Synthesis of pteridines derivatives from different heterocyclic compounds

1. Available online a www.derpharmachemica.com t Scholars Research Library Der Pharma Chemica, 2014, 6(3):194-219 (http://derpharmachemica.com/archive.html) ISSN 0975-413X CODEN (USA): PCHHAX Synthesis of pteridines derivatives from different heterocyclic compounds Sayed A. Ahmed*, Ahmed H. Elghandour and Hussein S. Elgendy Department of Chemistry, Faculty of Science, Beni-Suef University, Beni-Suef, Egypt _____________________________________________________________________________________________ ABSTRACT A great attention has been paid to synthesize new compounds with new sites of action. In this context, the synthesis of pterdinies derivatives has been extensively studied because of their biological importance. They are known to regulate many biological processes and their deficiency induces many disease processes. In this mini review we aim to summarize the structure and methods of pterdinies derivatives synthesis from pyrimidines, pyrazines and other different heterocyclic compounds. Keywords: Pteridines, Pyrimidines, Pyrazines, Heterocyclic compounds. _____________________________________________________________________________________________ INTRODUCTION In medicinal chemistry, the chemist attempts to design and synthesize a medicine or a pharmaceutical agent, which will benefit humanity. The chemistry of heterocyclic compounds is the most important in the discovery of new drugs. Study of these compounds is of great interest both in theoretical as well as practical aspects [1]. Pteridines, pyrazino[2,3-d]pyrimidine compounds, are a group of heterocyclic compounds composed of fused pyrimidine and pyrazine rings[2]. Pteridines research has long been recognized as important for many biological processes, such as amino acid metabolism, nucleic acid synthesis, neurotransmitter synthesis, cancer, cardiovascular function, and growth and development of essentially all living organisms. Defects in synthesis, metabolism and/or nutritional availability of these compounds have been implicated as major causes of common disease processes[3], e.g. cancer, inflammatory disorders, cardiovascular disorders, neurological diseases, autoimmune processes, and birth defects [4].In more detailed, pteridines are one of the most important heterocycles exhibiting remarkable biological activities because these compounds are constituents of the cells of the living matters[5]. For example, pteridine, is a precursor in the synthesis of dihydrofolic acid in many microorganisms. Where, pteridine and 4-Aminobenzoic acid are converted by the enzyme dihydropteroate synthetase into dihydrofolic acid in the presence of glutamate[6]. At structural level, pteridines have two major classes, ‘conjugated’ pteridines, which are characterized by relatively complex side chains, e.g. the vitamins folic acid, and ‘unconjugated’ pteridines, e.g. biopterin or neopterin bearing less complex side chains at the 6-position of the pterin[7]. Moreover, there are three main classes of naturally occurring pteridines namely, lumazines, isoalloxazine and pterins. Lumazines and isoalloxazines have oxo- substituents at the 2- and 4- positions with the difference being a phenyl ring annealed in the 6- and 7- position on the isoalloxazine. The most common class of naturally occurring pteridines are the pterins which have an amino group at the 2-position and an oxogroup at the 4-position[8]. Studies on developing new methods for new pteridines derivatives synthesis are getting increase therefore; here we aim to elucidate all available structures and methods related to pteridines. 194 www.scholarsresearchlibrary.com

2. Sayed A. Ahmed et al _____________________________________________________________________________ Der Pharma Chemica, 2014, 6 (3):194-219 2 Structure and compounds of pteridines. Pteridine ring 1 system is a pigment and consist of pyrazine ring and pyrimidine ring. This compound was found in the wings of insects and the eyes and skin of fish, amphibbia and reptiles. Pteridine also contains 4-hydroxy groups and two amino groups. - Xanthopterin 2 is butterfly wing pigments and it found in human urine, pancreas, kidneys, liver and wasp wings - Also isoxanthopterin 3, leucopterin 4 and erythropterin 5 are known as butterfly wing pigments. - Biopterin 6 is a widely occurring natural pterin, isolated from human urine, fruit fly, royal jelly of bees and Mediterranean flour moth. Folic acid 7, is one the most important compounds comprising pteridine nucleus in its molecules. N N N N 1 O O N H H N O N H N O N H H2 N N N H2 N N 3 2 Isoxanthopterin Xanthopterin O O H H O N O N H N H N OH H2 N N N N H O H2 N N OH H O 5 4 Erythropterin Leucopterin O H H CH3 N H N OH OH N H2 N N 6 Biopterin 195 www.scholarsresearchlibrary.com

3. Sayed A. Ahmed et al _____________________________________________________________________________ Der Pharma Chemica, 2014, 6 (3):194-219 3 Synthesis of pteridines:- 3. 1. From pyridines. Pteridines derivatives 10 can be prepared from Pyrimidines via Isay reaction [9-15]by condensation of 4,5-diamino pyrimidine-2,6-dione 8 with dicarbonyl compounds 9 (Scheme 1). N H + OH N COOH N CONHCH CH2NH N H2 N N CH2 7 Folic acid COOH O O 1 NH2 1 O R R N H N O N NH2 O R R N H2 N N H 9 8 10 Scheme 1 Also 2,4-di amino-5-nitroso pyrimidine-6-one 11 condensed with aldhydes and ketones to produce pteridines derivatives 12 (Scheme 2)[16,17]. Scheme 2 4,6-di amino-5-nitroso-2-phenyl pyrimidine 14 with an active methylene 13 give different compounds of pteridines according to condition of reaction(Scheme 3)[18-21]. O O NO C6H5COCH2CH3 N H N H N H2 N N NH2 C6H5 N H2 N N 12 11 196 www.scholarsresearchlibrary.com

