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Heterocyclyl Linked Anilines and Benzaldehydes As Precursors for Biologically Significant New Chemical Entities

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Heterocyclyl Linked Anilines and Benzaldehydes As Precursors for Biologically Significant New Chemical Entities J. Chem. Sci. Vol. 124, No. 5, September 2012, pp. 1063–1069. c Indian Academy of Sciences. Heterocyclyl linked anilines and benzaldehydes as precursors for biologically significant new chemical entities RAMAN K VERMAa,∗, VIJAY KUMARa, PRITHWISH GHOSHa and LALIT K WADHWAb aSynthetic Organic and Medicinal Chemistry Laboratory, Department of Chemistry, Punjabi University, Patiala 147 002, India bInd-Swift Laboratories Limited (Research and Development Centre), Plot No. E-5, Industrial Area, Phase-2, SAS Nagar, Mohali 160 055, India e-mail: [email protected] MS received 28 November 2011; revised 25 February 2012; accepted 8 March 2012 Abstract. Benzylidene and benzyl thiazolidinediones, oxazolidinediones, isoxazolidinediones and their acyclic analogs like alpha alkylthio/alkoxy phenylpropanoic acids, beta-keto esters and tyrosine-based com- pounds possess broad therapeutic potential in general and as Peroxisome Proliferator Activated Receptors (PPARs) agonists in particular in the management of hyperglycemia and hyperlipidaemia for the treatment of Type 2 Diabetes (T2D). We have synthesised and characterized some novel and suitably substituted hetero- cyclyl linked benzaldehydes and anilines, which can be easily and very readily derivatized to all the above mentioned classes to generate new chemical entities of broader biological significance. Synthesis of their benzylidene thiazolidinedione and diethyl malonate and also benzyl diethyl malonate and alpha-bromoesters derivatives is reported in some of the cases in the present work. Keywords. Benzimidazole; indole; acridone; benzaldehyde; aniline. 1. Introduction in drug discovery research. The compounds containing acridone structural unit may act potentially as antiher- It is well-documented in the literature that benzim- pesvirus agents, 12 antitumour agents, 13 NS3 helicase idazole, indole and acridone scaffolds are important inhibitor (that inhibits hepatitis C virus replication), 14 structural core in medicinal chemistry because their antimalarial agents. 15 derivatives exhibit illustrious biological and pharma- Aldehyde and amino, the two important func- cological activities. The synthesis of benzimidazole tional groups, are of versatile utility in the field of derivatives has gained importance during recent years organic synthesis. A medicinally significant library of because of their broad spectrum of activities as antivi- numerous compounds, which may prove to be potent ral, 1 antitumour, 2 antioxidant, 3 anticoagulant, 4 antihy- pharmacological agents, can be prepared starting pertensive 5 and antiparasitic agents. 