Synthesis of pteridines derivatives from different heterocyclic

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Der Pharma Chemica, 2014, 6(3):194-219 (http://derpharmachemica.com/archive.html)

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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.

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

NH

N N

NH

OO

NH2

NH

N NH

N

O

O

NH2

NH

N NH

NH

O

O

O

NH2

NH

N N

NH

OO

NH2

OH

OH OH

Xanthopterin Isoxanthopterin

Leucopterin Erythropterin

23

45

NH

N N

NO

NH2

H

OH OH

HCH3

Biopterin

6



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).

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].

N

N N

NOH

NH2 CH2NH CONHCH

CH2

COOH

COOH

Folic acid

7

NH

N

O

NH2O

NH2 R1

R

O

O

NH

NH

N

N

O

NH2 R

R1

+

8 910

NH

N

O

NH2NH2

NONH

N N

NO

NH2 C6H5

C6H5COCH2CH3

11 12



Scheme 3

Xu et al. was reported that Diels-Alder reaction leads to the formation of a pterin derivatives 21 (Scheme 4) [22].

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).

N

N NH2NH2

OBzNO

R

O

Cl

N

N NH

NH2

OBzNO

O

RN

N N

N

NH2

OBz

O

ROH

N

N NH

N

NH2

OBz

O

R

O

+

1718 19 20

21

KOAc

NH2NH2

N

N

NH2

NH2

ON

Ph

O

Ph

N

N

N

N

NH2

Ph

Ph

N

N

N

N

NH2

NH2 Ph

Ph

+

13 14

15

16



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].

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

NH

N NH2N

ONO

X

SO

NH

NN

O

N

NH

O

X

Na2S2O4

NH

NN

O

NH

NH

O

X

+

Br-

+

22 2324

25

N

N

NH2

NH2NH2

NO

N

Ph

N

N

NH2

NH2 N

N

NH2

Ph+

26 27

28

N

N

O

OR

1

R2

NH2

NO

O

O

O

O

N

N

O

OR

1

R2

NH

N

O

COOH

R1

R2

CH3

R1

R2

R1

C2H5 R2

+ Piperidine

Heat

= =

= = H

= , = H

29 30 31



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).

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].

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].

NH

N NH2SPh

NO

CNNC

Y

O O

OEt

NH

NSPh

CNNC

NH

N

O

Y

O

+EtONa / EtOH

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

32 33 34 a,b

N

N

NH2

NH2

NH2Ph H

CH3O

O

KOAc

NH2NH2

N

N N

NNH2

Ph CH3

N

N N

NNH2

Ph

CH3

+

35 36

37

38



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].

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].

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].

N

N

NH2

NH2

NH2

R1 N

O

R2

OHN

N N

NNH2

R2

R1

H, SCH3, NH2, C6H5R1

R2

X = Cl, Br

CH3, CH2CH3, CH2X, C6H5, p-CH3-C6H4

+ +2HX MeOH

31-97%

=

=

3940

41

N

N

NH2

NH2 NAc

O

ON

N NH

N

ONHAc

+EtOH, reflux

77%

4243 44

N

N

OR

MeX NH2

NH2

CO2Me

CO2Me

N

N

OR

MeX NH2

NCO2Me

CO2CH3

N

N NH

NO

R

MeX O

CH2CO2Me

+MeOH, rt

5 min

R = H , Me

X = O , S

45 4647 48



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].

N

NX

OR

1NH2

NH2

R 2

O

O

CN

CN

OEtEtO N

NX

OR

1

R 2NH2

O

OEt+EtOH

reflux

49 50 51

N

N

O

O

NH2

NH2

O

O

HN

N

O

O N

N R1

R2

R1

CH2Ph R2

R1

H R2

CH2Ph

N

N

NH2

NH2

NH2NH2

O

O

H N

N

NH2

NH2 N

NNH

NNH2 N

NO

NH

N

ONH2

NH2NH2

H

O

BrNH

N

O

NH2 N

NH

NH

N

O

NH2 N

N

+

= , = H (28%)

= , = (59%)

+ PH 9-10

60%

0.1 M NaOH

80%

+

52 53 54

55 53

56

57

5859

60 61



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

N

ONH2

NH2NH2

OH

OHR

NNH

Ph

OH

NH

N

O

NH2 N

N R

OH

OH

+

58 6263

N

N

O

O

NH2

NH2

R2

R1

NH

OEtEtO2C

NH

OMeNC

N

N

O

O N

N NH2

OHR

2

R1

N

N

O

OR

2

R1

N

N NH2

NH2

100%

5-63%

64

65

66

67

68



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].