4. Sayed A. Ahmed et al _____________________________________________________________________________ Der Pharma Chemica, 2014, 6 (3):194-219 NH2 Ph N N Ph N N 15 KOAc NH2 ON N O + Ph H2 N N Ph 14 NH2NH2 13 NH2 Ph N N Ph N H2 N N 16 Scheme 3 Xu et al. was reported that Diels-Alder reaction leads to the formation of a pterin derivatives 21 (Scheme 4)[22]. R R OBz H O OBz OBz NO NO N N N + N H Cl H2 N N NH2 H2 N N N R O H2 N N N O O 17 18 19 20 O OBz N R N O H2 N N N H 21 Scheme 4 Reaction[23] of nitrosopyrimidine 22 with dimethylphenacylsulfonium bromides 23 produced 7-aryl-2- dimethylamino-3,4,5,6-tetrahydropteridine-4,6-diones 24 which reduced by sodium dithionite to yield 7,8-dihydro derivatives 25 (Scheme 5). 197 www.scholarsresearchlibrary.com

5. Sayed A. Ahmed et al _____________________________________________________________________________ Der Pharma Chemica, 2014, 6 (3):194-219 O H O N O O H N NO S + H N + N N N Br- X N N NH2 X 24 23 22 Na2S2O4 O H O N H N N H N N X 25 Scheme 5 The use of methylenenitrile 27 in the condensation with 5-nitroso-2,4,6- triamino pyrimidine 26 provided triamterene 28 (Scheme 6)[24,25]. N NH2 N H2 N NH2 NH2 Ph NO N Ph N + N NH2 N H2 N N 27 26 28 Scheme 6 1,3-Dimethyl-2,4,7-trioxo-1,2,3,47,8 hexahydropteridine-6-carboxylic acid 31 was prepared by reaction of 6-amino- 5-nitroso uracils 29 with Meldrum’s acid 30 (Scheme 7)[26]. Scheme 7 Abdel-Latif et al[27] found that (6-Amino-5-nitroso-1-phenyl-2-thioxo-1,2,3,4-tetrahydropyrimidin-4-ylidene) malononitrile 32 reacts with ethylacetoacetate 33a and diethyl malonate 33b, in the presence of sodium ethoxide to O O O 2 NO R 2 COOH R N N Piperidine + N O O N R NH2 Heat O O N R N H O O 1 1 30 29 31 1 2 = CH3 R = R 1 2 = H R = R 1 2 = C2H5 , R = H R 198 www.scholarsresearchlibrary.com

6. Sayed A. Ahmed et al _____________________________________________________________________________ Der Pharma Chemica, 2014, 6 (3):194-219 afford (6-Acetyl-7-oxo-1-phenyl-2-thioxo-1,2,3,4,7,8-hexahydropteridin-4-ylidene) malononitrile 34a and Ethyl 4- dicyanomethylidene-7-oxo-1-phenyl-2-thioxo-1,2,3,4,7,8-hexahydropteridine-6-carboxylate (Scheme 8). Scheme 8 Methylglyoxal 36 with 2-phenylpyrimidine-4,5,6-triamine 35 yields 7-methyl derivative 37, however, in the presence of hydrazine the 6-methyl derivative 38 is isolated as the only product indicating the regiospecificity of the reaction (Scheme 9)[28-30]. N CH3 O + 34b respectively CN NC CN NC O N NO Y O O H N H N EtONa / EtOH + OEt N H O S N Ph 34 a,b Y S N Ph NH2 33 32 Y = Me (a) , EtO (b). NH2 N N CH3 Ph N N KOAc NH2 37 NH2 Ph N NH2 O H 35 36 NH2 NH2NH2 CH3 N N Ph N N 38 Scheme (9):- The regioselective, one-step synthesis of 2,6-disubstituted-4-aminopteridines 41 from 2-substituted-4,5,6- triaminopyrimidine 39, dihydrohalides and ketoaldoximes 40 (Scheme 10)[31]. 199 www.scholarsresearchlibrary.com

7. Sayed A. Ahmed et al _____________________________________________________________________________ Der Pharma Chemica, 2014, 6 (3):194-219 NH2 NH2 NH2 2 N O R N MeOH + 2HX + N 1 N 2 R N NH2 R OH 1 31-97% N R N 40 41 39 1 = H, SCH3, NH2, C6H5 R X = Cl, Br 2 = CH3, CH2CH3, CH2X, C6H5, p-CH3-C6H4 R Scheme 10 6-arylpteridin-7-one 44 can be prepared in good yield by the reaction of 4,5-diamino pyrimidine 42 with the N- acetylindolone 43 (Scheme 11)[32]. O NH2 N EtOH, reflux N N + ONHAc O 77% N NH2 N Ac N H N 42 44 43 Scheme 11 5,6-Diaminopyrimidines 45 reacted with dimethyl acetylenedicarboxylate (DMAD) 46 to afford the corresponding pteridines 48 on reflux in methanol in one step through formation an intermediate 47 (Scheme 12)[33]. O R NH2 N + 5 min O CO2Me O CO2Me CH2CO2Me N R N R MeOH, rt N N CO2CH3 MeX N H O N MeX N NH2 MeX N NH2 CO2Me 47 48 45 46 R = H , Me X = O , S Scheme 12 Ethyl 7-aminopteridine-6-carboxylates 51 can be synthesized by treatment of 1, 3-dialkyl-5,6-diaminouracils 49 by unsaturated carbonyl compounds such as diethyl (E)-2,3-dicyanobutenedioate 50 (Scheme 13)[34]. 200 www.scholarsresearchlibrary.com

