Journal of Medicinal Chemistry
Article
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1548, 1364, 1333, 1185, 1131 cm−1. H NMR (400 MHz, CDCl3) δ
(m, 6H, NCH, 5Ph), 6.46 (d, 1H, J = 3.0 Hz, H-4′, Ar), 5.01 (s, 2H,
CH2Ph). 13C NMR (101 MHz, CDCl3) δ 148.8 (C-2′, Ar), 132.4,
129.5, 129.3, 129.1 (Ph), 124.4, 124.2 (CN, C-5′, Ar), 117.5 (C-3′,
Ar), 114.2 (C-4′, Ar), 69.6 (CH2Ph); MS (EI) m/z: 281, 279 (M)+, 91.
MS (ESI) m/z: 282.0, 280.0 (M + H)+. Anal. Calcd for C12H10BrNO2:
C, 51.45; H, 3.60; N, 5.00; Br, 28.53. Found: C, 51.74; H, 3.69; N,
5.16; Br, 28.08.
10.29 (s, 1H, H-4′, Ar), 8.27 (s, 1H, NCH), 7.85 (d, 1H, J = 8.8 Hz,
H-8′, Ar), 7.63 (s, 1H, H-5′, Ar), 7.56 (d, 1H, J = 8.8 Hz, H-7′, Ar),
2.52 (s, 3H, CH3), 1.67 [s, 9H, C(CH3)3]. 13C NMR (101 MHz,
CDCl3) δ 148.0 (Ar), 145.5 (Ar), 137.6 (Ar), 136.5 (C-4′, Ar), 133.7
(C-7′, Ar), 127.8, 127.7 (C-5′, C-8′, Ar), 127.2 (Ar), 125.4 (CN),
122.7 (Ar), 72.3 [C(CH3)3], 28.3 [C(CH3)3)], 21.6 (CH3). MS (EI)
m/z: 276 (M)+, 241, 185, 167, 57. MS (ESI) m/z: 277.0 (M + H)+.
Anal. Calcd for C15H17ClN2O: C, 65.10; H, 6.19; N, 10.12; Cl, 12.81.
Found: C, 65.37; H, 5.91; N, 9.93; Cl, 13.07.
(Z)-N-[(2-Chloro-6-methylquinolin-3-yl)methylene]-1-phe-
nylmethanamine Oxide (3). Following the general procedure
(method A), reaction of commercial 2-chloro-6-methylquinoline-3-
carbaldehyde (200 mg, 0.97 mmol), Na2SO4 (410 mg, 2.92 mmol),
Et3N (0.30 mL, 1.95 mmol), and N-benzylhydroxylamine hydro-
chloride (310 mg, 1.95 mmol) in THF (4 mL), after 30 min, and
column chromatography (hexane/EtOAc, 7:3, v/v), gave nitrone 3
(192 mg, 64%) as a solid: mp 154−156 °C. IR (KBr) νmax 3436, 2918,
1569, 1555, 1429, 1342, 1180, 1146, 1048 cm−1. 1H NMR (400 MHz,
CDCl3) δ 10.20 (s, 1H, H-4′, Ar), 8.10 (s, 1H, NCH), 7.84 (d, 1H, J
= 8.3 Hz, H-8′, Ar), 7.62 (s, 1H, H-5′, Ar), 7.57 (d, 1H, J = 8.3 Hz, H-
7′, Ar), 7.54−7.51 (m, 2H, Ph), 7.47−7.41 (m, 3H, Ph), 5.16 (s, 2H,
CH2Ph), 2.52 (s, 3H, CH3). 13C NMR (101 MHz, CDCl3) δ 147.4,
145.6, 137.7 (3Ar), 136.8 (C-4′, Ar), 133.9 (C-7′, Ar), 132.7 (Ph),
129.5, 129.4, 129.3, 129.1 (CN, 3Ph), 127.8 (2Ar), 127.0 (C-8′, Ar),
122.2 (Ar), 72.2 (CH2Ph), 21.6 (CH3). MS (EI) m/z: 310 (M)+, 275,
91. MS (ESI) m/z: 311.0 (M + H)+. Anal. Calcd for C18H15ClN2O: C,
69.57; H, 4.86; N, 9.01; Cl, 11.41. Found: C, 69.52; H, 5.14; N, 9.30;
Cl, 11.63.