NH

N

ONH2

NH2NH2

ClF2CCOR NH

N

O

NH2 NH

N R

FF

ClF2CO2Et

NH

N

O

NH2 NH

NH

FF

O

BrCH2COCF3

NH

N

O

NH2 N

N CF3

NH

NNH2 NH2

NHO

CF3

NH

N

O

ClNH2

NO2CF3OH

NHCH2Ph

NH

N

O

NH2

NO2

NOH

CF3PhCH2

MsCl NH

N

O

NH2

NO2

NOMs

CF3PhCH2

H2/Pd

NH

N

O

NH2 N

N CF3

CF3COCOCF3

NH

N

O

NH2 N

N CF3

CF3 ClCF2COCF3

F

NH

N

O

NH2 NH

N CF3

F

+

+

i-

ii- DDQ

58

69

70

71

7273

74

7576 77

78

79



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].

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].

NH

N

O

ClNH2

NO2 O

NH2

NH

N

O

NH

NH2

NO2

O

NH

N

O

NH

NH2

NH2

O

NH

N NH

NO

NH2

+

7580

8182

83

N

N

OBu

NH2NH2

NH2 H

O

O

OR

I2/HCO2H N

N

OBu

NH2 N

NOH

ORN

N

OBu

NH2 N

NOH

OH

AcO

O

HH

+MeOH

aqous KOH

R =

84 85 86 87



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].

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].

N

N NH2O

RO

NH2

CH=NNHPh

CHOHCHOHCHOHCHOHCH2OH

MeOH/H2O/HClN

NO

RO

NH

N

O

OHOH

H

H

N

NO

RO

N

NOH

OH

OH+

2-mercapto ethanol

reflux

O

88

89

90 91

NH

N

O

NH2PhCH2S

HNO2

Na2S2O4

NH

N

O

NH2PhCH2S

NH2

R1

R1

O

O

NH

N

O

PhCH2S N

N R1

R1

R1

R1 CH2Ph

EtOH, reflux

a = Me 85%

b = 15%

92 9394

N

N

OHNH2

NH2NH2

R

R

O

O

N

N N

NOH

NH2

R

R

+11

a, R = R = H

b, R = R = CH3

c, R = R = OH

d, R = R = Ph

1

1

1

1

95 96



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].

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].

Scheme 25

N

N

OHNH2

NH2NH2

Br CH(OEt)2

CHON

N

OH

NH2 N

NH

CH(OEt)2

N

N

OH

NH2 N

NH

CHO+

1-[O]

2- H

95 9798 99

N

N

OHNH2

NH2NH2

Br CH2Br

CHOCORNH2

N

N N

N

NH2

OHCH2Q R

+ +

R= OH, OEt, GluEt

95100 101 102

N

N

OH

NH2 Cl

PhN2ClN

N

OH

NH2 Cl

N=NPhNH2CH2COR

N

N

OH

NH2 NHCH2COR

N=NPh N

N N

N ROH

NH2

N

N N

N OHOH

NH2

N

N

X

NH2 Cl

NO2

N

N

X

NH2

NO2

NHCH2COR

N

N N

N RX

NH2

Zn, HOAc, [O] heatR= Me

Zn, HOAc, [O] heatR= OEt

103 104 105 106

107

108 109 110



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].

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].

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].

NH

NH

S

S

NH2

NH2

O

O

OMe

OMe

NH

NH

S

S

N

N

OMe

OMe

N

N

SMe

SMe

N

N

OMe

OMe

(Bu)4NF, THF

MeI+

111 112113 114

N

N

Cl

NH2NH2

N

N

R 4

NH2NH2

RN

N N

NR 4

NH2

N

N N

NR 4

NH2

O

N

N N

NR 4

NH2

Cl

N

N N

NR 4

NH2

R 6

NH2

-

+

ad e f

g

116: R = H

117: R = NO

118: R =

R = ethoxy or isopropoxy4

b

c

115 116 119120

121

122



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].

N

N

NH2

CONH2

N

N

N

N

OH

HCOOH

130 131

N

N

OHR

NH2NH2

NH

N N

N

OMe

OMe

O

NH2

OMeO

MeONOH

OMeO

MeOO

OMeO

MeO

e

d

c

126 : R = H

127 : R = NO

128 : R = NH2

a

b

126

123124

125

129



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].

N

N

NH2

CNH2

X

N

N

N

NH

O

CH(OEt)3

Ac2O

X = O , S

132 133

N

N CONH2

CONH2N

N

NH

NH

O

ON

N CONH2

NCO

KOBr

134 135 136

N

N

NH2

NC CHO

N

N

NH2

NC CH(OMe)2

N

N N

NNH2

NH2

CH(OMe)2

N

N N

NOH

NH2

CH(OMe)2

N

N N

NOH

NH2

CHO

137 138139

140

141



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].

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].

N

N

NH2

CHO

N

N

N

N

RN

N

NHCOR

CHO NH3

142143 144

NH2

NH2NHN

N

Cl

MeO2CNH

N N

NO

NH2

N

N N

NO

NH2

Me

+

149 150 151152

N

N

N=PPh3

CO2Me

N

N

NCNR

CO2Me

R NH2

N

N

N

NR

O

NHR

N

N

N

NR

O

OR

RNCO

benzene , RT R OH

1

1

1

1145 146

147

148



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].

