7402
S.J. Canipa et al. / Tetrahedron 70 (2014) 7395e7403
ꢁ
EtOAc (4:1) as eluent gave alcohol (R)-21 (49 mg, 46%, 94:6 er by
23 (642 mg, 88% over two steps) as a white solid, mp 51e52 C, [
þ48.6 (c 1.05, CHCl ); R (9:1 EtOAc/MeOH) 0.6; IR (CHCl ) 3610,
3421, 3019, 1667 (C]O), 1537, 1216 cm H NMR (400 MHz,
CDCl
: 7.39e7.28 (m, 5H, Ph), 7.06 (br s, 1H, NH), 4.85 (dd, J¼8.0,
3.5 Hz, 1H, CHOH), 4.05 (d, J¼15.5 Hz, 1H, CH Cl), 4.01 (d,
J¼15.5 Hz, 1H, CH Cl), 3.72 (ddd, J¼13.5, 7.0, 3.5 Hz, 1H, NCH
3.37 (ddd, J¼13.5, 8.0, 5.0 Hz, 1H, NCH
NMR (100.6 MHz, CDCl
28.1 (Ph), 125.7 (Ph), 72.9 (CHOH), 47.1 (CH
a]
D
1
CSP-HPLC) as a colourless oil; H NMR (400 MHz, CDCl
3
)
d:
3
f
3
ꢀ
1
1
8
.28e8.26 (m, 2H, Ph), 7.65e7.63 (m, 2H, Ph), 5.62 (dt, J¼8.0, 4.0 Hz,
H, CHOH), 4.62 (dd, J¼14.0, 8.0 Hz, 1H, CH NO ), 4.57 (dd,
NO
), 3.23 (d, J¼4.0 Hz, 1H, OH); CSP-
HPLC: Daicel Chiracel OD 85:15 hexane/i-PrOH, 0.8 mL min
;
1
A
H
B
2
3
) d
J¼14.0, 4.0 Hz, 1H, CH
A
H
B
2
A B
H
ꢀ
1
,
A
H
B
A
H
B
),
C
1
3
2
54 nm, 25.9 min [(R)-21], 33.3 min [(S)-21]. Spectroscopic data are
A B
H ), 3.13 (br s, 1H, OH);
: 166.8 (C]O), 141.3 (ipso-Ph), 128.6 (Ph),
21
consistent with those reported in the literature.
3
)
d
1
2
), 42.5 (CH ); MS (ESI)
2
þ
35
4
.35. (S)-2-Nitro-1-(4-nitrophenyl)ethanol (S)-21 (Table 4,
m/z 236 [(MþNa) ]; HRMS (ESI) m/z calcd for C10
H12ClNO
2
entry 8)
(MþNa)þ 236.0449, found 236.0457 (þ3.5 ppm error).
Using general procedure D, 4-nitrobenzaldehyde (76
mL,
4.39. (S)-6-Phenylmorpholin-3-one (S)-24
0
.5 mmol), Cu[(þ)-2]Cl
2
(33 mg, 0.1 mmol, 20 mol %), nitromethane
(
54 L, 1.0 mmol) and Et
m
3
N (0.21 mL of a 1 vol % solution in MeOH,
A solution of the chloroacetamide (S)-23 (223 mg, 1.05 mmol) in
t-AmOH (5 mL) was added over 30 min to a stirred solution of t-
BuOK (148 mg, 1.26 mmol) in t-AmOH (2 mL) at rt under Ar. The
resulting solution was stirred at rt for 3 h. Then, MeOH (1 mL) and
water (1 mL) were added and the reaction mixture was stirred for
a further 20 min. The solvent was evaporated under reduced
pressure to give the crude product. Purification by flash chroma-
tography on silica with EtOAc/MeOH (95:5) as eluent gave lactam
ꢁ
0
.015 mmol, 3 mol %) in MeOH (1 mL) at 0 C for 24 h gave the crude
product. Purification by flash chromatography on silica with petrol/
EtOAc (4:1)aseluentgave alcohol (S)-21 (58 mg, 54%, 90:10 er byCSP-
HPLC) as a colourless oil, CSP-HPLC: Daicel Chiracel OD 85:15 hexane/
ꢀ
1
i-PrOH, 0.8 mL min , 254 nm, 16.3 min [(R)-21], 20.6 min [(S)-21].
