3-Hydrazino triazine, reaction with

Condensation of hydrazino derivative 716 with formic acid gave triazolo[4,3-6]- and [3,4-c][l,2,4]triazines 718 and 719. The reaction proceeded through N-2 acylation of the hydrazino group to give intermediate... 

The parent heterocycle of pyrido[2,3-e][l,2,4]triazine and its phenyl derivative 39 were prepared (89JHC475) by cyclization with polyphos-phoric acid of 3-acyIhydrazino-2-aminopyridines 36, obtained by reduction of the corresponding 3-acylhydrazino-2-nitropyridines 35. Compounds 35 were obtained from 3-fluoro-2-nitropyridine 34 either by reaction with benzoylhydrazine or by reaction with hydrazine and subsequent for-mylation of the initially formed 3-hydrazino-2-nitropyridine 38. Attempts to prepare 38 from 3-chloro-2-nitropyridine gave 2-hydrazino-3-chloropyridine 37. These results could be explained by semiempirical calculations (CNDO and MNDO calculations). 

The synthesis of the triazinotriazines 519 was achieved (87MI5) by reaction of 3-hydrazino-5,6-diphenyl[l,2,4]triazine 518 with 4-substituted phenacyl halides. These triazinotriazines were screened against P-388 lymphocytic leukemia in mice and were inactive. 

Arylidenepyruvic acids 522 on reaction with 3-hydrazino[l,2,4]triazine derivative 521 gave the triazinotriazine 523 (90MI2). The thioxo analogue 524 was obtained by the action of Lawesson s reagent on 523. 

This ring system is represented by tricyclic ring system 533 (76JHC1249). Reaction of 3-hydrazino[l,2,4]triazin-5-ones 531 with 3-imi-nobutyronitrile afforded 6-methyl- (or phenyl-) 3-[3-methyl-5-aminopyra-zolyl]-2,5-dihydro[l,2,4]triazin-5-ones 532A, which may exist in tautomeric form 532B. Its reaction with diethoxymethyl acetate (DEMA) or ortho-esters afforded the tricyclic compounds 533. 

The [(thioacyl)hydrazino]triazines 554 were synthesized from 6-amino-5-hydrazino[l,2,4]triazines 552 by reaction with 553. Cyclization of 554 with an aqueous mineral acid gave (88S778) the triazinothiadiazine 555. 

Cyclocondensation of 754 with phenacyl bromide gave (86JHC721) 3-phenyl-7,7,11 -trimethyl-8//-benzopyrano[4,3-e]imidazo[ 1,2-b] [1,2,4]-triazine 755. Cyclization of the 3-hydrazino derivative 756, with formic acid gave 757. Compounds 754 and 756 were prepared by reaction of the triazinobenzopyrane 753 with phosphorus oxychloride, followed by amination or hydrazinolysis (86JHC721). 

Thus, 5-aryl-3-hydrazino[l,2,4]triazine 200 was reacted with acid chlorides to yield 201 <2004AF42>, and reaction of 5,6-diphenyl-3-hydrazino[l,2,4]triazine 202 with carbon disulfide yielded a 3-mercapto product 203 <2000PJS214>. 

Other cyclizations to give tetrazolo[l,5-7][l,2,4]triazines published in recent years basically follow the established procedures discussed earlier in CHEC-II(1996) < 1996CHEC-II(8)499> and belong to two categories (1) reaction of 1,5-diaminotetrazole 42 with ct-dioxo reagents, and (2) reaction of a 3-hydrazino[l,2,4]triazine derivative with nitrous acid. 

Nucleophilic substitution of the 4-chloro group of the 4-pyranotriazines 103 with hydrazine gives the 4-hydrazino-triazines 104, which can be further elaborated to the corresponding azides 105 or cyclized upon reaction with formic acid or carbon disulfide to give the triazolotriazines 106 or thioxotriazolotriazines 107, respectively (Scheme 11) <2005HC0495>. 

It was reported that 7-chloro-3-phenyl-4H-pyridazino[6,1 -c ]-1,2,4-triazine underwent reaction with hydrazine to give the unexpected product (146) (69AC(R)552). However, it was later established that the assigned structure for this reaction product was incorrect, and the correct hydrazino structure (147) for this product was confirmed by an independent synthesis (70S180). 

This reaction course is common for all the 1,2,4-triazine substrates containing the same leaving groups at C-3 and C-5. Mono- or disubstitution reactions with amines and hydrazines yield 5-amino- (hydrazino)... 

Tetra(chIoro)hydrazo-l,3,5-triaziiie (prepared from cyanuric triazide [151]) is the starting material for both compounds. Its reaction with excess of hydrazine hydrate in acetonitrile forms 4,4, 6,6 -tetra(hydrazino)hydrazo-l,3,5-tri-azine which undergoes diazotization to TAHT. TAAT forms by oxidation of TAHT by chlorine in a water/chloroform suspension [147,148,150]. Simplified method of preparation of the key intermediate TAHT was pubhshed by Li et al. [152]. Instead of hydrazinolysis and diazotation they used nucleophilic substitution of 4,4, 6,6 -tetra(chloro)hydrazo-l,3,5-triazine with sodium azide for preparation of TAHT which they in the last step oxidized with A-bromosuccinimide. 

