Pradip C. Patel1 Aastha Pareek2, Dharma Kishore1
1Department of Chemistry, Banasthali Vidyapith, Banasthali (Rajasthan)-304022, India.
2Department of Chemistry, Madhav University Abu Road (Rajasthan)-307026, India.
*Corresponding Author E-mail: aastha.pareek15@gmail.com
ABSTRACT:
It was mentioned earlier in this chapter that a large number of compounds containing indole nucleus have been patented, as chemotherapeutic agents, antimicrobial, cytotoxic, anti-inflammatory, antitumor, anti-convulsant, antitubercular and anti-HIV. A wide range of indole derivatives were investigated using different conditions. In the present work we synthesized various indole derivatives which are given below in scheme-1.1 and summarized in after the scheme.
KEYWORDS: Anti-HIV, Chemotherapeutic agents, Anti-tumor, Anti-inflammatory, Anti-convulsant, Antitubercular.
INTRODUCTION:
Indole nucleus is present as a structural unit in many natural products. Indoles are a pervasive class of compounds found in abundance in biologically active compounds such as pharmaceuticals, agrochemicals and alkaloids. Indole derivatives have, therefore, captured the attention of organic synthetic chemists. Medicine and biochemistry are also interested in many aspects of indole chemistry. A number of indole derivatives are reported to exhibit antibacterial, antifungal, anti-tuberculosis, antithrombotic, anticancer, anti-inflammatory and CNS depressant activities. The indole alkaloids constitute the biggest single class of the alkaloids and account for about 20% of all known alkaloids.1, 2
Reaction Scheme
Scheme-1.1
Structures of compounds synthesized in this chapter are given below
4BPP001 4BPP022 4BPP003 4BPP004 4BPP005
4BPP006 4BPP007 4BPP008 4BPP009 4BPP010
4BPP011 4BPP012 4BPP013 4BPP014 4BPP015
4BPP016 4BPP017 4BPP018 4BPP019 4BPP020
4BPP021 4BPP022 4BPP023 4BPP024 4BPP025
4BPP026 4BPP027 4BPP028 4BPP029
RESULTS AND DISCUSSION:
This research article presents a stepwise procedure for the synthesis of various indole derivatives. The aim of this researc is to show how 4BPP001-4BPP029 synthesized following the scheme 1.1 The intermediate 2BPP005 undergoes Fischer-indolization to give key intermediate 4BPP001. The compound 4BPP001 undergo different reaction conditions viz. methylation, amidation, Suzuki coupling reaction and acid amine coupling reaction to get the final indole derivatives 4BPP002-4BPP029 respectively.
In the scheme-1.1, the reaction of compound 4BPP001 with methyl iodide in presence of K2CO3 gave a compound 4BPP002. In the second reaction of compound 4BPP001 with NH4Cl in presence of Py-BOP and HOBT in basic condition gave the compound 4BPP003. After the reaction, the bromo substituted phenyl ring was remains as it is. So we have try to react that bromo substituted phenyl ring with different alkyl and aryl boronic acid under Suzuki condition (Pd2dba3, X-phos, Na2CO3, ACN: H2O) in microwave to afford various Suzuki coupled product 4BPP004-4BPP024. Finally we had concentrated on acid substituted phenyl ring in that we have coupled free acid group of 4BPP001 with different five amines in presence of EDC.HCl, HOBT in basic medium to afford acid amine coupled product 4BPP025-4BPP029.
Table-1.1: Physical data of compounds (4BPP001-4BPP029)
|
S. No |
Structure of Compounds |
Name of compounds |
Mol Formula |
MW |
Yield |
Elemental Analysis |
|
4BPP001 |
|
3-(4-bromophenyl)-2-(5-ethyl-2,4-dihydroxyphenyl)-1H-indole-5-carboxylic acid |
C23H18BrNO4 |
452.3 |
68% |
