Journal of Medicinal Chemistry
Article
D O), 3.15 (m, 1H), 2.54−2.48 (m, 1H), 2.43 (s, 3H), 2.30 (m,
128.01, 127.11, 122.57, 121.09, 116.81, 73.45, 65.99, 65.28, 57.64,
41.86, 29.71, 26.26, 23.33.
2
1
3
1
1
2
H), 1.94−1.74 (m, 4H). C NMR (CDCl ) δ 143.82, 135.94,
3
31.53, 120.93, 107.65, 107.50, 74.07, 66.00, 65.29, 57.70, 42.10,
6.46, 23.37.
(S,R)-2-(N-Methyl-2′-pyrrolidinyl)-5-phenyl-1,4-benzodioxane
[(S,R)-4c]. Obtained as a light yellow oil in 85% yield after
chromatography on silica gel [toluene/ethyl acetate (9:1) + 0.5%
(
S,R)-2-(N-Methyl-2′-pyrrolidinyl)-5-amino-1,4-benzodioxane
(S,R)-1c]. Obtained as a beige solid in quantitative yield after
chromatography on silica gel [dichloromethane/methanol (95:5) +
2
5
1
[
TEA]: R = 0.26; [α] = +14.1 (c 0.5, CHCl ); H NMR (CDCl ) δ
f D 3 3
7.55 (d, J = 7.3 Hz, 2H), 7.42 (t, J = 7.3 Hz, 2H), 7.33 (t, J = 7.3 Hz,
1H), 6.96−6.87 (m, 3H), 4.32 (dd, J = 11.2, 1.8 Hz, 1H), 4.22 (td, J
= 7.2, 1.8 Hz, 1H), 4.00 (dd, J = 11.2, 7.2 Hz, 1H), 3.21−3.07 (m,
1H), 2.68 (m, 1H), 2.54 (s, 3H), 2.32 (m, 1H), 2.05−1.88 (m, 1H),
2
5
0
.5% NH ]: mp = 59.1 °C; R = 0.23; [α] = +26.9 (c 1, MeOH);
3 f D
1
H NMR (CDCl ) δ 6.64 (t, 1H, J = 7.8 Hz), 6.34 (dd, 1H, J = 1.5
3
and 7.8 Hz), 6.30 (dd, 1H, J = 1.5 and 7.8 Hz), 4.34 (dd, 1H, J = 2.1
and 11.1 Hz), 4.13 (dt, 1H, J = 2.1 and 7.3 Hz), 4.00 (dd, 1 H, J =
1
3
1.88−1.59 (m, 3H). C NMR (CDCl ) δ 143.58, 140.56, 137.66,
3
1
2
1
1
2
1.1 and 7.3 Hz), 3.72 (bs, 2H, exchange with D O), 3.12 (m, 1H),
130.57, 129.83, 129.41, 128.02, 127.11, 125.53, 122.58, 121.09,
116.67, 76.12, 65.70, 64.88, 57.94, 42.72, 30.31, 29.71, 27.30, 23.42.
General Procedure for Synthesis of Compounds 2a−2c and
2
.60 (m, 1H), 2.48 (s, 3H), 2.27 (q, J = 8.6 Hz, 1H), 2.00−1.89 (m,
1
3
H), 1.81−1.61 (m, 3H). C NMR (CDCl ) δ 143.50, 135.88,
3
3
c. The target compounds were obtained by treatment of a solution
31.48, 120.95, 107.74, 107.35, 76.29, 65.62, 64.74, 57.93, 42.65,
7.20, 23.44.
