S.-L. Tseng, T.-K. Yang / Tetrahedron: Asymmetry 15 (2004) 3375–3380
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1.4g) in 40mL of acetonitrile was added 1,4-dibromo-
butane (6mmol, 1.3g). The solution was then heated
to reflux for 18h, after which the TLC analysis of the
reaction mixture indicated the completion of the reac-
tion. The resulting solution was filtered and acetonitrile
evaporated. After removal of acetonitrile, 30mL of
water was added to the residual oil then extracted with
3 · 30mL of ethyl acetate. The combined organic layer
was dried over MgSO4 and concentrated in vacuo to
give the crude product, which was purified through col-
umn chromatography on silica gel to afford (3R,4S)-2,5-
solution filtered. The filtrate was concentrated to afford
our desired product (3R,4S)-2,5-dimethyl-4-(pyrrolidin-
1-yl)hexane-3-thiol (0.37g, 92%) 11a as a colorless
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1
oil; ½aꢁ ¼ þ13:7 (c 0.99, CHCl3); H NMR (400MHz,
D
CDCl3) d 0.89 [d, J = 6.4Hz, 3H, NCHCH(CH3)2],
0.92–1.06 [m, 3H, NCHCH(CH3)2], 0.92–1.06 [m, 6H,
SHCHCH(CH3)2], 1.62–1.72 [m, 4H, (CH2)2], 1.89–
1.95 [m, 1H, NCHCH(CH3)2], 2.13–2.25 (m, 1H,
SHCCHMe2), 2.52 (dd, J = 4.4, 8.0Hz, 1H, NCH),
2.64–2.73 (m, 4H, NCH2), 2.92 (dd, J = 4.4, 7.6Hz,
1H, CHS); 13C NMR (100MHz, CDCl3) d 17.63,
19.57, 21.57, 21.79, 24.14, 29.40, 29.69, 48.78, 50.03,
66.20.
dimethyl-4-(pyrrolidin-1-yl) hexan-3-ol 9a (0.84g, 84%)
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D
as a colorless oil; ½aꢁ ¼ þ45:7 (c 1.21, CHCl3); 1H
NMR (400MHz, CDCl3) d 0.83 (d, J = 6.8Hz, 3H,
NCHCH(CH3)2), 0.97 (d, J = 6.8Hz, 3H, NCH-
CHCH3), 1.02 (d, J = 1.2Hz, 3H, OCCHCH3), 1.04
(d, J = 1.2Hz, 3H, OCCHCH3), 1.63–1.73 (m, 4H,
NCH2), 1.74–1.83 [m, 1H, NCCH(CH3)2], 2.05–2.12
[m, 1H, OCCH(CH3)2], 2.21 (dd, J = 3.2, 4.0Hz, 1H,
NCH), 2.55–2.63 (m, 2H, NCH2), 2.65–2.72 (m, 2H,
NCH2), 3.41 (dd, J = 4.4, 9.2Hz, 1H, CHO); 13C
NMR(100MHz, CDCl3) d 19.20, 19.30, 19.62, 22.68,
23.40, 26.99, 30.59, 51.59, 68.34, 77.60.
4.5. (1R,2S)-3-Methyl-1-phenyl-2-(pyrrolidin-1-yl)butan-
1-ol 9b
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D
½aꢁ ¼ ꢀ41:3 (c 1.38, CHCl3); 1H NMR (400MHz,
CDCl3) d 0.80 (d, J = 6.8Hz, 3H, CCH3), 0.96 (d,
J = 6.8Hz, 3H, CCH3), 1.62–1.70 [m, 4H, (CH2)2],
1.72–1.82 [m, 1H, CH(CH3)2], 2.54 (dd, J = 4.4,
8.0Hz, 1H, NCH), 2.57–2.64 (m, 2H, NCH2), 2.68–
2.74 (m, 2H, NCH2), 4.92 (d, J = 4.0Hz, 1H, CHO),
7.14–7.34 (m, 5H, ArH); 13C NMR (100MHz, CDCl3)
d 20.28, 21.81, 23.78, 27.88, 51.47, 72.29, 72.51,
126.08, 126.62, 127.79, 142.88 (Ph).
4.3. (S)-(3R,4S)-2,5-Dimethyl-4-(pyrrolidin-1-yl)hexan-3-
yl ethanethioate 10a
4.6. S-(1R,2S)-3-Methyl-1-phenyl-2-(pyrrolidin-1-yl)-
butyl ethanethioate 10b
To a vigorously stirred solution of (3R,4S)-2,5-di-
methyl-4-(pyrrolidin-1-yl)hexan-3-ol 9a (4.0mmol,
0.8g), Et3N (12mmol, 1.8mL) in 30mL anhydrous
CH2Cl2 at 0ꢁC was added MsCl (8mmol, 0.62mL).
