The Journal of Organic Chemistry
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and neutralized by ammonium hydroxide producing a precipitate that
was filtered and dried. If no precipitate was formed, the aqueous
mixture was extracted with DCM (3 × 10 mL), and the organic layers
were combined, dried over Na2SO4, and concentrated under vacuum.
Nitration of Manzamine F (2). Manzamine F (100 mg, 0.172
mmol) and NaNO2 (13 mg, 0.188 mmol) were reacted by method A.
After workup, the crude nitromanzamine F products were purified by
silica column chromatography using n-hexane/acetone (9:1). Further
purification was carried out on a Phenomenex Luna C8 250 × 10 mm,
5 μm Luna reverse-phase HPLC column using gradient CH3CN (0.1%
TFA)/water (0.1% TFA) with flow rate of 6 mL/min to give the pure
nitro analogues.
Nitration of Harmane (6). Harmane (100 mg, 0.440 mmol) and
NaNO2 (33.4 mg, 0.480 mmol) were reacted by method A. After
workup, the crude nitro products of harmane were loaded onto a
column packed with 15 g of silica gel. 8-Nitroharmane (7) was eluted
first with 99:1 DCM/MeOH, followed by 6-nitroharmane (8) after the
mobile polarity was increased with 95:5 DCM/MeOH.
8-Nitroharmane (7).26 Data: (54 mg, 43%); yellow powder (mp
211−212 °C; lit. 209−210 °C); (Rf = 0.8, 9:1 DCM/MeOH); IR
3087, 3044, 2974, 2865, 2784, 1660, 1640, 1530,1491, 1339, 1288,
1
1202, 1184, 1131, 833 cm−1; H NMR (CDCl3) δ 9.87 (s, brd), 8.44
(1H, d, J = 5.6 Hz), 8.40 (1H, d, J=8.0 Hz), 8.37 (1H, d, J = 8.0 Hz),
7.78 (1H, d, J = 5.6 Hz), 7.33 (1H, t, J = 8.0 Hz), 2.86 (s); 13C NMR
(CDCl3) δ 143.3 (C), 140.6 (CH), 134.8 (C), 134.0 (C), 133.7 (C),
127.4 (CH), 127.6 (C), 126.4 (C), 124.2 (CH), 119.4 (CH), 112.6
(CH), 20.2 (CH3); HRESIMS m/z calcd for C12H10N3O2 (M + H)+
228.0773, found 228.0770.
Manzamine F (2). Data: 1H NMR (CDCl3) δ 8.41 (1H, d, J = 7.6
Hz), 7.88 (1H, d, J = 7.5 Hz), 7.63 (1H, d, J = 7.6 Hz), 7.61 (1H, d, J
= 7.6 Hz), 7.12 (1H, d, J = 7.6 Hz), 6.66 (1H, s), 5.60 (2H, m), 3.70
(1H, s), 3.11 (m), 2.92 (m), 2.57 (m), 2.38 (m), 2.10 (m); 13C NMR
(CDCl3) δ 211.0 (C), 143.7 (C), 143.1 (C), 141.3(C), 138.3 (CH),
137.7 (CH), 133.3 (C), 132.6 (C), 130.1 (C), 128.0 (CH), 123.4 (C),
121.1 (CH), 113.8 (CH), 112.2 (CH), 82.1 (CH), 69.6 (C), 63.5
(CH), 53.2 (CH2), 49.8 (CH2), 47.6 (C), 46.7 (CH2), 46.1 (CH2),
45.1 (CH2), 42.5 (CH), 39.9 (CH2), 38.9 (CH2), 34.2 (CH2), 32.7
(CH2), 26.9 (CH2), 25.7 (CH2), 25.2 (CH2), 24.6 (CH2), 21.5 (CH2).
7-Nitromanzamine F (3). Data: (21 mg, 20%); [α]2D5 +11.5 (c
0.05, MeOH); yellow solid; (Rf = 0.6, 9:1 DCM/MeOH); IR 3534
(br), 3211, 3050, 2959, 2924, 2852, 1711, 1650, 1574, 1507, 1457,
1421, 1260, 1072, 1024, 911, 802, 729 cm−1; 1H NMR (acetone-d6) δ
8.55 (1H, d, J = 7.6 Hz), 8.38 (1H, d, J = 7.5 Hz), 8.18 (1H, d, J = 7.6
Hz), 7.91 (1H, d, J = 7.6 Hz), 6.71 (1H, s), 5.65 (2H, m), 3.70 (1H,
s), 3.44 (m), 3.29 (m), 3.14 (m), 2.92 (m), 2.72 (m), 2.53 (m), 2.34
(m), 2.24 (m) 2.08 (s), 2.03 (m), 1.96 (m), 1.74 (m), 1.48 (m); 13C
NMR (acetone-d6) δ 211.0 (C), 150.9 (C), 139.6 (C), 136.1 (CH),
135.2 (CH), 133.7 (CH), 132.6 (C), 131.4, 129.1 (CH), 122.3 (C),
121.7 (C), 121.6 (C), 119.6 (C), 115.4 (CH), 113.3 (CH), 79.8
(CH), 70.6 (C), 69.2 (CH2), 58.8 (CH2), 55.7 (CH), 51.1 (CH2),
47.3 (CH2), 45.6 (CH2), 41.6 (CH2), 36.6 (CH2), 36.3 (CH2), 34.7
(CH2), 28.1 (CH2), 25.1 (CH2), 24.3 (CH2), 22.9 (CH2), 20.7
(CH2); HRESIMS m/z calcd for C36H44N5O5 (M + H)+ 626.3342,
found 626.3335.