8. Sayed A. Ahmed et al _____________________________________________________________________________ Der Pharma Chemica, 2014, 6 (3):194-219 O O O 1 CN O NH2 R 1 EtOH N R OEt OEt N + EtO X N R NH2 CN reflux O NH2 X N R 2 2 50 49 51 Scheme 13 The reaction of 4,5-diamino-1,3-dimethyluracil 52 with benzylglyoxal 53 gave a mixture of pteridines, which were separated by column chromatography. However, when 2,4,5,6-tetraaminopyrimidine 55 reacted with benzylglyoxal 53 at pH 9–10, only the 7-benzyl pteridine 56 was obtained, which on hydrolysis afforded thecorresponding 4- oxopteridine 57. On the other hand, if the reaction was carried out at a pH below 8, a mixture of 6- and 7- benzylpteridines formed. In yet another method for introducing differentiated reactivity at carbon, the 6- benzylpteridine 61 was obtained selectively by the reaction of 2, 4, 5-triaminopyrimidin-5(1H)-one 58 with 2- bromo-3-phenylpropanal 59 (Scheme 14)[35]. Scheme 14 Condensation of 2,5,6 tri aminopyrimidine-4-(3H)-one 58 with the phenyl hydrazon derivative of a sugar 62 leads to the 6 substituted 2-aminopteridin-4(3H)-one 63 (Scheme 15)[36]. O O 2 , 1 NH2 = = H (28%) 1 R CH2Ph R O R N N N + H 1 2 , = H O N NH2 R 2 CH2Ph R = (59%) R N O N O 52 53 54 NH2 NH2 O NH2 N O N N PH 9-10 + 0.1 M NaOH N H N H H2 N N NH2 60% N H2 N N 80% H2 N N N O 53 55 56 57 O O O O H NH2 N N H N H H N + H N Br H2 N N NH2 N H2 N N H2 N N N 59 58 60 61 201 www.scholarsresearchlibrary.com

9. Sayed A. Ahmed et al _____________________________________________________________________________ Der Pharma Chemica, 2014, 6 (3):194-219 OH O OH O H O NH2 R N R H N H N + OH OH N N H2 N N NH2 N H2 N N H Ph 63 58 62 Scheme 15 5, 6-diaminouracils derivatives 64 can be reacted with Ethoxy-imino-acetic acid ethyl ester 65 and 2-Nitrilo- acetamidic acid methyl ester 67 to yield 6-amino,7-hydroxy-tetrahydropteridine-2,4-dione 66 derivatives and 6,7- diaminolumazines 68 respectively ( Scheme 16)[37,38]. Scheme 16 2,4,5-Triaminopyrimidine-5(1H)-one 58 reacted with aliphatic fluorinated precursors to give different fluro pterins. In the case of bromotrifluoroacetone as the aliphatic precursor, the pyrimidooxazine was also isolated. 2-Amino-6- chloro-5-nitropyrimidin-4(3H)one 75 reacted with amino alcohol to give the 6-substituted pyrimidine 77 which on activation of the OH group with mesyl chloride and reduction of the nitro group with H2/Pd gave the 6- trifluoromethylpterin 79 (Scheme 17)[39-41]. NH O O EtO2C OEt 1 1 N NH2 R NH2 R 65 N N OH N O N R O N R NH2 100% 2 2 66 64 NH 5-63% NC OMe 67 O 1 NH2 N R N NH2 N O N R 2 68 202 www.scholarsresearchlibrary.com

10. Sayed A. Ahmed et al _____________________________________________________________________________ Der Pharma Chemica, 2014, 6 (3):194-219 O CF3 F N H N N H H2 N N F O 70 CF3 N H N CF3 N H2 N N CF3COCOCF3 ClCF2COCF3 69 O O R N NH2 ClF2CCOR H N H N F H2 N N N H H2 N N NH2 F 71 ClF2CO2Et 58 BrCH2COCF3 O CF3 H O N O H N O F CF3 N H N NH N H H2 N N F H N + N H2 N N NH2 H2 N N 72 73 74 O O O H O CF3 NO2 NO2 H N NO2 H N MsCl H N + OH H N CH2Ph H2 N N Cl OMs H2 N N N H2 N N N CF3 PhCH2 CF3 PhCH2 75 77 76 78 i- H2/Pd ii- DDQ O CF3 N H N N H2 N N 79 Scheme 17 Condensing of 6-chloro-5-nitro-pyrimidine 75 with amino carbonyl compounds 80, in a reaction known as the Polonovski–Boon cyclization [42,43]to form dihydropterin which can be oxidized to afford fully oxidized pterin. This regiospecific reaction has been used in synthesizing functionalized tetrahydrobiopterin 83 (Scheme 18)[44,45]. 203 www.scholarsresearchlibrary.com