4
.36. (R)-1-Cyclohexyl-2-nitroethanol (R)-22 (Table 4, entry 9)
(
S)-24 (179 mg, 96%, 95:5 er by CSP-HPLC) as a white solid, mp
ꢁ
Using general procedure D, cyclohexanecarbaldehyde (61
mL,
78e80 C, [
a
]
D
þ145.5 (c 0.95, CHCl
3 f
);R (95:5 EtOAc/MeOH) 0.4; IR
0
.5 mmol), Cu[(ꢀ)-1]Cl
2
(37 mg, 0.1 mmol, 20 mol %), nitromethane
(CHCl
1022 cm ; H NMR (400 MHz, CDCl
(br s, 1H, NH), 4.76 (dd, J¼9.5, 4.0 Hz, PhCHO), 4.45 (d, J¼17.0 Hz,1H,
CH O), 3.58e3.48 (m, 2H, CH N);
O) 4.35 (d, J¼17.0 Hz, 1H, CH
C NMR (100.6 MHz, CDCl : 169.1 (C]O), 137.6 (ipso-Ph), 128.6
3
) 3230 (NH), 3066, 2878, 1680 (C]O), 1494, 1426, 1340, 1108,
ꢀ
1 1
(
54
m
L, 1.0 mmol) and Et
3
N (0.21 mL of a 1 vol % solution in MeOH,
3
) d: 7.40e7.33 (m, 5H, Ph), 7.23
ꢁ
0
.015 mmol, 3 mol %) in MeOH (1 mL) at 0 C for 24 h gave the crude
product. Purification by flash chromatography on silica with petrol/
EtOAc (4:1) as eluent gave alcohol (R)-22 (13 mg, 15%, 95:5 er by
A
H
B
A
H
B
2
1
3
3
) d
1
CSP-HPLC) as a colourless oil; H NMR (400 MHz, CDCl
3
)
d
: 4.49 (dd,
NO ),
.12e4.10 (m, 1H, CHOH), 2.48e2.46 (m, OH), 1.86e1.66 (m, 5H),
(Ph), 128.5 (Ph), 125.9 (Ph), 75.0 (PhCHO), 67.9 (CH
2
O), 47.7 (CH
2
N);
þ
J¼13, 3 Hz, 1H, CH
A
H NO
B 2
), 4.43 (dd, J¼13, 9 Hz, 1H, CH
A
H
B
2
MS (ESI) m/z 200 [(MþNa) ]; HRMS (ESI) m/z calcd for C10
H11NO
2
þ
4
(MþNa) 200.0682, found 200.0684 (þ1.8 ppm error); CSP-HPLC:
ꢀ1
1
8
.60e1.42 (m, 1H), 1.32e1.06 (m, 5H); CSP-HPLC: Daicel Chiracel OD
5:15 hexane/i-PrOH, 0.8 mL min , 254 nm, 13.0 min [(R)-22],
Daicel Chiracel OD, 1:4 v/v i-PrOH/hexane, 0.5 mL min , 254 nm,
23.7 min [(S)-24], 25.6 min [(R)-24].
ꢀ1
1
3.9 min [(S)-22]. Spectroscopic data are consistent with those
21
reported in the literature.
