Sodium amidines

Another approach uses the reaction of 6-chloro-5-nitropyrimidines with a-phenyl-substituted amidines followed by base-catalyzed cyclization to pteridine 5-oxides, which can be reduced further by sodium dithionite to the heteroaromatic analogues (equation 97) (79JOC1700). Acylation of 6-amino-5-nitropyrimidines with cyanoacetyl chloride yields 6-(2-cyanoacetamino)-5-nitropyrimidines (276), which can be cyclized by base to 5-hydroxypteridine-6,7-diones (27S) or 6-cyano-7-oxo-7,8-dihydropteridine 5-oxides (277), precursors of pteridine-6,7-diones (278 equation 98) (75CC819). 

Treatment of the l,5-diamino-l,2,4-triazolo[l,5-c]quinazolinium bromide 131 with sodium hydroxide gave the amidine 134 as a result of Nl-C8a bond cleavage without fragmentation [79JCS(P2)1708] (Scheme 51). 

Intermediate arylamidine, 6S, is prepared by the aluminum chloride-catalyzed addition of aniline to the nitrile function of 4-cyanothiazole (67), Amidine, 65, is then converted to its N-chloro analog (69) by means of sodium hypochlorite. On base treatment, this apparently undergoes a nitrene insertion reaction to produce thiabendazole (70), ... 

Neither the oxide nor the amidine function are in fact required for activity. Treatment of the oxime, 7, with chloro-acetyl chloride in the presence of sodium hydroxide proceeds directly to the benzodiazepine ring system (14)(the hydroxyl ion presumably fulfills a role analogous to methylamine in the above rearrangement). Reduction of the N-oxide function of 14 leads to diazepam (15). ... 

The synthesis of pyrido[2,3-d]pyrimidin-7(8H)-ones has also been achieved by a microwave-assisted MCR [87-89] that is based on the Victory reaction of 6-oxotetrahydropyridine-3-carbonitrile 57, obtained by reaction of an Q ,/3-unsaturated ester 56 and malonitrile 47 (Z = CN). The one-pot cyclo condensation of 56, amidines 58 and methylene active nitriles 47, either malonitrile or ethyl cyanoacetate, at 100 °C for benzamidine or 140 °C for reactions with guanidine, in methanol in the presence of a catalytic amount of sodium methoxide gave 4-oxo-60 or 4-aminopyridopyrimidines 59, respectively, in only 10 min in a single-mode microwave reactor [87,88]... 

N-Trimethylsilylamides or lactams 344 react with sodium trimethylsilanolate 96 to generate the anhydrous N-sodium salts 345 and hexamethyldisiloxane 7 in practically quantitative yield [125]. Likewise, silylated succinimide 201 is converted by sodium trimethylsilanolate 96 into hexamethyldisiloxane 7 and the anhydrous sodium salt 346, which reacts with aldehydes RCHO (R=C2H5, n-C Hy), in the presence of catalytic amounts of 96 to give, via 346, the silylated adducts 347 in 43-62% yield [125]. The imide chloride 348 gives, analogously, sodium chloride and 7 and the N-sodium salt 349, which condenses in situ with unreacted imide chloride 348 to give 91% of the amidine 350 [126] (Scheme 4.46). 

Because free or esterified imidazole(4,5)-acetates 745 are currently accessible only via a rather tedious multistep synthesis via (4,5)hydroxymethylimidazole [224— 226], it seemed obvious to react amidines such as isobutyraminidine-HCl 742 with commercially available methyl or ethyl 4-chloroacetoacetates 743a, b to obtain 745 directly in one step. Because of the low reactivity of the 4-chlorine in 743, however, reaction of 743, e.g. with isobutyramidine-HCl 742 in the presence of sodium methylate in methanol, affords exclusively 2-isopropyl-6-chloromethyl-pyri-midin-4-one 744 [227], whereas treatment of 743b with NaOEt in EtOH gives, in the absence of amidines, 2,5-bis(ethoxycarbonyl)cyclohexane-l,4-dione in nearly quantitative yield [228, 229]. 

Tetranudear gold(I) amidinate complexes are synthesized by the reaction of Au(THT)Cl with the potassium or sodium salt of the amidinate ligand in THF, Figure 1.4. Syntheses involving various substituted amidinates resulted in tetra-nuclear gold(I) clusters, [Au4(ArNC(H)NAr)4]. The C-functionalized substituted amidine ligands, ArNC(Ph)NHAr and ArNC(Me)NHAr, Ar=-QH5, were synthesized and reacted with Au(THT)Cl after deprotonation. Only tetranudear clusters were isolated. 

The amidine bond formed is quite stable at acid pH however, it is susceptible to hydrolysis and cleavage at high pH. A typical reaction condition for using imidate crosslinkers is a buffer system consisting of 0.2 M triethanolamine in 0.1 M sodium borate, pH 8.2. After conjugating two proteins with a bifunctional imidoester crosslinker, excess imidoester functional groups may be blocked with ethanolamine. 

