European Journal of Organic Chemistry
10.1002/ejoc.201801236
FULL PAPER
1
-((S)-2-methoxy-1-phenylethoxy)-2-((R)-1-(4-methoxyphenyl)but-3-
126.2, 125.6, 125.3, 125.2, 125.0, 124.1, 120.3, 115.9, 112.6, 78.7, 77.0,
2
6
+
en-1-yl)benzene (10g): [α]
D
= –112.5 (c = 0.61, CHCl
3
). IR (neat): ṽ =
59.2, 39.5, 38.3 ppm. HRMS: calcd. for C29
found 431.1984.
H
28
O
2
[M + Na] 431.1982,
–
1
1
1
7
6
511, 1487, 1452, 1245, 1127, 751, 701 cm
.
H NMR (CDCl ): δ =
3
.38–7.23 (m, 1H), 7.23–7.12 (m, 5H), 6.97 (dt, J = 2.0, 8.5 Hz, 1H),
.94–6.89 (m, 2H), 6.89–6.81 (m, 3H), 6.59 (d, J = 8.0 Hz, 1H), 5.83 (ddt,
2-((R)-1-(2-((S)-2-methoxy-1-phenylethoxy)phenyl)but-3-en-1-
2
5
J = 17.5, 10.5, 7.0 Hz, 1H), 5.32 (dd, J = 8.0, 3.5 Hz, 1H), 5.07 (dd, J =
yl)naphthalene (10l): [α] ). IR (neat): ṽ =
D
= –110.1 (c = 0.26, CHCl
3
–
1 1
1
1
7.5, 2.0 Hz, 1H), 4.98 (dm, J = 10.5 Hz, 1H), 4.54 (dd, J = 8.5, 7.5 Hz,
H), 3.80 (s, 3H), 3.78 (dd, J = 10.5, 8.0 Hz, 1H), 3.60 (dd, J = 10.5, 3.5
1488, 1451, 1237, 1126, 749, 701 cm . H NMR (CDCl ): δ = 7.84–7.79
3
(m, 1H), 7.79–7.72 (m, 2H), 7.66 (s, 1H), 7.48–7.41 (m, 2H), 7.40 (dd, J =
8.5, 1.5 Hz, 1H), 7.32 (dd, J = 7.5, 1.5 Hz, 1H), 7.05 (t, J = 7.5 Hz, 1H),
6.98 (dt, J = 1.5, 8.0 Hz, 1H), 6.93–6.85 (m, 3H), 6.72 (d, J = 7.5 Hz, 1H),
6.59 (d, J = 8.0 Hz, 1H), 5.87 (ddt, J = 17.0, 10.5, 7.0 Hz, 1H), 5.31 (dd, J
= 8.0, 3.5 Hz, 1H), 5.08 (dd, J = 17.0, 1.5 Hz, 1H), 4.98 (dd, J = 10.5, 1.5
Hz, 1H), 4.73 (dd, J = 8.0, 7.5 Hz, 1H), 3.74 (dd, J = 10.5, 8.0 Hz, 1H),
Hz, 1H), 3.47 (s, 3H), 2.87 (dt, J = 14.5, 7.0 Hz, 1H), 2.76 (dt, J = 14.5,
1
3
7
1
1
.0 Hz, 1H) ppm. C NMR (CDCl
3
): δ = 157.7, 154.9, 138.4, 137.4, 136.9,
33.5, 129.5, 128.4, 127.7, 127.3, 126.8, 126.3, 120.3, 115.9, 113.4,
12.9, 78.8, 77.3, 59.4, 55.3, 43.1, 39.3 ppm. HRMS: calcd. for C26
H
28
O
3
+
[
M + Na] 411.1931, found 411.1929.
3
.54 (dd, J = 10.5, 3.5 Hz, 1H), 3.47 (s, 3H), 2.97 (dt, J = 14.0, 7.0 Hz,
1
3
1
1
1
-chloro-2-((S)-1-(2-((S)-2-methoxy-1-phenylethoxy)phenyl)but-3-en-
3
1H), 2.89 (dt, J = 14.0, 7.0 Hz, 1H) ppm. C NMR (CDCl ): δ = 154.9,
2
6
-yl)benzene (10h): [α]
D
= –185.2 (c = 0.46, CHCl
3
). IR (neat): ṽ =
142.3, 138.1, 137.2, 133.5, 133.0, 132.0, 128.2, 128.2, 127.7, 127.7,
127.51, 127.48, 127.0, 126.7, 126.2, 126.2, 125.7, 125.1, 120.3, 116.1,
–
1 1
488, 1452, 1238, 1128, 751, 700 cm
.