of the compounds 18a−18c and 28 in CPME with Aquivion-Fe (5
mol %) and 37 wt % aqueous formaldehyde (10 mol). The resulting
mixture was vigorously stirred at 40 °C for 4 h. After cooling down
(
S,S)-2-(N-Methyl-2′-pyrrolidinyl)-6-hydroxy-1,4-benzodioxane
(S,S)-3b]. Obtained as a white solid in 88% yield after
chromatography on silica gel [dichloromethane/methanol (95:5) +
[
to 0 °C, NaBH (1 mol) and MeOH were added and the mixture
4
2
5
0
.5% NH ]: mp 126.85 °C; R = 0.31; [α] = −108.0 (c 0.5,
was stirred for 30 min. Afterward, water was added and the
suspension was filtered to remove the Aquivion-Fe catalyst. The
organic phase was separated and the aqueous one was extracted twice
with ethyl acetate. The combined organic phases were dried over
3
f
D
1
CHCl ); H NMR (CDCl ) δ 6.75 (d, 1H, J = 8.8 Hz), 6.39 (d, 1H,
3
3
J = 2.8 Hz), 6.31 (dd, 1H, J = 2.8 and 8.8 Hz), 4.24 ( dd, 1H, J = 1.9
and 11.0 Hz), 4.08 (ddd, 1H, J = 1.9, 4.1 and 8.3 Hz), 3.97 (dd, 1H,
J = 11.0 and 8.3 Hz), 3.14 (m, 1H), 2.50 (m, 1H), 2.43 (s, 3H), 2.28
Na SO and concentrated under vacuum to obtain a crude that was
2 4
1
3
(
1
2
m, 1H), 2.00−1.70 (m, 4H). C NMR (CDCl ) δ 150.69, 143.80,
purified by flash chromatography.
3
37.39, 117.92, 108.92, 104.39, 72.95, 66.53, 65.81, 57.72, 41.99,
6.08, 23.28.
(S,S)-2-(N-Methyl-2′-pyrrolidinyl)-7-nitro-1,4-benzodioxane
[
(S,S)-2a]. Obtained as a light yellow oil in 93% yield after
(
S,R)-2-(N-Methyl-2′-pyrrolidinyl)-6-hydroxy-1,4-benzodioxane
(S,R)-3b]. Obtained as a white solid in 86% yield after
chromatography on silica gel [dichloromethane/methanol (95:5) +
chromatography on silica gel [dichloromethane/methanol (95:5) +
2
5
1
[
0.5% NH
3
]: R
f
= 0.40; [α]
D
= −141.6 (c 0.5, CHCl ); H NMR
3
(CDCl ) δ 7.83 (d, 1H, J = 2.6 Hz), 7.74 (dd, 1H, J = 2.6 and 9.0
3
2
5
0
.5% NH ]: mp = 166.40 °C; R = 0.20; [α] = +12.6 (c 0.5,
Hz), 6.92 (d, 1H, J = 9.0 Hz), 4.43 (m, 1H), 4.14−4.06 (m, 2H),
3.10 (m, 1H), 2.62 (m, 1H), 2.43 (s, 3H), 2.34−2.26 (m, 1H),
3
f
D
1
CHCl ); H NMR (CDCl ) δ 6.71 (d, 1H, J = 8.5 Hz), 6.37 (d, 1H,
3
3
1
3
J = 2.8 Hz), 6.32 (dd, 1H, J = 2.8 and 8.5 Hz), 4.25 (dd, 1H, J = 1.9
and 11.0 Hz), 4.06 (dt, 1H, J = 1.9 and 7.2 Hz), 3.96 (dd, 1H, J =
1.96−1.75 (m, 4H). C NMR (CDCl ) δ 149.32, 143.27, 141.87,
3
117.34, 116.92, 113.59, 74.72, 66.35, 64.87, 57.65, 42.33, 26.83,
23.61.
7
.2 and 11.0 Hz), 3.15 (m, 1H), 2.62 (m, 1H), 2.52 (s, 3H), 2.35
13
(
m, 1H), 2.07−1.85 (m, 1H), 1.85−1.60 (m, 3H). C NMR
CDCl ) δ 150.69, 143.81, 136.96, 117.74, 109.09, 104.61, 76.34,
(S,R)-2-(N-Methyl-2′-pyrrolidinyl)-7-nitro-1,4-benzodioxane
[(S,R)-2a]. Obtained as a light yellow oil in 81% yield after
chromatography on silica gel [dichloromethane/methanol (95:5) +
(
3
6
6.28, 65.12, 58.18, 43.21, 27.64, 23.30.
