 7.19−7.7.18 (m, 2H), 4.83 (dd, J = 13.04 and
11.28 Hz, 1H), 4.68 (dd, J = 13.04 and 4.2 Hz, 1H), 3.77 (dd, J =
11.28 and 4.2 Hz, 1H), 1.13 (s, 3H), 1.00 (s, 3H). HPLC analysis:
69% ee, Chiral HPLC using CHIRACEL OD-H (hexane/IPA: 80/
20), flow rate 1.0 mL/min, tR= 16.53 (minor) and 23.38 min (major).
(3R,3aS,7aR)-3-(Naphthalen-2-yl)octahydro-1H-indole (34a)
and (3R,3aS,7aS)-3-(Naphthalen-2-yl)octahydro-1H-indole
(34b).22,28 To a stirred solution of 31b (200 mg, 0.67 mmol) in
methanol (10 mL) was added 20% Pd(OH)2 on carbon and the
mixture was stirred under a hydrogen atmosphere at room
temperature for 16 h in a Parr shaker at 50 psi pressure. After
completion of the reaction, the mixture was filtered through Celite
bed and the filtrate was concentrated in vacuo. The crude product was
purified by preparative HPLC to afford (3R,3aS,7aR)-3-(naphthalen-
2-yl)octahydro-1H-indole 34a (80 mg, 47%) as a light-brown
semisolid and (3R,3aS,7aS)-3-(naphthalen-2-yl)octahydro-1H-indole
34b (51 mg, 30%) as an off-white solid.
(S)-2-((R)-2-Nitro-1-thiophen-3-yl-ethyl)-cyclohexanone (31j).22
White solid (237 mg, 94% yield);[α]2D5 −17.2 (c 1.01, CHCl3); [lit
[α]2D5 −28.2 (c 0.42, CHCl3)]; H NMR (400 MHz, CDCl3): δ 7.29
1
(dd, J = 4.92 and 2.96 Hz, 1H), 7.0 (s, 1H), 6.92 (dd, J = 4.96 and
1.16 Hz, 1H), 4.83 (dd, J = 12.32 and 4.88 Hz, 1H), 4.62 (dd, J =
12.32 and 9.28 Hz, 1H), 3.99−3.93 (m, 1H), 2.69−2.62 (m, 1H),
2.47−2.32 (m, 2H), 2.10−2.06 (m, 1H), 1.83−1.66 (m, 4H), 1.30−
1.21 (m, 1H); HPLC analysis: 97% ee, Chiral HPLC using
CHIRALPAK 1A, EtOH, flow rate 0.5 mL/min, tR = 10.36 min
(minor) and 11.49 min (major).
(S)-2-((S)-1-Cyclopropyl-2-nitro-ethyl)-cyclohexanone (31k).22
Purified by flash chromatography on silica gel (eluted with hexane/
EtOAc, 3/1). Colorless liquid (160 mg, 76% yield);[α]2D5 −33.17 (c
0.52, CHCl3); [lit. [α]D25 −17.81 (c 0.5, CHCl3)]; H NMR (400
1
MHz, CDCl3): δH 4.69 (dd, J = 11.68 and 6.12 Hz, 1H), 4.50 (dd, J =
11.68 and 4.84 Hz, 1H), 2.70−2.64 (m, 1H), 2.42−2.33 (m, 3H),
2.12−2.09 (m, 1H), 1.95−1.92 (m, 1H), 1.75−1.66 (m, 3H), 1.48
(brs, 1H), 0.79−0.73 (m, 1H), 0.54 (d, J = 7.64 Hz, 2H), 0.23−0.16
(m, 2H); GCMS (M-NO2)+ = 164.25; HPLC analysis: 98% ee, Chiral
5223
J. Org. Chem. 2021, 86, 5213−5226