11. Sayed A. Ahmed et al _____________________________________________________________________________ Der Pharma Chemica, 2014, 6 (3):194-219 O O O NO2 O NO2 H N NH2 H N H N + H2 N N Cl H2 N H2 N N N H H2 N N N H 80 O O 75 81 82 O N H N N H H2 N N 83 Scheme 18 Treatment of 2,4,5-triamino-6-butoxypyrimidine 84 by 2-formyloxiranes 85 to afforded 6-(1-hydroxyalkyl)- substituted pteridines (Biopterin) 87(Scheme 19)[46,47]. N O I2/HCO2H + MeOH OBu OH OBu OH OBu NH2 H N N aqous KOH N N O H2 N N NH2 OR OH H2 N N N N H2 N N OR 85 84 86 87 O R = H H AcO Scheme 19 Condensation of 5,6-diamino-2-methoxypyrimidin-4(3H)-ones 88 with protected pentose phenyl hydrazones 89 of both D- and L-series such as D-ribose, D- and L-xylose, D- and L-arabinose which yielded pyrano[3,2-g]pteridines 91 (Scheme 20)[48-53]. 204 www.scholarsresearchlibrary.com

12. Sayed A. Ahmed et al _____________________________________________________________________________ Der Pharma Chemica, 2014, 6 (3):194-219 CH=NNHPh CHOH CHOH CHOH CHOH CH2OH O OH O OH O NH2 H R MeOH/H2O/HCl N R OH N N R N N OH + O 2-mercapto ethanol O N NH2 OH O N N H O O N N H reflux 88 91 90 89 Scheme 20 6-Amino-2-(benzylsulfanyl)pyrimidin-4(3H)-one 92 was treated to give 5,6-Diamino-2-(benzylsulfanyl) pyrimidin- 4(3H)-one 93 to react with biacetyl to yield 2-(Benzylsulfanyl)-6,7-dimethyl-4(3H)-pteridinone 94 (Scheme 21) [54]. N H N H O O O 1 1 N R EtOH, reflux R O NH2 H N HNO2 1 1 PhCH2S N N Na2S2O4 R O R PhCH2S N NH2 PhCH2S N NH2 94 93 92 1 a = Me 85% R 1 15% CH2Ph = b R Scheme 21 Reaction of 2,4,5-tri amino-6-hydroxy pyrimidine 95 with glyoxal, Bi acetyl, oxalic acid and benzil afforded to 2- amino-4-hydroxy pteridine, 2-amino-4-hydroxy-6,7-di methyl pteridine, 2-amino-4,6,7-tri hydroxy pteridine and 2- amino-6,7-di phenyl peteridine respectively 96 a-d (Scheme 22)[47,55]. Scheme 22 Reaction of α-bromo-β,β-diethoxypropanal 97 with 2,4,5-triamino-6-hydroxy pyrimidin 95 which by oxidation of the resulting 5,6-dihydropterin 98 and hydrolysis of the acetal (Scheme 23)[56]. OH OH NH2 O R R N N N + 1 1 H2 N N NH2 O R R H2 N N N 95 96 1 a, R = R = H 1 b, R = R = CH3 1 c, R = R = OH d, R = R = Ph 1 205 www.scholarsresearchlibrary.com

13. Sayed A. Ahmed et al _____________________________________________________________________________ Der Pharma Chemica, 2014, 6 (3):194-219 OH OH 1-[O] NH2 H CH(OEt)2 Br OH N CH(OEt)2 H N + N CHO N 2- H CHO N H2 N N NH2 N H2 N N H2 N N N 97 95 98 99 Scheme 23 Waller et al found that condensation of 2,4,5-triamino-6-hydoxypyrimidine 95 and 2,3 - Dibromopropionaldehyde 100 and p-aminobenzoylglutamic acid 101 were afforded Ptereidines derivatives 102 (Scheme 24)[57]. OH NH2 N H2 + + OH CH2Br Br CH2Q R N N N COR CHO N H2 N N H2 N N NH2 100 101 95 102 R= OH, OEt, GluEt Scheme 24 Condensation of 5-arylazo-4-chloropyrimidines 104 with α-aminoketones or esters, followed by reduction (usually with Zn/HOAc) and thermal cyclization. The phenylazo moiety serves both as a precursor of the 5-amino group. This also prepared from 5-nitro-4-chloropyrimidines 108 (Scheme 25)[58]. Zn, HOAc, [O] heat R= Me OH OH OH OH N=NPh PhN2Cl N R N N N=NPh NH2CH2COR N N H2 N N Cl H2 N N Cl H2 N N N NHCH2COR H2 N N 105 103 104 106 Zn, HOAc, [O] heat R= OEt OH OH N N H2 N N N 107 X X X NO2 NO2 N R N N N H2 N N Cl H2 N N NHCH2COR N H2 N N 109 108 110 Scheme 25 206 www.scholarsresearchlibrary.com