C, 61.08; H, 4.01; Br, 17.67; N, 3.10; O, 14.15 |
|
4BPP002 |
|
methyl 3-(4-bromophenyl)-2-(5-ethyl-2,4-dimethoxyphenyl)-1-methyl-1H-indole-5-carboxylate |
C27H26BrNO4 |
508.4 |
85% |
C, 63.79; H, 5.15; Br, 15.72; N, 2.76; O, 12.59 |
|
4BPP003 |
|
3-(4-bromophenyl)-2-(5-ethyl-2,4-dihydroxyphenyl)-1H-indole-5-carboxamide |
C23H19BrN2O3 |
451.31 |
60% |
C, 61.21; H, 4.24; Br, 17.70; N, 6.21; O, 10.64 |
|
4BPP004 |
|
3-(4-biphenyl)-2-(5-ethyl-2,4-dihydroxyphenyl)-1H-indole-5-carboxylic acid |
C29H23NO4 |
449.5 |
50% |
C, 77.49; H, 5.16; N, 3.12; O, 14.24 |
|
4BPP005 |
|
3-(4-(4I-fluorobiphenyl)-2-(5-ethyl-2,4-dihydroxyphenyl)-1H-indole-5-carboxylic acid |
C29H22FNO4 |
467.49 |
45% |
C, 74.51; H, 4.74; F, 4.06; N, 3.00; O, 13.69 |
|
4BPP006 |
|
3-(4-(4I-3-pyridylphenyl)-2-(5-ethyl-2,4-dihydroxyphenyl)-1H-indole-5-carboxylic acid |
C28H22N2O4 |
450.49 |
39% |
C, 74.65; H, 4.92; N, 6.22; O, 14.21 |
|
4BPP007 |
|
3-(4-(4I-4-pyridylphenyl)-2-(5-ethyl-2,4-dihydroxyphenyl)-1H-indole-5-carboxylic acid |
C28H22N2O4 |
450.49 |
40% |
C, 74.65; H, 4.92; N, 6.22; O, 14.21 |
|
4BPP008 |
|
3-(4-(2i-morpholinediphenyl)-2-(5-ethyl-2,4-dihydroxyphenyl)-1H-indole-5-carboxylic acid |
C33H30N2O5 |
534.6 |
36% |
C, 74.14; H, 5.66; N, 5.24; O, 14.96 |
|
4BPP009 |
|
3-(4-(4i-thiomethylbiphenyl)-2-(5-ethyl-2,4-dihydroxyphenyl)-1H-indole-5-carboxylic acid |
C30H25NO4S |
495.59 |
40% |
C, 72.71; H, 5.08; N, 2.83; O, 12.91; S, 6.47 |
|
4BPP010 |
|
3-(4-(2-trifluoromethylbiphenyl)-2-(5-ethyl-2,4-dihydroxyphenyl)-1H-indole-5-carboxylic acid |
C30H22F3NO4 |
517.5 |
45% |
C, 69.63; H, 4.29; F, 11.01; N, 2.71; O, 12.37 |
|
4BPP011 |
|
3-(4-cyclopropylphenyl)-2-(5-ethyl-2,4-dihydroxyphenyl)-1H-indole-5-carboxylic acid |
C26H23NO4 |
413.47 |
25% |
C, 75.53; H, 5.61; N, 3.39; O, 15.48 |
|
4BPP012 |
|
3-(4-(3I-fluorobiphenyl)-2-(5-ethyl-2,4-dihydroxyphenyl)-1H-indole-5-carboxylic acid |
C29H22FNO4 |
467.49 |
35% |
C, 74.51; H, 4.74; F, 4.06; N, 3.00; O, 13.69 |
|
4BPP013 |
|
3-(4-(4I-fluoro-3i-chlorobiphenyl)-2-(5-ethyl-2,4-dihydroxyphenyl)-1H-indole-5-carboxylic acid |
C29H21ClFNO4 |
501.93 |
30% |
C, 69.39; H, 4.22; Cl, 7.06; F, 3.79; N, 2.79; O, 12.75 |
|
4BPP014 |
|
3-(4-(4i-fluoro-3i-carboxy biphenyl)-2-(5-ethyl-2,4-dihydroxyphenyl)-1H-indole-5-carboxylic acid |
C30H22FNO6 |
511.5 |
35% |
C, 70.44; H, 4.34; F, 3.71; N, 2.74; O, 18.77 |
|
4BPP015 |
|
3-(4-(3i-fluoro-4i-propoxybiphenyl)-2-(5-ethyl-2,4-dihydroxyphenyl)-1H-indole-5-carboxylic acid |
C32H28FNO5 |
525.57 |
36% |
C, 73.13; H, 5.37; F, 3.61; N, 2.67; O, 15.22 |
|
4BPP016 |
|
3-(4-(4i-naphtalenephenyl)-2-(5-ethyl-2,4-dihydroxyphenyl)-1H-indole-5-carboxylic acid |
C33H25NO4 |
499.56 |
40% |
C, 79.34; H, 5.04; N, 2.80; O, 12.81 |
|
4BPP017 |
|
3-(4-(2i-methyl-4i-propoxybiphenyl)-2-(5-ethyl-2,4-dihydroxyphenyl)-1H-indole-5-carboxylic acid |
C33H31NO5 |
521.6 |
32% |
C, 75.99; H, 5.99; N, 2.69; O, 15.34 |
|
4BPP018 |
|
3-(4-(2i-methyl,4i-propoxybiphenyl)-2-(5-ethyl-2,4-dihydroxyphenyl)-1H-indole-5-carboxylic acid |
C33H31NO5 |
521.6 |
34% |
C, 75.99; H, 5.99; N, 2.69; O, 15.34 |
|
4BPP019 |
|
3-(4-4i(3i-methoxy pyridylphenyl)-2-(5-ethyl-2,4-dihydroxyphenyl)-1H-indole-5-carboxylic acid |
C29H24N2O5 |
480.51 |
33% |
|
|
4BPP020 |
|
3-(4-(4i-methane sulfonyl biphenyl)-2-(5-ethyl-2,4-dihydroxyphenyl)-1H-indole-5-carboxylic acid |
C30H25NO6S |
527.59 |
42% |
C, 72.49; H, 5.03; N, 5.83; O, 16.65 |
|
4BPP021 |
|
2-(5-ethyl-2,4-dihydroxyphenyl)-3-(4-octylphenyl)-1H-indole-5-carboxylic acid |
C31H35NO4 |
485.61 |
22% |
C, 76.67; H, 7.26; N, 2.88; O, 13.18 |
|
