Methanol amidines

Complete reduction of the azepine ring to hexahydroazepine has been effected with hydrogen and palladium,40 or platinum,135 239 catalysts. For example, ethyl 1 f/-azepine-l-carboxylate is reduced quantitatively at room temperature to ethyl hexahydroazepine-l-carboxylate (92% bp 118 —120 3C).134 136 TV-Phenyl-S/Z-azepin -amine (1), however, with platinum(IV) oxide and hydrogen in methanol yields the hexahydroazepine 2 in which the amidine unit is preserved in the final product.34 The same result is obtained using 5% palladium/barium carbonate, or 2 % palladium/Raney nickel, as catalyst. 

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]... 

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]. 

A,A-Dialkylformamide acetals (7) react with primary amines to give the corresponding amidines (8). Kinetics of the reaction of a range of such acetals with ring-substituted anilines—previously measured in neutral solvents such as methanol or benzene —have been extended to pyridine solution. In pyridine, the reactions are irreversible, with first-order kinetics in each reactant, and mechanistically different from those in non-basic solvents. Two mechanisms are proposed to explain Hammett plots for a range of anilines, in which the p value switches from negative to positive at a cr value of ca 0.5. The pyridine solvent substantially enhances the rate in the case of very weakly basic anilines. 

Keimg et al. describes the optimization of 2-imino-piperazines using Lewis acids to catalyze the multicomponent a-amino amidine synthesis to make piperazines 39 (Scheme 6) [26]. A, Af -(jimethylethylenediamine 36 was used with an aldehyde 37 and isocyanide 38 in methanol with scandium (III) trifluoromethane sulfonate (Sc(OTf)3) as a catalyst to obtain the piperazine 39 in 57% yield. 

In accordance with expectations, the isolable trifluoromethyl substituted ketene imines (186-188) were found to react readily with nucleophilic agents. In the case of 186, the reaction with methanol and aniline led to lactim ether 187a and amidine 187b, respectively (137). 

Wird als a-Dicarbonyl-Verbindung Glyoxylsaure und statt des Amidins N-Methyl-hamstoff eingesetzt, so erhalt man bei Durchfuhrung der Reaktion in Methanol als Losungsmittel 2,5-Dihydroxy-4-methoxy- 1-methyl-imidu.zol134, das in der tautomeren 2,4-Dioxo-Form vorliegt. 

Die Edukte werden zuerst bei 20° in Ethanol oder Methanol geriihrt, der Alkohol anschlie-Bend entfernt und das so erhaltene rohe Amidin durch Erhitzen mit konz. Salzsaure182 oder 4-Methyl-benzolsulfonsaure183 cyclisiert z. B. ... 

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). 

Treatment of 18 with ethylenediamine afforded the desired triazolo piperazine 3 at room temperature albeit in low yields. Attempts to improve the reaction revealed that when the oxadiazole was added to two equivalents of ethylenediamine in methanol at 0 °C, a new species crystallized directly from the reaction mixture. This solid was isolated, identified as the amidine 20, and was found to convert to 3 by refiuxing in methanol for 4h (Scheme 5.11). The formation of amidine 20 was curious since it suggested that initial attack of ethylenediamine did not occur at the carbon of the oxadiazole vicinal to the trifluoromethyl group. Of the three carbons of the oxadiazole which need to react with ethylenediamine, this would easily be rationalized as the most electrophilic. In order to understand the mecha-... 

Isolated amidine 20 could be converted to 3 thermally or by acid or base catalysis. Since 3 was best isolated as its HCl salt, the reaction was run by addihon of 1 equivalent of concentrated HCl to a slurry of amidine 20 at reflux in methanol. Under optimized conditions, triazole 3 was isolated by filhation of the reachon slurry at 0°C in 92% yield [14],... 

The halonitro compounds and the methanol used were of purum or pract. quality from Fluka. The amidine derivatives (in the form of their salts) were purchased from Fluka or Aldrich (purum or pract.). The N,N-dialkyl-formamidine acetates were prepared by analogy to a published procedure (ref. 8) from cyanamide and used as isolated (containing ca. 10% ammonium acetate). 

Metal chelates with different sized metallocycles and coordination units MN4 have been created (Sec. 2.2.4.2) on the basis of amidines 214, triazenes 215, dioximes 216, azomethines 217-222, (5-aminovinylimines 223, o-aminoazocompounds 224, hydrazoneimines 225, and formazanes 226, 228, 229. In the majority of cases, the syntheses of these complexes have been carried out by interaction of the ligands above and metal salts (mostly metal acetates) in alcohol medium (methanol,... 