3
H NMR (CDCl ): δ = 7.45–7.39
(
m, 1H), 7.30 (d, J = 7.5 Hz, 1H), 7.21–7.10 (m, 3H), 7.10–7.04 (m, 2H),
.04–6.97 (m, 2H), 6.87 (t, J = 7.5 Hz, 1H), 6.69 (d, J = 7.5 Hz, 1H), 6.57
d, J = 8.0 Hz, 1H), 5.90 (ddt, J = 17.0, 10.0, 7.0 Hz, 1H), 5.32 (dd, J =
112.8, 78.7, 77.3, 59.4, 44.1, 39.1 ppm. HRMS: calcd. for C29
H
28
O
2
[M +
+
7
Na] 431.1982, found 431.1981.
(
8
1
.0, 3.5 Hz, 1H), 5.12 (dd, J = 8.0, 7.5 Hz, 1H), 5.07 (dd, J = 17.0, 1.5 Hz,
H), 4.99 (dd, J = 10.0, 1.5 Hz, 1H), 3.81 (dd, J = 10.5, 8.0 Hz, 1H), 3.54
Synthesis of (R)-Tolterodine (Scheme 2)
(
dd, J = 10.5, 3.5 Hz,1H), 3.46 (s, 3H), 2.86 (dt, J = 14.0, 7.0 Hz, 1H),
1-((S)-2-methoxy-1-phenylethoxy)-4-methyl-2-((R)-1-phenylbut-3-en-
1-yl)benzene (12): To a solution of FeCl (23.5 mg, 0.14 mmol) in
CH Cl (1.2 mL) at room temperature was successively added
allyltrimethylsilane (115.0 µL, 0.72 mmol). After cooling to –40 °C,
diarylmethanol 11 (171.8 mg, 0.49 mmol) in CH Cl (0.3 mL + 0.3 mL
rinse (twice)) was added into the mixture. The reaction mixture was
stirred for 20 h at the same temperature and then it was quenched with 1
M HCl. The organic layer was separated and the aqueous layer was
1
3
2
1
1
.76–2.66 (m, 1H) ppm. C NMR (CDCl
3
): δ = 155.0, 142.8, 138.2, 136.6,
3
2
2
34.5, 131.6, 129.4, 129.3, 128.3, 127.7, 127.6, 127.2, 126.9, 126.6,
26.0, 119.9, 116.2, 112.4, 78.4, 77.3, 59.3, 40.0, 38.5 ppm. HRMS:
+
2
2
calcd. for C25
H
25ClO
2
[M + Na] 415.1435, found 415.1434.
1
-((R)-1-(3-chlorophenyl)but-3-en-1-yl)-2-((S)-2-methoxy-1-
2
6
phenylethoxy)benzene (10i): [α]
neat): ṽ = 1487, 1452, 1238, 1127, 752, 699 cm . H NMR (CDCl
.38–7.19 (m, 8H), 7.07 (dt, J = 1.5, 7.5 Hz, 1H), 6.99–6.91 (m, 3H), 6.66
d, J = 8.0 Hz, 1H), 5.94–5.82 (m, 1H), 5.38 (dd, J = 8.0, 4.0 Hz, 1H),
D
= –130.6 (c = 0.27, CHCl
3
). IR
extracted with CH
2 2
Cl . The combined organic layer was dried over
–
1 1
Na SO . After filtration of the mixture and evaporation of the solvent, the
(
3
): δ =
2
4
crude product was purified by preparative thin layer chromatography on
7
silica (toluene/EtOAc = 50/1) to afford the desired compound 12 (172.2
(
29
mg, 94% yield, dr = 90:10) as a pale yellow oil. [α]
D
= –113.9 (c = 1.35,
1
5
8
3
1
1
3
4
.14 (dd, J = 17.5, 1.5 Hz, 1H), 5.08 (d, J = 10.5 Hz, 1H), 4.60 (dd, J =
–1
CHCl
3
). IR (neat): ṽ = 1495, 1238, 1129, 700 cm
.