4BPP022 |
|
3-(4-(2i-methoxy biphenyl)-2-(5-ethyl-2,4-dihydroxyphenyl)-1H-indole-5-carboxylic acid |
C30H25NO6S |
527.59 |
33% |
C, 75.14; H, 5.25; N, 2.92; O, 16.68 |
|
4BPP023 |
|
3-(4-(4i-methylcarboxylbiphenyl)-2-(5-ethyl-2,4-dihydroxyphenyl)-1H-indole-5-carboxylic acid |
C31H25NO6 |
507.53 |
41% |
C, 73.36; H, 4.96; N, 2.76; O, 18.91 |
|
4BPP024 |
|
3-(4-(3i- propoxybiphenyl)-2-(5-ethyl-2,4-dihydroxyphenyl)-1H-indole-5-carboxylic acid |
C32H29NO5 |
507.58 |
41% |
C, 75.72; H, 5.76; N, 2.76; O, 15.76 |
|
4BPP025 |
|
3-(4-bromophenyl)-2-(5-ethyl-2,4-dihydroxyphenyl)-N-(4-morpholinophenyl)-1H-indole-5-carboxamide |
C33H30BrN3O4 |
612.51 |
30% |
C, 64.71; H, 4.94; Br, 13.05; N, 6.86; O, 10.45 |
|
4BPP026 |
|
3-(4-bromophenyl)-2-(5-ethyl-2,4-dihydroxyphenyl)-N-(4-(4-methylpiperazin-1-yl)phenyl)-1H-indole-5-carboxamide |
C34H33BrN4O3 |
625.55 |
35% |
C, 65.28; H, 5.32; Br, 12.77; N, 8.96; O, 7.67 |
|
4BPP027 |
|
3-(4-bromophenyl)-2-(5-ethyl-2,4-dihydroxyphenyl)-N-(2-fluorophenyl)-1H-indole-5-carboxamide |
C29H22BrFN2O3 |
545.4 |
29% |
C, 63.86; H, 4.07; Br, 14.65; F, 3.48; N, 5.14; O, 8.80 |
|
4BPP028 |
|
N-(6-(2-(dimethylamino)ethoxy)-5-methylpyridin-3-yl)-3-(4-bromophenyl)-2-(5-ethyl-2,4-dihydroxyphenyl)-1H-indole-5-carboxamide |
C33H33BrN4O4 |
629.54 |
25% |
C, 62.96; H, 5.28; Br, 12.69; N, 8.90; O, 10.17 |
|
4BPP029 |
|
N-(3-(trifluoromethyl)benzyl)-3-(4-bromophenyl)-2-(5-ethyl-2,4-dihydroxyphenyl)-1H-indole-5-carboxamide |
C31H24BrF3N2O3 |
609.43 |
36% |
C, 61.09; H, 3.97; Br, 13.11; F, 9.35; N, 4.60; O, 7.88 |
Table-1.2: Spectral data of compounds (4BPP001-4BPP029)
|
S. No |
Structure of Compounds |
Name of compounds |
1H NMR |
LCMS Purity |
MS Observed |
RT (LCMS) |
|
4BPP001 |
|
3-(4-bromophenyl)-2-(5-ethyl-2,4-dihydroxyphenyl)-1H-indole-5-carboxylic acid |
0.869-0.951(3H,t) 2.296-2.351(2h,q) 6.458(1H,s)6.772(1H,s) 7.268-7.289(2H,d) 7.440-7.462 (1H,d) 7.539-7.560 (2H,d) 7.718-7.739 (2H,d) 8.207 (1H,s) 9.404(1H,s)9.427 (1H,s)11.519 (1H,s) 12.383 (1H,s) |
91.66% |
452.02 454.02 |
3.11 |
|
4BPP002 |
|
methyl 3-(4-bromophenyl)-2-(5-ethyl-2,4-dimethoxyphenyl)-1-methyl-1H-indole-5-carboxylate |
0.932-0.969 (3H,t) 2.400-2.427 (2H,q) 3.555 (3H,s) 3.763 (3H,s) 3.845 (3H,s) 3.899 (3H,s) 6.781 (1H,s) 6.833 (1H,s) 7.154-7.175 (2H,d) 7.512-7.533 (2H,d) 7.630-7.652 (1H,d) 7.845-7.867 (1H,d) 8.255 (1H,s) |
95.36% |
508.10 510.10 |
4.15 |
|
4BPP003 |
|
3-(4-bromophenyl)-2-(5-ethyl-2,4-dihydroxyphenyl)-1H-indole-5-carboxamide |
0.834-0.955 (3H,t) 2.319-2.337 (2H,q) 6.455 (1H,s) 6.766 (1H,s) 7.084 (1H,s) 7.297-7.315 (2H,d) 7.385-7.406 (1H,d) 7.508-7.527 (2H,d) 7.655-6.676 (1H,d) 7.866 (1H,s) 8.151 (1H,s) 9.341(1H,s) 9.377 (1H,s) 11.353 (1H,s) |
93.88% |
450.82 452.82 |
3.39 |
|
4BPP004 |
|
3-(4-biphenyl)-2-(5-ethyl-2,4-dihydroxyphenyl)-1H-indole-5-carboxylic acid |
0.883-0.920 (3H,t) 2.279-2.337 (2H,q) 6.480 (1H,s) 6.813 (1H,s) 7.328-7.368 (1H,m) 7.442-7.480 (5H,m) 7.671-7.748(5H,m) 8.289 (1H,s) 9.404 (1H,s) 9.443 (1H,s) 11.479 (1H,s) 12.406 (1H,s) |
97.06% |
450.28 451.29 |
3.33 |
|
4BPP005 |
|
3-(4-(4I-fluorobiphenyl)-2-(5-ethyl-2,4-dihydroxyphenyl)-1H-indole-5-carboxylic acid |
0.885-0.923 (3H,t) 2.298-2.338 (2H,q) 6.477 (1H,s) 6.811 (1H,s), 7.261-7.306 (2H,t) 7.424-7.473 (3H,m) 7.652-7.672 (2H,d) 7.722-7.742 (3H,m)8.283(1H,s)9.397(1H,s) 9.429 (1H,s) 11.478 (1H,s) 12.396 (1H,s) |
97.11% |
467.82 468.82 |
3.34 |
|
4BPP006 |
|
3-(4-(4I-3-pyridylphenyl)-2-(5-ethyl-2,4-dihydroxyphenyl)-1H-indole-5-carboxylic acid |
