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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 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.

N N

N N

1 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. O O H N N O NH NH H N N N O 2 H H2N N N 3 2 Isoxanthopterin Xanthopterin

O O H H N O N O NH NH OH H N N N O H N N N 2 H 2 OH OH 5 4 Leucopterin Erythropterin

- Biopterin 6 is a widely occurring natural pterin, isolated from human urine, fruit fly, royal jelly of bees and Mediterranean flour moth.

O H H N CH NH 3 OH OH H N N N 2 6

Biopterin

Folic acid 7, is one the most important compounds comprising pteridine nucleus in its molecules.

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OH

N COOH N

H2N N N CH2NH CONHCH

CH 7 2

Folic acid COOH

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).

O O 1 1 NH2 O R NH N R + NH

O N NH O R 2 H N N N R 2 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].

O O NO C6H5COCH2CH3 N NH NH

H2N N NH2 H2N N N C6H5

11 12

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].

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NH2 Ph N N

N N Ph

KOAc 15

NH2 ON O N + H N N Ph Ph 2

14 13 NH2NH2

NH2 Ph N N

H2N N N Ph

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 OBz OH OBz NO NO N N N + N Cl H 2NH N NH2 NH N N R 2 NH N N O O 2 17 O 18 19 20

OBz O N N R

NH N N O 2 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).

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O H O O N O NH NO S NH + + N N N - N N NH X Br 2 X 24 22 23

Na2S2O4

O H N O NH

N N N H 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].

NH 2 NH NO Ph 2 N N Ph + N

H2N N NH2 N H2N N N NH2

26 27 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].

O 2 O O R NO 2 N R N COOH + O Piperidine N

O N NH2 Heat 1 O O O N N O R 1 H R 29 30 31 1 2 R = R = CH 3 1 2 R = R = H

1 R = C H , 2 2 5 R = H 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

198 www.scholarsresearchlibrary.com 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 34b respectively (Scheme 8).

NC CN NC CN O

NO N NH O O EtONa / EtOH NH Y +

S N NH Y OEt S N N O 2 H Ph Ph

34 a,b 32 33

Y = Me (a) , EtO (b).

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]. NH 2 N N

Ph N N CH3

NH KOAc 2 37 NH2 N O CH3 + Ph N NH 2 O H

35 36

NH2 NH NH N CH 2 2 N 3

Ph N N

Scheme (9):- 38

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].

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NH 2 NH NH N 2 2 2 O MeOH N R 1 + 2HX + N 2 N R N NH2 R OH 1 31-97% R N N

40 41 39

1 R = H, SCH , NH , C H 3 2 6 5 X = Cl, Br

2 R = CH3, CH2CH3, CH2X, C6H5, p-CH3-C6H4

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 NH N N 2 EtOH, reflux + N O NHAc N NH2 N 77% N N O H Ac 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 O CO Me O CO Me 2 R NH 2 R N R N CH CO Me N 2 MeOH, rt N N 2 2 + 5 min CO CH MeX N NH MeX N NH 2 3 MeX N N O 2 CO Me 2 2 H 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].

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O 1 O CN O O 1 R NH2 N OEt EtOH R + EtO N OEt

X N NH2 CN O reflux 2 X N NH R 2 R 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].

O O 1 2 NH 1 = CH Ph , R = H (28%) N 2 O N R R 2 + N H 1 2 O N NH 2 R = H , R = CH Ph (59%) 2 O N N R 2 O 52 53 54

NH2 NH NH2 2 O N O N + PH 9-10 0.1 M NaOH N H N NH 2NH N NH2 60% NH N N 80% O 2 2NH N N 55 53 56

57

O O O O H NH2 NH H N N + NH NH NH N NH Br 2 2 NH N N NH N N 2 2 59 58 60 61

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].

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OH O O OH OH NH2 N R NH R NH + OH OH H N N NH N H N N N 2 2 2 NH 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].

NH O O 1 EtO C OEt 1 R NH 2 R N NH 2 65 N 2 N

O N NH 100% O N N OH 2 2 2 R R 66

64 NH

5-63% NC OMe

67

O 1 R N NH N 2

O N N NH 2 2 R

68

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 H 2/Pd gave the 6- trifluoromethylpterin 79 (Scheme 17) [39-41].

