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M. Zielinska-Błajet et al. / Tetrahedron xxx (2016) 1e7
5
(2C), 131.1 (2C), 136.5. IR (film): 2934, 1724, 1584, 1479, 1439, 1385,
1276, 1181, 1026, 907, 741, 691 cmꢀ1. HRMS (ESI): calcd for
[C19H26S3þH]þ: 351.1269; found 351.1163.
129.8 (2C), 131.6, 133.1 (2C), 137.6. IR (film): 3364, 2922, 1492, 1460,
1385, 1095, 1046, 810 cmꢀ1. HRMS (ESI): calcd for [C17H24OSþH]þ:
277.1621; found: 277.1612.
4.3.3. (1S,2S,3S,5R)-6,6-Dimethyl-2-(2-dithiane)-3-((4-methyl)phe-
nylsulfanyl)bicyclo[3.1.1]heptane (4b). Yield 94%, colorless oil,
4.5. Preparation of bis-sulfide 6a
20
Rf¼0.69 (AcOEt/n-hexane, 9:1), [
a
]
D
¼þ30.0 (0.60, CH2Cl2). 1H NMR
A solution of alcohol 5a (0.262 g, 1.0 mmol), Ph2S2 (1.256 g,
3.0 mmol), and Bu3P (0.713 mL, 4.0 mmol) in dry toluene (5 mL)
was placed under argon in a reaction ampoule. The sealed tube was
heated at 65 ꢁC for 3 d. Thereafter, the cooled mixture was diluted
with ether (10 mL) and washed with 5% aqueous NaOH, H2O, brine,
and dried (Na2SO4). After evaporation, the crude product was pu-
rified by chromatography on silica gel (n-hexane/CH2Cl2, 4:1 v/v),
yielding the product 6a.
(600 MHz, CDCl3):
d
¼1.00 (s, 3H), 1.18e1.20 (m, 4H), 1.89e1.92 (m,
2H), 2.05e2.08 (m, 1H), 2.19 (dt, J¼14.3, 3.7 Hz, 1H), 2.25e2.36 (m,
5H), 2.39e2.44 (m, 1H), 2.49e2.52 (m, 1H), 2.73e2.87 (m, 3H),
2.95e2.98 (m, 1H), 3.74 (ddd, J¼9.5, 5.7, 3.8 MHz, 1H), 4.26 (d,
J¼10.8 Hz, 1H), 7.09 (d, J¼7.7 Hz, 2H), 7.37 (m, J¼7.9 Hz, 2H). 13C
NMR (150 MHz, CDCl3):
d
¼21.1, 23.1, 26.0, 27.0, 29.1, 30.4, 30.5, 37.1,
38.0, 40.5, 41.4, 42.8, 51.8, 52.4,129.6 (2C), 131.9 (2C), 132.4,136.7. IR
(film): 2933, 1725, 1492, 1471, 1422, 1276, 1181, 909, 809 cmꢀ1
.
HRMS (ESI): calcd for [C20H28S3þH]þ: 365.1426; found 365.1413.
4.5.1. ((1S,2R,3S,5R)-6,6-Dimethyl-2-(phenylsulfanylmethyl)bicyclo
[3.1.1]hept-3-yl)(phenyl)sulfane (6a). Yield 91%, white crystals, mp
20
82e84 ꢁC; [
a]
¼þ58.7 (0.92, CH2Cl2). 1H NMR (300 MHz, CDCl3):
4.3.4. (1S,2S,3S,5R)-6,6-Dimethyl-2-(2-dithiane)-3-((4-tert-butyl)-
phenylsulfanyl)bicyclo[3.1.1]heptane (4c). Yield 91%, colorless oil,
D
d
¼0.87 (d, J¼8.8 Hz, 1H), 1.03 (s, 3H), 1.20 (s, 3H), 1.93 (tt, J¼5.8,
20
Rf¼0.68 (AcOEt/n-hexane, 9:1), [
a]
¼þ33.3 (0.60, CH2Cl2). 1H NMR
D