Sodium methylate, potassium acetate, and piperidine were also applied as catalysts in the reactions of amidines and dialkyl malonates (53USP2638480). 

The ring closure of the amidine derivative (1328) in refluxing ethanol in the presence of sodium ethylate afforded pyrimidin-4(3//)-one (1329) (59BCJ188). 

The direct nitration of imidazole with acidic reagents is difficult due to facile nitrogen protonation (pA aH 7). Nitration of imidazoles proceeds in the 4- and 5-positions with the amidine 2-position being quite inert. Imidazole can be directly nitrated to 4,5-dinitroimidazole but no further. 2,4,5-Trinitroimidazole (TNI) can be prepared from the successive nitration of 2-nitroimidazole the latter synthesized from the diazotization of 2-aminoimidazole in the presence of excess sodium nitrite and a copper salt. The nitrative cleavage of polyiodoimidazoles also provides a route to polynitroimidazoles. " ... 

There is one report of reductive cleavage of the imidazole ring. Treatment of 122 with sodium dithionate in aqueous ammonia yielded amidine 123, which on hydrolysis with acid gave 124. Compound 124 was obtained directly on reduction with sodium dithionate in aqueous ethanolic sodium bicarbonate (83JHC1003). 

Hydroxythiazolo[3,2-fi][l,2,4]triazoles (176, R = OH) are also available by this route. Treating 167 with methyl chloroformate (sodium hydroxide) and subsequently with sodium methoxide yields 176 (R = OH) (71GEP1942015 72GEP2032173, 72USP3682943). Thiazolo[3,2-fi][l,2,4] triazoles are also available from 2-aminothiazoles via amidines 178. Lead tetra-acetate dehydrogenation of 178 leads to 179 (94MI1). 

Tertiary benzylic nitriles are useful synthetic intermediates, and have been used for the preparation of amidines, lactones, primary amines, pyridines, aldehydes, carboxylic acids, and esters. The general synthetic pathway to this class of compounds relies on the displacement of an activated benzylic alcohol or benzylic halide with a cyanide source followed by double alkylation under basic conditions. For instance, 2-(2-methoxyphenyl)-2-methylpropionitrile has been prepared by methylation of (2-methoxyphenyl)acetonitrile using sodium amide and iodomethane. In the course of the preparation of a drug candidate, the submitters discovered that the nucleophilic aromatic substitution of aryl fluorides with the anion of a secondary nitrile is an effective method for the preparation of these compounds. The reaction was studied using isobutyronitrile and 2-fluoroanisole. The submitters first showed that KHMDS was the superior base for the process when carried out in either THF or toluene (Table I). For example, they found that the preparation of 2-(2-methoxyphenyl)-2-methylpropionitrile could be accomplished h... 

Reaction of the 5-substituted aminothiadiazole (88 R = Bu ) with aryl nitriles produced amidines (89) in yields dependent on the reactivity of the nitriles (Scheme 14). Decreasing the electron density of the cyano group by such electron-withdrawing groups as p-nitrophenyl-, and 2- and 4-cyanopyridyl, led to higher yields as compared to unsubstituted benzonitrile. A bis thiadiazole (92 R = Bu ) was prepared by reacting the sodium salt of (88) with 2-methanesulfonyl-5-(-butyl-1,3,4-thiadiazole (91) <84JHC1377>. 

Preparation of the prototype drug departs from the phenylenediamine strategy used in all of the previous examples. Condensation of thiazolo nitrile (53-2) with aniline catalyzed by aluminum chloride affords the amidine addition product (53-3). This is then converted to its reactive A -chloro derivative (53-4) by reaction with sodium hypochlorite. Treatment of that intermediate with a base such as potassium hydroxide leads directly to the cyclization product and thus the benzimidazole thiabendazole (53-6) [56]. The reaction can be rationalized by invoking as the first step the abstraction of chloride to leave behind a nitrene species such as (53-5) this would then readily insert in the CH bond at the ortho position. 

The amino and bromo substituents in the 3//-azepine (111 X = Br) are susceptible to nucleophilic displacement and are hydrolyzed surprisingly easily by aqueous methanol or DMF to the azepine-2,7-dione. Sodium thiocyanate in DMF yields the aminothiocyanate (111 R = SCN) (67JOC2367). It has been noted that amidine formation with the lactim thioether (112) is much slower than with isomer (113) (77JHC933). 

The synthesis of a C-labelled version of naratriptan (3b) is highlighted in Scheme The indole ring of naratriptan hydrochloride (3) was oxidatively cleaved using sodium periodate to give ketoformanilide 45. Cyanation of 45 with potassium [ C]cyanide in aqueous ethanol gave the intermediate amidine 46, which was reduced directly with NaBH4 in acetic acid to afford C-labelled naratriptan (3b), which was isolated as the hydrochloride salt. 

Section 3.09.5). Similar methoxyimines give only the derived amidines with ammonia, but these are efficiently ring closed with sodium methoxide (65JA1995). 

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