Amidine preparation

As a class of compounds, nitriles have broad commercial utility that includes their use as solvents, feedstocks, pharmaceuticals, catalysts, and pesticides. The versatile reactivity of organonitnles arises both from the reactivity of the C=N bond, and from the abiHty of the cyano substituent to activate adjacent bonds, especially C—H bonds. Nitriles can be used to prepare amines, amides, amidines, carboxyHc acids and esters, aldehydes, ketones, large-ring cycHc ketones, imines, heterocycles, orthoesters, and other compounds. Some of the more common transformations involve hydrolysis or alcoholysis to produce amides, acids and esters, and hydrogenation to produce amines, which are intermediates for the production of polyurethanes and polyamides. An extensive review on hydrogenation of nitriles has been recendy pubHshed (10). 

Reactions. Although carbapenems are extremely sensitive to many reaction conditions, a wide variety of chemical modifications have been carried out. Many derivatives of the amino, hydroxy, and carboxy group of thienamycin (2) have been prepared primarily to study stmcture—activity relationships (24). The most interesting class of A/-derivatives are the amidines which are usually obtained in good yield by reaction of thienamycin with an imidate ester at pH 8.3. Introduction of this basic but less nucleophilic moiety maintains or improves the potency of the natural material while greatiy increasing the chemical stabiUty. Thus /V-formimidoyl thienamycin [64221-86-9] (MK 0787) (18), C 2H yN204S, (25) was chosen for clinical evaluation and... 

Cyanopyridazines add ammonia, primary and secondary amines and hydroxylamine to give amidines or amidoximes. Substituted amides, thioamides and carboximidates can be also prepared. With hydrazine, 3-pyridazinylcarbohydrazide imide is formed and addition of methylmagnesium iodide with subsequent hydrolysis of the imine affords the corresponding pyridazinyl methyl ketone. 

A major type of reaction in this class is the cyclization of 4-amino- or 4-halo-pyrimidines carrying 5-cyanoethyl or 5-ethoxycarbonylethyl groups, which cyclize to 7-amino or 7-oxo derivatives of 5,6-dihydropyrido[2,3- f]pyrimidine, e.g. (131)->(63). The intermediates may sometimes be prepared by reaction of 4(6)-aminopyrimidines with acrylonitrile, or even via a pyrimidine ring synthesis from an amidine and a cyanoacetic ester or malononitrile derivative, e.g. (132) -> (133) (7lJOC2 85, 72BCJ1127). 

Several related derivatives have also been utilized in this type of synthesis. Imino-chloromethanesulfenyl chlorides (184), prepared by the controlled addition of chlorine to isothiocyanates, react with amidines (161) to give 1,2,4-thiadiazolines (185) (71T4117). Chlorocarbonylsulfenyl chloride (186), prepared by the hydrolysis of trichloromethanesulfenyl chloride with sulfuric acid, reacted with ureas, thioureas and guanidines to give 1,2,4-thiadiazolidine derivatives (187) <70AG(E)54, 73CB3391). 

A more versatile synthesis of 11.1 (and the selenium analogue) involves the cyclocondensation of trisilylated amidines with sulfur dichloride or SeCl2 generated in situ (Eq. 11.3). This route can be used to prepare the prototypal systems [HCNEEN]" (E = S, Se). It is also readily extended to the synthesis of multi-dichalcogenadiazolium cations such as 1,3- or 1,4-C6H4(CNEEN)2] (H-2, E = S, Se), °... 

Examples of the C2N3S ring system containing three- or four-coordinate sulfur are also well known. The monohalogenated derivatives 12.2 (E = S, Se), are best prepared by the condensation of imidoyl amidines with SCI2 or SeCU, respectively (Scheme 12.1)." In the case of the selenium derivative, the initial product is heated at 60°C and then at 120°C in order to convert it to 12.2 (E = Se) via (PhC)2(NH)N2SeCl2. In the solid state this intermediate is a weakly associated, centrosymmetric dimer with Se-Cl and Se Cl distances of 2.42 and 3.39 A, respectively. ... 

Many pyrimidine derivatives have been prepared via the Pinner procedure. Amidines react with 1,3-dicarbonyl compounds to form 2, 4, 6-trisubstituted pyrimidines. ... 

Ghosh et al reported a modified procedure for the preparation of highly substituted pyrimidines by condensation of a 1,3-dicarbonyl compound 22 with tri-(trimethylsilyl)amidine (23) in good yield as compared to the lesser yield obtained from employing a classical Pinner procedure. ... 

Cyanothiophenes have been converted to amidines, and thienyl-substituted tetrazoles have been prepared from them for pharmacological evaluation. ... 

Substances of this type have hitherto received little attention. One of the reasons appears to be the limited possibilities of preparation. The only known method of preparation, described by Woolley et ai./ proceeds from the derivatives of 4-aminoimidazole-5-carboxylic acid. The amide of this acid (142) is treated with nitrous acid to yield 4-hydroxyimidazo [4,5-d]-i -triazine (2-azahypoxanthine) (143), the amidine (144) yielding the 4-amino derivative (2-azaadenine) (145) under the same conditions. 2-Azahypoxanthine was probably obtained in the same way earlier but was not identified. ... 

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). 