0.926-1.061 (3H,t) 2.318 (2H,q), 6.544 (1H,s) 6.794 (1H,s) 6.924(1H,s) 7.374 (1H,d) 7.469-7.490 (4H,m) 7.733-7.754(2H,d) 7.987-8.016 (1H,m) 8.543-8.554 (1H,d) 8.924 (1H,s) 9.491(1H,s) 9.591 (1H,s) 11.591 (1H,s) 12.383 (1H,s) |
79.18% |
451.26 452.26 |
2.74 |
|
4BPP007 |
|
3-(4-(4I-4-pyridylphenyl)-2-(5-ethyl-2,4-dihydroxyphenyl)-1H-indole-5-carboxylic acid |
0.831-0.917 (3H,t) 2.327(2H,q) ,6.024-6.056 (1H,s) 6.489(1H,s) 6.812(1H,s) 7.370 (1H,m) 7.487-7.509 (2H,m) 7.573-7.591 (1H,m) 7.724-7.743 (2H,d) 7.814-7.835 (2H,m) 8.605-8.615 (2H,d) 9.432 (1h,S) 9.440 (1H,S) 11.369 (1H,S ) 12.385 (1H,S) |
74.30% |
451.26 452.26 |
3.92 |
|
4BPP008 |
|
3-(4-(2i-morpholinediphenyl)-2-(5-ethyl-2,4-dihydroxyphenyl)-1H-indole-5-carboxylic acid |
0.851-0.915 (3H,t) 2.275-2.308 (2H,q) 3.144 -3.169 (4H,m) 3.744- 3.772 (4H,m) 6.474 (1H,s) 6.807 (1H,s) 7.013-7.035 (2H,d) 7.376-7.396 (2H,d) 7.444-7.465 (1H,d) 7.574-7.625 (4H,m) 7.714-7.736 (1H,d) 8.273 (1H,s) 9.391 (1H,s) 9.431 (1H,s) 11.442 (1H,s) 12.386 (1H,s) |
97.35% |
534.96 535.97 |
3.11 |
|
4BPP009 |
|
3-(4-(4i-thiomethylbiphenyl)-2-(5-ethyl-2,4-dihydroxyphenyl)-1H-indole-5-carboxylic acid |
0.831-0.923 (3H,t) 1.990 (3H,s) 2.278-2.343 (2H,q) 6.478 (1H,s) 6.815 (1H,s) 7.332-7.354 ( 2H,d) 7.418-7.438 (2H,m) 7.452-7.474 (1H,m) 7.649-7.672 (4H,m) 7.723-7.745 (1H,d) 8.286 (1H,s) 9.399 (1H,s) 9.430 (1H,s) 11.477 (1H,s) 12.395 (1H,s) |
96.38% |
496.02 497.02 |
3.46 |
|
4BPP010 |
|
3-(4-(2-trifluoromethylbiphenyl)-2-(5-ethyl-2,4-dihydroxyphenyl)-1H-indole-5-carboxylic acid |
0.839-0.902 (3H,t) 2.246-2.381 (2H,q) 6.515 (1H,s) 6.752 (1H,s) 6.929 (1H,s) 7.129-7.184 (1H,m) 7.250 (1H,m) 7.314-7.334 (2H,d) 7.410-7.427 (2H,d) 7.478-7.499 (2H,m) 7.612 (1H,t) 7.727-7.748 (2H,m) 7.831-7.851 (1H,d) 8.261 (1H,s) 9.411 (1H,s) 9.571 (1H,s) 11.448 (1H,s) 12.418 (1H,s) |
82.77% |
517.95 518.96 |
3.48 |
|
4BPP011 |
|
3-(4-cyclopropylphenyl)-2-(5-ethyl-2,4-dihydroxyphenyl)-1H-indole-5-carboxylic acid |
0.380(2H,m)0.630(2H,m)1.50(1H,m)1.24(3H,t)2.59(2H,t)6.21(1H,s)7.00(1H,s)7.19(2H,m)7.40(3H,m)8.02(2H,m) 9.411 (1H,s) 9.433 (1H,s) 11.486 (1H,s) 12.414 (1H,s) |
82.21% |
414.16 415.16 |
3.15 |
|
4BPP012 |
|
3-(4-(3I-fluorobiphenyl)-2-(5-ethyl-2,4-dihydroxyphenyl)-1H-indole-5-carboxylic acid |
0.975-1.010 (3H,t) 2.280-2.337 (2H,q) 6.475 (1H,s) 6.809 (1H,s) 7.150-7.191 (1H,m) 7.456-7.470 (2H,m) 7.482-7.497 (1H,s) 7.519-7.585 (2H,m) 7.691-7.742(3H,m) 8.288 (1H,s) 9.413 (1H,s) 9.436 (1H,s) 11.506 (1H,s) 12.422 (1H,s) |
84.94% |
467.03 468.03 |
3.33 |
|
4BPP013 |
|
3-(4-(4I-fluoro-3i-chlorobiphenyl)-2-(5-ethyl-2,4-dihydroxyphenyl)-1H-indole-5-carboxylic acid |
0.897-0.935 (3H,t) 2.289-2.347 (2H,q) 6.479 (1H,s) 6.823 (1H,s) 7.441-7.473 (3H,m) 7.699-7.786 (4H,m) 7.851 (1H,d) 7.923 (1H,m) 8.296 (1H,s) 9.405 (1H,s) 9.428 (1H,s) 11.501 (1H,s) 12.400 (1H,s) |
53.48% |
502.93 503.93 |
2.95 |
|
4BPP014 |
|
3-(4-(4i-fluoro-3i-carboxy biphenyl)-2-(5-ethyl-2,4-dihydroxyphenyl)-1H-indole-5-carboxylic acid |
0.897-0.935 (3H,t) 2.289-2.347 (2H,q) 6.479 (1H,s) 6.823 (1H,s) 7.441-7.473 (3H,m) 7.699-7.786 (4H,m) 7.851 (1H,d) 7.923 (1H,m) 8.296 (1H,s) 9.405 (1H,s) 9.428 (1H,s) 11.501 (1H,s) 11.547(1H,s)12.400 (1H,s) |
73.47% |
512.15 513.15 |
3.95 |
|
4BPP015 |
|
3-(4-(3i-fluoro-4i-propoxybiphenyl)-2-(5-ethyl-2,4-dihydroxyphenyl)-1H-indole-5-carboxylic acid |
0.888-0.926 (3H,t) 0.980-1.017 (3H,t) 1.742-1.794 (2H,m) 2.281-2.318 (2H,q) 4.034-4.067 (2H,m) 6.476 (1H,s) 6.810 (1H,s) 7.207-7.251 (1H,m) 7.399-7.420 (2H,d) 7.448-7.490 (2H,m) 7.565-7.598 (1H,d) 7.654-7.674 (2H,d) 7.723-7.744 (1H,d) 8.282 (1H,s) 9.411 (1H,s) 9.433 (1H,s) 11.486 (1H,s) 12.414 (1H,s) |