(Z)-N-[(5-Bromofuran-2-yl)methylene]-2-methylpropan-2-
amine Oxide (7). Following the general procedure (method A),
reaction of commercial 5-bromofuran-2-carbaldehyde (150 mg, 0.86
mmol), Na2SO4 (730 mg, 5.14 mmol), Et3N (0.52 mL, 3.43 mmol),
and N-t-butylhydroxylamine hydrochloride (430 mg, 3.42 mmol) in
THF (5 mL), after 1 h, and column chromatography (hexane/EtOAc,
6:4, v/v), gave nitrone 7 (150 mg, 71%) as a solid: mp 93−5 °C. IR
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(KBr) νmax 3436, 2978, 1476, 1357, 1202, 1116, 1013 cm−1. H NMR
(400 MHz, CDCl3) δ 7.71 (d, 1H, J = 3.3 Hz, H-3′, Ar), 7.69 (s, 1H,
NCH), 6.46 (d, 1H, J = 3.3 Hz, H-4′, Ar), 1.57 (s, 9H, CH3). 13C
NMR (101 MHz, CDCl3) δ 149.6 (C-2′, Ar), 123.9 (CN), 120.6
(C-3′, Ar), 117.0 (C-4′, Ar), 114.0 (C-5′, Ar), 69.9 [C(CH3)3], 28.0
[C(CH3)3]. MS (EI) m/z: 247, 245 (M)+, 191, 189, 79, 57. MS (ESI)
m/z: 248.0, 246.0 (M + H)+. Anal. Calcd for C9H12BrNO2: C, 43.92;
H, 4.91; N, 5.69; Br, 32.47. Found: C, 43.80; H, 4.75; N, 5.81; Br,
31.93.
(Z)-2-Methyl-N-(4-(3-(nitrooxy)propoxy)benzylidene)-
propan-2-amine Oxide (8). Following the general procedure
(method A), reaction of 3-(4-formylphenoxy)propyl nitrate20 (67
mg, 0.30 mmol), Na2SO4 (128 mg, 0.90 mmol), Et3N (0.09 mL, 0.60
mmol), and N-t-butylhydroxylamine hydrochloride (75 mg, 0.60
mmol) in THF (4 mL), after 18 h, and column chromatography
(hexane/EtOAc, 2:8, v/v), gave nitrone 8 (56 mg, 63%) as a solid: mp
99−101 °C. IR (KBr) νmax 3436, 2982, 1623, 1609, 1513, 1281, 1269,
1177, 1109 cm−1. 1H NMR (400 MHz, CDCl3) δ 8.28 (d, 2H, J = 8.5
Hz, H-2′, Ph), 7.48 (s, 1H, NCH), 6.92 (d, 2H, J = 8.5 Hz, H-3′,
Ph), 4.67 (t, 2H, J = 6.0 Hz, CH2ONO2), 4.12 (t, 2H, J = 6.0 Hz,
CH2OAr), 2.23 (q, 2H, J = 6.0 Hz, CH2CH2CH2), 1.61 [s, 9H,
C(CH3)3]. 13C NMR (101 MHz, CDCl3) δ 159.6 (C-4′, Ph), 130.8
(C-2′ Ph), 129.6 (CN), 124.4 (C-1′, Ph), 114.2 (C-3′ Ph), 70.2
[C(CH3)3], 69.8 (CH2ONO2), 63.6 (CH2OAr), 28.3 [C(CH3)3], 26.9
(CH2CH2CH2). MS (EI) m/z: 296 (M)+, 240, 194, 177, 136, 57. MS
(ESI) m/z: 297.0 (M + H)+. Anal. Calcd for C14H20N2O5: C, 56.75; H,
6.80; N, 9.45. Found: C, 56.76; H, 6.50; N, 9.24.
