HETEROCYCLES

Review | Regular issue | Vol. 81, No. 6, 2010, pp. 1393-1418
Received, 23rd February, 2010, Accepted, 5th April, 2010, Published online, 7th April, 2010.
DOI: 10.3987/REV-10-668

■ Synthesis and Chemistry of 4-Amino-1,2,4-triazin-5-ones

Magdy A. Ibrahim*

Department of Chemistry, Faculty of Education, Ain Shams University, El-Maqreezy St, Roxy, Heliopolis, Cairo 11711, Egypt

Abstract

This review summarizes research results concerning the synthesis and chemical reactivity of 4-amino-1,2,4-triazin-5-ones and their related compounds.

CONTENTS
1. INTRODUCTION
2. SYNTHETIC APPROACHES FOR 4-AMINO-1,2,4-TRIAZIN-5-ONES
2.1. Synthesis from thiocarbohydrazide
2.2. Synthesis from acid hydrazides
2.3. Synthesis from oxadiazole
2.4. Synthesis from N4-phenyl-1,2,4-triazine
2.5. Synthesis from N4-nitroso-1,2,4-triazine
3. REACTIONS OF 4-AMINO-1,2,4-TRIAZIN-5-ONES
3.1. Alkylation
3.2. Acetylation
3.3. Sulfonation
3.4. Silylation
3.5. Formylation
3.6. Oxidation
3.7. Reduction
3.8. Photolysis
3.9. Aza-Wittig reaction
3.10. Rearrangement
3.11. Nucleophilic displacement at position 3
3.12. Condensation reactions
3.13. Cycloaddition reactions
3.14. Electrochemical reactions
3.15. Formation of complexes
4. REFERENCES

1. INTRODUCTION
Various substituted 1,2,4-triazin-5-one derivatives have a great importance as biological agents in medicinal and agricultural fields.1-7 Recently, significant activities have been directed toward this class of compounds, in particular, 4-amino-1,2,4-triazin-5-one derivatives which have considerable interest because of their herbicidal,8,9 antimicrobial,10-12 anti-HIV,13 and anticancer activities.14,15 In view of the above observations, the intention of the present review is to cover research results concerning the synthesis and reactions of 4-amino-1,2,4-triazin-5-one derivatives which have not been reviewed hitherto.

2. SYNTHETIC APPROACHES FOR 4-AMINO-1,2,4-TRIAZIN-5-ONES
2.1. Synthesis from thiocarbohydrazide
4-Amino-3-thioxo-6-substituted-1,2,4-triazine derivatives 2 are commonly prepared by condensation of thiocarbohydrazide 1 with α-ketocarboxylic acids (Scheme 1).16–28

Reaction of thiocarbohydrazide hydrochloride with 2-(tert-butylimino)-3,3-dimethylbutanenitrile 3 in DMF produced 5-imino-4,5-dihydro-1,2,4-triazine 4 which was hydrolyzed in ethanol containing hydrochloric acid to give 3-mercapto-4-amino-6-tert-butyl-1,2,4-triazin-5-one 2 (Scheme 2).29

Condensation of 1 with 2-(1-methyl-2-chloro-2,3,3-trifluoro-cyclobut-1-yl)-2-oxoacetamide 5 in 1N HCl yielded 4-amino-6-(1-methyl-2-chloro-2,3,3-trifluoro-cyclobut-1-yl)-1,2,4-triazin-5(4H)-one 6 (Scheme 3).30

Also, direct condensation of 1 with oxazolone 7 gave 4-amino-3-thioxo-1,2,4-triazine derivative 2 (Scheme 4).9

Cyclocondensation of 1 with phenylglyoxal and diacetyl yielded 4-aminotriazinethiones 8 and 9, respectively (Scheme 5).31

Condensation of benzil with 1-(carbothioamide)thiocarbohydrazide 10, obtained from 1 and potassium isothiocyanate, afforded 5-hydroxy-5,6-diphenyl-1,2,4-triazin-3(2H)-thione 11 which on dehydration in acid medium gave 1,9-dihydro-8,9-diphenyl-1,2,4-triazolo[2,3-d][1,2,4]triazine-3,6-dithione 12 (Scheme 6).32-34