6 from substituted benzaldehydes and aminobenzenes. Indole nucleus is another heterocyclic pharma- Pharmacologically active 2,4-thiazolidinediones, 16 cophoric component of immense medicinal signifi- oxazolidinediones, 17 isoxazolidine-3,5-dione, 18 1,3-di- cance. Suitably substituted or fused indole ring carbonyls, 18 (1,3-diacids, 1,3-diesters, 1,3-diamides), 18 containing compounds demonstrate antiproliferative and α-alkoxy carboxylic acids 19,20 (figure 1)have activity in many types of human cancer cells, 7 agonism been prepared from variously heterocyclyl linked to cannabinoid receptors, 8 antitumour activity, 9 free benzaldehydes. Similarly, there are reports of phar- radical scavenging activity, 10,11 anti-inflammatory acti- macologically active 2,4-thiazolidinediones 21,22 and vity. 11 Similarly, acridone nucleus is also indispensible thiazolidinone derivatives 23 prepared from heterocycle linked aminobenzenes. The α-bromopropanoic acid ester derivative prepared from substituted aminoben- zene leads to α-alkylthiocarboxylic acids 19 and Tyro- sine derivatives 24 are of immense importance for the treatment of T2D. Reviewing the synthetic application of the discussed, our work is projected upon three ∗For correspondence heterocycles and the two functional groups mentioned. 1063 1064 RamanKVermaetal. O O O NH N N S NH NH O N N S S O O N O O O O Pioglitazone Rosiglitazone BRL 49653 BRL 48482 O O O NH NH S N O N O O O O DRF 2189 Reglitazar JTT 501 O O O O O O OH OH N N N O O O O O O O JTT Compound Ragaglitazar DRF 2725 Novo Nordisk Compound O O H O O O H N O HN O HN N O O O GW 409544 Farglitazar Figure 1. PPAR activating molecules. 2. Experimental catalyst was filtered through diatomaceous earth/celite and the filtrate was evaporated under reduced pressure 2.1 Materials and methods to give a residue which upon trituration with hexane or upon column chromatography (hexane/EtOAc, 1:5) All the chemicals used in the present work were pur- gave the desired compound as a solid. chased from SD Fine Chemical and Aldrich Chemi- cal Company. The melting/boiling points reported here were recorded using an open conc. sulphuric acid bath 2.2a 4-[(1-Methyl-1H-benzimidazol-2-yl)methoxy]- and are uncorrected. The Infrared and 1H NMR spec- aniline (compound 3,scheme1): Yield: 75%, tra of these compounds were recorded on Perkin-Elmer mp: 138–140◦C; FTIR (KBr): 3447, 3317, 2942, Spectrum RX FTIR Spectrophotometer and AC400F, 2840, 1512, 1480, 1446, 1364, 1246, 1035, 831, −1 1 400 MHz Bruker spectrometer at RSIC, Panjab Uni- 747. cm ; H NMR (CDCl3)δ: 7.76 (d, 2H), 7.36– versity, Chandigarh. LCMS of these compounds were 7.27 (m, 3H), 6.89 (d, J = 6.56 Hz, 1H), 6.63 (d, J = recorded on LCMS LCQ Finnigan Matt (APCI +ve 6.64 Hz, 2H), 5.30 (s, 2H), 3.88 (s,3H), 2.78 (br.s, 2H); + mode) at Central Instrumentation Lab, NIPER, SAS LCMS m/z (254) [M+1] ; Anal. Calcd for C15H15N3O: Nagar, Mohali, Punjab. GCMS and Elemental analy- C, 71.13; H, 5.97; N, 16.59. Found: C, 71.75; H, 5.68; sis of these compounds were carried out on Shimadzu N, 16.82. GCMS-QP2010 Plus and VarioMICRO VI Elemen- tal Analyzer respectively at Instrumental Laboratory, 2.2b 4-[(1-Methyl-1H-indol-2-yl)methoxy]aniline Department of Chemistry, Punjabi