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O N CF NH 3 F NH N N 2 F O H N CF 70 NH 3

2NH N N CF3 CF COCOCF 3 3 ClCF2COCF3 69 O O NH ClF CCOR N R NH 2 2 NH F NH N NH NH N N F 2 2 2 H 71 ClF CO Et 2 2 58 BrCH2COCF3

O H CF N O 3 NH O O F N CF NH 3 NH N N F NH 2 H + NH NH N N 2 NH 72 2NH N 2 73 74

O O OH CF O NO2 3 NH NO2 NH MsCl NO2 + NH NH OH 2NH N Cl OMs 2NH N N CH Ph 2NH N N 2 CF PhCH2 3 CF 75 PhCH2 3 77 76 78

i- H2/Pd ii- DDQ

O N CF NH 3

2NH 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].

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O O O NO2 O NH NO2 NH + NH NH 2

H2N N Cl H2N H2N N N H N N N H 2 80 O H 75 O 81 82

O N NH

H N N N 2 H

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].

OBu OBu OH OBu OH NH2 N H I /HCO H O 2 2 N aqous KOH N + N N O 2NH N NH2 MeOH OR OH OR 2NH N N 2NH N N

84 85 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].

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CH=NNHPh O O OH NH CHOH O OH R 2 MeOH/H O/HCl H N CHOH 2 R N OH R N + N O N OH CHOH O N NH 2-mercapto ethanol OH 2 CHOH O N N O O N N reflux H H CH OH 88 2 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].

O O O 1 1 O R EtOH, reflux N R HNO NH2 NH NH 2 NH 1 1 PhCH2S N N Na2S2O4 PhCH S N NH O R R PhCH2S N NH2 2 2 94 92 93

1 a = Me 85% R 1 b = CH Ph 15% R 2 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]. OH OH NH N 2 O R N R N + H N N NH 1 1 2 2 O R H N N N R 2 95 96 1 a, R = R = H 1 b, R = R = CH3 c, R = R 1 = OH

d, R = R 1 = Ph

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].

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OH NH OH 1-[O] 2 Br CH(OEt) H OH N 2 N CH(OEt) H + N 2 N CHO CHO 2- H N 2NH N NH2 NH N N 2 NH N N 95 97 2 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 OH Br CH Br N CH Q R NH2 2 2 N COR N + + H2N CHO H N N N H2N N NH2 2

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] OH OH heat OH OH PhN Cl N=NPh R= Me N 2 N NH CH COR N=NPh N R 2 2 N N NH N Cl NH N Cl 2 2 NH N N 2NH N NHCH2COR 2

103 104 105 106

Zn, HOAc, [O] heat R= OEt

OH N OH N

2NH N N

107

X X NO X 2 NO N 2 N R N N

2NH N Cl 2NH N NHCH2COR 2NH N N

108 109 110

Scheme 25

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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].

OMe OMe (Bu)4NF, THF OMe S S SMe O NH2 N MeI N NH NH N + O S N NH2 S N N SMe N N H H 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% H 2O2 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 N N Cl N R d e N N N N f N + 2NH N NH2 NH N N 2NH N NH2 2NH N N NH N N 2 2 - 116 O 121 115 b 119 116: R = H 120

117: R = NO g

c 6 R 118: R = NH2 R 4 4 N N R = ethoxy or isopropoxy

2NH 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].

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OH OMe R O N e N NH OMe H2N N NH2

126 H2N N N

126 : R = H 129 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).

OH N CONH 2 N HCOOH N

N NH 2 N N

130 131

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].

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X O CNH N 2 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).

O N CONH N CONH2 N 2 KOBr NH

N CONH N NCO N N O 2 H

134 135 136

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].

NC N CHO NC N CH(OMe) 2 NH2 N CH(OMe) OH N 2 2NH N NH N N CH(OMe) 2 N 2 2NH N N 137 138 2NH N N 139 140

OH N CHO N

2NH N N 141

Scheme 32

4-Unsubstituted pteridines 144 have been prepared by a modification of this route using pyrazinecarbaldehydes 142 as starting materials (Scheme 33) [67].

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N CHO N CHO NH N 3 N

N NH2 N NHCOR N N R 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 N N NHR 1 R NH 2 147

N CO Me N CO2Me RNCO 2 1 N NCNR O N N=PPh3 benzene , RT R OH N NR 145 146 1 N N OR

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].

O O NH MeO C N 2 2 N N + NH N NH NH 2 Cl N H N N N H N N N 2 2 Me 149 150 151 152

Scheme 35

Guanidine 149 was reacted again with Pyrazine derivatives 153 to afford new 4-imino pteridine derivatives 154 (Scheme 36) [72].