3.0 Hz, 1H), 2.11 (ddd, J¼14.1, 5.7, 2.8 Hz, 1H), 2.20e2.28 (m, 1H),
2.35 (d, J¼5.6 Hz, 2H), 2.49e2.57 (m, 1H), 2.97 (dd, J¼13.0, 10.9 Hz,
1H), 3.29 (dd, J¼13.0, 4.4 Hz, 1H), 3.43 (ddd, J¼13.0, 7.3, 5.7 Hz, 1H),
7.16e7.22 (m, 1H), 7.25e7.41 (m, 9H). 13C NMR (75 MHz, CDCl3):
(300 MHz, CDCl3):
d
¼1.02 (s, 3H), 1.20e1.23 (m, 4H), 1.30 (s, 9H),
1.90e1.97 (m, 2H), 2.03e2.13 (m, 1H), 2.22 (dt, J¼14.2, 3.6 Hz, 1H),
2.27e2.38 (m, 2H), 2.46e2.54 (m, 2H), 2.73e2.92 (m, 3H),
2.93e3.05 (m, 1H), 3.78 (ddd, J¼9.5, 5.8, 3.8 Hz, 1H), 4.25 (d,
J¼10.7 Hz, 1H), 7.29e7.34 (m, 2H), 7.38e7.42 (m, 2H). 13C NMR
d
¼23.4, 27.6, 32.6, 37.4, 38.6, 38.8, 42.0, 43.6, 44.1, 48.9, 125.9, 127.2,
128.9 (4C), 129.2 (2C), 132.4 (2C), 135.6, 136.8. IR (film): 2988, 2916,
1579, 1479, 1412, 1081, 740, 690 cmꢀ1. HRMS (ESI): calcd for
[C22H26S2þH]þ: 355.1549; found 355.1563.
(75 MHz, CDCl3):
d
¼23.3, 26.2, 27.1, 29.9, 30.6, 30.7, 31.4 (3C), 34.6,
37.4, 38.2, 40.3, 41.6, 43.1, 52.1, 52.5, 126.0 (2C), 131.3 (2C), 132.8,
149.9. IR (film): 2954, 1682, 1463, 1268, 1120, 1014, 909, 829,
741 cmꢀ1. HRMS (ESI): calcd for [C23H34S3þH]þ: 407.1895; found
407.1883.
4.6. Preparation of selenide 7a
To a solution of alcohol 5a (0.262 g, 1.0 mmol) and PhSeCN
(0.147 mL, 1.2 mmol) in toluene (5 mL) stirred at 0 ꢁC under an
argon atmosphere a solution of Bu3P (0.214 mL, 1.2 mmol) in tol-
uene (1 mL) was added by syringe for 10 min. The mixture was
allowed to warm to rt and further stirred for 3.5 h. Thereafter the
mixture was diluted with Et2O (4 mL) and washed with 5% NaOH
(4 mL). The organic phase was washed with water, brine, dried over
Na2SO4, and the solvent was evaporated. Chromatography (silica
gel, n-hexane/CH2Cl2, 4:1 v/v) afforded product 7a.
4.4. Preparation of alcohols 5
To a suspension of LiAlH4 (0.129 g, 6.8 mmol) in absolute ether
(15 mL) at 0 ꢁC was added gradually to aldehydes 2 (3.4 mmol) and
the mixture was stirred at 0 ꢁC for 15 min and next allowed to warm
to room temperature. Then, the reaction was quenched with ether
saturated with water and 5% H2SO4 was added dropwise to pre-
cipitate a white solid. The suspension was filtered through a Celite
pad and washed with ether. The combined organic phase was
washed with brine, dried over Na2SO4 and evaporated to give an-
alytically pure products 5.