3
H NMR (CDCl ): δ =
.0, 7.5 Hz, 1H), 3.86–3.79 (m, 1H), 3.68–3.63 (m, 1H), 3.55 (s, 3H),
7
.33–7.10 (m, 8H), 7.07 (d, J = 2.0 Hz, 1H), 6.88–6.82 (m, 2H), 6.75 (dd,
1
3
.00–2.92 (m, 1H), 2.88–2.79 (m, 1H) ppm. C NMR (CDCl
3
): δ = 154.9,
J = 8.0, 1.5 Hz, 1H), 6.46 (d, J = 8.5 Hz, 1H), 5.83 (ddt, J = 17.5, 10.0,
7.0 Hz, 1H), 5.27 (dd, J = 8.0, 4.0 Hz, 1H), 5.06 (dd, J = 17.5, 2.0 Hz, 1H),
47.0, 138.1, 136.7, 133.8, 132.1, 129.3, 128.8, 128.5, 127.9, 127.2,
4
.97 (dm, J = 10.0 Hz, 1H), 4.54 (dd, J = 8.0, 7.5 Hz, 1H), 3.75 (dd, J =
27.2, 126.8, 126.2, 125.9, 120.4, 116.4, 113.0, 78.9, 77.2, 59.4, 43.9,
+
11.0, 8.0 Hz, 1H), 3.56 (dd, J = 11.0, 4.0 Hz, 1H), 3.46 (s, 3H), 2.87 (dt, J
8.9 ppm. HRMS: calcd. for C25
15.1437.
H
25ClO
2
[M + Na] 415.1435, found
13
=
(
1
14.0, 7.0 Hz, 1H), 2.82–2.72 (m, 1H), 2.20 (s, 3H) ppm. C NMR
CDCl ): δ = 152.7, 144.8, 138.5, 137.3, 132.8, 129.3, 128.6, 128.4,
28.1, 128.0, 127.7, 127.1, 126.2, 125.7, 115.9, 112.7, 78.9, 77.3, 59.4,
3
+
1
-((R)-1-(4-chlorophenyl)but-3-en-1-yl)-2-((S)-2-methoxy-1-
43.9, 39.2, 20.7 ppm. HRMS: calcd. for C26H28O2 [M + Na] 395.1982,
found 395.1979.
2
7
phenylethoxy)benzene (10j): [α]
D
= –121.3 (c = 0.73, CHCl
3
). IR
–
1 1
(
neat): ṽ = 1489, 1452, 1238, 1127, 752, 701 cm . H NMR (CDCl ): δ =
3
(
R)-3-(2-((S)-2-methoxy-1-phenylethoxy)-5-methylphenyl)-3-
phenylpropanal (13): To a solution of 12 (54.3 mg, 0.146 mmol) in
CH Cl /MeOH (0.75 mL/0.75 mL) at –78 °C was inletted ozone until the
reaction was completed (monitored by TLC). After ozone was replaced
with nitrogen, PPh (78.7 mg, 0.30 mmol) was added into the mixture at –
7
6
.29–7.22 (m, 3H), 7.21–7.13 (m, 5H), 6.99 (dt, J = 1.5, 8.0 Hz, 1H),
.90–6.81 (m, 3H), 6.60 (d, J = 8.0 Hz, 1H), 5.80 (ddt, J = 17.0, 10.5, 7.0
2
2
Hz, 1H), 5.30 (dd, J = 7.5, 3.5 Hz, 1H), 4.99 (dd, J = 10.5, 1.5 Hz, 1H),
4
.53 (dd, J = 7.5, 7.0 Hz, 1H), 3.74 (dd, J = 11.0, 7.5 Hz, 1H), 3.56 (dd, J
11.0, 3.5 Hz, 1H), 3.45 (s, 3H), 2.87 (dt, J = 14.0, 7.0 Hz, 1H), 2.73 (dt,
3
=
78 °C. The reaction mixture was stirred for 10 min at room temperature
and then the solvent was evaporated. The crude product was purified by
preparative thin layer chromatography on silica (toluene/EtOAc = 9/1) to
afford the desired compound 13 (46.3 mg, 85% yield, single
diastereomer) as a colorless oil. [α]
(
(
1
3
J = 14.0, 7.5 Hz, 1H) ppm. C NMR (CDCl
3
): δ = 154.9, 143.4, 138.2,
36.8, 132.5, 131.4, 130.0, 128.5, 128.1, 127.9, 127.22, 127.17, 126.2,
20.4, 116.3, 113.0, 78.9, 77.3, 59.3, 43.5, 39.0 ppm. HRMS: calcd. for
1
1
2
7
+
D
= –70.0 (c = 0.61, CHCl
3
). IR
): δ = 9.84
dd, J = 2.5, 2.0 Hz, 1H), 7.42–7.22 (m, 8H), 7.05–6.99 (m, 2H), 6.96 (s,
H), 6.84 (dd, J = 8.5, 1.5 Hz, 1H), 6.56 (d, J = 8.0 Hz, 1H), 5.35 (dd, J =
C
25
H
25ClO
2
[M + Na] 415.1435, found 415.1437.