Treatment of 2-ethylbutanoyl chloride 13 with Me3SiCN afforded 3-ethyl-2-oxo-pentanenitrile 14 which on hydrolysis with HBr followed by addition of thiocarbohydrazide 1 afforded 4-amino-3-mercapto-6-(3-pentyl)-1,2,4-triazin-5(4H)-one 15 (Scheme 7).35

Similarly, Kranz et al.36,37 obtained 4-amino-1,2,4-triazin-5(4H)ones 17 by converting RCMe2CO2H into the corresponding acid chloride, then treating with Me3SiCN to give acyl cyanides, 3,3-dimethyl-2-oxo-4-phenylbutanenitrile derivaives 16, followed by cyclocondensation with thiocarbohydrazide 1 (Scheme 8). Condensation of 17 with Me2CHCHO afforded the corresponding hydrazones which are a better herbicides, with greater selectivity, than 6-(2-fluoro-1,1-dimethylethyl)-4-(2-methylpropylidene)amino-3-methylthio-1,2,4-triazin-5(4H)-one.

Thiocarbohydrazide 1 reacted with isatin 18 in glacial acetic acid to give 4-amino-2,4-dihydro-3H-[1,2,4]triazino[5,6-b]indole-3-thione 20 via the intermediate isatin α-thiocarbohydrazone 19 (Scheme 9).38

On the other hand, 6-alkyl(aryl)-4-amino-3-thioxo-1,2,4-triazin-5(2H,4H)-ones 21 were prepared by reaction of diethyl oxalate with Grignard reagents followed by treatment with 1 in refluxing EtOH containing HCl (Scheme 10).39

Treatment of α-bromoacetamide with hydrazine hydrate gave α-hydrazinoacetamide 22, which on refluxing with CS2 followed by addition of hydrazine hydrate yielded thiocarbohydrazide derivative 23. Cyclization of the latter compound in acid medium gave the thione derivative 24 (Scheme 11).40

2.2. Synthesis from acid hydrazides
Reaction of methyl 2-[2(2,2-dimethylpropanoyl)hydrazono]butanoate 25 with hydrazine hydrate in pyridine containing KOH gave 4-amino-1,2,4-triazin-5-one 27 via the hydrazide 26 (Scheme 12).41

Metamitron 30 was prepared by condensation of phenylglyoxate 28 with acetohyhrazide to give N-acetyl ester 29 followed by cyclocondensation with hydrazine hydrate in pyridine (Scheme 13).42

2.3. Synthesis from oxadiazole
Reaction of chloroacetone with trifluoromethyl-1,3,4-oxadiazol-2(3H)-one 31 in NaH/DMF gave the acetone derivative 32 which on treatment with hydrazine hydrate produced 2,3,4,5-tetrahydro-3-oxo-4-amino-6-(trifluoromethyl)-1,2,4-triazine 33 as insecticide (Scheme 14).43

2.4. Synthesis from N4-phenyl-1,2,4-triazine
Direct nitrosation of 6-phenyl-3-thioxo-2,3-dihydro-1,2,4-triazine-5(4H)-one with sodium nitrite in hydrochloric acid medium at 0 ºC gave 4-nitroso-6-phenyl-3-thioxo-2,3-dihydro-1,2,4-triazine-5(4H)-one 3745 Reaction of compound 37 with acetylacetone (like the Ehrlich-Sachs reaction of aromatic compound) in weakly alkaline medium resulted in formation of 4-(diacetylmethyleneamino)-6-phenyl-3-thioxo-2,3-dihydro-1,2,4-triazine-5(4H)-one 38.46 Hydrolysis of 38 in acid medium gave 4-amino-6-phenyl-3-thioxo-2,3-dihydro-1,2,4-triazine-5(4H)-one 39. Compound 39 was also obtained directly from reduction of 39 with zinc powder in acetic acid (Scheme 16).47