4.6.1. ((1S,2S,3S,5R)-6,6-Dimethyl-2-(phenylselanylmethyl)bicyclo
[3.1.1]hept-3-yl)(phenyl)sulfane (7a). Yield 99%, solidifying yellow
20
oil, Rf¼0.70 (AcOEt/n-hexane, 9:1), [
a
]
D
¼þ25.0 (1.00, CH2Cl2). 1
H
4.4.1. ((1S,2R,3S,5R)-6,6-Dimethyl-3-(phenylsulfanyl)bicyclo[3.1.1]
NMR (300 MHz, CDCl3):
d
¼0.90 (d, J¼8.9 Hz,1H),1.00 (s, 3H),1.17 (s,
hept-2-yl)methanol (5a). Yield 95%, colorless oil, Rf¼0.59 (AcOEt/
20
3H), 1.93 (sept, J¼2.8 Hz, 1H), 2.11 (ddd, J¼14.1, 5.5, 2.8 Hz, 1H),
2.28e2.37 (m, 3H), 2.48e2.57 (m, 1H), 3.00 (dd, J¼11.9, 10.7 Hz, 1H),
3.26 (dd, J¼12.0, 4.8 Hz, 1H), 3.44 (ddd, J¼9.8, 7.2, 5.6 Hz, 1H),
n-hexane, 9:1), [
a
]
¼þ91.1 (0.90, CH2Cl2). 1H NMR (300 MHz,
D
CDCl3):
d
¼0.97 (s, 3H), 1.04 (d, J¼9.8 Hz, 1H), 1.21 (s, 3H), 1.66 (s,
1H), 1.95 (sept, J¼3.1 Hz, 1H), 2.11e2.15 (m, 2H), 2.24 (dt, J¼7.4,
1.9 Hz, 1H), 2.36e2.40 (m, 1H), 2.49e2.54 (m, 1H), 3.43 (ddd,
J¼9.8, 7.4, 5.5 Hz, 1H), 3.64 (dd, J¼10.5, 7.9 Hz, 1H), 3.75 (dd,
J¼10.5, 6.8 Hz, 1H), 7.21e7.28 (m, 1H), 7.28e7.36 (m, 2H),
7.21e7.43 (m, 10H, ArH). 13C NMR (75 MHz, CDCl3):
d¼23.3, 27.5,
32.6, 33.4, 37.4, 38.6, 41.9, 44.5, 44.8, 49.8, 126.7, 127.1, 127.8, 128.9,
129.1, 129.2, 131.0, 131.6, 131.7, 132.4, 132.5, 135.6. 77Se NMR
7.42e7.48 (m, 2H). 13C NMR (75 MHz, CDCl3):
d
¼23.6, 27.6, 32.6,
(115 MHz, CDCl3):
d 462.9. IR (film): 3056, 2922, 1575, 1475, 1021,
734, 688 cmꢀ1. HRMS (ESI): calcd for [C22H26SSeþH]þ: 403.0999;
37.6, 38.6, 40.5, 42.1, 43.2, 52.2, 66.9, 127.2, 129.0 (2C), 132.1 (2C),
135.7. IR (film): 3365, 2924, 1585, 1479, 1438, 1385, 1095, 1046,
1026, 743, 691 cmꢀ1. HRMS (ESI): calcd for [C16H22OSþH]þ:
263.1464; found 263.1470.
found 403.1008.
4.7. Preparation of amines 8
4.4.2. ((1S,2R,3S,5R)-6,6-Dimethyl-3-((4-methyl)-phenylsulfanyl)bi-
Alcohol 5 (2.0 mmol) and triphenylphosphine (0.682 g,
cyclo[3.1.1]hept-2-yl)methanol (5b). Yield 97%, colorless oil, Rf¼0.60
2.6 mmol, 1.3 equiv) were dissolved in dry toluene (10 mL) and
cooled in an ice bath. A 1M solution of HN3 in benzene (2.65 mL,
2.6 mmol, 1.3 equiv) was then added in one portion under argon,
followed by a DEAD (0.405 mL, 2.6 mmol, 1.3 equiv), which was
added dropwise over 20 min. The reaction mixture was stirred
overnight under argon. The obtained azide was reduced to amine
8 by addition triphenylphosphine (0.787 g, 3.0 mmol, 1.5 equiv)
and the reaction mixture was heated overnight at reflux. The
¼þ90.0 (1.00, CH2Cl2). 1H NMR
20
(AcOEt/n-hexane, 9:1),
[
a]
D
(300 MHz, CDCl3):
d
¼0.95 (s, 3H), 0.99 (d, J¼9.8 Hz, 1H), 1.20 (s, 3H),
1.67 (s, 1H), 1.93 (sept, J¼2.8 Hz, 1H), 2.06e2.15 (m, 2H), 2.24 (dq,
J¼7.2, 1.9 Hz, 1H), 2.33 (s, 3H), 2.39e2.51 (m, 1H), 3.36 (ddd, J¼13.0,
7.3, 5.7 Hz, 1H), 3.62 (dd, J¼10.5, 7.8 Hz, 1H), 3.73 (dd, J¼10.5, 7.0 Hz,
1H), 7.13 (d, J¼7.8 Hz, 2H), 7.37 (d, J¼6.4 Hz, 2H). 13C NMR (75 MHz,
CDCl3):
d
¼21.2, 23.6, 27.6, 32.7, 37.4, 38.6, 41.2, 42.1, 43.3, 52.2, 66.9,
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