The Journal of Organic Chemistry
Note
1
yellow oil) was prepared from 3b in 82% yield: H NMR (CDCl , 500
34.0, 25.4, 21.6; HRMS (EI, magnetic sector) m/z calcd for
3
+
MHz) δ 4.12 (s, 2H), 3.63 (s, 2H), 3.42 (t, J = 5.0 Hz, 1H), 3.05 (s,
C H NO S (M ) 405.1609, found 405.1603.
21
27
5
3
1
6
H), 2.94 (s, 3H), 1.68−1.42 (m, 6H), 1.38−1.20 (m, 4H), 0.91 (s,
4-(2-(Dimethylamino)-2-oxoethoxy)octyl 4-Methylbenzene-
2H), 0.07 (s, 6H); 13C NMR (CDCl , 75 MHz) δ 169.8, 80.2, 68.8,
sulfonate (7b). According to GP3, 7b (820 mg, thick colorless oil)
3
1
3.3, 37.0, 35.6, 33.2, 31.1, 29.6, 28.5. 27.5, 26.1, 23.0, 18.5, 14.2, −5.1;
was prepared from 6b in 98% yield: H NMR (CDCl , 500 MHz) δ
3
+
HRMS (EI, magnetic sector) m/z calcd for C H NO Si (M )
3
7.80 (d, J = 8.3 Hz, 2H), 7.36 (d, J = 8.2 Hz, 2H), 4.14−4.04 (m, 4H),
3.37 (quintet, J = 5.6 Hz, 1H), 3.03 (s, 3H), 2.95 (s, 3H), 2.47 (s, 3H),
1.83−1.70 (m, 3H), 1.60−1.50 (m, 2H), 1.44−1.40 (m, 1H), 1.33−
18
39
3
45.2699, found 345.2697.
2
-((6-((t-Butyldimethylsilyl)oxy)-2-methylhexan-3-yl)oxy)-
N,N-dimethylacetamide (5c). According to GP1, 5c (117 mg, pale
yellow oil) was prepared from 3c in 86% yield: H NMR (CDCl , 500
1.24 (m, 4H), 0.91 (t, J = 7.4 Hz, 3H); 13C NMR (CDCl , 75 MHz) δ
3
1
169.4, 144.7, 133.2, 129.8, 127.9, 79.4, 70.9, 68.2, 36.6, 35.4, 32.9, 29.3,
3
MHz) δ 4.13 (s, 2H), 3.67−3.50 (m, 2H), 3.16 (dd, J = 6.5, 11.0 Hz,
27.2, 24.7, 22.8, 21.6, 14.0; HRMS (EI, magnetic sector) m/z calcd for
+
1
1
7
1
H), 3.07 (s, 3H), 2.94 (s, 3H), 1.89 (dd, J = 6.5, 12.5 Hz, 1H), 1.70−
C H NO S (M ) 385.1922, found 385.1918.
19
31
5
1
3
.40 (m, 4H), 0.98−0.80 (m, 15H), 0.09 (s, 6H); C NMR (CDCl ,
4-(2-(Dimethylamino)-2-oxoethoxy)-5-methylhexyl 4-
3
5 MHz) δ 169.8, 85.5, 69.7, 63.4, 37.1, 35.5, 30.3, 28.9, 26.1, 18.5,
8.4, 17.9, −5.1; HRMS (EI, magnetic sector) m/z calcd for
Methylbenzenesulfonate (7c). According to GP3, 7c (619 mg,
1
thick colorless oil) was prepared from 6c in 88% yield: H NMR
+
C H NO Si (M ) 331.2543, found 331.2547.
(CDCl , 500 MHz) δ 7.80 (d, J = 8.1 Hz, 2H), 7.36 (d, J = 7.8 Hz,
3
1
7
37
3
General Procedure for Deprotection of Silyl Ether 5a−c
2H), 4.16−4.02 (m, 4H), 3.15−3.12 (m, 1H), 3.03 (s, 3H), 2.94 (s,
3H), 2.46 (s, 3H), 1.90−1.76 (m, 2H), 1.75−1.64 (m, 2H), 1.54−1.43
(
GP2). To a solution of silyl ether 5a (3.81 g, 10.4 mmol) in
1
3
anhydrous THF (52 mL) was added TBAF (11.9 mL, 11.9 mmol, 1.0
M solution in THF) at 0 °C. The mixture was stirred for 6 h at room
temperature and concentrated at reduced pressure. The resulting
residue was dissolved in EtOAc. The solution was washed with brine,
(m, 1H), 0.88 (d, J = 6.9, Hz, 3H), 0.85 (d, J = 6.9, Hz, 3H); C NMR
(CDCl , 75 MHz) δ 169.4, 144.7, 133.1, 129.8, 127.9, 84.6, 71.0, 69.0,
3
36.7, 35.3, 29.9, 25.6, 25.1, 21.6, 18.4, 17.2; HRMS (EI, magnetic
+
sector) m/z calcd for C H NO S (M ) 371.1766, found 371.1762.