94.30% |
525.92 526.92 |
3.64 |
|
4BPP016 |
|
3-(4-(4i-naphtalenephenyl)-2-(5-ethyl-2,4-dihydroxyphenyl)-1H-indole-5-carboxylic acid |
0.908-0.946 (3H,t) 2.299-2.354(2H,q) 6.491 (1H,s) 6.853 (1H,s) 7.465-7.544 (5H,m) 7.736-7.757 (1H,d) 7.833-7.853 (2H,d) 7.886-7.912 (2H,m) 7.978-8.014 (2H,t) 8.261 (1H,s) 8.323 (1H,s) 9.404(1H,s) 9.434(1H,s)11.500 (1H,s) 12.402 (1H,s) |
95.74% |
499.86 500.86 |
3.62 |
|
4BPP017 |
|
3-(4-(2i-methyl-4i-propoxybiphenyl)-2-(5-ethyl-2,4-dihydroxyphenyl)-1H-indole-5-carboxylic acid |
0.832-0.896 (3H,t) 0.944-1.008 (3H,t) 1.696-1.783 (2H,m) 2.257 (3H,s) 2.268-2.328 (2H,q) 3.932-3.965 (2H,m) 6.497 (1H,s) 6.770 (1H,s) 6.801-6.808 (1H,s) 6.824-6.829 (1H,s) 7.143-7.164 (1H,d) 7.290-7.310 (2H,d) 7.373-7.394 (2H,d) 7.465-7.468 (1H,d) 7.717-7.738 (1H,d) 8.262 (1H,s) 9.398 (1H,s) 9.530 (1H,s) 11.420 (1H,s) 12.390 (1H,s) |
95.02% |
521.76 522.77 |
3.81
|
|
4BPP018 |
|
3-(4-(2i-methyl,4i-propoxybiphenyl)-2-(5-ethyl-2,4-dihydroxyphenyl)-1H-indole-5-carboxylic acid |
0.832-0.847 (3H,t) 0.886-0.923 (3H,t) 1.744-1.797 (2H,m) 2.224(3H,s) 2.278-2.384 (2H,q) 3.961-3.994 (2H,m) 6.480 (1H,s) 6.814 (1H,s) 6.928 (1H,s) 6.975-6.996 (1H,d) 7.384-7.402 (2H,d) 7.451-7.498 (3H,m) 7.596-7.618 (2H,d) 7.721-7.742 (1H,m) 8.278 (1H,s) 9.385(1H,s)9.419(1H,s) 11.444 (1H,s) 12.427 (1H,s) |
85.27% |
522.31 523.31 |
3.25 |
|
4BPP019 |
|
3-(4-4i(3i-methoxy pyridylphenyl)-2-(5-ethyl-2,4-dihydroxyphenyl)-1H-indole-5-carboxylic acid |
0.669-0.927 (3H,t) 2.298-2.363 () 3.781 (3H,s) 6.487 (1H,s) 6.805 (1H,s) 6.927-7.007 (1H,s) 7.104-7.124 (1H,d) 7.313-7.317 (2H,d) 7.370-7.391 (2H,d) 7.442-7.519 (4H,m) 8.274 (1H,s) 9.390 (1H,s) 9.474 (1H,s) 11.435 (1H,s) 12.427 (1H,s) |
75.12% |
481.24 482.24 |
3.36 |
|
4BPP020 |
|
3-(4-(4i-methane sulfonyl biphenyl)-2-(5-ethyl-2,4-dihydroxyphenyl)-1H-indole-5-carboxylic acid |
0.911-0.933 (3H,t) 2.229-2.346 (2H,q) 3.264 (3H,s) 6.485 (1H,s) 6.824 (1H,s) 7.462-7.509 (4H,m) 7.629(1H,s) 7.735-7.798 (2H,m) 7.987 ( 4H,m) 8.307 (1H,s) 9.417(1H,s) 9440 (1H,s) 11.533 (1H,s) 12.427(1H,s) |
86.04% |
Comp. could not ionise |
2.89 |
|
4BPP021 |
|
2-(5-ethyl-2,4-dihydroxyphenyl)-3-(4-octylphenyl)-1H-indole-5-carboxylic acid |
0.960-1.005(3H,m)1.332-1.339(2H,m)1.292-1.354(10H,m)1.622-1.632(2H,m)2.552-2.559(2H,m)6.210(1H,s)7.021(1H,s)7.190-8.001(2H,m)7.423-7.429(1H,s)8.052-8.063(2H,m) 9.390 (1H,s) 9.474 (1H,s) 11.435 (1H,s) 12.427 (1H,s) |
69.26% |
486.26 487.26 |
3.95 |
|
4BPP022 |
|
3-(4-(2i-methoxy biphenyl)-2-(5-ethyl-2,4-dihydroxyphenyl)-1H-indole-5-carboxylic acid |
0.869-0.927 (3H,t) 2.298-2.363 (2H,q) 3.781 (3H,s) 6.487 (1H,s) 6.805 (1H,s) 6.927-7.007 (1H,d) 7.104-7.124 (1H,d) 7.313-7.317 (2H,d) 7.370-7.391 (2H,d) 7.442-7.519 (4H,m) 7.718-7.782 (1H,d) 8.274 (1H,s) 9.390 (1H,s) 9.474 (1H,s) 11.435 (1H,s) 12.427 (1H,s) |
93.42% |
480.10 481.10
|
3.32 |
|
4BPP023 |
|
3-(4-(4i-methylcarboxylbiphenyl)-2-(5-ethyl-2,4-dihydroxyphenyl)-1H-indole-5-carboxylic acid |
0.868-0.931 (3H,t) 2.228-3.362(2H,q) 3.877 (3H,s) 6.373-6.394 (1H,s) 6.824 (1H,s) 7.460-7.490 (3H,m) 7.732-7.784 (3H,m) 7.862-7.909 (2H,d) 8.022-8.043 (2H,d) 8.301 (1H,s) 9.412-(1H,s)9.429 (1H,s)11.519 (1H,s) 12.406 (1H,s) |
95.02% |
508.07 509.07 |
3.24 |
|
4BPP024 |
|
3-(4-(3i- propoxybiphenyl)-2-(5-ethyl-2,4-dihydroxyphenyl)-1H-indole-5-carboxylic acid |
0.883-0.925 (3H,t) 0.984-1.020 (3H,t) 1.599-1.677 (2H,m) 2.281-2.320 ( 2H,q) 3.994-4.021 (2H,m) 6.481 (1H,s) 6.811 (1H,s) 7.133 (1H,s) 7.205-7.235 (1H,d) 7.330-7.369 (1H,t) 7.420-7.453 (4H,m) 7.669-7.689 (2H,d) 7.724-7.746 (1H,d)8.289(1H,s) 9.386-9.422 (2H,s) 11.467 (1H,s) 12.506 (1H,s) |
