The Journal of Organic Chemistry
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1.74 and 1.88 (s, 6H, 2CH3); 2.24, 2.25, and 2.28 (s, 9H, 3CH3-Ar);
2.76 and 2.90 (dd, J = 14, 7 Hz, 2H, CH2); 6.35 (dt, J = 7, 1 Hz, 1H,
CH); 6.84 (m, 2H, Ph); 7.70 (d, J = 7 Hz, 1H, CH-N); 10.50 (bs, 1H,
NH). 13C NMR (CD3COCD3) δ: 19.4; 19.5; 21.5; 25.3; 26.9; 49.0;
64.3; 84.1; 124.3; 124.8; 129.1; 134.4; 135.0; 135.4; 139.2; 140.5;
143.6; 150.2; 157.5; 157.8; 167.9. Anal. Calcd for C19H22N3O4F
(375.40): C, 60.79; H, 5.91; N, 11.19. Found: C, 60.81; H, 5.91; N,
11.21.
45.9; 63.8; 82.7; 124.0; 124.3; 124.4; 124.6; 125.7; 126.4; 126.6; 126.8;
126.9; 127.8; 128.5; 129.6; 130.5; 130.6; 138.2; 138.4; 141.5; 148.8;
156.5; 156.8; 164.2. Anal. Calcd for C24H20O4N3F (433.42) C, 66.51;
H, 4.65; N, 9.70. Found: C, 66.51; H, 4.64; N, 9.71.
22Ac: (0.29 g, 97%) White solid from ethanol, mp 185−188 °C. IR:
νNH 3067, νCO 1728 cm−1. 1H NMR (DMSO) δ: 1.83 (s, 3H, CH3);
2.03 (s, 3H, CH3); 2.84 (m, 2H, CH2); 6.12 (1H, t, J = 6 Hz, O-CH-
N); 7.58 (m, 4H, arom.); 7.72 (s, 1H, N-CH); 7.86 (d, 1H, J = 8 Hz,
arom.); 8.00 (d, 1H, J = 8 Hz, arom.); 8.12 (m, 2H, arom.); 8.67 (s,
1H, arom.); 11.78 (s, 1H, NH). 13C NMR (DMSO) δ: 24.8; 25.7;
46.3; 63.7; 83.1; 107.9; 124.3; 125.6; 125.7; 126.4; 126.8; 126.9; 127.9;
128.6; 130.4; 130.5; 130.6; 136.7; 149.2; 158.6; 164.4. Anal. Calcd for
C24H20O4N3Cl (449.89) C, 64.07; H, 4.48; N, 9.34. Found: C, 64.08;
H, 4.49; N, 9.31.
22Mc: (0.24 g, 93%) White crystals from acetone, mp 208−211 °C.
1
IR: νNH 3167, νCO 1709 cm−1. H NMR (CD3COCD3) δ: 1.73 and
1.87 (s, 6H, 2CH3); 2.25, 2.26, and 2.31 (s, 9H, 3CH3-Ar); 2.83 and
2.95 (dd, J = 14, 7 Hz, 2H, CH2); 6.29 (dt, J = 7, 1 Hz, 1H, CH); 6.85
and 6.89 (1, 1H + 1H, Ph); 7.68 (s, 1H, CH-N); 10.60 (bs, 1H, NH).
13C NMR (CD3COCD3) δ: 19.4; 19.5; 21.5; 25.1; 49.7; 64.2; 84.5;
109.8; 129.1; 129.2; 134.2; 135.0; 135.3; 137.3; 139.3; 150.6; 159.6;
168.2. Anal. Calcd for C19H22N3O4Cl (391.85): C, 58.24; H, 5.66; N,
10.72. Found: C, 58.22; H, 5.69; N, 10.71.
22Ad: (0.31 g, 95%) White solid from ethanol, mp 167−170 °C.
