Synthesis of 5-membered heterocycles using benzoylacetonitriles as synthon

Turkish Journal of Chemistry http://journals.tubitak.gov.tr/chem/ Review Article Turk J Chem (2013) 37: 685 – 711 c TÜBİTAK ⃝ doi:10.3906/kim-1211-31 Synthesis of 5-membered heterocycles using benzoylacetonitriles as synthon 1 Received: 21.11.2012 Rizk Elsayed KHIDRE,1,∗Bakr Fathy ABDELWAHAB2 Chemistry Department, Faculty of Science, Jazan University, Saudi Arabia 2 Shaqra University, Al-Dawadami, Saudi Arabia • Accepted: 08.03.2013 • Published Online: 16.09.2013 • Printed: 21.10.2013 Abstract: This review article represents a survey covering the synthetic strategies leading to 5-membered heterocycles. The reactions are subdivided into groups that cover the synthetic methods of those heterocycles, i.e. pyrroles, furans, thiophenes, pyrazoles, isoxazoles, thiazoles, and others, utilizing benzoylacetonitriles as starting precursor from 1985 up to the present. The reactions are subdivided into groups that cover the synthetic methods for those heterocycles from benzoylacetonitriles. Key words: Benzoylacetonitrile, pyrroles, furans, thiophenes, pyrazoles, isoxazoles, thiazoles 1. Introduction Benzoylacetonitrile derivatives are easily available and have high chemical reactivity due to the presence of 3 active moieties: nitrile, carbonyl, and active methylene functions. Benzoylacetonitrile, known as phenacylcyanide or ω -cyanoacetophenone, was named as 3-oxo-3-phenylpropanenitrile using the IUPAC system. Benzoylacetonitriles are versatile and convenient intermediates in organic synthesis and have attracted a great deal of interest. 1 Benzoylacetonitriles opened up an important area of heterocyclic chemistry on account of the fact that many of them are subunits of natural products and pharmaceutical agents, e.g., antimicrobial, 2,3 antineoplastic, 4,5 antiviral, 6,7 and anti-inflammatory agents; 8,9 as inhibitors of poly(adp-ribose) polymerase (PARP); 10,11 as GABAB allosteric enhancers for treating CNS disorders 12 and pain; 13 and as allosteric enhancers at the human A1 adenosine receptor. 14−16 Despite this important versatility, and in connection with our previous review articles, 17 the utility of benzoylacetonitrile in the synthesis of 5-membered heterocycles has not been previously reviewed. The present review aims to demonstrate the synthetic applications of benzoylacetonitrile in the synthesis of 5-membered heterocycles from 1985 up to the end of 2011 and provide useful and up-to-date data for organic and medicinal chemists. 2. Synthesis of 5-membered rings with 1 heteroatom 2.1. Pyrroles and their fused derivatives Synthesis of 4-cyanopyrroles via mild Knorr reactions with β -ketonitriles was achieved. Ethyl 3-(4-bromophenyl)4-cyano-5-phenyl-1H -pyrrole-2-carboxylate 3 was prepared by reaction of ethyl 3-(4-bromophenyl)-2-(hydroxyimino)-3-oxopropanoate 2 with compound 1. 18 Azoalkenes 4 were reacted with 1 to afford methyl 1-amino-4cyano-5-phenyl-1H -pyrrole-3-carboxylates 5. 19 1-Cyanoformanilide 6 was reacted with 1 in refluxed ethanol in ∗ Correspondence: 685 KHIDRE and ABDELWAHAB/Turk J Chem the presence of triethylamine to give 3-amino-4-benzoyl-5-imino-1-phenyl-1H -pyrrol-2(5H) -one 7. 20 Regioselective synthesis of 2,3,4-trisubstituted pyrrole 10 has been achieved via [3,3] sigmatropic rearrangements of O -vinyl oximes 9. O -allyl oximes 8 enable rapid access to O -vinyl oximes (Scheme 1). 