Amidine hydrochloride

A combination of the preceding type of synthesis and of cyclization of 4-amino-5-arylazopyrimidine can be seen in the novel procedure of Richter and Taylor. Proceeding from phenylazomalonamide-amidine hydrochloride (180), they actually close both rings in this synthesis. The pyrimidine ring (183) is closed by formamide, the triazole (181) one by oxidative cyclization in the presence of cupric sulfate. Both possible sequences of cyclization were used. The synthetic possibilities of this procedure follow from the combination of the two parts. The synthesis was used for 7-substituted 2-phenyl-l,2,3-triazolo[4,5-d]-pyrimidines (184, 185). An analogous procedure was employed to prepare the 7-amino derivatives (188) from phenylazomalondiamidine (186). 

As already discussed in Section 5.5.2, amidine hydrochlorides 743 react with O-silylated methyl (or ethyl) 4-chloroacetoacetate 746, in which the 4-chlorine atom... 

Interaction of iV-pentafluorophenylcarbonimidoyl dichloride with benzonitrile and aluminium trichloride leads to l-pentafluorophenyl-4,6-diphenyl-13 -triazin-2-one along with urea derivatives . Reaction of perfluoro-5-azanon-4-ene with a range of bidentate nitrogen nucleophiles (urea, substituted amidine hydrochlorides and guanidine), in the presence of triethylamine or potassium hydroxide, effectively provides fluorinated 1,3,5-triazines 16-19 <00JFC(103)105>. 

Fluoroethyl fluoroacetate is a compound of considerable toxicity. Its l.c. 50 for rabbits (inhalation) is 0-05 mg./l., i.e. about half as great as for M.F.A. It is therefore placed in class A. Other factors apart from hydrolysis to fluoroethanol and fluoroacetic acid appear to be operative, and it seems that the molecule is toxic per se. The related fluoroacetylimino-2-fluoro-ethyl ether hydrochloride, [CH2F C( NH2) O CH2 CH2F]+CT, is also placed in class A. This is understandable as it is readily hydrolysed by water to 2-fluoroethyl fluoroacetate. Other fluoroacetylimino ether hydrochlorides containing, however, only one fluorine atom fall into class B, as does also fluoroacet-amidine hydrochloride itself. 

Malonaldehyde is unstable and is therefore used as its diacetal, 1,1,3,3-tetramethoxypropane 641, in reactions with amidine hydrochlorides 642. Reaction occurs best in a sealed tube at 175 °C <1997SC2521>. 

Amino-l,2,4-thiadiazoles are usually prepared by treating amidine hydrochlorides with halogen and thiocyanates to yield the 3-alkyl derivatives or treating alkylisothiouronium salts similarly to yield the 3-alkylthio derivatives (56CB2742). Diazonium salts derived from 5-amino-l,2,4-thiadiazole derivatives, which are prepared in acetic acid, are extremely reactive and are capable of coupling with m -xylene (60CB397). 

Dibromo-4,4 -dicyano-a,y-diphenoxypropane (3.0 g) and anhydrous ethanol (3.0 ml) were dissolved in anhydrous chloroform (40 ml). The solution was saturated at 0°C with dry hydrogen chloride and set aside for 7 day. The iminoether hydrochloride which crystallised out, was filtered off and washed with light petroleum. The solid was added to 12% ammoniacal ethanol (47 c.c.) and the mixture was heated at 60°C for 6 hours. Solution was obtained after 3 hours and the amidine hydrochloride began to cryistallise. The mixture was ice-cooled, and the white crystalline solid was filtered off, washed with 2 N hydrochloric acid, and recrystallised twice from 0.5 N hydrochloric acid. 

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... 

Malonamide amidine hydrochloride (102) and the sodium derivative of 79 give 2-amino-3-carboxamido-6,7-dihydro-5 M-pyrindine (103).76 Compound 103a was converted into 103b-e via conventional reactions. 

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],... 

Similar to )V-acyl- and (V-cyanoimidates, A-acyl- and jV-cyanoimidodithiocarbonates 20 react with amidines to form sulfanyl-substituted 1,3,5-triazines 21.425 427a,b The amidine hydrochloride is treated with an equimolar amount of base to liberate the amidine, which is reacted in alcoholic solution with the activated iminodithiocarbonate. When evolution of methanethiol has subsided, the reaction products are crystallized by cooling the reaction mixture.4,25... 

The 4//-l,3-benzoxazin-4-one (1 mol) and the amidine hydrochloride (1.1 mol) were dissolved or suspended in MeOH. While stirring, a solution of NaOMe (59.4 g, 1.1 mol) in MeOH was added slowly. In most cases the product began to separate from the mixture and in some cases it was necessary to add some additional MeOH in order to continue stirring the mixture. Then, the suspension was heated to reflux for a short period of time, cooled and the 1,3,5-triazine 19 was collected by suction. After washing with H20 and MeOH, the residue was recrystallized. 