98.47% |
508.05 509.05 |
3.68 |
|
4BPP025 |
|
3-(4-bromophenyl)-2-(5-ethyl-2,4-dihydroxyphenyl)-N-(4-morpholinophenyl)-1H-indole-5-carboxamide |
0.919-0.957 (3H,t) 2.302-2.358 (2H,q) 3.054-3.078 (4H,m) 3.729-3.752 (4H,m) 6.462 (1H,s) 6.775 (1H,s) 6.914-6.937 (2H,d) 7.323-7.344 (2H,d) 7.454-7.475 (2H,d) 7.527-7.549 (1H,d) 7.615-7.637 (2H,d) 7.733-7.755 (2H,d) 7.756 (1H,d) 8.219 (1H,s) 9.394(1H,s) 9.417 (1H,s) 9.958 (1H,s) 11.437 (1H,s) |
97.94% |
611.87 613.87 |
3.92 |
|
4BPP026 |
|
3-(4-bromophenyl)-2-(5-ethyl-2,4-dihydroxyphenyl)-N-(4-(4-methylpiperazin-1-yl)phenyl)-1H-indole-5-carboxamide |
0.911-0.957 (3H,t) 2.263 (4H,m)2.301-2.358 (2H,q) 3.107 (4H,m) 3.172 (3H,s) 6.441-6.491 (1H,s) 6.889-6.928 (2H,d) 6.867 (1H,s) 7.323-7.344 (2H,d) 7.375-7.388 (1H,d) 7.473-7.548 (2H,d) 7.660-7.732 (2H,d) 8.216 (1H,s) 9.395(1H,s)9.431 (1H,s)9.942 (1H,s) 9.966 (1H,s) 11.434 (1H,s) |
70.05% |
623.14 625.14 |
3.59 |
|
4BPP027 |
|
3-(4-bromophenyl)-2-(5-ethyl-2,4-dihydroxyphenyl)-N-(2-fluorophenyl)-1H-indole-5-carboxamide |
0.905-0.950 (3H,t) 2.334-2.351 (2H,q) 6.441-6.491 (1H,s) 6.662-6.684 (2H,d) 6.687-6.689 (2H,d) 7.234-7.255 (2H,d) 7.473-7.548 (2H,d) 7.596-7.618 (1H,d) 7.636-7.660 (2H,d) 9.395(1H,s)9.417(1H,s)9.966 (2H,s) 11.434 (1H,s) |
69.71% |
546.24 548.24 |
3.75 |
|
4BPP028 |
|
N-(6-(2-(dimethylamino)ethoxy)-5-methylpyridin-3-yl)-3-(4-bromophenyl)-2-(5-ethyl-2,4-dihydroxyphenyl)-1H-indole-5-carboxamide |
0.914-0.951 (3H,t) 2.297-2.334 (3H,s) 2.386 (6H,s) 2.858 (2H,t) 2.634-2.637 (2H,q) 4.539 (2H,t) 6.606 (1H,s) 6.771 (1H,s) 6.827-6.849 (1H,d) 7.319-7.340 (2H,d) 7.466-7.497 (1H,d) 7.536-7.557 (2H,d) 7.755-7.776 (1H,d) 8.033-8.084 (1H,d) 8.248 (1H,s) 8.505-8.511 (1H,s) 9.442(1H,s)9.459 (1H,s)10.198 (1H,s) 11.499 (1H,s) |
85.27% |
629.17 631.17 |
3.45 |
|
4BPP029 |
|
N-(3-(trifluoromethyl)benzyl)-3-(4-bromophenyl)-2-(5-ethyl-2,4-dihydroxyphenyl)-1H-indole-5-carboxamide |
0.911-0.949 (3H,t) 2.293-2.349 (2H,q) 4.522-4.566 (2H,s) 6.454 (1H,s) 6.760 (1H,s) 7.292-7.313 (2H,d) 7.426-7.447 (1H,d) 7.514-7.535 (2H,d) 7.551-7.599 (3H,m) 7.613-7.717 (2H,m) 8.171 (1H,s) 9.018-9.048 (1H,t) 9.387(1H,s)9.415 (1H,s)11.423 (1H,s) |
90.96% |
608.83 610.86 |
4.28 |
Interpretation of spectral data for the elucidation of structure of compounds
1H NMR Spectral data interpretation
1H NMR spectrum of compound 4BPP001 to 4BPP029 at 400 MHz in CDCl3 + DMSO- d6 displayed characteristic signals for the presence of desire protons in the molecules. We have described each proton of few compounds given as below:
(i)Interpretation of 1H NMR of compound 4BPP001
1H NMR spectrum of compound 4BPP001 in DMSO-d6 displayed signals for the presence 18 protons of which 14 protons were bonded to carbon atom and 3 protons were bonded to oxygen atom and 1 proton bound to nitrogen atom. Formation of compound 4BPP001 was confirmed by the appearance of one triplet at δ 0.869-0.951 for CH3 and one quartet δ 2.296-2.351 for CH2 of ethyl group presence in the phenolic ring of the molecule. Appearance of 7 signal in aromatic region between δ 6.458 to δ 8.207 for 10H show the presence of 10H in aromatic rings. A broad singlet of two protons at δ 9.404 and δ 9.427 for two proton of phenol group in phenyl ring. One broad signal of one proton at δ 11.519 shows the presence of 1H attached with nitrogen in indole ring. Appearance of one broad singlet at δ 12.383 for 1H indicates the presence of COOH group on the molecule.