14. Sayed A. Ahmed et al _____________________________________________________________________________ Der Pharma Chemica, 2014, 6 (3):194-219 Condensation between 4,5-diamino-2,6-dimercaptopyrimidine 111 and p-dimethoxybenzil 112 to afforded 6,7-Bis- (p-methoxyphenyl)-2,4-(1H,3H)-pteridinedithione 113 which by S-Methylation tetrabutylammonium fluoride (TBAF), as base, and an excess of methyl iodide, as alkylating agent, afforded dimethyl derivatives 114 (Scheme 26)[59]. S NH2 N H + OMe (Bu)4NF, THF OMe OMe SMe S O MeI N N H N N O S N H NH2 SMe N N S N H N OMe OMe OMe 112 111 113 114 Scheme 26 De Jonghe et al[60] found that, 5,6-diamino-pyrimidine derivatives were prepared by action of sodium ethoxide or sodium isopropoxide on 2,6-diamino-4-chloro-pyrimidine 115, to introduce an alkoxy substituent. Nitrosation of the pyrimidine ring, followed by reduction of the nitroso group (using sodium dithionite in water), the product was reacted with glyoxal, affording 2-amino-4-alkoxy-pteridine [61]Oxidation of product in trifluoroacetic acid with 30% H2O2 afforded the N-(8)-oxide derivative. The chlorine was introduced using acetyl chloride and trifluoroacetic acid, yielding 2-amino-4-alkoxy-6-chloro-pteridine 122 (Scheme 27)[62]. Cl 4 4 4 R R R 4 R a Cl N N R N + N e d f N N N N H2 N N NH2 N H2 N N N H2 N N H2 N N 116 NH2 H2 N N N O - 121 119 115 b 120 116: R = H g 117: R = NO c 6 R NH2 118: R = 4 R N 4 N R = ethoxy or isopropoxy H2 N N N 122 Scheme 27 Reagents and conditions: (a) R4H, Na, 160 _C, 6 h, 72%; (b) NaNO2, CH3COOH, H2O, 80 _C, 68%; (c) Na2S2O4, H2O, 60 _C, 61%; (d) glyoxal, ethanol or isopropanol, reflux, 4 h, 62%; (e) TFA, H2O2, 4 _C, 2 d, 32%; (f) AcCl, TFA, _40–0 _C, 72%; (g) ArB(OH)2, Na2CO3, Pd(PPh3)4, dioxane, reflux, 4 h, 20–70%. Introduction of a nitroso group at position 5 of 2,6-diamino-4-hydroxy-pyrimidine 126 and its subsequent reduction yielded the 5,6-diamino-pyrimidine derivative 128. The 6-(3,4-dimethoxyphenyl)-pteridine 129 was constructed by condensation reaction between pyrimidine and a-ketoaldoxime (which was prepared from the corresponding acetophenone derivative by oxidation with SeO2, followed by displacement reaction(Scheme 28)[60]. 207 www.scholarsresearchlibrary.com

15. Sayed A. Ahmed et al _____________________________________________________________________________ Der Pharma Chemica, 2014, 6 (3):194-219 OH OMe R O N e N OMe H N H2 N N NH2 H2 N N N 126 129 126 : R = H a 127 : R = NO O MeO b 128 : R = NH2 NOH MeO 125 d O O MeO MeO c O MeO MeO 123 124 Scheme 28 Reagents and conditions: (a) NaNO2, CH3COOH, H2O, 97%; (b) Na2S2O4, H2O, rt, 83%; (c) SeO2, dioxane, H2O, 50 _C; (d) acetonoxime, CH3OH, H2O, 50 _C, 2 h, 71% (over 2 steps); (e) 15, CH3OH, reflux, 3 h, 85. 3.2. From Pyrazines. 4-hydroxy pteridine[63] 131 can be prepared by the condensation of 3-amino pyrazine-4-carboxamide 130 with formic acid(Scheme 29). Scheme 29 Cyclisation of 3-aminopyrazine-2-carboxamide 132 or its thio-analogue with triethyl orthoformate in acetic anhydride gave pteridin-4-one or-4-thione 133, respectively(Scheme 30)[64]. OH CONH2 N N HCOOH N N NH2 N N 131 130 208 www.scholarsresearchlibrary.com

16. Sayed A. Ahmed et al _____________________________________________________________________________ Der Pharma Chemica, 2014, 6 (3):194-219 X O CNH2 N N CH(OEt)3 NH N NH2 Ac2O N N 133 132 X = O , S Scheme 30 Gabriel et al[65] found that pyrazine-2,3-dicarboxamide 134 by Hofmann reaction into lumazine (pteridine-2,4- dione) 136 (Scheme 31). Scheme 31 2-amino-3-cyanopyrazine-5-carbaldehyde 137 was converted to dimethylacetal 138 which was cyclized to 2,4- diamino-5-formyl pteridinemethylacetal 139 with guanidine gave the dimethylacetal of 6-formylpterin 140, which was converted to 6-Formylpterin 141 with formic or trifluoroacetic acid(Scheme 32)[66]. Scheme 32 4-Unsubstituted pteridines 144 have been prepared by a modification of this route using pyrazinecarbaldehydes 142 as starting materials(Scheme 33)[67]. O CONH2 N N CONH2 N KOBr NH NCO N O N H N CONH2 N 135 134 136 CHO NC N CH(OMe)2 NC N NH2 OH CH(OMe)2 N N H2 N N CH(OMe)2 N H2 N N N N H2 N N 137 138 H2 N N N 139 140 OH CHO N N N H2 N N 141 209 www.scholarsresearchlibrary.com