Rapid access to an array of fused 3-aminoimidazoles was conveniently achieved by a Sc(OTf)3 catalyzed three-component cyclocondensation of heterocyclic amidines (such as 2-aminopyridine) and aldehydes with isocyanides (Ugi MCR) [52] or, alternatively, with trimethylsilylcyanide (TMS-CN) [53]. AT-Unsubstituted 3-aminoimidazo[ l,2-a]pyridincs 28 were formed in the latter case (Scheme 19). Microwave dielectric heating of the methanolic... 

Abb. 7.14. Imidic acid ester hydrochlorides (F)—to be prepared from nitriles, hydrogen chloride (gas) and methanol acc. to Fig. 7.13—, their trans-formability into orthoester (A) or amidine (I) and the corresponding reaction mechanisms. 

Methyl /3-hydroxypropionimidates (12) (prepared from ethylene cyanohydrin, methanol, and HO) condense with aminoacetaldehyde dimethylacetal (13) to yield an amidine hydrochloride (14) which undergoes ring closure to an imidazole.87 Applications of this reaction have been used in the synthesis of 2-phenylimidazole and its 4-alkyl derivatives,88 some new 2-mercaptoimidazoles,89 and isohistamine .90 Isohistamine [2-(2 -aminoethyl)imidazole], originally reported in error by Jones,01 was prepared in 50% yield by an adaptation of the method of Ellinger and Goldberg92 and proved by NMR spectroscopy to be the authentic compound. The compound prepared... 

A number of aromatic amidines have been readily obtained by boiling a primary or secondary amine with a substituted amide in a solution of phosphorus trichloride. Several aliphatic amides undergo a similar condensation with amines and phosphorus oxychloride. An imino chloride, RC(C1)=NR, is an intermediate in this process. N-Phenylbenzarnidine, CsHsC(NHC6Hs)= NH, is obtained by the action of methanolic ammonia on... 

The special advantage of amidine-based stoichiometric non-covalent interactions is illustrated in Fig. 4.7. The templates 15 were removed from an imprinted polymer and then the polymer was re-offered different amounts of template 15 in methanol for rebinding. Figure 4.7 shows a nearly stoichiometric uptake with a reloading yield of about 99%. This is in marked contrast to non-stoichiometric non-covalent interactions in which only around 15% of the cavities can be reloaded. 

The general approach of amidine cyclization ha.s been applied to the synthesis of a variety of 2-substitutcd imidazoles. Aminoacetaldehyde dimethyl and diethyl acetals are readily available commercially, and the N-subsiituted derivatives can be made with little difficulty, providing access to 1-substituted imidazoles on reaction with a suitable imidate. Thus, methyl -hydroxypropanimidate (2), prepared from 3-hydroxypropanenitrilc, and methanolic HCl, condenses with an aminoacetaldehyde acetal to give the amidine hydrochloride (3), which ring closes when heated in acidic medium to form the 1-substituted 2-hydroxyethylimidazolc (4) (Scheme 2.2.3) [6J. The reaction has been adapted to the preparation of 2-arylimidazoles [5, 7-11],... 

The aldehyde (5) can be made in high yield from the amidine (6) via the unisolated 2-dichloromethylimidazole (Scheme 2.2.3). Dichloroacetonitrile is converted into its imidate with methanolic sodium methoxide, and then into the amidine with aminoacetaldehyde dimcthylacetal. When (6) is heated in formic acid it is converted almost quantitatively into the 2-carbaldehyde the use of trifluoroacctic acid at reflux gives around 60% of (5). Using essentially the same method, imidazole-2-carboxylic acid and its ethyl ester can also be made veiy efficiently when trichloroacctonitrilc and the acetal arc used to prepare the amidine [16],... 

There are standard methods available for synthesis of amidines 10] and guanidines. In particular, reaction of an acylated thiourea with an amine, followed by removal of the acyl group(s) from the acylguanidine intermediate provides a mild and efficient synthesis [11]. When dihydroxyacetonc is treated with formamidine acetate in liquid ammonia, imidazole-4-methanol is isolated in 65-70% yield as its hydrochloride (3) (Scheme 4.3.2). This convenient synthesis is much less tedious than the old approach based on the reaction of fructose with ammonia [16]. 

Imidazoles can also be made by heating 4-tosyloxazolines in saturated methanolic ammonia or monoalkylamines. These reactions proceed through intermolecular condensation of a-aminoketones and amidines and intramolecular cyclization of a-ainidinoketones, respectively [49] (see Section 4.2). When A -unsubstituted 4-oxazolin-2-ones are added to isocyanates, the 2-oxo-4-oxazoline-3-carboxamide products cleave under the influence of strong acids and heat. Subsequent ring closure gives 4-imidazolin-... 

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