2.5. Synthesis from N4-nitroso-1,2,4-triazine
Direct nitrosation of 6-phenyl-3-thioxo-2,3-dihydro-1,2,4-triazine-5(4H)-one with sodium nitrite in hydrochloric acid medium at 0 ºC gave 4-nitroso-6-phenyl-3-thioxo-2,3-dihydro-1,2,4-triazine-5(4H)-one 37.45 Reaction of compound 37 with acetylacetone (like the Ehrlich-Sachs reaction of aromatic compound) in weakly alkaline medium resulted in formation of 4-(diacetylmethyleneamino)-6-phenyl-3-thioxo-2,3-dihydro-1,2,4-triazine-5(4H)-one 38.46 Hydrolysis of 38 in acid medium gave 4-amino-6-phenyl-3-thioxo-2,3-dihydro-1,2,4-triazine-5(4H)-one 39. Compound 39 was also obtained directly from reduction of 39 with zinc powder in acetic acid (Scheme 16).47

3. REACTIONS OF 4-AMINO-1,2,4-TRIAZIN-5-ONES
The chemical reactivity of 4-amino-1,2,4-triazin-5-one derivatives toward a variety of reagents are summarized below.

3.1. Alkylation
Alkylation of 4-amino-3-mercapto-1,2,4-triazin-5(4H)-ones 2 with a various alkylating agents produced the corresponding 3-alkylthio analog 40 as herbicides (Scheme 17).48-51 While alkylation of 2 in aqueous sodium hydroxide solution gave a mixture of 3-alkylthio derivatives 40 and N2-alkyl derivatives 41 (Scheme 18).52,53

Herbicidal and insecticidal N4-methylamino-3-alkylthio-6-substituted-1,2,4-triazin-5(4H)-ones 42 were obtained via methylation of the corresponding 4-amino-3-alkylthiotriazine 40 using Bu4N+Br- as a phase transfer catalysis (Scheme 19).54

On the other hand, alkylation of 4-amino/alkylideneamino-3-thioxo-1,2,4-triazine-5-ones 43 in ethanolic KOH gave the corresponding alkylthio analogous 44 as herbicides (Scheme 20).55

3.2. Acetylation
Acetylation of 4-amino-3-methylthio-6-phenyl-1,2,4-triazin-5-one 40 afforded the acetylated derivative 45 (Scheme 21).56

The diacetylamino derivative 46 was obtained when 4-amino-l,2,4-triazin-5-one 2 was treated with an excess of acetyl chloride in pyridine (Scheme 22).17

3.3. Sulfonation
6-t-Butyl-3-methylthio-4-sulfimido-1,2,4-triazin-5-ones 47 were obtained as herbicides from treatment of N4-aminotriazine 40 with sulfonyl chloride derivatives in DMSO at -8 ºC (Scheme 23).57

3.4. Silylation
Bis(trimethylsilyl)amino-1,2,4-triazin-5-one 48 was obtained when metamitron 30 was refluxed with Me3SiCN at 175 ºC. Compound 48 more effective preemergence herbicides than currently used herbicides (Scheme 24).58

3.5. Formylation
4-Formylamino-6-t-butyl-1,2,4-triazin-5-ones 50 were obtained as herbicides via treatment of the corresponding N4-aminotriazine 49 with a mixture of HCO2H/ Ac2O in dry ether as reported by Roy et al. (Scheme 25).59

3.6. Oxidation
Oxidation of 4-amino-3-methylthio-1,2,4-triazin-5-one 40 (R = H) with bromine in water yielded 4-amino-1,2,4-triazine-5,6-dione derivative 51 (Scheme 26).53 While the corresponding isomer, 4-aminotriazine-3,5-dione 52 was obtained by heating 40 in the presence of 2-mercaptoethanol60 or from oxidation on the surface of silica gel at 50-70 °C.61

3.7. Reduction
3-Methylthio-4-methylamino-1,6-dihydro-1,2,4-triazin-5-one 53 was obtained by the reduction of 2 and successive methylation using methyl iodide (Scheme 27).62

3.8. Photolysis
Photo-induced deamination reactions of 4-amino-3-methylthio-1,2,4-triazinones 40 by sunlight gave the deaminated product 54 (Scheme 28).63,64