17. Sayed A. Ahmed et al _____________________________________________________________________________ Der Pharma Chemica, 2014, 6 (3):194-219 CHO N N CHO N NH3 N N NH2 R N N NHCOR N 142 144 143 Scheme 33 Methyl-3-(triphenylphosphoranylideneamino)pyrazine-2-carboxylate 145 used to obtain different pteridines by reaction with isocyanates followed by adding alcohols or amines(Scheme 34)[68,69]. O N NR 1 NHR N N 1 R NH2 147 CO2Me N CO2Me N RNCO 1 O NCNR N N=PPh3 N benzene , RT R OH N NR 146 1 145 OR N N 148 Scheme 34 Methyl 3-chloropyrazine-2-carboxylate 150 and guanidine 149 were reacted to yield 2-aminopteridin-4-one 151. The product is best purified via the sodium salt; Methylation of pterin gives the unexpected N-methylated product 152 (Scheme 35)[70,71]. Scheme 35 Guanidine 149 was reacted again with Pyrazine derivatives 153 to afford new 4-imino pteridine derivatives154 (Scheme 36)[72]. O O NH2 MeO2C N N N H N N + NH2 H N Cl N H2 N N N H2 N N N Me 150 149 151 152 210 www.scholarsresearchlibrary.com

18. Sayed A. Ahmed et al _____________________________________________________________________________ Der Pharma Chemica, 2014, 6 (3):194-219 Ph NAc Ph Ac NH N N NH2 NC N N + NH2 H N Me N Me N H2 N MeNH Me N 153 149 154 Scheme 36 Substituted amidines have been found to react in good yield to give 6,7-unsubstituted pteridines from the corresponding pyrazine. Similarly, methyl-2-aminopyrazine-3-carboxylate bis(dithioimidate) 158 giving access to an unusual N-3-substituted 2-methylthiopteridine-4-one 160. Also 1,3- dimethyllumazine system 163 can be prepared from methyl isocyanate 161 and a 5-aminomethyl-6-cyanopyrazine 162.The 5-chloromethylpyrazine 164 was reacted firstly with substituted aromatic amines and then with guanidine to form the compounds for evaluation(Scheme 37)[73]. Scheme 37 159 condensed, with the NH2 NH N NC N N + H2 N EtO OEt N N H2 N N 155 157 156 CO2Et O MeO2C N N N EtO2C N + H2 N N MeS SMe MeS N N 158 159 160 O Me NC N Br N Me N N + H N Me N O N Me N O 161 162 163 NH2 NC N Cl Ar N i- ArNHMe N Me N H2 N N ii- guanidine, 61-87% H2 N N N 164 165 , Ar = n-C6H13 Cl 211 www.scholarsresearchlibrary.com

19. Sayed A. Ahmed et al _____________________________________________________________________________ Der Pharma Chemica, 2014, 6 (3):194-219 2-aminopyrazine also reacted with isothiocyanates, isocyanates, or dithioketals to afford the corresponding pteridines. For example, with ethyl isothiocyanatoacetate, and ethyl isocyanatoacetate, the corresponding thioureidopyrazine and urethane derivatives, respectively, were obtained, which, on cyclization in the presence of sodium ethoxide, gave 2-thio and oxo-N-3-protected pteridines in good yields. on reaction with methyl iodide, afforded a 2-methylthiopteridine 171 was also obtained directly from by the condensation with ethyl N- [bis(methylthio)methylene]glycinate also reacted with phosphorusoxychloride to give a 2-chloro derivative 168, which was reacted with pyrrolidine, giving 2-pyrrolodinyl pteridine-4-one derivatives 169. Hydrazine hydrate reacted with 2-methylthioderivatives to give N-aminolactam derivatives 172 (Scheme 38)[74]. N N N R C O2M e N C O2M e N X C N O O E t N N H C X N H C H2C O O E t a X = S b X = O N N H2 1 7 0 1 6 6 C O O E t N N a O E t M e S S M e O O N N C O O E t C O O E t N M e I N S M e N N N H X N 1 7 1 1 6 7 P O C l3 N H2N H2. H2O O O O N N N H2N H2. H2O N C O O E t N N N N N H2 C l N N 1 7 2 1 6 8 a m in e s O N C O O E t N 1 6 9 N H - C5H1 1 a N R = b N R = N N O c N R = Scheme 38 212 www.scholarsresearchlibrary.com