1
IR: νNH 3058, νCO 1726 cm−1. H NMR (DMSO) δ: 1.83 (s, 3H,
CH3); 2.03 (s, 3H, CH3); 2.85 (m, 2H, CH2); 6.12 (t, 1H, J = 6 Hz,
O-CH-N); 7.57 (m, 4H, arom.); 7.81 (s, 1H, N-CH); 7.86 (d, 1H, J =
8 Hz, arom.); 7.97 (d, 1H, J = 8, 4 Hz, arom.); 8.13 (m, 2H, arom.);
8.67 (s, 1H, arom.); 11.73 (s, 1H, NH). 13C NMR (DMSO) δ: 24.9;
25.7; 46.1; 63.7; 83.1; 96.5; 124.3; 125.6; 126.4; 126.9; 127.8; 128.6;
130.4; 130.5; 139.2; 149.4; 158.7; 164.4. Anal. Calcd for
C24H20O4N3Br (494.33) C, 58.31; H, 4.08; N, 8.50. Found: C,
58.31; H, 4.11; N, 8.51.
22Md: (0.27 g, 95%) White crystals from methanol, mp 114−120
1
°C. IR: νNH 3168, νCO 1700 cm−1. H NMR (CD3COCD3) δ: 1.72
and 1.86 (s, 6H, 2CH3); 2.25 and 2.32 (s, 9H, 3CH3-Ar); 2.84 and
2.96 (dd, J = 14, 7 Hz, 2H, CH2); 6.28 (t, J = 6 Hz, 1H, CH); 6.87 (m,
2H, Ph); 7.74 (s, 1H, CH-N); 10.51 (bs, 1H, NH). 13C NMR
(CD3COCD3) δ: 19.5; 19.6; 21.5; 25.1; 26.9; 49.8; 64.2; 84.6; 97.8;
129.0; 129.3; 134.2; 135.0; 135.3; 139.3; 139.8; 150.8; 159.6; 168.3.
Anal. Calcd for C19H22N3O4Br (436.30): C, 52.31; H, 5.08; N, 9.63.
Found: C, 52.25; H, 5.09; N, 9.55.
22Ae: (0.35 g, 99%) White solid from ethanol, mp 164−166 °C. IR:
νNH 3059, νCO 1724 cm−1. 1H NMR (DMSO) δ: 1.83 (s, 3H, CH3);
2.03 (s, 3H, CH3); 2.86 (m, 2H, CH2); 6.13 (t, 1H, J = 6 Hz, O-CH-
N); 7.58 (m, 4H, arom.); 7.85 (d, 2H, J = 7 Hz, arom.); 7.86 (s, 1H,
N-CH); 7.96 (d, 1H, J = 8 Hz, arom.); 8.13 (m, 2H, arom.); 8.67 (s,
1H, arom.); 11.60 (s, 1H, NH). 13C NMR (DMSO) δ: 25.0; 25.7;
45.9; 63.7; 70.6; 82.8; 124.3; 125.6; 126.4; 126.9; 127.0; 127.8; 128.6;
130.4; 130.5; 143.9; 149.8; 160.1; 164.4. Anal. Calcd for C24H20O4N3I
(541.32) C, 53.25; H, 3.72; N, 7.76. Found: C, 53.22; H, 3.72; N, 7.80.
22Af: (0.24 g, 86%) White solid from ethanol, mp 155−157 °C. IR:
νNH 3058, νCO 1719 cm−1. 1H NMR (DMSO) δ: 1.63 (s, 3H, CH3);
1.84 (s, 3H, CH3); 2.05 (s, 3H, CH3); 2.78 (m, 2H, CH2); 6.19 (t, 1H,
J = 7 Hz, O-CH-N); 7.29 (d, 1H, J = 1 Hz, N-CH); 7.59 (m, 4H,
arom.); 7.86 (d, 1H, J = 9 Hz); 8.04 (m, 1H, arom.); 8.13 (m, 2H,
arom.); 8.66 (s, 1H, arom.); 11.23 (s, 1H, NH). 13C NMR (DMSO) δ:
11.5; 24.4; 25.5; 45.9; 63.3; 81.6; 109.7; 123.9; 124.3; 125.2; 126.0;
126.2; 126.4; 126.5; 127.4; 128.1; 128.2; 130.0; 130.1; 134.4; 149.7;
162.9; 163.8. Anal. Calcd for C25H23O4N3 (429.46) C, 69.91; H, 5.40;
N, 9.79. Found: C, 69.91; H, 5.41; N, 9.75.