–1 1
neat): ṽ = 1723, 1495, 1239, 1128, 701 cm . H NMR (CDCl
3
1
-((R)-1-(2-((S)-2-methoxy-1-phenylethoxy)phenyl)but-3-en-1-
1
3
1
yl)naphthalene (10k): [α]
D
= –112.4 (c = 0.39, CHCl
3
). IR (neat): ṽ =
): δ = 8.36–8.30
8.0, 3.5 Hz, 1H), 5.02 (dd, J = 8.0, 7.5 Hz, 1H), 3.82 (dd, J = 10.5, 8.0 Hz,
1H), 3.63 (dd, J = 10.5, 3.5 Hz, 1H), 3.50 (s, 3H), 3.26 (ddd, J = 16.0, 7.0,
2
–
1 1
1
487, 1452, 1235, 1126, 751, 700 cm
.
H NMR (CDCl
3
1
3
.0 Hz, 1H), 3.18 (ddd, J = 16.0, 8.0, 2.5 Hz, 1H), 2.25 (s, 3H) ppm.
C
(
m, 1H), 7.89–7.83 (m, 1H), 7.75 (d, J = 8.5 Hz, 1H), 7.50–7.39 (m, 3H),
NMR (CDCl
3
): δ = 202.1, 152.6, 143.2, 138.3, 131.5, 129.7, 128.5,
7
6
2
.32 (d, J = 6.5 Hz, 1H), 7.24 (dd, J = 7.5, 1.5 Hz, 1H), 7.18–7.08 (m, 3H),
.97 (dt, J = 1.5, 8.0 Hz, 1H), 6.82 (dt, J = 1.5, 7.5 Hz, 1H), 6.79–6.74 (m,
H), 6.60 (d, J = 8.0 Hz, 1H), 5.91 (ddt, J = 17.0, 10.0, 7.0 Hz, 1H), 5.46
1
5
3
28.40, 128.35, 128.2, 127.83, 127.78, 126.3, 126.2, 113.1, 79.2, 77.2,
+
9.2, 48.6, 38.6, 20.7 ppm. HRMS: calcd. for C25
97.1774, found 397.1772.
26 3
H O [M + Na]
(
t, J = 7.5 Hz, 1H), 5.31 (dd, J = 8.0, 3.5 Hz, 1H), 5.11 (dd, J = 17.0, 1.5
[
2b,2c,2g,2h]
Hz, 1H), 4.96 (dd, J = 10.0, 1.5 Hz, 1H), 3.47 (dd, J = 11.0, 8.0 Hz, 1H),
(4R)-6-methyl-4-phenylchroman-2-ol (14)
: To a solution of 13
3
1
1
.42 (s, 3H), 3.39 (dd, J = 11.0, 3.5 Hz, 1H), 2.99 (dt, J = 14.0, 7.0 Hz,
(48.3 mg, 0.129 mmol) in CH
2 2
Cl (1.3 mL) at –78 °C was successively
1
3
added BBr in CH Cl (1 M, 195.0 µL, 0.195 mmol). After stirring for 19 h
3
2
2
H), 2.94–2.86 (m, 1H) ppm. C NMR (CDCl
3
): δ = 154.7, 141.2, 138.2,
3 2 2
at the same temperature, BBr in CH Cl (1 M, 195.0 µL, 0.195 mmol)
37.3, 133.8, 133.4, 132.2, 128.7, 128.4, 127.8, 127.7, 126.9, 126.4,
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