20. Sayed A. Ahmed et al _____________________________________________________________________________ Der Pharma Chemica, 2014, 6 (3):194-219 series of imino thioacetals[74] 2-(methylthio)-2-thiazoline 177a ,5,6-dihydro-2-(methylthio)-4H-1,3-thiazine 177b, 2-(methylthio)-2-imidazoline 173, 2-(methylthio)-1,4,5,6-tetrahydropyrimidine 175 and 2-(methylthio)-2-pyrazine 179 ,reacted readily with 2 aminopyrazine 159 to give the desired tricyclic fusion products, thiazolo[2,3-b]pteridine derivative 178a, thiazino[2,3-b]pteridine derivative178b [75,76], imidazo[2,1-b]pteridine derivative 174, pyrimido[2,1-b]pteridine derivative 176 and pyrazino[2,1-b]pteridine derivative 180 respectively by one-step reaction(Scheme 39). N O O N (CH2)n N (CH2)n N N (CH2)n (CH2)n N MeS N N S S MeS N N N N 177 a; n=1 b; n=2 173 178 174 178a; n=1 178b; n=2 CO2Me N N N N NH2 SMe N N 175 Cl 159 179 O O N N N N N N N N N N 180 176 Scheme 39 6-anilinomethylpteridine derivatives 187 were prepared by the reaction of glycolic acid 182 with 5-metyl Pyrazine- 2,3-dicarbonitrile 181 (Scheme 40)[72]. N CN CH2OH COOH MnO2 PhNH2 2- CN N CN HOH2C N S2O8 , AgNO3 X + Me CN N Me CN N CN N 184 183 182 181 MeNH2 CN NH N Et3SiH-CF3CO2H PhN CN N N NH=C(NH2)2 PhNH N PhNH Me NHMe N Me NHMe N NH2 Me N N Me 185 186 187 Scheme 40 213 www.scholarsresearchlibrary.com

21. Sayed A. Ahmed et al _____________________________________________________________________________ Der Pharma Chemica, 2014, 6 (3):194-219 The synthesis of 2-alkoxymethylpteridines has been achieved by the reaction of 3-aminopyrazine-2-carboxamide 130 with orthoesters 188 to give 2-alkoxymethylpteridine derivatives 191, which was synthesized by condensing 3- aminopyrazine-2-carbonitrile 156 with the acetoxyamidine 189 followed by the base hydrolysis(Scheme 41)[77]. Scheme 41 6-bromo-3-methyl amino Pyrazine-2-carbonitrile 162 underwent cross-coupling with propyne in the presence of bis(dibenzylidineacetone) palladium(0), tri-o-tolylphosphine, and copper (I) iodide to provide The pyrazines which was cyclized with methyl isocyanate to give corresponding pteridines 193 (Scheme 42)[78]. N Br NEt3, MeCN NC O O O Ac2O N NH2 N H N + O RO NH2 N N N OR O 191 188 130 aq.NaOH NH2 N NH EtOH NH2 N N RO + NH2 RO N N CN N 189 190 156 Pd(dba)2,P(o-tolyl)3,CuI Me Me O NC N N MeNCO N hydrolysis Me H N N N N O N N 192 162 193 Scheme 42 Methyl-3-isothiocyanatopyrazine-2-carboxylate 194 reacted with (R)-(_)-2-amino-1-butanol 195 in the absence of base, which provided the pteridine derivative 196 and uncyclized pyrazine derivative 197 in similar amounts (Scheme 43)[79]. Et O COOMe N COOMe N Et N H O THF, rt, 24h N + + CH2OH H2 N CH2OH N NH N NCS S N H N S N H Et 195 197 194 196 Scheme 43 214 www.scholarsresearchlibrary.com

22. Sayed A. Ahmed et al _____________________________________________________________________________ Der Pharma Chemica, 2014, 6 (3):194-219 3.3. From different Heterocyclic compounds. Condensation of ethyl α-aminocyanoacetate 199 with diisonitrosoacetone 198 to give ethyl 2-amino-5- oximinomethylpyrazine-3-carboxylate1-oxide 200, which was cyclized with guanidine to pterin-6-carboxaldehyde oxime 8-oxide 201 direct hydrolysis of the oxime was not possible, but conversion to was achieved by reduction with sodium sulphite which gave 6-aminomethylpterin 202 followed by oxidation with iodine(Scheme 44)[80]. CH=NOH O NH2 N H2 OH CH=NOH EtOOC N + CN EtOOC CH=NOH N + + guan. N CH=NOH N O N N O H2 N - 199 198 - 200 201 Na2SO4 I2 OH N CHO N N N H2 N 202 Scheme 44 O O O R R RO2C N NH2 RO2C N R N R H N + H N + CN N OH + H2 N N O N N H H2 N H2 N N N O - - 204 207 205 203 206 O R N H N H2 N N N 208 NH2 NH2 OHC CH2Cl NC N NH2 N N NC N N + + + CN N OH H2 N N O CH2Cl N N O CH2Cl H2 N N N CH2Cl H2 N - - 209 210 212 213 211 NH2 N N CH=CHPh H2 N N N 214 Scheme 45 215 www.scholarsresearchlibrary.com