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Ph Ac Ph Ac NH N N NH N 2 NC N N + NH NH 2 H N N N Me MeNH N Me 2 Me 149 153 154

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 159 condensed, with the 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]. NH NH 2 NC N N N NH + 2 EtO OEt NH N N N 2 155 156 157

CO2Et O MeO C N 2 N N EtO C N + 2 NH N MeS SMe 2 MeS N N

158 159 160

O Me NC N Br Me N N N + O NH N O N N Me Me 161 162 163 NH NC N 2 Cl N Ar i- ArNHMe N N NH N 2 ii- guanidine, Me 61-87% NH N N 2 164 165

, Ar = n-C H Cl 6 13

Scheme 37

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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 CO M e N CO M e 2 XCN O O E t 2 N NHCXNHCH C O O E t 2 N NH 2 1 7 0 1 6 6 a X = S b X = O N C O O E t NaO Et M e S S M e

O O N N N C O O E t M e I N C O O E t

N N X N N S M e H 1 7 1 1 6 7

P O C l 3 NH 2 NH 2 .H 2 O

O O N O N NH NH .H O N N C O O E t 2 2 2 N N N NH N N C l 2 1 6 8 1 7 2

am in es

O N N C O O E t

N N NR

1 6 9

NH-C H a N R = 5 1 1

b N R = N

c N R = N O

Scheme 38

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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 derivative 178b [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).

O O N N (CH )n N 2 N (CH2)n N (CH2)n N (CH2)n N N S MeS S MeS N N N N

177 a; n=1 173 178 b; n=2 174 178a; n=1 178b; n=2 N N CO2Me N

SMe N NH2 N N Cl 179 159 175 O N O 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].

2- MnO2 N CN HOH C N CN N CN S2O8 , AgNO3 2 PhNH CH OH 2 X + 2 COOH N CN Me N CN Me N CN

181 182 183 184

MeNH2

NH N CN N CN Et SiH-CF CO H PhN N NH=C(NH ) PhNH 3 3 2 PhNH N 2 2 Me N NHMe Me N NHMe Me N N NH 2 185 Me 186 187

Scheme 40

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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].

O O O Ac O N NH2 2 N NH + O NH RO N 2 N N OR O 191 188 130

aq.NaOH NH 2 NH N N NH EtOH N 2 RO + NH RO 2 N N N CN 189 190 156

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].

Pd(dba) ,P(o-tolyl) ,CuI 2 3 Me O Me NC N Br NEt3, MeCN NC N MeNCO N N N N Me H N N hydrolysis O N N

162 192 193

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 N COOMe N COOMe Et OH N THF, rt, 24h N + + H2N CH2OH N NH CH OH N NCS S N N 2 H S N Et H 195 194 196 197

Scheme 43

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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].

CN EtOOC N CH=NOH OH O CH=NOH EtOOC + + N CH=NOH guan. N CH=NOH NH2 H2N N + O- H N N N 2 198 199 200 O - 201

Na2SO4

I2

OH N CHO N

H2N N N

202 Scheme 44

O R O O NH RO2C N R RO2C 2 N R N R + NH NH CN + N + 2NH N OH NH N N NH N N O - 2 - 2 H O 204 207 203 205 206

O N R NH

2NH N N

208

NH NH OHC CH Cl 2 2 2 NC N NC NH2 N N + N N CN N + + 2NH N CH2Cl NH N N CH Cl 2 2 2NH N N CH2Cl OH O- - O 209 210 211 212 213

NH2 N N

NH N N CH=CHPh 2 214

Scheme 45

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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].

NC CN NC N CH(OMe)2 . TsOH NH + N NOCl 2 HON=CHCOCH(OMe)2 NH N 2 - O CH(OMe)2 O 215 216 217

OH NH2 N CH(OMe) NC N CH(OMe) 2 N CH(OMe) 2 N N 2 NH N 2NH N N 2 2NH N N 220 219 218 OH N CHO N

2NH N 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 O OH 222 N NC N OC2H5 O O H + O NH O O 2 N O Cl O - O 224 225 O 226 223

NH NC N 2 NH O N CO H 2 N 2 N N O 2NH N NH N N 2 227 2NH 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

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Cl NH2 Cl Cl O Cl NH2 2NH CN AR N CN NH N + N O NH CN 2 Cl Cl N CN N N AR

Cl Cl

230 231 232 233

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.