21 H N Ph CO 2Et NC R 3 , 54% Ar = 4-BrC 6 H4 O CO2 Et R 2 HN R1 N R Ph NC R 4 CO2 Me NOH i) Zn, EtOH; ii) AcOH O O PhHN CN CN 6 R1 N N OMe O Ph 1 MeONa Ph N O H2 N Et3 N, EtOH NH COPh 7 5, 65% a O NH 2 . HCl O N N b Ph O Ph Me Ph 8 CN NC 9 CN H N 10 Me R = Me, Et; R1 = CO 2Me, CO2 CMe 3, CONH 2, CONHPh a: i) AcONa, MeOH, 30 min, 25°C; ii) MeOH, 5 min, 25°C; 12 h, 60°C b: [(cod)IrCl] 2, AgO3 SCF3 , NaBH 4, THF, 75°C, 24 h Scheme 1. Three-component 1-pot condensation reactions of ethyl glycinate 11, 3-hydroxybutan-2-one 12, and 1 yielded ethyl 2-(3-cyano-4,5-dimethyl-2-phenyl-1H -pyrrol-1-yl)acetate 13, which was consequently hydrolyzed to produce the corresponding carboxylic acid 14 (Scheme 2). 9 O O O O NH2 . HCl EtO 11 + Me Me OH 12 + 1 NaHCO 3 EtOH, PhMe Me N OEt Ph Me H 3O Me Me 13 CN N O H Ph 14 CN Scheme 2. 2-Formyl-1,4-dihydropyridines 15 underwent the tandem Knoevenagel condensation/aminonitrile cyclization with 1 to afford methyl 2-cyano-5-methyl-3-phenylindolizine-8-carboxylate 17 in 65%–93% yields (Scheme 3). 22 2.2. Furans and their fused derivatives 2.2.1. Michael addition reaction 4-Cyano-2,3-dihydrofuran-3-carboxamides 19 were obtained in moderate yields by the oxidative cyclization of 1 with unsaturated amides using manganese(III) acetate. Treatment of 3-oxopropanenitriles 1 with (2 E)-3-(5methyl-2-furyl)acrylamide 18 gave dihydrofuran-3-carboxamides 19 in moderate yields (Scheme 4). 23,24 686 KHIDRE and ABDELWAHAB/Turk J Chem R2 O R2 MeO2C R1 CO2Me + 1 a or b Me R2 CO 2Me R1 Ph NH Me N N N CHO Ph CN H R1 Me 17 15 16 R 1, R 2 = EtO 2C, 2-O2 NC 6H 4 (93%); a, pip., EtOH R 1, R 2 = MeCO, 3-O 2NC6 H4 (88%); Me 2CHO 2C, 5-nitro-2-furyl (65%); b, AcOH, 30 min, reflux Scheme 3. O CN R1 X R2 R3 O + Mn(OAc)3 /AcOH R4 1 70°C, 30-60 min R3 O R1 X NC 19 O 18 R2 R4 R 1 = Ph, 4-MeC 6H 4 , 4-MeOC 6 H4 , 4-ClC 6 H4 , 2-thienyl, 2-benzofuryl, t-butyl R2 = Me, R3 = H, R4 = NH2 , X = O (42%-64%) R2 = R3 = Me, H, R4 = NH2 , OEt, X = S (45%-91%) Scheme 4. 4,5-Dihydro-3-furancarbonitrile derivatives 21 were obtained through radical cyclization of 1, mediated either by manganese(III) acetate in acetic acid 2,25,26 or by cerium(IV) ammonium nitrate in THF 27 with substituted ethylene 20. Cerium(IV)/THF radical cyclization was compared with that performed with manganese(III) acetate/AcOH; the cerium(IV)/THF system turned out to be much more efficient. The synthesized compounds showed better results against test bacteria than some known antibiotics. 2 Similarly 1-pot synthesis of tetrasubstituted furan derivatives 23, catalyzed by acidic alumina and in the absence of solvent, was reported from the reaction between compound 1 and ethyl 3-nitrooct-2-enoate 22 (Scheme 5). 28 R2 NO 2 Ph NC O C5 H11 CO2 Et 23 EtO2C 22 Al2 O3, 3 h, rt, 3 h, 60°C R1 = Ph R3 O C 5H 11 R1 20 R4 R1 O CN 1 R2 R3 a or b NC R4 21 a) Mn(OAc) 3, AcOH, 80 oC; R 1 = Ph; R 2 = Ph, 2-thienyl; R 3 = Me, Ph, n-Pr, H; R4 = Et, Ph, H (40-83%) b) Ce(NH4 )2 (NO3) 6, NaHCO3 ,THF, 10 - 30 min, 60°C; R 1 = R2 = R3 = Ph, R4 = H(97%);R1 = R2 = R 3 = Ph, R4 = Et (83%); R 1 = Ph, R 2 = R 3 = 4-FC6 H4 , R 4 = H (86%); R 1 = 2-f uranyl, R 2 = R3 = Ph, R 4 = H (90%); R1 = 1benzof uran-2-yl, R2 = R3 = Ph, R4 = H (96%); R1 = R 2 = Ph,R 3 = R 4 = H (42%); R1 = R2 = Ph,R 3 = H, R 4 = Me (75%); R 1 = R 2 = Ph,R 3 = Me, R 4 = H (80%) Scheme 5. Propargyl bromide 24 was reacted with 1 in the presence of copper iodide and 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (DBU) in toluene to give 5-methyl-2-phe (...truncated)