6-Nitroharmane (8).26 Data: (56 mg, 45%); yellow powder (mp
297−299 °C; lit. 299−300 °C); (Rf = 0.7, 9:1 DCM/MeOH); IR
3305, 3086, 2869, 1673, 1640, 1531, 14942, 1434, 1338, 1201, 1138,
832 cm−1; 1H NMR (CDCl3) δ 8.83 (1H, d, J = 2.4 Hz), 8.13 (1H, d, J
= 2.4 Hz), 8.11 (1H, d, J=2.4 Hz), 8.08 (1H, d, J = 6.8 Hz), 7.96 (1H,
d, J = 6.8 Hz), 7.38 (1H, d, J = 8.0 Hz), 2.87 (s); 13C NMR (CDCl3) δ
150.0 (C), 144.2 (C), 137.0 (C), 134.8 (CH), 129.6 (CH), 123.8
(CH), 119.7 (CH), 119.4 (CH), 117.0 (CH), 19.6 (CH3); HRESIMS
m/z calcd for C12H10N3O2 (M + H)+ 228.0773, found 228.0770.
Nitration of β-Estradiol (9). β-Estradiol (100 mg, 0.36 mmol) was
nitrated with method B. After workup, the crude nitro products were
purified with silica column eluted with DCM/MeOH (95:5). The
hydroxy group was oxidized under these conditions.
2-Nitroestrone (10).27 Data: (19.8 mg, 17%); [α]2D5 +96.2 (c 0.1,
DCM); yellow powder (mp 178−179 °C; lit. 178−180 °C); (Rf =
0.56, 100% DCM); IR 3078, 2928, 2857, 1736, 1631, 1525, 1479,
1433, 1374, 1310, 1263, 1053, 897, 734, 703 cm−1; 1H NMR (CDCl3)
δ 7.99 (1H,s), 6.88 (1H,s), 2.97 (2H, m), 2.53 (1H, dd, J = 17.0, 8.3
Hz), 2.46 (1H, m), 2.31−1.97 (6H, m), 1.75−1.40 (8H, m), 0.91
(3H,s); 13C NMR (CDCl3) δ 220.1 (C), 153.0 (C), 148.9 (C), 133.2
(C), 131.7 (C), 121.7 (CH), 119.1 (CH), 50.5 (CH), 48.0 (C), 43.6
(CH), 37.8 (CH), 35.9 (CH2), 31.4 (CH2), 29.8 (CH2), 26.0 (CH2),
25.8 (CH2), 21.7 (CH2), 13.9 (CH3); HRESIMS m/z calcd for
C18H22NO4 (M + H)+ 316.1549, found 316.1552.
5-Nitromanzamine F (4). Data: (21 mg, 20%); [α]2D5 +12.1 (c
0.05, MeOH); pale orange solid; (Rf = 0.50, 9:1 DCM/MeOH); IR
3194 (br), 3090, 2964, 2930, 2854, 2802, 1710, 1671, 1649, 1560,
1456, 1417, 1335, 1202, 1194, 1073, 1026, 911, 820, 805, 729 cm−1;
1H NMR (acetone-d6) δ 8.70 (1H, d, J = 7.6 Hz), 8.53 (1H, d, J = 7.5
Hz), 8.12 (1H, d, J = 7.6 Hz), 7.12 (1H, d, J = 7.6 Hz), 6.99 (1H, s),
5.65 (2H, m), 3.70 (1H, s), 3.44 (m), 3.29 (m), 3.14 (m), 2.92 (m),
2.72 (m), 2.53 (m), 2.34 (m), 2.24 (m) 2.08 (s), 2.03 (m), 1.96 (m),
1.74 (m), 1.48 (m); 13C NMR (acetone-d6) δ 211.0 (C), 149.3 (C),
141.7 (C), 141.0 (C), 136.0 (CH), 135.1 (C), 132.5 (CH), 131.9
(CH), 129.4 (C), 122.5 (C), 121.7 (C), 118.0 (CH), 117.1 (CH),
115.2 (CH), 114.0 (CH), 79.0 (CH), 72.0 (CH2), 67.5 (CH2), 56.6
(CH2), 56.3 (CH), 53.5(CH2), 52.2 (CH2), 49.3 (CH2), 46.3(CH2),
42.4 (CH), 36.8(CH2), 36.6 (CH2), 33.4 (CH2), 30.6 (CH2), 29.6
(CH2), 29.2 (CH2), 28.6 (CH2), 27.5 (CH2), 25.2 (CH2), 22.1 (CH2),
20.0 (CH2); HRESIMS m/z calcd for C36H44N5O5 (M + H)+
626.3342, found 626.3335.