(ii)Interpretation of 1H NMR of compound 4BPP002
1H NMR spectrum of compound 4BPP002 in DMSO-d6 displayed signals for the presence 26 protons and all protons were bonded to carbon atom. Compound 4BPP002 has similar 1H NMR spectrum as compound 4BPP001 but differentiate at four positions. Appearance of four singlet at δ 3.555, δ 3.763, δ 3.845, δ 3.899 for 4 CH3 and disappearance of 4H at δ 9.404, δ 9.427, δ 11.519, δ12.8383 from the molecule indicate the formation of compound 4BPP002.
(iii) Interpretation of 1H NMR of compound 4BPP003
1H NMR spectrum of compound 4BPP003 in DMSO-d6 displayed signals for the presence of 19 protons of which 14 protons were bonded to carbon atom and 2 protons were bonded to oxygen atom and 3 proton bound to nitrogen atom. Compound 4BPP003 has similar 1H NMR spectrum as compound 4BPP001 but differentiate at four positions. Disappearance of one singlet at δ 12.383 and addition of two proton signals in aromatic region indicates the formation of compound 4BPP003.
1H NMR spectral data of compound 4BPP004 to 4BPP029 are given in the Table-4.2
LCMS spectrum data
Purity of compounds 4BPP001 to 4BPP029 were confirmed by liquid chromatography mass spectrum (LCMS) and the LCMS data (retention time and purity) of compound 4BPP001 to 4BPP029 are given in the Table-4.2.
LCMS Method
To check the purity of compounds by LCMS, 0.4-0.5 mg sample of compounds was dissolved in 2 ml of suitable solvent (acetonitrile, methanol, DMSO, water etc.) and then 0.2 ml of sample was injected in the LCMS instrument and run the sample for 10-15 min by using acetonitrile and 5%mmol solution of ammonium acetate as a mobile phase A and B.
EXPERIMENTAL SECTION:
1. Melting points are determined in open glass capillaries and are uncorrected.
2. The purity of the compounds was checked by TLC on silica gel (G) plates.
3. H1 NMR spectra were recorded on model AC-300F (Brucker) using CDCl3-DMSO-d6 as solvent. Chemical shift are expressed in dppm.
4. Before analysis all samples were dried for one hour under reduced pressure.
5. Physical and spectral data for all the compounds are given in Table-4.1 and 4.2.
Synthetic Procedures
(i) Synthesis of compound (4-bromophenyl)-2-(5-ethyl-2,4-dihydroxyphenyl)-1H-indole-5-carboxylic acid (4BPP001)
2-(4-bromophenyl)-1-(5-ethyl-2,4-dihydroxyphenyl)ethanone(2BPP005)(10g,0.0298mol,1eq) and 4-hydrazinylbenzoic acid(5.44g,0.0358mol,1.2eq) were taken in CH3COOH (200 ml) in 2N RBF attached with water condenser in oil bath. Then reaction mixture was heated at 500C for 30 min. then con. HCl (50ml) was added drop wise into the reaction mixture at 500C within 20 min. Then reflux the reaction mixture for 4 to 6 hrs. Reaction monitor by TLC. In work up procedure, poured reaction mixture into ice-water and extracted by ethyl acetate. Combine ethyl acetate layer dried over sodium sulfate and concentrated under vacuum to get crude mass. Compound purify by coloumn chromatography to get 5.2 g of desire product as a brown solid. (Yield-32.09%)
(Silica-230-400 mess, Solvent- 20% Ethyl acetate: Hexane)
TLC:- 50% Ethyl acetate: Hexane
(ii) Synthesis of methyl 3-(4-bromophenyl)-2-(5-ethyl-2,4-dimethoxyphenyl)-1-methyl-1H-indole-5-carboxylate (4BPP001)
Dissolved 4-bromophenyl)-2-(5-ethyl-2,4-dihydroxyphenyl)-1H-indole-5-carboxylicacid (4BPP001) (200 mg, 0.00044mol, 1eq) in DMF (10 ml) and K2CO3 (305mg, 0.0021 mol, 5eq) was added and cool the reaction mix down to 00C. Then CH3I (0.137ml, 0.0021mol, 5eq) was added drop wise and stir for 30 min at RT. Then rise temperature up to RT and stir for 2 hrs. Reaction monitor by TLC. In work up procedure reaction mixture diluted with water (30 ml) and extracted by ethyl acetate (20x3ml). Combine ethyl acetate layer dried over sodium sulfate and concentrated under vacuum to get crude mass. Compound purifies by column chromatography .to get 190 mg of desire product as a light yellow solid. (Yield-85.20%)
(Silica-230-400 mess, Solvent- 10% Ethyl acetate: Hexane)
TLC:- 30% Ethyl acetate: Hexane
(iii) Synthesis of 3-(4-bromophenyl)-2-(5-ethyl-2,4-dihydroxyphenyl)-1H-indole-5-carboxamide (4BPP003)