4.40. (S)-2-Phenylmorpholine (S)-25
4
.37. (S)-1-Cyclohexyl-2-nitroethanol (S)-22 (Table 4, entry 10)
A solution of the lactam (S)-24 (96 mg, 0.54 mmol) in THF (3 mL)
was added to a stirred suspension of LiAlH
4
(82 mg, 2.17 mmol) in
ꢁ
Using general procedure D, cyclohexanecarbaldehyde (76
mL,
THF (5 mL) at 0 C under Ar. The resulting solution was stirred and
heated at reflux for 16 h. The suspension was allowed to cool to rt
and then 2 M NaOH(aq) (1 mL) was added dropwise. The solids were
0
.5 mmol), Cu[(þ)-2]Cl
2
(33 mg, 0.1 mmol, 20 mol %), nitromethane
(
54
m
L, 1.0 mmol) and Et
3
N (0.21 mL of a 1 vol % solution in MeOH,
ꢁ
Ò
0
.015 mmol, 3 mol %) in MeOH (1 mL) at 0 C for 24 h gave the crude
removed by filtration through a pad of Celite and were washed
product. Purification by flash chromatography on silica with petrol/
EtOAc (4:1) as eluent gave alcohol (S)-22 (17 mg,19%, 92:8 er by CSP-
HPLC) as a colourless oil, CSP-HPLC: Daicel Chiracel OD 85:15 hexane/
with CH
rated under reduced pressure to give the crude product. Purifica-
tion by flash chromatography on silica with CH Cl /MeOH (7:3) as
eluent gave morpholine (S)-25 (42 mg, 48%) as a colourless oil, [
2
Cl
2
(2ꢃ5 mL). The filtrate was dried (MgSO
4
) and evapo-
2
2
ꢀ
1
i-PrOH, 0.8 mL min , 254 nm, 13.3 min [(R)-22], 14.0 min [(S)-22].
a]
D
2
6
þ19.8 (c 0.4, MeOH) (lit.
er); R (7:3 CH Cl /MeOH) 0.3; IR (CHCl
2909, 2850, 1451, 1090 cm
.38e7.28 (m, 5H, Ph), 4.50 (dd, J¼10.5, 2.5 Hz, 1H, PhCHO), 4.05
(dd, J¼12.0, 2.5 Hz, 1H, CH O), 3.79 (td, J¼12.0, 2.5 Hz, 1H,
CH ), 3.01 (td, J¼12.0,
O), 3.07 (dd, J¼12.5, 2.5 Hz, 1H, CHCH
2.5 Hz, 1H, CH N), 2.81 (dd,
N), 2.90 (dt, J¼12.0, 2.5 Hz, 1H, CH
J¼12.5, 10.5 Hz, 1H, CHCH ), 1.97 (br s, 1H, NH); C NMR
(100.6 MHz, CDCl : 140.4 (ipso-Ph), 128.3 (Ph), 127.7 (Ph), 126.0
[
a
]
D
þ12.6 (MeOH) for (S)-25 of ꢂ99:1
) 3307 (NH), 3062, 2946,
H NMR (400 MHz, CDCl
4
.38. 2-Chloro-N-((S)-2-hydroxy-2-phenylethyl)acetamide
f
2
2
3
ꢀ
1
1
(S)-23
;
3
) d:
7
Pd/C (10 wt % on activated carbon, 181 mg, 0.20 mmol) was
added to a stirred solution of nitro alcohol (S)-18 (567 mg,
.40 mmol) in MeOH (10 mL) at rt under Ar. The resulting solution
was degassed by evacuation and flushed three times with Ar. Then,
the reaction flask was flushed with H and stirred at rt under a H
A B
H
A
H
B
A B
H
3
A
H
B
A B
H
13
A B
H
2
2
3
) d
atmosphere (using a balloon) for 24 h. The reaction mixture was
filtered through Celite and the solvent was evaporated under re-
duced pressure to give the crude amino alcohol as a grey solid.
Then, chloroacetyl chloride (0.30 mL, 3.77 mmol) was added to
(Ph), 79.3 (PhCHO), 68.3 (CH
2
O), 53.2 (CH
2
N), 45.6 (CH
2
N); MS (ESI)
Ò
þ
þ
m/z 164 [(MþH) ]; HRMS (ESI) m/z calcd for C10
H13NO (MþH)
164.1070, found 164.1071 (þ0.6 ppm error). Spectroscopic data are
26
consistent with those reported in the literature.
3
a stirred solution of Et N (0.57 mL, 4.11 mmol) and the crude amino
alcohol (3.40 mmol maximum) in MeCN/MeOH (6:1) (3 mL) at
Acknowledgements
ꢁ
ꢀ10 C under Ar. The resulting solution was stirred at rt for 16 h.
After warming to rt, the solvent was evaporated under reduced
pressure to give the crude product. Purification by flash chroma-
tography on silica with EtOAc/MeOH (9:1) as eluent gave amide (S)-
We thank the Engineering and Physical Sciences Research
Council and Hoffmann-La Roche for funding, and Dr A. C. Whit-
wood for X-ray crystallography.