2,4-Dinitroestrone (11).27 Data: (64 mg, 55%); [α]2D5 +90.1 (c
0.1, DCM); yellow powder (mp 186−188 °C; lit. 185−188 °C); (Rf =
0.4, 100% DCM); IR 3350, 3008, 2987, 1734, 1631, 1532, 1345, 1308,
1
1259, 1061, 897 cm−1; H NMR (CDCl3) δ 8.14 (1H,s), 2.88 (2H,
m), 2.53 (1H, dd, J = 17.0, 8.3 Hz), 2.46 (1H, m), 2.31−1.97 (6H, m),
1.75−1.40 (8H, m), 0.91 (3H,s); 13C NMR (CDCl3) δ 220.1 (C),
144.8 (C), 141.7 (C), 139.2 (C), 133.6 (C), 132.1 (C), 122.7 (CH),
50.0 (CH), 47.7 (C), 43.5 (CH), 37.0 (CH), 35.7 (CH2), 31.2 (CH2),
28.2 (CH2), 25.8 (CH2), 24.9 (CH2), 24.8, 21.5 (CH2), 13.7 (CH3);
HRESIMS m/z calcd for C18H21N2O6 (M + H)+ 361.1399, found
361.1402.
Nitration of Quinine (12). Quinine (100 mg, 0.31 mmol) was
nitrated by method B. After workup, the crude product was
fractionated using solid phase extraction (SPE-C18), and the fraction
eluted with H2O/MeOH (80:20) was further purified on a
Phenomenex Luna C8 250 × 22 mm, 5 μm Luna reverse-phase
HPLC column using gradient CH3CN (0.1% TFA)/water (0.1%
TFA) with flow rate of 20 mL/min to give the pure nitro analogue.
Quinine (12). Data: 1H NMR (methanol-d4) δ 8.61 (1H, d, J = 8.0
Hz), 7.90 (1H, d, J = 8.0 Hz), 7.65 (1H, d, J = 4.0 Hz), 7.36 (1H, s),
7.33 (1H, s), 6.23 (1H, d, J = 4.0 Hz), 5.65 (1H, m), 5.56 (1H, m),
4.82 (1H, m), 3.92 (3H, s), 3.65 (1H, m), 3.07 (2H, m), 2.63 (2H, m),
2.26 (1H, m), 1.82 (2H, m), 1.70 (1H, m), 1.52 (1H, m), 1.36 (1H,
m); 13C NMR (methanol-d4) δ 159.5 (C), 150.6 (C), 148.0 (CH),
144.7 (C), 142.7 (CH), 131.4 (CH), 131.3, 128.0 (C), 123.2 (CH),
120.0 (CH), 119.9, 114.9 (CH2), 102.3 (CH), 72.2 (CH), 60.1 (CH),
57.7 (CH2), 56.4 (CH3), 44.1 (CH2), 40.1 (CH), 29.2 (CH), 28.2
(CH2), 21.6 (CH2).
5,7-Dinitromanzamine F (5). Data: (46 mg, 43%); [α]2D5 +18.5 (c
0.1, MeOH); orange solid; (Rf = 0.4, 9:1 DCM/MeOH); IR 3239
(br), 3050, 2932, 2854, 2797, 1693, 1562, 1446, 1418, 1365, 1330,
1271, 1245, 1112, 1075, 823, 789 cm−1; 1H NMR (acetone-d6) δ 8.59
(1H, d, J = 7.6 Hz), 8.21 (1H, d, J = 7.5 Hz), 8.20 (1H, s), 6.52 (1H,
s), 5.36 (2H, m), 3.70 (1H, s), 3.44 (m), 3.29 (m), 3.14 (m), 2.92
(m), 2.72 (m), 2.53 (m), 2.34 (m), 2.24 (m) 2.08 (s), 2.03 (m), 1.96
(m), 1.74 (m), 1.48 (m); 13C NMR (acetone-d6) δ 212.0 (C), 151.1
(C), 143.6 (C), 141.5 (C), 138.4 (CH), 137.7 (CH), 136.9 (C), 133.5
(C), 131.8 (CH), 130.2 (CH), 128.3 (C), 124.1 (C), 120.2 (C), 114.3
(CH), 109.3 (CH), 80.5 (CH), 70.1 (CH2), 69.9 (CH2), 57.1 (CH2),
55.7 (CH2), 53.9 (CH), 51.4 (CH2), 46.8 (CH2), 43.3 (CH), 39.7
(CH2), 36.6 (CH2), 36.4 (CH2), 34.6 (CH2), 32.7 (CH2), 27.3 (CH2),
25.2 (CH2), 24.3 (CH2), 22.1 (CH2), 21.0 (CH2); HRESIMS m/z
calcd for C36H43N6O7 (M + H)+ 671.3193, found 671.3207.
11-Nitro-10-hydroxyquinine (13). Data: (63 mg, 53%); [α]D25
+133.0 (c 1, MeOH); yellow-orange powder mp 167−170 °C); (Rf =
F
dx.doi.org/10.1021/jo300303d | J. Org. Chem. XXXX, XXX, XXX−XXX