Dissolved 4-bromophenyl)-2-(5-ethyl-2,4-dihydroxyphenyl)-1H-indole-5-carboxylic acid (4BPP001)(100mg, 0.00022mol, 1eq)was taken in DMF (5ml) in 2N RBF at RT. Then NH4Cl (71mg, 0.00132mol, 6eq), Py-BOP (90mg, 0.000286, 1.3eq), HOBT (36mg, 0.00264mol, 1.2eq) and DIPEA (0.1ml, 0.00066mol, 3eq) was added at RT and stir the reaction mixture at RT for overnight. Reaction monitor by TLC. In work up procedure reaction mixture diluted with water (25 ml) and extracted by ethyl acetate (15x3 ml). Combine ethyl acetate layer dried over sodium sulfate and concentrated under vacuum to get crude mass. Compound purify by column chromatography to get 50 mg of desire product as off white solid. (Yield-50.50%)
(Silica-230-400 mess, Solvent- 20% Ethyl acetate: Hexane)
TLC:- 50% Ethyl acetate: Hexane
(iv) Synthesis of 3-(4-biphenyl)-2-(5-ethyl-2,4-dihydroxyphenyl)-1H-indole-5-carboxylic acid (4BPP004)
4-bromophenyl)-2-(5-ethyl-2,4-dihydroxyphenyl)-1H-indole-5-carboxylic acid (4BPP001) (100mg, 0.00022 mol, 1eq) and phenyl boronic acid (27mg, 0.00022mol, 1eq) were taken in acetonitrile water: (4:1) (6ml) in Microwave vial. Then X-Phos (10mg, 0.000022mol, 0.1eq) and Na2CO3 (69mg, 0.00066mol, 3eq) was added at RT. Then purge nitrogen into the reaction mixture for 15 min. After that Pd2dba3 (10mg, 0.000011mol, 0.05eq) was added and close vial, heat the reaction mixture into micro wave at 1200C for 30 min. Reaction monitor by TLC. In work up procedure reaction mixture diluted with water (25 ml) and extracted by ethyl acetate (20 x 3ml). Combine ethyl acetate layer dried over sodium sulfate and concentrated under vacuum to get crude mass. Compound purify by column chromatography to get 35 mg of desire product as a yellow solid. (Yield-35.71%)
(Silica-230-400 mess, Solvent- 5% Methanol: DCM)
TLC:- 10% Methanol: DCM
Same procedure was used to synthesis of compound 4BPP005-4BPP024, details of those compounds given in the above Table-4.1 and 4.2.
(v) Synthesis of 3-(4-bromophenyl)-2-(5-ethyl-2,4-dihydroxyphenyl)-N-(4-morpholinophenyl)-1H-indole-5-carboxamide (4BPP025)
4-bromophenyl)-2-(5-ethyl-2,4-dihydroxyphenyl)-1H-indole-5-carboxylic acid (4BPP001)
(100mg, 0.00022 mol, 1eq) and 4-morpholinobenzenamine (46mg, 0.000264mol, 1.2eq) were taken in DMF (6 ml) in 2N RBF at RT. TEA (0.1ml, 0.00066mol, 3eq) and HOBT (36mg, 0.00264mol, 1.2eq) were added into the reaction mixture at RT for 20 min. Then EDC.HCl (54 mg, 0.000286, 1.3eq) was added to the reaction mixture and stirs the reaction mixture at RT for overnight. Reaction monitor by TLC. In work up procedure reaction mixture diluted with water and extracted by ethyl acetate. Combine ethyl acetate layer dried over sodium sulfate and concentrated under vacuum to get crude mass. Compound purify by column chromatography (Silica-230-400 mess, Solvent- 30% Ethyl acetate: Hexane) to get 56 mg of desire product as a yellow solid. (Yield-41.79%)
TLC: - 50% Ethyl acetate: Hexane
Same procedure was used to synthesis of compound 4BPP026-4.029, details of those compounds given in Table-4.1 and 4.2
SPECTRA OF THE SYNTHESIZED COMPOUNDS
1H NMR Spectra
(4BPP001)
(4BPP002)
(4BPP003)
(4BPP004)
(4BPP005)
(4BPP008)
(4BPP009)
(4BPP010)
(4BPP012)
(4BPP013)
(4BPP015)
(4BPP016)
(4BPP017)
(4BPP018)
(4BPP022)
(4BPP023)
(4BPP024)
(4BPP025)
(4BPP029)
LCMS Spectra
(4BPP001)
(4BPP003)
(4BPP004)
(4BPP005)
(4BPP008)
(4BPP009)
(4BPP010)
(4BPP012)
(4BPP015)
(4BPP016)
(4BPP018)
(4BPP022)
(4BPP023)
(4BPP024)
(4BPP025)
(4BPP029)
REFERENCES
1. (i) G. A. WileyInterscience: Introduction to Alkaloids: A Biogenetic Approach Cordell, New York. 10(4);1981:10-14
(ii) Pelletier S. W. Ed. Wiley In Alkaloids: Chemical and Biological Perspectives New York.13(3);1983:13-16
(iii) Hesse M. Wiley-VCH Alkaloids: Nature’s Cure or Blessing, Weinheim.41(4); 2002:56-60
2. Cordell G. A. Quinn-Beattie and M. L. Farnsworth, The potential of alkaloids in drug discovery N. R. Phytother. Res. 15 (3); 2001:180-183.
Received on 10.06.2016 Modified on 26.06.2016
Accepted on 30.06.2016 © AJRC All right reserved
Asian J. Research Chem. 2016; 9(7): 296-328.
DOI: 10.5958/0974-4150.2016.00048.1