3.9. Aza Wittig Reaction
Aza Wittig-type reaction of iminophosphorane 55, obtained from 2 and triphenylphosphine, with several types of iso(thio)cyanate leads to 1,3,4-thiadiazolo[2,3-c][1,2,4]triazines 56 which displayed mesoionic or zwitter ionic character (Scheme 29).65

3.10. Rearrangement
Rearrangement of 4-amino-3-[(cyanomethyl)thio]-6-methyl-1,2,4-triazin-5(4H)-one 57 in ethanol containing HCl gave ethyl 2-[(5-mercaptomethyl-1,2,4-triazol-3-yl)hydrazone]propionate 58. Thermal cyclization of 58 gave 59, while oxidation with peroxid in dioxane afforded the disulphide 60 (Scheme 30).66

3.11. Nucleophilic displacement at position 3
Nucleophilic displacement of an unsubstituted mercapto group in 4-aminotriazin-3-thiones 2 with ammonia,67 hydrazine hydrate68,69 and hydroxylamine hydrochloride70 afforded 3,4-diamino-1,2,4-triazine 61, 4-amino-3-hydrazino-1,2,4-triazine 62 and 4-amino-3-hydroxyamino-1,2,4-triazine 63, respectively. Also, condensation of 2 with thiocarbohydrazide 1 in 2:1 molar ratio in boiling DMF furnished the bis 1,2,4-triazinyl derivative 64 as anticancer agent. Treatment of 64 with carbon disulfide in ethanolic potassium hydroxide led to the direct formation of bistriazinotetrazine derivative 65 (Scheme 31).27

Methylthio groups in N4-aminotriazin-5-ones are readily displaced by a variety of nucleophiles. Treatment of 40 with dicarbodiimides,70,71 malonodinitrile,16 and carbon disulfide72,73 afforded fused systems 66-68, respectively. Cyclo-dimerization of 40 afforded bis[1,2,4]triazino[4,3-b:4',3'-e][1,2,4,5]tetrazine 69 (Scheme 32).16

Amination of 70 using methylamine and dimethylamine in isopropyl alcohol containing AcOH and small amount of toluene sulphonic acid gave 71 and 72, respectively (Scheme 33).48,74,75

Fusion of compound 2 with cyanamide and ethanolamine afforded [1,2,4]triazolino[5,1-c][1,2,4]triazin-4-one 73 and [1,2,4]triazino[4,3-b][1,2,4]triazin-4-one 74, respectively (Scheme 34).15

3.12. Condensation reactions
Condensation of 2,3,4,5-tetrahydro-4-amino-3-oxo-1,2,4-triazine 75 with pyridine-2-carboxaldehyde and pyridine-3-carboxyaldehyde-N-oxide in ethanol gave the corresponding hydrazones 76 and 77, respectively (Scheme 35).76,77

Condensation of 3-cyanoethylthiotriazinone 78 with aromatic aldehydes yielded the corresponding hydrazone 79 (Scheme 36).78

Condensation of 6-arylmethyl-4-aminotriazinones 2 with aromatic aldehydes in EtOH containing H2SO4 gave the corresponding hydrazones 80 which on treatment with Mannich bases afforded 2-aminomethyl-4-(arylidene)amino-1,2,4-triazin-5(4H)-ones 81 of high antifungal activity (Scheme 37).26

Also, condensation of 2 with 3-formylchromone 82a and its 2-amino analog 82b afforded the hydrazones 83a,b of high antifungal activity (Scheme 38).79,80

Condensation of 2 with aromatic aldehydes produced the hydrazone 84 which upon cycloaddition with mercaptoacetic acid yielded 3-thiazolidinyl-1,2,4-triazine derivative 85 as anticancer agents (Scheme 39).27

Condensation of 2 with cyclic oxygen compounds such as 3,1-benzoxazin-4-one 86, pyridine-2,3-dicarboxylic anhydride 87, and oxazolinone 88 in dry pyridine furnished 1,2,4-triazine derivatives connected with quinazolinone 89, pyridine-2,3-dicarboximide 90 and imidazolinone 91 moieties (Scheme 40).27,81