The resulting solution was stirred for 1h at 0ꢁC, after
the TLC analysis of the reaction mixture indicated the
completion of reaction, then CH2Cl2 was removed in
vacuum. To the residue was added benzene (30mL)
and NEt3 (12mmol, 1.8mL) and thioacetic acid
(8mmol, 0.57mL) and then heated to reflux for 8h
while monitoring the completion of reaction by TLC.
After removal of solvent, the residued oil was purified
through column chromatography (eluent: n-hexane–
NEt3 = 100:1) on silica gel to afford (S)-(3R,4S)-2,5-di-
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D
½aꢁ ¼ ꢀ240:8 (c 1.02, CHCl3); 1H NMR (400MHz,
CDCl3) 0.90 (d, J = 6.8Hz, 3H, CCH3), 0.99 (d,
J = 6.4Hz, 3H, CCH3), 1.45–1.55 [m, 4H, (CH2)2],
1.92–2.04 [m, 1H, CH(CH3)2], 2.26 (s, 3H, SCOCH3),
2.60–2.69 (m, 4H, NCH2), 2.97 (t, J = 6.4Hz, 1H,
NCH), 4.99 (d, J = 6.4Hz, 1H, SCH), 7.14–7.41 (m,
5H, ArH); 13C NMR (100MHz, CDCl3) d 19.82,
21.62, 24.31, 30.57, 30.59, 49.69, 50.42, 69.33, 126.73,
127.86, 128.70, 141.80, 194.60.
4.7. (1R,2S)-3-Methyl-1-phenyl-2-(pyrrolidin-1-yl)-
butane-1-thiol 11b
methyl-4-(pyrrolidin-1-yl) hexan-3-yl ethanethioate 10a
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(0.66g, 64%) as a colorless oil; ½aꢁ ¼ þ53:9 (c 1.23,
D
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D
½aꢁ ¼ ꢀ489:0 (c 1.00, CHCl3); 1H NMR (400MHz,
CHCl3); 1H NMR (400MHz, CDCl3) d 0.88 [d,
J = 6.8Hz, 3H, NCHCH(CH3)2], 0.90–0.98 (m, 9H,
CH3), 1.66–1.71 (m, 4H, CCH2), 1.88–2.00 [m, 1H,
NCCH(CH3)], 2.01–2.12 (m, 1H, SCCHMe2), 2.34 (s,
3H, SCOMe), 2.62–2.70 (m, 2H, NCH2), 2.62–2.70 (m,
1H, NCH), 2.71–2.77 (m, 2H, NCH2), 3.79 (dd,
J = 5.2, 6.4Hz, 1H, CHS); 13C NMR (100MHz, CDCl3)
d 18.63, 19.99, 21.11, 21.60, 24.02, 30.45, 30.55, 30.71,
49.25, 50.81, 64.74, 195.38.
CDCl3) d 0.95 (d, J = 7.2Hz, 3H, CHCH3), 0.99 (d,
J = 6.4Hz, 3H, CCH3), 1.37–1.48 [m, 4H, (CH2)2],
2.06–2.15 [m, 1H, CH(CH3)2], 2.54–2.70 (m, 4H,
NCH2), 3.00 (dd, J = 5.2, 7.6Hz, 1H, NCH), 4.30
(d, J = 7.6Hz, 1H, SCH), 7.12–7.40 (m, 5H, ArH); 13C
NMR (100MHz, CDCl3) d 18.95, 21.67, 24.46, 30.42,
50.60, 70.03, 77.20, 126.73, 127.9, 128.1, 144.57 (Ph).
4.8. (1R,2S)-1,2-Diphenyl-2-(pyrrolidin-1-yl)ethanol 9c
4.4. (3R,4S)-2,5-Dimethyl-4-(pyrrolidin-1-yl)hexane-3-
thiol 11a
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D
½aꢁ ¼ ꢀ87:5 (c 1.00, CHCl3); mp 114ꢁC; 1H NMR
(400MHz, CDCl3) d 1.82–1.85 [m, 4H, NCH2(CH2)2],
2.59–2.62 (m, 2H, NCH2), 2.74–2.76 (m, 2H, NCH2),
3.30 (d, J = 3.2Hz, 1H, NCH), 5.24 (d, J = 3.0Hz, 1H,
CHOH), 6.97–7.25 (m, 10H, ArH); 13C NMR
(100MHz, CDCl3) d 23.47, 52.94, 73.99, 77.31, 126.08,
126.70, 127.02, 127.19, 127.42, 129.25, 137.47, 140.69
(2Ph).
To a suspension solution of LAH (4mmol, 0.16g) in
10mL of dry Et2O in an ice bath, then a solution
of (S)-(3R,4S)-2,5-dimethyl-4-(pyrrolidin-1-yl)hexan-3-
yl ethanethioate 10a (2mmol, 0.52g) in 20mL of dry
Et2O was added. After 1h, 2M aqueous NaOH
(0.5mL) was added under a nitrogen system and the