22Ag: (0.04 g, 48%) White solid from ethanol, mp 188−191 °C. IR:
νNH2 3362, 3171, νCO 1664 cm−1. 1H NMR (DMSO) δ: 1.87 (s, 3H,
CH3); 1.98 (s, 1.98, CH3); 2.59 e 2.84 (m, 1H + 1H, CH2); 5.53 (d,
1H, J = 7 Hz, CH-CN); 6.22 (t, 1H, J = 6 Hz, O-CH-N); 7.18 (d, 2H,
NH2); 7.39 (d, 1H, J = 7 Hz, N-CH); 7.58 (m, 4H, arom.); 7.88 (d,
1H, J = 8 Hz, arom.); 8.00 (m, 1H, arom.); 8.13 (m, 2H, arom.); 8.66
(s, 1H, arom). 13C NMR (DMSO) δ: 22.8; 25.1; 26.0; 47.2; 63.4;
82.7; 94.7; 124.3; 124.8; 125.6; 125.7; 126.4; 126.6; 126.8; 126.9;
127.7; 128.5; 128.6; 130.5; 130.6; 140.0; 154.4; 163.8; 165.3. Anal.
Calcd for C24H22O3N4 (414.45) C, 69.55; H, 5.35; N, 13.52. Found:
C, 69.51; H, 5.31; N, 13.52.
22Me: (0.29 g, 91%) White crystals from methanol, mp 106−110
1
°C. IR: νNH 3169, νCO 1690 cm−1. H NMR (CD3COCD3) δ: 1.72
and 1.87 (s, 6H, 2CH3); 2.25 and 2.34 (s, 9H, 3CH3-Ar); 2.82 and
2.96 (dd, J = 14, 7 Hz, 2H, CH2); 6.27 (t, J = 6 Hz, 1H, CH); 6.85 (m,
2H, Ph); 7.80 (s, 1H, CH-N); 10.45 (bs, 1H, NH). 13C NMR
(CD3COCD3) δ: 19.5; 19.8; 21.5; 25.0; 26.9; 49.9; 64.2; 69.9; 84.4;
129.0; 129.4; 134.1; 135.0; 135.3; 139.2; 144.7; 151.2; 160.8; 168.4.
Anal. Calcd for C19H22N3O4I (483.30): C, 47.22; H, 4.59; N, 8.69.
Found: C, 47.15; H, 4.55; N, 8.49.
22Mf: (0.19 g, 78%) White crystals from ethyl acetate, mp 99−104
1
°C. IR: νNH 3170, νCO 1700 cm−1. H NMR (CD3COCD3) δ: 1.74
and 1.88 (s, 6H, 2CH3); 1.83 (s, 3H, CH3-C); 2.22, 2.25, and 2.27 (s,
9H, 3CH3-Ar); 2.74 and 2.86 (dd, J = 14, 7 Hz, 2H, CH2); 6.39 (t, J =
7 Hz, 1H, CH); 6.82 (m, 2H, Ph); 7.43 (d, J = 1 Hz, 1H, CH-N);
10.08 (bs, 1H, NH). 13C NMR (CD3COCD3) δ: 12.8; 19.5; 21.4;
25.3; 26.9; 48.6; 64.3; 83.3; 112.1; 129.0; 134.3; 134.9; 135.5; 135.8;
139.0; 151.6; 164.2; 167.7. Anal. Calcd for C20H25N3O4 (371.42): C,
64.67; H, 6.78; N, 11.31. Found: C, 64.65; H, 6.75; N, 11.25.
22Mg: (0.11 g, 46%) White crystals from ethyl acetate, mp 107−
110 °C. IR: νNH2 3360, 3170, νCO 1640 cm−1
.