Acylation and aroylation of 2 using acid chlorides in DMF yielded N4-acyl/aroylamino-3-mercapto-6-substituted-1,2,4-triazin-5-one 92 which upon cyclization using conc. H2SO4 gave 3-substituted-7-methyl/furyl-3-yl-[1,2,4]triazino[3,4-b][1,3,4]thiaziazol-4-one 93.81 Also, a facile route to synthesis some fused 1,2,4-triazino[3,4-b]thiadiazolone 94-96 was achieved from the condensation of 2 with CS2, aromatic aldehydes and aromatic carboxylic acid, respectively.7,82-86 On the other hand, condensation of 2 with oxalic acid in POCl3 gave bis[1,2,4]triazino[3,4-b][1,3,4]thiadiazol-4-one 97 of high anti-tumor activity (Scheme 41).82

Some novel N,N`-bis(1,2,4-triazin-4-yl)dicarboxylic acid amides 98 were obtained by heating 2 with different carboxylic acids (oxalic, malonic, fumaric, maleic, succinic, phthalic) in POCl3 (Scheme 42).81

Condensation of 3,4-diamino-1,2,4-triazin-5-ones 61 with acetone in the presence of weak organic acid gave 1,2,3,7-tetrahydro[1,2,4]triazlo[3,2-c][1,2,4]triazin-7-ones 99 (Scheme 43 ).87

On the other hand, some [1,2,4]triazino[3,4-b][1,3,4]thiadiazinone derivatives 100-105 were prepared from the reaction of compound 2 with chloroacetaldehyde-dimethylacetal, phenacyl bromide, 2-bromo-propionylbromide, glyoxalic acid, oxalyl chloride, and dimedone, respectively (Scheme 44).82,88

Thiazolo[4,5-d]pyridazino[2,3-c]-2H-triazine 107 was yielded from heating 5-acetylthiazole 106 in acid medium (Scheme 45).89

7-(2-Oxo-2H-1-benzopyran-3-yl)-3-methyl-4H,8H-[1,2,4]triazino[3,4-b][1,3,4]thiadiazin-4-ones 109 were prepared from condensation of 2 with 3-(ω-bromoacetyl)coumarins 108 (Scheme 46).90

Fusion of 2 with 2-(4-bromophenoxy)acetic acid hydrazide 110 gave N1-[4-amino-6-(tert-butyl)-5-oxo-4,5-dihydro-1,2,4-triazin-3-yl]-N2-[2-(4-bromophenoxy)acetyl]hydrazine 111. While, fusion with hydrazide 112 gave 8-amino-6-(tert-butyl)-3-(4-substituted)-7,8-dihydro[1,2,4]triazolo[4,3-b][1,2,4]triazin-7-one 113 (Scheme 47).91

1,2,4-Triazino[3,4:2,3][1,2,4]thiadiazino[5,6-c]cinnolin-9-one 115 was prepared by cyclocondensation of the 2 with 3,4-dichlorocinnoline 114 (Scheme 48).92

Cyclocondensation of 4-amino-3-methylthiotriazine 40 with anthranilic acid yielded 1,2,4-triazino[3,2-b]quinazolines 116a (R1=NH2). Heating N-benzylidene derivative of 40 (R1 = NCH-Ar) with anthranilic acid afforded the deaminated product 116 (R1 = H) with extrusion of PhCN as reported by Badwy et al. (Scheme 49).93

Also, thieno[2,3-e][1,2,4]triazines 117 were prepared by the action of phosphorus pentasulphide on 4-amino-6-styryl-triazin-5-ones 40 with concomitant deamination of the N4-amino group as published by Eid and coworkers (Scheme 50).94