S,S)-2-(N-Methyl-2′-pyrrolidinyl)-6-phenyl-1,4-benzodioxane
(S,S)-4b]. Obtained as a white solid in 93% yield after
chromatography on silica gel [dichloromethane/methanol (95:5) +
2
5
1
(
0.5% NH
3 f D 3
]: R = 0.53; [α] = +36.2 (c 0.5, CHCl ); H NMR
[
(CDCl ) δ 7.80 (m, 2H), 6.92 (d, 1H, J = 8.8 Hz), 4.41 (dd, 1H, J =
3
2.2 and 11.4 Hz), 4.19 (td, 1H, J = 1.8 and 7.9 Hz), 4.06 (dd, 1H, J
2
5
0
.5% NH ]: mp = 87.49 °C; R = 0.65; [α] = −132.4 (c 0.5,
= 7.9 and 11.4 Hz), 3.12 (m, 1H), 2.71 (m, 1H), 2.49 (s, 3H), 2.28
3
f
D
1
13
CHCl ); H NMR (CDCl ) δ 7.54 (m, 2H), 7.40 (m, 2H), 7.29 (m,
(m, 1H), 2.02−1.91 (m, 1H), 1.82−1.66 (m, 3H). C NMR
3
3
1
H), 7.11 (m, 2H), 7.02 (d, 1H, J = 8.3 Hz), 4.32 (dd, 1H, J = 1.9
(CDCl3) δ 149.25, 143.07, 141.83, 117.48, 116.90, 113.47, 76.23,
66.12, 64.73, 57.81, 42.67, 27.20, 23.60.
and 11.0 Hz), 4.17 (ddd, 1H, J = 1.9, 4.1 and 7.9 Hz), 4.06 (dd, 1H,
J = 7.9 and 11.0 Hz), 3.15 (m, 1H), 2.56 (m, 1H), 2.46 (s, 3H), 2.29
(S,S)-2-(N-Methyl-2′-pyrrolidinyl)-6-nitro-1,4-benzodioxane
[(S,S)-2b]. Obtained as a white solid in 85% yield after
chromatography on silica gel [dichloromethane/methanol (95:5) +
1
3
(
1
7
m, 1H), 2.05−1.75 (m, 4H). C NMR (CDCl ) δ 143.88, 143.48,
3
40.88, 134.73, 128.92, 127.01, 126.98, 120.43, 117.99, 115.79,
4.36, 66.36, 65.52, 57.93, 42.30, 26.67, 23.64.
2
5
0.2% NH
]: mp = 93.09 °C; R
= 0.42; [α]
= −171.3 (c 1, CHCl );
3
f
D
3
1
(
S,R)-2-(N-Methyl-2′-pyrrolidinyl)-6-phenyl-1,4-benzodioxane
(S,R)-4b]. Obtained as a white solid in 94% yield after
chromatography on silica gel [dichloromethane/methanol (95:5) +
H NMR (CDCl ) δ 7.79 (m, 2H), 7.00 (d, 1H, J = 7.0 Hz), 4.37
3
[
(dd, 1H, J = 2.2 and 11.4 Hz), 4.19 (m, 1H), 4.07 (dd, 1H, J = 11.4
and 7.9 Hz), 3.17 (m, 1H), 2.63 (m, 1H), 2.45 (s, 3H), 2.37 (m,
2
5
13
0
.5% NH ]: mp = 95.77 °C; R = 0.21; [α] = +29.6 (c 0.5, CHCl );
1H), 1.98−1.76 (m, 4H). C NMR (CDCl ) δ 149.48, 143.21,
3
f
D
3
3
1
H NMR (CDCl ) δ 7.53 (m, 2H), 7.40 (m, 2H), 7.29 (m, 1H),
141.65, 117.71, 117.34, 113.21, 75.25, 65.83, 64.93, 57.62, 42.26,
26.71, 23.58.