18
29
5
dried over anhydrous MgSO , and concentrated in vacuo. The
General Procedure for Cyclization of Tosylate 7a−c (GP4).
To a solution of tosylate 7a (50.0 mg, 0.13 mmol) in anhydrous THF
(13.0 mL) was added dropwise KHMDS (0.3 mL, 0.15 mmol, 0.5 M
4
resulting residue was purified by flash column chromatography on
silica gel (hexanes/EtOAc, 1:1) to give alcohol 6a (2.51 g, colorless
oil) in 98% yield.
in THF) at −78 °C under a N atmosphere. The mixture was stirred at
2
2
-(4-Hydroxy-1-phenylbutoxy)-N,N-dimethylacetamide (6a).
the same temperature for 5 min. The mixture was warmed to −30 °C
1
H NMR (CDCl , 500 MHz) δ 7.38−7.31 (m, 5H), 4.49 (dd, J = 8.3,
immediately and stirred at this temperature for 11 h. The reaction
3
4
(
1
1
.3 Hz, 1H), 4.12 (d, J = 13.9, 1H), 3.90 (d, J = 14.1, 1H), 3.73−3.68
mixture was quenched with saturated aqueous NH Cl, and
4
m, 2H), 2.94 (s, 3H), 2.88 (s, 3H), 2.42 (brs, 1H), 2.01−1.96 (m,
concentrated in vacuo. The residue was diluted with water and
extracted with EtOAc thrice. The combined organic layers were
13
H), 1.85−1.71 (m, 3H); C NMR (CDCl , 75 MHz) δ 169.3, 141.6,
3
28.6, 127.8, 126.8, 82.6, 67.1, 62.8, 36.2, 35.4, 35.2, 29.1; HRMS (EI,
washed with brine, dried over MgSO , and concentrated in vacuo. The
4
+
magnetic sector) m/z calcd for C H NO (M ) 251.1521, found
resulting residue was purified by flash column chromatography on
silica gel (hexanes/EtOAc, 10:1) to give cis-8a (24.0 mg, colorless oil,
82%) along with trans-8a (1.2 mg, colorless oil, 4%).
14
21
3
2
51.1528.
-((1-Hydroxyoctan-4-yl)oxy)-N,N-dimethylacetamide (6b).
2
1
According to GP2, 6b (81 mg, colorless oil) was prepared from 5b
THP 8a. Data for cis-8a: H NMR (CDCl
3
, 500 MHz) δ 7.38−7.34
1
in 82% yield: H NMR (CDCl , 500 MHz) δ 4.20 (d, J = 13.3 Hz,
(m, 4H), 7.30−7.28 (m, 1H), 4.45 (dd, J = 11.3, 1.6 Hz, 1H), 4.30
(dd, J = 11.1, 2.4 Hz, 1H), 3.13 (s, 3H), 2.97 (s, 3H), 2.10−2.07 (m,
3
1
1
1
H), 4.09 (d, J = 13.3 Hz, 1H), 3.70−3.57 (m, 2H), 3.46−3.41 (m,
13
H), 3.03 (s, 3H), 2.94 (s, 3H), 2.21 (brs, 1H), 1.72−1.54 (m, 6H),
1H), 1.96−1.69 (m, 5H); C NMR (CDCl , 75 MHz) δ 169.9, 142.6,
3
13
.34−1.25 (m, 4H), 0.89 (t, J = 6.9 Hz, 3H); C NMR (CDCl , 75
128.3, 127.4, 125.8, 80.6, 77.3, 37.1, 35.9, 33.3, 26.9, 23.5; HRMS (EI,
3
+
MHz) δ 169.8, 80.4, 68.2, 63.0, 36.7, 35.6, 33.1, 30.0, 28.4, 27.6, 23.0,
magnetic sector) m/z calcd for C14
H
19NO
2
(M ) 233.1415, found
+
1
1
4.2; HRMS (EI, magnetic sector) m/z calcd for C H NO (M )
233.1414. Data for trans-8a: H NMR (CDCl , 500 MHz) δ 7.37−
3
12
25
3
2
31.1834, found 231.1830.
7.35 (m, 4H), 7.30−7.29 (m, 1H), 4.77−4.73 (m, 1H), 4.54 (dd, J =
10.8, 2.2 Hz, 1H), 3.11 (s, 3H), 3.00 (s, 3H), 2.10−2.07 (m, 1H),
2
-((6-Hydroxy-2-methylhexan-3-yl)oxy)-N,N-dimethyl-
13
acetamide (6c). According to GP2, 6c (58 mg, colorless oil) was
prepared from 5c in 89% yield: H NMR (CDCl , 500 MHz) δ 4.22
1.96−1.69 (m, 5H); C NMR (CDCl , 75 MHz) δ 171.2, 142.9,
3
1
128.3, 127.3, 125.9, 75.2, 72.0, 37.6, 35.9, 32.7, 25.6, 20.0; HRMS (EI,
3
+
(
3
d, J = 13.5 Hz, 1H), 4.09 (d, J = 13.0 Hz, 1H), 3.73−3.60 (m, 2H),
magnetic sector) m/z calcd for C H NO (M ) 233.1415, found
14
19
2
.23−3.18 (m, 1H), 3.03 (s, 3H), 2.95 (s, 3H), 2.23 (t, J = 6.0 Hz,
233.1416.