1H NMR
(CD3COCD3) δ: 1.75 and 1.83 (s, 6H, 2CH3); 2.21, 2.24, and 2.26
(s, 9H, 3CH3-Ar); 2.60 and 2.83 (dd, J = 14, 7 Hz, 2H, CH2); 5.88 (d,
J = 8 Hz, 1H, CH); 6.43 (t, J = 7 Hz, 1H, CH); 6.81 (m, 2H, Ph); 7.38
(s, 2H, NH2); 7.56 (d, J = 8 Hz, 1H, CH-N). 13C NMR (CD3COCD3)
δ: 19.5; 21.4; 23.6; 25.6; 27.1; 49.5; 64.0; 84.2; 95.7; 128.8; 128.9;
129.0; 129.5; 134.3; 134.9; 135.5; 139.0; 141.4; 156.1; 167.3. Anal.
Calcd for C19H24N4O3 (356.41): C, 64.02; H, 6.79; N, 15.72. Found:
C, 63.90; H, 6.65; N, 15.55.
Competition Experiments. Equimolecular amounts (20 equiv) of
3-methyl-2-buten-1-ol and the corresponding acetate and methyl ether
were allowed to react with 1 equiv of either benzonitrile oxide or
mesitonitrile oxide in the presence of 1.2 equiv of NMO in anhydrous
DCM as solvent. After the workup previously described, the reaction
mixtures were submitted to chromatographic separation for the
isolation and quantification of the ene obtained from the yields given
in Table 1 (see Table 2).
Biological Tests. Primary screen (dose response): determination
of a 90% inhibitory concentration (IC90). The initial screen is
conducted against Mycobacterium tuberculosis H37Rv (ATCC 27294)
in BACTEC 12B medium using the microplate Alamar Blue assay
(MABA). Compounds are tested in ten 2-fold dilutions, typically from
100 to 0.19 μg/mL. The IC90 is defined as the concentration effecting
a reduction in fluorescence of 90% relative to controls. This value is
determined from the dose−response curve using a curve-fitting
22Aa: (0.26 g, 97%) White solid from ethanol, mp > 200 °C. IR:
νNH 3167, νCO 1686 cm−1. 1H NMR (DMSO) δ: 1.84 (s, 3H, CH3);
2.03 (s, 3H, CH3); 2.79 (m, 2H, CH2); 5.49 (d, 1H, J = 8 Hz, CH-
CO); 6.17 (dd, 1H, J = 7, 6 Hz, O-CH-N); 7.59 (m, 5H, arom.); 7.86
(d, 1H, J = 8 Hz, N-CH); 7.99 (m, 1H, arom.); 8.12 (m, 2H, arom.);
8.66 (s, 1H, arom.); 11.22 (s, 1H, NH). 13C NMR (DMSO) δ: 25.1;
25.8; 46.2; 63.6; 82.3; 102.3; 124.3; 124.7; 125.6; 126.3; 126.7; 126.8;
126.9; 127.8; 128.5; 128.6; 130.4; 130.5; 140.0; 150.1; 162.6; 164.4.
Anal. Calcd for C24H21O4N3 (415.43) C, 69.38; H, 5.10; N, 10.12.
Found: C, 69.39; H, 5.05; N, 10.13
22Ab: (0.26 g, 93%) White solid from ethanol, mp > 200 °C. IR:
νNH 3168, νCO 1720 cm−1. 1H NMR (DMSO) δ: 1.83 (s, 3H, CH3);
2.04 (s, 3H, CH3); 2.79 (m, 2H, CH2); 6.16 (t, 1H, J = 7 Hz, O-CH-
N); 7.58 (m, 4H, arom.); 7.81 (d, 1H, J = 7 Hz, N-CH); 7.86 (d, 1H, J
= 9 Hz, arom.); 8.04 (m, 1H, arom.); 8.13 (m, 2H, arom.); 8.67 (s,
1H, arom.); 11.75 (s, 1H, NH). 13C NMR (DMSO) δ: 24.9; 25.7;
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dx.doi.org/10.1021/jo302346a | J. Org. Chem. 2013, 78, 516−526