Crude yield. h Determined by IR spectroscopy. Ratio (amidine/triazine) 6 1. Determined by MS. Amidine hydrochloride. 

When triethyl l,3,5-triazine-2,4,6-tricarboxylate is treated with acetimidamide hydrochloride7 or propionimidamide hydrochloride8,9 in dimethylformamide at 90-100°C the corresponding pyrimidines are formed in 80-85% yield. The reaction proceeds by reversible in-situ tautomerism of the amidine hydrochloride to the alkene-1,1-diamine and its participation in a [4 + 2] cycloaddition with the triazine. The cycloaddition is followed by a retro Diels-Alder reaction with loss of ammonia and ethyl cyanoformate. The thermal conditions (>80°C) required for effecting the retro-Diels-Alder reaction and the deliberate use of the amidine hydrochlorides facilitates the amidine tautomerism and seems to be essential for aromatization of the initially formed cycloadduct.7-9... 

In a detailed study, the scope and limitations of the Diels-Alder reaction of amidines and related compounds with 1,3,5-triazines arc discussed.10 The reactions with the amidine hydrochlorides 15 (X = NH2) are best conducted at temperatures of 90-100 °C and in polar aprotic solvents (particularly in dimethylformamide). As expected for inverse electron demand Diels-Alder reactions, the reaction exhibits characteristic 1,3,5-triazine substituent effects (C02Et >HI> SMe). Thioimidates, e.g. 15 (X — SMe), undergo a similar reaction with 1,3,5-tri-azines with varying yields and competing amine or thiol elimination while imidates, e.g. 15 (X = OMe) are unreactive under the examined reaction conditions.10... 

The following general procedure is recommended for preparation of unsubstituted amidine hydrochlorides 822... 

An approximately 10 % solution or suspension of 0.1 mole of an imidic ester hydrochloride in anhydrous ethanol containing 0.13 mole of ammonia is shaken in a closed vessel for 2 to 3 days at room temperature. The precipitated ammonium chloride is filtered off, the filtrate is diluted with ether, and the precipitated amidine hydrochloride is collected and recrystallized from ethyl methyl ketone and alcohol. 

The reaction proceeds best with the amidine hydrochloride salts at temperatures around 90-100 °C in polar aprotic solvents. The reaction seems to be essentially urMfTected by the diene-dienophile ratio, but is subject to triazine substituent effects. The general reaction is shown in Scheme 11 [94JOC4950]. 

The derivatives of 4-(lH)-quinazolinone 138 are formed with yields of 58-63% when the amidine hydrochlorides 139 are boiled with the anhydrides 140 in pyridine [79],... 

Recently, Fu and coworkers reported an alternative method for assembly of primary aryl amines [17]. In their reaction amidine hydrochlorides were used as the ammonia surrogates (Scheme 9.3). The ligand was also L-proUne (LI) and heating (110°C) was required for good yields. 

Conversion of 1,3-diketones 315 into 2-substituted 7,8-dihydroquinazolin-5(6//)-ones 569 by a reaction with substituted amidine hydrochloride and dimethylform-amide dimethyl acetal (DMF-DMA) was achieved under MWI and in aqueous media. The aqueous conditions led to an environmentally friendly work-up. Compounds 569 were obtained in 21-68% yields within 2 min (Scheme 112). The reaction is a tandem addition-elimination/cyclodehydration that took place via a Michael addition of the terminal amino group of the substituted amidine to form intermediate 568, followed by an intramolecular cyclodehydration to give dihydroquinazoli-none derivatives 569 (02S1669). 

A soln. of 5-acetamido-l,3,4-thiadiazole-2-carbonitrile in tetrahydrofuran treated with methanol, ice-cooled, satd. with anhydrous HCl, kept 22 hrs. at 5°, the crude imino ether hydrochloride obtained added to an ice-cooled mixture of aminoacetaldehyde dimethyl acetal and methanol, refluxed 19 hrs., coned, under reduced pressure, the resulting crude dry amidine hydrochloride added portion-wise to coned. H2SO4 with water-cooling if necessary, and the product isolated after a complete soln. has been obtained -> 2-acetamido-5-(2-imidazolyl)-l,3,4-thiadiazole. Y 56%. W. A. Remers, G. J. Gibs, and M.J. Weiss, J. Heterocyclic Chem. 6, 835 (1969). 

Both compound classes can be obtained in moderate to good yields. In the case of 2,6-disubstituted pyrimidin-4(3fl)-ones 54 electroneutral and electron-rich amidine hydrochlorides 36 are favorable as well as electroneutral and electron-deficient terminal alkynes 5. For the synthesis of the 1,5-disubstituted 3-hydroxypyrazoles 55 alkyl-substituted hydrazine hydrochlorides 20 generally provide higher yields. 

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