(Z)-N-(3,5-Di-tert-butyl-4-hydroxybenzylidene)-1-phenylme-
thanamine Oxide (4).22 Following the general procedure (method
A), reaction of commercial 3,5-di-t-butyl-4-hydroxybenzaldehyde (200
mg, 0.82 mmol), Na2SO4 (470 mg, 3.29 mmol), Et3N (0.25 mL, 1.64
mmol), and N-benzylhydroxylamine hydrochloride (260 mg, 1.64
mmol) in THF (4 mL), after 40 min, and column chromatography
(hexane/EtOAc, 6:4, v/v), gave nitrone 4 (264 mg, 95%) as a solid:
mp 225−6 °C. IR (KBr) νmax 3623, 3430, 2956, 1593, 1438, 1412,
1239, 1146, 1119 cm−1. H NMR (400 MHz, CDCl3) δ 8.16 (s, 2H,
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H-2′, Ar), 7.50−7.34 (m, 6H, NCH, 5Ph), 5.61 (s, 1H, OH), 5.03
(s, 2H, CH2Ph), 1.45 (s, 18H, CH3). 13C NMR (101 MHz, CDCl3) δ
155.9 (C-4′, Ar), 135.8 (C-3′, Ar), 135.1 (CN), 133.5, 129.1, 128.8,
128.7 (CH2Ph), 126.4 (C-2′, Ar), 122.2 (C-1′, Ar), 70.6 (CH2Ph), 34.3
[C(CH3)3], 30.1 [C(CH3)3]. MS (EI) m/z: 339 (M)+, 323, 266, 91.
MS (ESI) m/z: 340.3 (M + H)+. Anal. Calcd for C22H29NO2: C,
77.84; H, 8.61; N, 4.13. Found: C, 77.51; H, 8.43; N, 4.30.
(Z)-2-Methyl-N-(4-(2-(nitrooxy)ethoxy)benzylidene)propan-
2-amine Oxide (9). Following the general procedure (method A),
reaction of 2-(4-formylphenoxy)ethyl nitrate20 (120 mg, 0.57 mmol),
Na2SO4 (480 mg, 3.41 mmol), Et3N (0.35 mL, 2.27 mmol), and N-t-
butylhydroxylamine hydrochloride (290 mg, 2.27 mmol) in THF (4
mL), after 20 h, and column chromatography (hexane/EtOAc, 2:8, v/
v), gave nitrone 9 (72 mg, 45%) as a solid: mp 66−9 °C. IR (KBr)
(Z)-N-(3,5-Di-tert-butyl-4-hydroxybenzylidene)-2-methyl-
propan-2-amine Oxide (5).22 Following the general procedure
(method A), reaction of commercial 3,5-di-t-butyl-4-hydroxybenzalde-
hyde (120 mg, 0.49 mmol), Na2SO4 (280 mg, 1.95 mmol), Et3N (0.15
mL, 0.98 mmol), and N-t-butylhydroxylamine hydrochloride (123 mg,
0.98 mmol) in THF (4 mL), after 16 h, and column chromatography
(hexane/EtOAc, 6:4, v/v), gave nitrone 5 (105 mg, 70%) as a solid:
mp 230−3 °C. IR (KBr) νmax 3436, 2969, 1438, 1360, 1195, 1093
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νmax 3436, 2981, 1636, 1604, 1285, 1259, 1111 cm−1. H NMR (400
MHz, CDCl3) δ 8.29 (d, 2H, J = 8.6 Hz, H-2′, Ph), 7.47 (s, 1H, N
CH), 6.91 (d, 2H, J = 8.6 Hz, H-3′, Ph), 4.82 (t, 2H, J = 4.4 Hz,
CH2ONO2), 4.29 (t, 2H, J = 4.4 Hz, CH2OAr), 1.60 [s, 9H,
C(CH3)3]. 13C NMR (101 MHz, CDCl3) δ 159.2 (C-4′, Ph), 131.0
(C-2′ Ph), 129.6 (CN), 125.1 (C-1′, Ph), 114.4 (C-3′ Ph), 71.0
(CH2ONO2), 70.5 [C(CH3)3], 64.2 (CH2OAr), 28.5 [C(CH3)3]. MS
(EI) m/z: 282 (M)+, 180, 163, 57. MS (ESI) m/z: 283.0 (M + H)+.