Condensation of 2 with phenylphosphonic dichloride, acetyltriphenylphosphonium chloride and phenacyltriphenylphosphonium bromide afforded 6-methyl-2-oxido-2-phenyl-1,2-dihydro-7H-[1,3,4,2]thiadiazaphospholo[5,4-c][1,2,4]triazin-5-one 118, [1,2,4]triazino[4,3-e][1,4,5,2]-
thiadiazaphosphinine 119 and [1,2,4]triazino[4,3-f][1,5,6,2]thiadiazaphosphepine 120, respectively (Scheme 51).95

Kabachnik-Fields reaction96 using 3,4-diamino-6-methyl-1,2,4-triazin-5(4H)-one 61, acetaldehyde and diethyl phosphonate gave [1,2,4]triazino[4,3-b][1,2,4,5]triazaphosphinine derivative 121 (Scheme 52).95

On the other hand, condensation of 62 with acetaldehyde/phenylphosphonic dichloride and acetaldehyde/diethyl phosphonate afforded [1,2,4,3]triazaphospholo[5,1-c][1,2,4]triazine 122 and [1,2,4]triazino[3,2-c][1,2,4,5]triazaphosphinine 123, respectively (Scheme 53).95

Novel six and seven-membered phosphorus heterocycles, namely 2,7-dimethyl-2-oxido-1,2,3,4-tetrahydro-8H-[1,2,4]triazino[4,3-e][1,2,4,5,3]tetrazaphosphinin-8-one 124 and 4,8-dimethyl-3,3,3-triphenyl-2,3-dihydro[1,2,4]triazino[4,3-e][1,2,5,6,3]tetrazaphosphepin-7(1H)-one 125 were obtained by cyclocondensation of 62 with bis(dimethylamino)methylphosphonate and acetyltriphenylphosphonium chloride, respectively (Scheme 54).95

3.13. Cycloaddition reactions
2-Alkylthio-6-substituted-5-oxo-5H-1,3,4-thiadiazolo[2,3-c][1,2,4]triazines 126 were obtained by cycloaddition of 2 to RSCN catalyzed by polyphosphoric acid (Scheme 55).97

3.14. Electrochemical reactions
Electrochemical oxidation of catechols 127a-c in the presence of 4-amino-6-methyl-1,2,4-triazine-3-thione 2 as a nucleophile afforded [1,2,4]triazino[3,4-b][1,3,4]thiadiazines 128a,b and 129 (Scheme 56).98

3.15. Formation of complexes
Reaction of 4-amino-6-methyl-5-oxo-1,2,4-triazine-3-thione (AMTTO, 2) with palladium(II) chloride in THF produced palladium complex [(AMTTO)PdCl2]3.4.5THF in excellent yield. Treating 2 with palladium(II) chloride in methanol and palladium(II) bromide in THF gave the complexes [(AMTTO)PdCl2].MeOH and [(AMTTO)PdBr2]2.3.5THF, respectively.99

4-Amino-l,2,4-triazin-5-ones are biochemically highly active substances and their use as herbicides has been suggested, for example 4-amino-6-t-butyl-3-methylthio-l,2,4-triazin-5-one (Metribuzin, 40) and 4-amino-3-methyl-6-phenyl-1,2,4-triazin-5-one (Goltix, 30).100 This type of compounds can also be used for the determination of metal ions because of their ability to form complex compounds,101 but no transition metal complex of these ligands has been isolated in the solid state. On the other hand, cobalt(II) and nickel(II) complexes of 4-amino-6-methyl-5-oxo-3-phenylamino-l,2,4-triazine (ATAZ, 127) afforded MX2(ATAZ)2.2H2O complexes (M = Co or Ni: X = C1, Br, I or NCS).17,102,103

A few (1:1) and (1:2) metal complexes of cobalt(II), nickel(II), copper(II) and zinc(II) have been isolated with the ligand derived from the condensation of 4-amino-3-mercapto-6-methyl-5-oxo-1,2,4-triazine 2 with 2-acetylpyridine,10 (Figures 1 and 2). Due to insolubility in water and most of the common organic solvents and infusibility at higher temperatures, all the complexes are thought to be polymeric in nature. A square-planar geometry was suggested for copper(II) and octahedral for cobalt(II), nickel(II) and zinc(II) complexes. The metal complexes have higher antimicrobial effect than the free ligand.

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