3
7
1
.11 (m, 2H), 6.95 (d, 1H, J = 8.3 Hz), 4.34 (dd, 1H, J = 2.2 and
1.0 Hz), 4.22 (dt, 1H, J = 2.2 and 7.2 Hz), 4.04 (dd, 1H, J = 7.2
(S,R)-2-(N-Methyl-2′-pyrrolidinyl)-6-nitro-1,4-benzodioxane
[(S,R)-2b]. Obtained as a light yellow solid in 64% yield after
chromatography on silica gel [dichloromethane/methanol (95:5) +
and 11.0 Hz), 3.19 (m, 1H), 2.75 (m, 1H), 2.52 (s, 3H), 2.32 (m,
1
3
1
1
7
H), 2.08−1.65 (m, 4H). C NMR (CDCl ) δ 143.8, 143.07,
3
2
5
40.84, 134.79, 128.91, 127.02, 126.96, 120.47, 117.83, 115.74,
6.60, 66.00, 65.12, 58.16, 42.91, 27.52, 23.67.
0.5% NH
3
]: mp = 91.22 °C; R
f D 3
= 0.47; [α] = +72.3 (c 1, CHCl );
1
H NMR (CDCl ) δ 7.81 (m, 2H), 6.97 (m,1H), 4.39 (dd, 1H, J =
3
(
S,S)-2-(N-Methyl-2′-pyrrolidinyl)-5-phenyl-1,4-benzodioxane
(S,S)-4c]. Obtained as a light yellow oil in 85% yield after
chromatography on silica gel [toluene/ethyl acetate (9:1) + 0.5%
2.4 and 11.6 Hz), 4.26 (td, 1H, J = 2.4 and 7.5 Hz), 4.03 (dd, 1H, J
= 7.5 and 11.6 Hz), 3.17 (m, 1H), 2.75 (m, 1H), 2.50 (s, 3H), 2.44−
[
1
3
2.30 (m, 1H), 2.03−1.93 (m, 1H), 1.85−1.66 (m, 3H). C NMR
25
1
TEA]: R = 0.30; [α] = −64.7 (c 0.5, CHCl ); H NMR (CDCl ) δ
.53 (m, 2H), 7.45 (m, 2H), 7.32 (t, 1H, J = 7.3 Hz), 6.97 (dd, 1H, J
4.2 and 5.7 Hz), 6.90 (d, 1H, J = 5.7 Hz), 6.89 (d, 1H, J = 4.2 Hz),
.30 (dd, 1H, J = 2.2 and 11.2 Hz), 4.18 (ddd, 1H, J = 2.2, 4.1 and
.0 Hz), 3.99 (dd, 1H, J = 8.0 and 11.2 Hz), 3.13 (m, 1H), 2.49 (m,
H), 2.45 (s, 3H), 2.26 (q, 1H, J = 8.4 Hz), 1.99−1.70 (m, 4H).
NMR (CDCl ) δ 143.89, 140.58, 137.69, 130.67, 129.83, 129.40,
(CDCl ) δ 149.18, 143.14, 141.75, 117.71, 117.24, 113.20, 77.10,
f
D
3
3
3
7
=
65.59, 64.81, 57.84, 42.70, 27.31, 23.61.
(S,S)-2-(N-Methyl-2′-pyrrolidinyl)-5-nitro-1,4-benzodioxane
4
8
1
[(S,S)-2c]. Obtained as a light yellow oil in 81% yield after
chromatography on silica gel (ethyl acetate + 5% triethylamine): R
f
1
3
25
1
C
= 0.72; [α]D = −90.1 (c 1, MeOH). H NMR (CDCl ) δ 7.46 (dd,
3
1H, J = 1.6 and 8.3 Hz), 7.17 (dd, 1H, J = 1.6 and 8.3 Hz), 6.88 (t,
3
R
J. Med. Chem. XXXX, XXX, XXX−XXX