217 www.scholarsresearchlibrary.com Sayed A. Ahmed et al Der Pharma Chemica, 2014, 6 (3):194-219 ______

[26] Mohit L. D, Pulak J. Bhuyan., Synthetic Communications, 36: 3085–3090, 2006. [27] Abdel-Latif, E.; Mustafa, H. M.; Etman, H. A. and Fadda, A. A. Russian Journal of Organic Chemistry, 2007 , 43, 443. [28] Forrest, H. S. and Walker, J. J. Chem. Soc. 1949 , 2077. [29] Ivery, M. T. G. and Gready, J. E. Biol. Chem. Hoppe-Seyler , 1992 , 373, 1125. [30] Waring, P. and Armarego, W. L. F. Aust. J. Chem. , 1985 , 38, 629. [31] Taghavi-Moghadam, S. and Pfleiderer, W. Tetrahedron Lett., 1997 , 38, 6835. [32] Bergman, J.; Damberg, C. and Vallberg, H. Recl. Trav. Chim. Pays-Bas, 1996 , 115, 31. [33] Molina, S.; Cobo, J.; Sanchez, A.; Nogueras, M. and De Clercq, E. J. Heterocycl. Chem., 1999 , 36, 435. [34] Yamada, Y.; Yasuda, H.; Yoshihara, Y. and Yoshizawa, K. J. Heterocycl. Chem ., 1999 , 36, 1317. [35] Kim, Y.; Kang, Y. and Baek, D. Bull. Korean Chem. Soc., 2001 , 22, 141. [36] Soyka, R.; Pfleiderer, W. and Prewo, R. Helv. Chim. Acta , 1990 , 73, 808. [37] Abou-Hadeed, K. and Pfleiderer, W. Pteridines, 1998 , 9, 175. [38] Singh, R. and Geetanjali, Russ. J. Org. Chem., 2006 , 42, 136. [39] Dunn, C.; Gibson, C. L. and Suckling, C. J. Tetrahedron, 1996 , 52, 13017. [40] Kolos, N. N.; Chebanov, V. A.; Orlov, V. D. and Surov, Y. N. Chem. Heterocycl. Compd., 2001, 37, 755. [41] Wamhoff, H. and Tzanova, M. Collect. Czech. Chem. Commun., 2003 , 68, 965. [42] Boon, W. R.; Jones, W. G. M. and Ramage, G.R. J. Chem. Soc., 1951 , 96. [43] Polonovski, M. and Jerome, H. Compt. Rend., 1950 , 230, 392. [44] Bailey, S. W., Chandrasekaran, R. Y. and Ayling, J. E. J. Org. Chem. , 1992 , 57, 4470. [45] Bailey, S.W.; Rebrin, I.; Boerth, S.R. and Ayling, J.E. J. Am. Chem. Soc., 1995 , 117, 10203. [46] Murata, S.; Sugimoto, T.; Ogiwara, S.; Mogi, K. and Wasada, H., Synthesis , 1992 , 303. [47] Murata, S.; Kiguchi, K. and Sugimoto, T . Heterocycles, 1998 , 48, 1255. [48] Lopez, M. D.; Quijano, M. L.; Sanchez, A.; Nogueras, M. and Low, J. N. J. Heterocycl. Chem., 2001 , 38, 727. [49] Yao, Q. Z.; Zhang, Z. X. and Xiao, L. Acta Chim. Sin., 2002 , 60, 343. [50] Guiney, D.; Gibson, C. L. and Suckling, C. J. Org. Biomol. Chem., 2003 , 1, 664. [51] Gibson, C. L.; La Rosa, S. and Suckling, C. J. Tetrahedron Lett., 2003 , 44, 1267. [52] Gibson, C. L.; La Rosa, S. and Suckling, C. J. Org. Biomol. Chem., 2003 , 1, 1909. [53] Crean, C. W.; Camier, R.; Lawler, M.; Stevenson, C.; Davies, R. J. H.; Boyle, P. H. and Kelly, J. M. Org. Biomol. Chem ., 2004 , 2, 3588. [54] Adcock, J.; Gibson, C. L.; Huggan, J. K. and Suckling, C. J. Tetrahedron , 2011 , 67, 3226. [55] Ikan R., Natural Products A laboratory guide ; 2 nd ed. New Delhi Academic Press Elsevier; 2005: p 331-343. [56] Cain CK., US Patent. 2,667, 486 (Cl.260-251.5); 1954 Jan 26 US appl. 228, 139, 1951 . May 24. [57] Sletzinger, M.; Reinhold, D.; Grier, J.; Beachem, M. and Tishler, M. J. Am. Chem. soc., 1955 , 77, 6365. [58] Waller, C.W.; Hutchings, B.L.; Mowat, J.H.; Stokstad, E.L.R.; Boothe, J.H.; Angier, R.B.; Semb, J.; SubbaRow, Y.; Cosulich, D.B.; Fahrenbach, M. J.; Hultquist, M. E.; Kuh, E.; Northey, E. H.; Seeger, D. R.; Sickels, J. P. and Smith, J. M. J. Am. Chem. soc., 1948, 70, 19. [59] Boon, W. R. and Leigh, T. J. Chem. soc., 1951 , 1497. [60] Martins Alho, M. A.; D’Accorso, N. B.; Ochoa, C.; Castro, A.; Calderón, F.; Chana, A.; Reviriego, F.; Páez, J. A.; Campillo, N. E.; Martínez-Grueiro, M.; López-Santa Cruz, A. M. and Martínez, A. R. Bioorg. Med. Chem ., 2004 , 12, 4431. [61] De Jonghe, S.; Marchand, A.; Gao, L.; Calleja, A.; Cuveliers, E.; Sienaert, I.; Herman, J.; Clydesdale, G.; Sefrioui, H.; Lin, Y.; Pfleiderer, W.; Waer, M. and Herdewijn, P. Bioorg. Med. Chem . Lett., 2011 , 21, 145. [62] Pfleiderer, W. and Lohrmann, R. Chem. Ber. 1961 , 94, 12. [63] Mohr, D.; Kazimierczuk, Z. and Pfleiderer, W. Helv. Chim. Acta , 1992 , 75, 2317. [64] Albert; Brown and Cheeseman, J. chem. Soc., 1951 , 474. [65] Gabriel, S. and Sonn, A. Ber., 1907 , 40, 4850. [66] Taylor, E.C.; Henrie , R. N. and Portnoy, R.C. J. Org. Chem., 1978 , 43, 736. [67] Albert and Okta, K. J. chem. Soc. C , 1971 , 2357. [68] Okawa, T.; Eguchi, S. and Kakehi, A. J. Chem.Soc.,Perkin Trans.1 , 1996 , 247. [69] Okawa, T.; Kawase, M. and Eguchi, S. Synthesis, 1998 , 1185. [70] Dick and Wood, J. chem. Soc., 1955 , 1379. [71] Brown, D. J. and Jacobsen, N. W. ibid, 1961 , 4413. [72] Tada, M.; Asawa, Y. and Igarashi, M. J. Heterocycl. Chem ., 1997 , 34, 973. [73] Rosowsky, A.; Wright, J. E.; Vaidya, C. M.; Forsch, R. A. and Bader, H. J. Med. Chem., 2000 , 43, 1620. [74] Chowdhury, A.; Shibata, Y.; Morita, M.; Kaya, K. and Hiratani, K. J. Heterocycl. Chem., 2001 , 38, 1173.