1
(
H), 1.93 (ddd, J = 6.5, 13.0, 19.0 Hz, 1H), 1.71−1.52 (m, 4H), 0.90
THP cis-8b. According to GP4, cis-8b (47 mg, colorless oil) was
dd, J = 7.0, 17.5 Hz, 6H); 13C NMR (CDCl , 75 MHz) δ 169.9, 85.9,
prepared from 7b in 95% yield: H NMR (CDCl , 500 MHz) δ 4.06
1
3
3
6
9.1, 63.0, 36.8, 35.6, 30.2, 28.9, 26.2, 18.8, 17.6; HRMS (EI, magnetic
(dd, J = 10.6, 2.9 Hz, 1H), 3.38−3.32 (m, 1H), 3.11 (s, 3H), 2.97 (s,
+
sector) m/z calcd for C H NO (M ) 217.1678, found 217.1676.
3H), 1.98−1.92 (m, 1H), 1.82−1.70 (m, 2H), 1.63−1.49 (m, 4H),
11
23
3
1
3
General Procedure for Tosylation of Alcohol 6a−c (GP3). To
1.47−1.41 (m, 2H), 1.37−1.25 (m, 4H), 0.91 (t, J = 7.4 Hz, 1H); C
a solution of alcohol 6a (480 mg, 1.90 mmol) in CH Cl (10.0 mL)
NMR (CDCl , 75 MHz) δ 170.2, 79.9, 76.4, 37.0, 36.1, 35.7, 31.3,
2
2
3
were added pyridine (3.0 mL) and a solution of p-tosyl chloride (656
27.9, 27.2, 23.1, 22.7, 14.0; HRMS (EI, magnetic sector) m/z calcd for
+
mg in 4.0 mL anhydrous CH Cl , 3.43 mmol) at room temperature.
C H NO (M ) 213.1728, found 213.1724. The expected minor
2
2
12 23
2
The mixture was stirred for 5 h. The reaction mixture was quenched
product trans-8b could not be isolated.
with saturated aqueous NaHCO , diluted with water, and extracted
with EtOAc thrice. The combined organic layers were washed with
THP cis-8c. According to GP4, cis-8c (45 mg, colorless oil) was
3
1
prepared from 7c in 88% yield: H NMR (CDCl , 500 MHz) δ 4.04
3
brine, dried over MgSO , and concentrated in vacuo. The resulting
residue was purified by flash column chromatography on silica gel
(dd, J = 11.2, 2.4 Hz, 1H), 3.11 (s, 3H), 3.07−3.03 (m, 1H), 2.96 (s,
4
3H), 1.99−1.95 (m, 1H), 1.80−1.63 (m, 5H), 1.32−1.24 (m, 1H),
(
hexanes/EtOAc, 4:1) to give tosylate 7a (745 mg, thick colorless oil)
in 99% yield.
-(2-(Dimethylamino)-2-oxoethoxy)-4-phenylbutyl 4-
0.96 (d, J = 6.7 Hz, 3H), 0.92 (d, J = 7.0 Hz, 3H); 13C NMR (CDCl ,
3
75 MHz) δ 170.3, 84.1, 76.6, 37.0, 35.7, 33.3, 28.1, 27.2, 23.1, 18.8,
+
4
18.7; HRMS (EI, magnetic sector) m/z calcd for C H NO (M )
11
21
2
1
Methylbenzenesulfonate (7a). H NMR (CDCl , 500 MHz) δ
199.1572, found 199.1569. The expected minor product trans-8c
could not be isolated.
(S)-2-(4-((t-Butyldimethylsilyl)oxy)-1-(4-methoxyphenyl)-
butoxy)-N,N-dimethylacetamide (13). To a solution of alcohol 12
(523 mg, 1.68 mmol) in THF (6.0 mL) at room temperature was
added NaHMDS (1.0 M solution in THF, 2.5 mL, 2.52 mmol). The
3
7
4
2
1
1
.78 (d, J = 8.2 Hz, 2H), 7.37−7.26 (m, 7H), 4.38−4.36 (m, 1H),
.13−4.09 (m, 1H), 4.07−4.03 (m, 2H), 3.87 (d, J = 13.2 Hz, 1H),
.92 (s, 3H), 2.89 (s, 3H), 2.46 (s, 3H), 1.90−1.84 (m, 2H), 1.77−
.71 (m, 2H); 13C NMR (CDCl , 75 MHz) δ 169.1, 144.6, 141.0,
3
33.2, 129.8, 128.5, 128.0, 127.9, 126.8, 81.7, 70.6, 67.1, 36.3, 35.3,
D
J. Org. Chem. XXXX, XXX, XXX−XXX