23. Sayed A. Ahmed et al _____________________________________________________________________________ Der Pharma Chemica, 2014, 6 (3):194-219 Reaction of 3,3-dimethoxy- 1-pyrrolidinopropene 215 with nitrosyl chloride and addition of aminomalononitrile tosylate to the resulting oxime gave 2-amino-3-cyano-5-(dimethoxymethy1)pyrazine-1-oxide 217 which was deoxygenated to dimethylaceta with trimethyl phosphate then produce 6-aminomethylpterin 221 (Scheme 46)[85]. CN NC . TsOH CH(OMe)2 NC N NH2 + NOCl N HON=CHCOCH(OMe)2 H2 N N O - O CH(OMe)2 216 217 215 OH NH2 CH(OMe)2 NC N N CH(OMe)2 CH(OMe)2 N N N H2 N N N N H2 N N N H2 N 218 220 219 OH N CHO N N N H2 N 221 Scheme 46 2,4-Diaminopteridine-6-carboxlic acid 229 was prepared by base catalyzed condensation of 2-acetyl furan 222 and 2-furoyl chloride 223 to yield β-keto ester which by hydrolysis in KOH aqueous furnished the β-carboxlic acids which was treated with sodium nitrite and acidified leading to oximinoketone, Condensation of oximinoketone with malanonitrile tosylate in 2-propanol was gave the Pyrazine-N-oxide 226. The latter was deoxygenated giving aminocyanopyrazine 227 which cyclized readily with guanidine to give 2,4-diaminopeteridines 228 then oxidation to yield 2,4-diaminopeteridine-6-carboxlic acid 229 (Scheme 47)[86]. O OH O NC N N + 222 OC2H5 O O H O H2 N O N O O O Cl - 224 O 225 O 226 223 NC N NH2 NH2 O CO2H N N N O H2 N N N N H2 N N 227 N H2 N N 229 228 Scheme 47 5,8-dichloro-2,3-dicyanoquinoxaline 233 was prepared by reaction of 3,3,6,6- tetrachloro-1,2-cyclohexanedione 230 with diaminomaleonitrile 231 followed by treatment with pyridine then treated with an equimolar amount of 216 www.scholarsresearchlibrary.com

24. Sayed A. Ahmed et al _____________________________________________________________________________ Der Pharma Chemica, 2014, 6 (3):194-219 benzamidine in the presence of triethylamine to produce 4-amino-2-aryl-6,9-dichlorobenzo[g]pteridine 233 (Scheme 48)[87]. Scheme 48 CONCLUSION Taken together, we have described some recent advances in the synthesis of pteridines derivatives from heterocyclic compounds. This review showed the significant development in pteridines synthetic methods, however, these derivatives are now being more popular because of its efficiency, and many new methods will probably be developed. Acknowledgment The authors are gratefully indebted to Dr. Emadeldin M. Kamel, Chemistry department, Faculty of science, Beni Suef University for his help. REFERENCES [1] Vachala S. D., Der Pharma Chemica, 2012, 4, 255. [2] Hahn, F.E. and Jahnke, M.C. Angew. Chem. Int. Ed., 2008, 47, 3122. [3] Delgado JN and Remers WA, Wilson and Giswold’s-Textbook of Organic Chemistry Medicinal and Pharmaceutical Chemistry, 10th ed. Philadelphia:Lippincott Raven, 1998. [4] Milstien, S., Kapatos, G., Levine, R.A., Shane, B, Chemistry and Biology of Pteridines and Folates, Proceedings of the 12th International Symposium on Pteridines and Folates, National Institutes of Health, Bethesda, Maryland, 2002, XXIII, 677 p. [5] Sasada, T.; Kobayashi, F.; Sakai, N. and Konakahara, T. Organic Letters, 2009, 11, 2161. [6] Voet, D.; Voet, J.G. (2004). Biochemistry (3rd ed.). John Wiley & Sons. [7] Enzinger C, Wirleitner B, Spöttl N, Böck G, Fuchs D, Baier-Bitterlich G. Reduced pteridine derivatives induce apoptosis in PC12 cells. Neurochem Int. 2002. [8] Negishi, E.; Hu, Q.; Huang, Z.; Qian, M. and Wang, G. Aldrichimica Acta, 2005, 38, 71. [9] Lehbauer, J. and Pfleiderer, W. Nucleosides Nucleotides 1997, 16, 869. [10] Purrmann, R. Justus Liebigs Ann. Chem., 1941, 548, 284. [11] Sen S. E. and Roach, S. L. Synthesis 1995, 756. [12] Elion, G.B.; Hitchings, G.H. and Russell, P.B. J. Am. Chem. Soc., 1950, 72, 78. [13] Marchal, A.; Melguizo, M.; Nogueras, M.; Sanchez, A. and Low, J. N. Synlett 2002, 255. [14] Forrest, H.S. and Walker, J. J. Chem. Soc.1949, 79. [15] Pfleiderer, W.; Zondler, H. and Mengel, R. Justus Liebigs Ann. Chem., 1970, 741, 64. [16] Timmis, G.M. Nature, 1949, 164,139. [17] Steinlin, T. and Vasella, A. Helv. Chim. Acta, 2008, 91,435. [18] Pachter, I. J.; Nemeth, P. E. and Villani, A. J. J. Org. Chem., 1963, 28, 1197. [19] Pachter, I. J.; Nemeth, P. E. J. Org. Chem., 1963,28, 1187. [20] Pachter, I. J.; Nemeth, P. E. J. Org. Chem., 1963,28, 1203. [21] Pachter, I. J. J. Org. Chem., 1963,28, 1191. [22] Xu, M. and Vasella, A. Helv. Chim. Acta, 2006, 89, 1140. [23] Taylor, E. C.; Takahashi, M. and Kobayashi, N. Heterocycles, 1996, 43, 437. [24] Baur, R.; Sugimoto, T. and Pfleiderer, W. Helv. Chim. Acta, 1988, 71, 53. [25] Greenber, S. and Moffatt, J. G. J. Am. Chem. Soc. 1973, 95, 4016. NH2 Cl Cl Cl NH2 Cl O CN H2 N AR CN N NH N + N O CN H2 N CN N Cl Cl AR N N Cl Cl 231 230 232 233 217 www.scholarsresearchlibrary.com

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