218 www.scholarsresearchlibrary.com Sayed A. Ahmed et al Der Pharma Chemica, 2014, 6 (3):194-219 ______

[75] Southon, I. W. and Pfleiderer, W. Chem. Ber., 1978 , 111, 971. [76] Falch, E. Acta Chem. Scand. B., 1977 , 31, 167. [77] Ferrand, G.; Dumas, H.; Depin, J. C. and Quentin, Y. Eur. J. Med. Chem., 1996 , 31, 273. [78] Sato, N. and Fukuya, S. J. Chem. Soc., Perkin Trans. 1 , 2000 , 89. [79] Urleb, U. J. Heterocycl. Chem., 1998 , 35, 693. [80] Taylor, E.C. and Lenard, K. Liebigs Ann. Chem., 1969 , 726, 100. [81] Taylor and Paudler, W. W. Chem. and Ind , 1955 , 1061. [82] Taylor and Lenard, K. J. Amer. chem. Soc., 1968 , 90, 2424. [83] Taylor, E. C.; Perlman, K. L.; Sword, I. P.; Sequin-Frey, M. and Jacobi, P. A. J. Amer. chem. Soc., 1973 , 95, 6407. [84] Taylor and Kobayashi, T. J. org. Chem., 1973 , 38, 2817. [85] Taylor, E.C. and Dumas, D. J. J. Org. Chem., 1981 , 46, 1394. [86] Sato, N. and Saito, N. J. Heterocyclic Chem. , 1988 , 25, 1737. [87] Guirado, A.; López Sánchez, J. I.; Ruiz-Alcaraz A. J.; García-Peñarrubia, P.; Bautista, D. and Gálve, J. Eur. J. Med. Chem., 2013 , 66, 269.

219 www.scholarsresearchlibrary.com