Scheme 37

NH2

NH2NHN

N

MeNH Me

NCN

AcPh

N

N

Me

NAcPh

N

N

NH

MeNH2

+

149 153154

NH2

NH

OEt N

N

NH2

NCN

N N

NNH2

EtO

N

MeS SMe

CO2Et

N

N

NH2

MeO2CN

N N

NO

MeS

EtO2C

N

O

Me

N

N Br

NH

NC

Me

N

N N

NO

O

Me

Me

N

N

NH2

NCCl

N

N N

NNH2

NH2

NAr

Me

Cl n-C6H13

+

+

+

i- ArNHMe

ii- guanidine, 61-87%

Ar = ,

155156 157

158 159 160

161162 163

164165



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].

Scheme 38

N

N

N H 2

C O 2 M e

N

N

N H C X N H C H 2 C O O E t

C O 2 M eO O E tX C N

M e S S M e

N C O O E t

N

N

N

N

O

S M e

C O O E t

N

N

N

O

NN

O

N H 2

N H 2 N H 2 . H 2 O

N

N

NH

N

O

C O O E t

X

P O C l 3

N

N

N

N

O

C l

C O O E t N H 2 N H 2 . H 2 O

N

N

N

N

O

N R

C O O E t

N H - C 5 H 1 1

N

ON

M e I

N a O E t

a m in e s

a X = Sb X = O

a N R =

b N R =

c N R =

1 6 6

1 6 7

1 6 8

1 6 9

1 7 0

1 7 1

1 7 2



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).

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].

Scheme 40

N

N

NH2

CO2Me

(CH2)nN

NMeS

(CH2)n

N

N

N

N

N

O

N

N

Cl

N

N

N

O

N

N

N

N

SMe

N

N

N

O

N

N

(CH2)nN

SMeS

(CH2)n

S

N

N

N

N

O

159

173174

175

176

177178

179

180

178a; n=1178b; n=2

a; n=1b; n=2

N

N CN

CN

CH2OHCOOH

S2O8 , AgNO3

N

N

Me

CN

CN

HOH2CMnO2

PhNH2

N

N

Me

CN

CN

X

MeNH2

N

N

Me

CN

NHMe

PhNEt3SiH-CF3CO2H

N

N

Me

CN

NHMe

PhNHNH=C(NH2)2

N

N

Me

PhNH

N

N

NH

NH2

Me

+

2-

181 182 183 184

185186

187



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].

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].

Scheme 43

N

N NH2

O

NH2

O

O

O

OR

Ac2O

N

NNH

N

O

RO

N

N NH2

CN

RONH2

NH

N

NN

N

NH2

RO

+

+

EtOH

aq.NaOH

130 188

156189

190

191

N

N Br

N

NC NEt3, MeCN

Pd(dba)2,P(o-tolyl)3,CuI

Me H N

N

N

NCMe

N

NMe

N

N

O

O

MeNCO

hydrolysis

162 192193

N

N COOMe

NCSNH2 CH2OH

EtN

NH

N

NO

S

EtOH

N

N COOMe

NH

NH

EtS

CH2OH+

THF, rt, 24h+

194 195 196 197



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].

Scheme 44

Scheme 45

CH=NOH

CH=NOHO

NH2

CNEtOOC

N

N CH=NOH

NH2

EtOOC

O N

N CH=NOH

O

N

N

OH

NH2

Na2SO4

I2

N

NN

N

OH

NH2

CHO

+ +

-+

-

guan.

198 199200

201

202

NH2

CN

RO2CRO

NOH

N

N

O

RRO2C

NH2 N

N

O

RNH

N

O

NH2NH

N RNH

N

O

NH2

N

N RNH

N

O

NH2

NH2

CN

NCCH2Cl

NOH

OHC

N

N

ONH2

NC

CH2Cl N

N

OCH2Cl

N

N

NH2

NH2 N

N

CH2Cl

N

N

NH2

NH2

N

N

CH=CHPh

N

N

NH2

NH2

+ +

-+

-

++

-

+

-

203 204 205 206 207

208

209 210 211 212 213

214



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].

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].

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

N

O CH(OMe)2

HON=CHCOCH(OMe)2

NH2

CNNC

N

N CH(OMe)2

NH2

O

NC

N

N CH(OMe)2

NH2

NC

N

N CH(OMe)2N

N

NH2

NH2N

N CH(OMe)2N

N

OH

NH2

N

NN

N

OH

NH2

CHO

NOCl. TsOH

+

-

215 216 217

218219220

221

OO

OO

Cl

OO

OC2H5

O OO

H

N

OH

ON

NNH2

NC

O

ON

NNH2

NC

N

N N

N O

NH2

NH2

N

N N

NNH2

NH2

CO2H

+

-

222

223

224225

226

227

228229



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.

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Cl Cl

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CN

CNN

NCl

Cl

CN

CN

AR

NH2

NH

N

N

N

N

Cl

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230 231 232 233



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Synthesis of pteridines derivatives from different heterocyclic