Anal. Calcd for C13H18N2O5: C, 55.31; H, 6.43; N, 9.92. Found: C,
55.54; H, 6.18; N, 9.92.
cm−1. H NMR (400 MHz, CDCl3) δ 8.21 (s, 2H, H-2′, Ar), 7.44 (s,
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1H, NCH), 5.56 (s, 1H, OH), 1.60 [s, 9H, NC(CH3)3], 1.46 [s,
18H, ArC(CH3)3]. 13C NMR (101 MHz, CDCl3) δ 155.6 (C-4′, Ar),
135.7 (C-3′, Ar), 130.6 (CN), 126.5 (C-2′, Ar), 122.9 (C-1′, Ar),
69.9 [NC(CH3)3], 34.4 [ArC(CH3)3], 30.2 [ArC(CH3)3], 28.5
[NC(CH3)3]. MS (EI) m/z: 305 (M)+, 249, 234, 57. MS (ESI) m/
z: 306.3 (M + H)+. Anal. Calcd for C19H31NO2: C, 74.71; H, 10.23; N,
4.59. Found: C, 74.83; H, 10.12; N, 4.81.
(Z)-N-(4-(3-(Nitrooxy)propoxy)benzylidene)-1-phenylme-
thanamine Oxide (10). Following the general procedure (method
A), reaction of 3-(4-formylphenoxy)propyl nitrate20 (80 mg, 0.36
mmol), Na2SO4 (200 mg, 1.42 mmol), Et3N (0.11 mL, 0.71 mmol),
and N-benzylhydroxylamine hydrochloride (113 mg, 0.71 mmol) in
THF (3 mL), after 4 h, and column chromatography (hexane/EtOAc,
3:7, v/v), gave nitrone 10 (102 mg, 87%) as a solid: mp 96−98 °C. IR
(Z)-N-[(5-Bromofuran-2-yl)methylene]-1-phenylmethan-
amine Oxide (6). Following the general procedure (method A),
reaction of commercial 5-bromofuran-2-carbaldehyde (110 mg, 0.63
mmol), Na2SO4 (360 mg, 2.51 mmol), Et3N (0.19 mL, 1.25 mmol),
and N-benzylhydroxylamine hydrochloride (200 mg, 1.25 mmol) in
THF (4 mL), after 30 min, and column chromatography (hexane/
EtOAc, 6:4, v/v), gave nitrone 6 (142 mg, 81%) as a solid: mp 108−
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(KBr) νmax 3436, 1624, 1605, 1282, 1256, 1174 cm−1. H NMR (400
MHz, CDCl3) δ 8.20 (d, 2H, J = 8.0 Hz, H-2′, Ph), 7.50−7.31 (m, 6H,
NCH, 5CH2Ph), 6.90 (d, 2H, J = 8.0 Hz, H-3′, Ph), 5.03 (s, 2H,
CH2Ph), 4.66 (t, 2H, J = 6.0 Hz, CH2ONO2), 4.10 (t, 2H, J = 5.6 Hz,
CH2OAr), 2.22 (t, 2H, J = 6.0, 5.6 Hz, CH2CH2CH2). 13C NMR (101
110 °C. IR (KBr) νmax 3436, 1477, 1222, 1134, 1010 cm−1. H NMR
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(400 MHz, CDCl3) δ 7.71 (d, 1H, J = 3.0 Hz, H-3′, Ar), 7.44−7.43
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dx.doi.org/10.1021/jm201105a | J. Med. Chem. 2012, 55, 153−168