University, Patiala. (compound 7,scheme2): Yield: 50%, mp: 141– 143◦C; FTIR (KBr): 3500–3200, 2923, 2840, 1656, − 2.2 General procedure for the synthesis 1593, 1511, 1468, 1380, 1232, 1010, 832, 751 cm 1; 1 )δ of heterocyclyl linked anilines 3, 7 and 11 H NMR (CDCl3 : 7.59 (d, 1H), 7.33–7.31 (m, 1H), 7.25–7.21 (m, 1H), 7.11–7.07 (m, 1H), 6.84 (d, J = To (3.1 mmol) of the respective nitro compound 8.8Hz, 2H), 6.66–6.63 (d„ J = 8.8Hz, 2H), 6.54 (s, 1H), (2,6,10) placed in a Parr bottle with 10% Palladium 5.10 (s, 2H), 3.80 (s, 3H); LCMS m/z (253) [M+1]+; on charcoal (300 mg) and methanol/dioxane (150 ml), Anal. Calcd for C16H16N2O: C, 76.16; H, 6.39; N, and the mixture was hydrogenated at 20 psi for 2 h. The 11.10. Found: C, 76.45; H, 6.07; N, 11.44. Heterocyclyl linked anilines and benzaldehydes 1065 O O O N Br + O N ONd N ONH2 e - N c O 3a N N N OH 2 3 N O f O N O NH 1a h N S N Cl H O g O N 4 N N 4a 1b a i b O O NH2.HCl N O O O N NHCH3.HCl 4b d 1 O O N O O O N 4c Scheme 1. Synthesis of benzimidazolyl linked compounds. a: Glycolic acid, H2O, Reflux; b: chloroacetic acid, H2O, reflux; c: 4-chloronitrobenzene, NaH, DMF, rt; d: Pd/C-H2, methanol, rt; e: methanol, acetone,HBr, NaNO2, methyl acrylate,Cu2O; f: 4- fluorobenzaldehyde, NaH, DMF, rt; g: 4-hydroxybenzaldehyde, NaH, DMF, rt; h: 2,4- thiazolidinedione, piperidinium acetate, toluene, reflux; i: diethyl malonate, piperidinium acetate, toluene, reflux. O + ONd ONH2 - O c N N OH 6 7 O N O NH e S O O f O 5b H N N 8 8a b g O N O O 5a O a O O O N O 8b N O 5 H Scheme 2. Synthesis of indolyl linked compounds. a: CH3I, NaH, DMF; b: LiAlH4- THF; c: 4-chloro nitrobenzene, NaH, DMF, rt; d: Pd/C-H2, methanol; e: 4-fluoro- benzaldehyde, NaH, DMF, rt; f: 2,4-thiazolidinedione, piperidinium acetate, toluene, reflux; g: piperidinium acetate, toluene, reflux. + 2.2c 10-[3-(4-Aminophenoxy)propyl]acridin-9(10H)- 100) [M+1] ; Anal. Calcd for C22H20N2O2: C, 76.72; one (compound 11,scheme3): Yield: 86%, mp: 151– H, 5.85; N, 8.13. Found: C, 76.59; H, 5.57; N, 8.29. 153◦C; FTIR (KBr): 3335, 3500–3200, 2924, 2840, 1629, 1595, 1509, 1491, 1459,1375, 820, 753 cm−1; 1 )δ H NMR (CDCl3 : 8.60–8.57 (m, 2H), 7.71–7.67 2.3 General procedure for the synthesis of (m, 2H), 7.64–7.62 (d, 2H), 7.31–7.27 (m, 2H), 6.81 heterocyclyl linked benzaldehydes 4 and 8 (d, J = 8.8 Hz, 2H), 6.68 (d, J = 8.8 Hz, 2H), 4.63 (t, J = 7.5 Hz, 2H), 4.08 (t, J = 5.3 Hz, 2H), 3.48 (br.s, To a stirred suspension of sodium hydride (1.4 mmol, 2H), 2.38 (quintet, J = 2.8 Hz, 2H); LCMS m/z (345, 60% w/w dispersion) in dry DMF (20 ml) was added 1066 RamanKVermaetal. O + N - O O + NH2 HO N - O c N O a N O O O + O N - 11 O 10 Br O 9a OHN b O O H H 9 Br O 9b N O O a 12 O H HO Scheme 3. Synthesis of acridonyl linked compounds. a: 1,3-Dibromopropane, K2CO3, acetone; b: KOH, DMF (MW); c: Pd/C-H2, methanol. (1a/5b) (1.2 mmol) in dry DMF (5 ml) at 0◦C, and 2H), 7.62 (d, 1H), 7.35–7.33 (m, 1H), 7.28–7.24 (m, the mixture was stirred for 30 min at room tempera- 1H), 7.13 (d, J = 8.76 Hz, 2H), 6.63 (s, 1H), 5.29 ture (rt) (ca.
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