Direct bromination readily yields the 6-bromo derivative (111), just as with uracil. Analogous chlorination and iodination requires the presence of alkalies and even then proceeds in low yield. The 6-chloro derivative (113) was also obtained by partial hydrolysis of the postulated 3,5,6-trichloro-l,2,4-triazine (e.g.. Section II,B,6). The 6-bromo derivative (5-bromo-6-azauracil) served as the starting substance for several other derivatives. It was converted to the amino derivative (114) by ammonium acetate which, by means of sodium nitrite in hydrochloric acid, yielded a mixture of 6-chloro and 6-hydroxy derivatives. A modified Schiemann reaction was not suitable for preparing the 6-fluoro derivative. The 6-hydroxy derivative (115) (an isomer of cyanuric acid and the most acidic substance of this group, pKa — 2.95) was more conveniently prepared by alkaline hydrolysis of the 6-amino derivative. Further the bromo derivative was reacted with ethanolamine to prepare the 6-(2-hydroxyethyl) derivative however, this could not be converted to the corresponding 2-chloroethyl derivative. Similarly, the dimethylamino, morpholino, and hydrazino derivatives were prepared from the 6-bromo com-pound. ... 

Reactions of 3-hydrazino-l,2,4-triazine 1-oxide 31 or 3-hydrazinopyrido [2,3-c]-l,2,4-triazine 1-oxide 32 with diethoxymethyl acetate or triethyl orthoformate proceed as cyclization reactions at the N(4) atom and the amino group to form the corresponding pyrazolo[3,4-c]-l,2,4-triazine 6-oxides 33 and 34 (74MI, 80JOC5421, 80MI). 

The methoxy group is replaced in the reaction of 3-methoxy-5-phenyl-1,2,4-triazine 1-oxide 46 with ammonia, resulting in 3-amino-5-phenyl-1,2,4-triazine 1-oxide 47. The treatment of 3-methoxy-1,2,4-triazine 1-oxide 20 with hydrazine leads to 3-hydrazino-1,2,4-triazine 1-oxide 48 (71JOC787). 

Furo[2, 3 4,5]pyrrolo[l,2-d][l,2,4]triazolo[3,4-/][l,2,4]triazines 667 were prepared by reaction of 664 with phosphorus pentasulfide to give 665 followed by conversion to the hydrazino derivative 666 and subsequent cyclization with ortho-esters (84CCC65, 84M13). Similarly, the indolo analogue 670 was prepared from 668 by sulfurization and hydrazinolysis to give 669, which cyclized with ortho-esters (84CCC1529). 

Amino groups react very easily with aldehydes or ketones, and with aldehydes in the presence of amines, they can be acylated by the usual acylating agents, and they react with amidacetals, Vilsmeier reagents and nitroso compounds (Scheme 12). As mentioned earlier, alkylation leads mainly to AT(2)-alkylated products. The hydrazino group reacts in the same way as the amino group with aldehydes or ketones, with acyl chlorides or carboxylic anhydrides, with sulfonyl chlorides, ortho esters, carbon disulfide and with nitrous acid. The last three reactions have mainly been used for the synthesis of condensed 1,2,4-triazines. 

Reaction of 4-aryl-3-methylthio-l,2,4-triazin-5-ones (342) with hydrazine led to 4-amino-3-arylamino-l,2,4-triazin-5-ones (343) instead of the expected 4-aryl-3-hydrazino derivatives (344). This is explained by nucleophilic attack of the hydrazine at the 5-position, ring opening and subsequent reclosure. The same result was obtained when 4-aryl-3-thioxo-... 

Reaction of diaminoguanidine (478) with 1,2-dicarbonyl compounds (452) was used for the synthesis of 3-hydrazino-l,2,4-triazines (479) (78HC(33)189, p. 396). 

One of the classical methods for the generation of imidoyl azides as precursors to mono- and disubstituted tetrazoles is based on reactions of amidrazoles with sodium nitrite. This procedure developed by Kaufmann et al. in the middle of thel960s <2004SOS(13)861> has found an extension and advancement in recent studies. By this method, 5-hydrazino-3-methyl-l-phenyl-l//-pyrazolo[4,3-< ][l,2,4]triazine 503 through a cyclic imidoyl azide 504 was converted into 5-phcnyl-l //-pyra/olo[4,3-<,]tetrazolo[4,5- tria/inc 505 (Scheme 64) <2005JCX151>. 

Condensed 1,2,4-triazines can be obtained by the cyclization of hydrazones (e.g., 467) with nitronium or nitrosonium cations as exemplified by Scheme 244 <1999M819, CHEC-III(9.02.7.3.2)174>. Similar pyrimidotriazines (e.g., 469) can be made by the reaction of 2,4-diamino-6-hydrazino-5-nitrosopyrimidine 468 with l,l-diethoxy-2-chloroethane (Scheme 245) <2003BML2895>. 

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