During a study of azonitrones (70), Forrester and Thomson showed that reaction with toluene-p-sulfinic acid resulted in nitrogen evolution and formation of the hydroxamic acid (66) together with the pyrrolidone (71) and the amidine (72). These workers suggested the following reaction course. Although the yield of hydroxamic acid was high, the method is not likely to be of preparative value. 

Among other bicyclic amidine catalysts, 3,4,6,7,8,9-hexahydro-2//-pyrido[l,2-n]pyrimidine was also applied in the preparation of /3-alkoxy nitriles from Q ,/3-unsaturated nitriles and alcohols (99GEP 19803515). The azido group could be smoothly converted into a trifluoroacetylamido group by treatment with (Cp3CO)2 in the presence of Ph3P and 2,3-dihydro-2//-pyrido[l,2-n]pyrimidin-2-one under Ar in THE (99HCA2380). 

The low structural specificity in the local anesthetic sell cs is perhaps best illustrated by phenacalne (91), a local an-I -.lhetic that lacks not only the traditional ester or amide func-I ion but the basic aliphatic nitrogen as well. First prepared at I lie turn of the century, a more recent synthesis starts by con-ili iusation of p-ethoxyaniline with ethyl orthoacetate to afford I he imino ether (90), Reaction of that intermediate with a sec-I liil mole of the aniline results in a net displacement of ethanol, iiobably by an addition-elimination scheme. There is thus ob-I.lined the amidine, 91, phenacalne. 

A somewhat different approach is used to prepare the compounds containing the amine at the 4 position. Condensation of the amidine from acetonitrile (138) with the enol ether from formylacetonitrile (137) leads to the requisite pyrimidine (139). 

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), ... 

Fusion of an additional heterocyclic ring onto that already present in the benzodiazepines has led to some medicinal agents with considerable activity. Treatment of an intermediate like 15 with phosphorus pentasulfide affords the corresponding thio-amide (37). Condensation of this intermediate with acetyl hydra-zide affords triazolam )37). The same agent can be prepared by reaction of the amidine, 38, ° with acetylhydrazide. ... 

Furthermore we found that kasugamycin forms a chelate compound with basic cupric carbonate (7), which is stable to acid and unstable to heat and base. This evidence together with the results obtained above strongly supports the amidine structure (13) for kasugamycin. Finally the amidine compound was successfully prepared by the reaction of kasuganobiosamine with the diethyl ester of oxalimidic acid (14) and... 

The amidines 10, prepared by condensation of the corresponding imidates with aminoacetal-dehyde dimethyl acetal, undergo cyclization with a variety of acids to l//-3-benzazcpin-2-amines 11 45 Method A has proved to be successful on an industrial scale. 

The first dibenz[/>,e]azepine 23 was prepared by cyclization of amidine 22 with phosphoryl chloride in refluxing nitrobenzene.103... 

This procedure illustrates a broadly applicable method which is essentially that of Roth, Dubs, Gotschi, and Eschenmoser,2 for the synthesis of enolizable /1-dicarbonyl compounds. Although there are various methods for the preparation of /3-dicarbonyl systems,3 the scheme of sulfide contraction widens the spectrum of available methods. The procedure can also be utilized in the synthesis of aza and diaza analogs of /3-dicarbonyl systems. Eschenmoser2 has utilized the method to produce vinylogous amides and amidines in connection with the total synthesis of corrins and vitamin B12.4... 

The imidazole nucleus is often found in biologically active molecules,3 and a large variety of methods have been employed for their synthesis.4 We recently needed to develop a more viable process for the preparation of kilogram quantities of 2,4-disubstituted imidazoles. The condensation of amidines, which are readily accessible from nitriles,5 with a-halo ketones has become a widely used method for the synthesis of 2,4-disubstituted imidazoles. A literature survey indicated that chloroform was the most commonly used solvent for this reaction.6 In addition to the use of a toxic solvent, yields of the reaction varied from poor to moderate, and column chromatography was often required for product isolation. Use of other solvents such as alcohols,7 DMF,8 and acetonitrile9 have also been utilized in this reaction, but yields are also frequently been reported as poor. 

In conclusion, a scaleable process for the preparation of 2,4-subsituted imidazole from amidines and a-halo ketones is described. This method avoids the use of chloroform as solvent and affords the desired products in consistently good to excellent yields. 

However, more-rigorous treatment (5% acetic acid, 100°C, 17 hours) opened the imidazole ring and produced /V -cyclohexyl-a-formylaminoacetamidine (57), characterized as the crystalline picrate. Amidine 57 produced no dye in the Bratton-Marshall assay. The same behavior can be expected from AIR (46), although the product of hydrolytic ring-opening was not actually isolated. On the other hand, it was observed that a solution of AIRs (0.2 mM in 0.01-M ammonium hydroxide) prepared by biosynthesis, when stored at 4°C, did not change appreciably within a day. A decrease in the concentration of AIRs of about 30% occurred within a month. 

A similar strategy has been used to prepare pyrimidines, as well as pyra-zoles and isoxazoles by reacting the enamine intermediate with a variety of bidentate nucleophiles [78]. Microwave irradiation of a cyclic 1,3-diketone 49 and acetal 45 in water generated the corresponding enaminoketone 50 in situ which reacted with amidines, substituted hydrazines or hydroxylamine in only 2 min in a one-pot process to give 4-acylpyrimidines, pyrazoles or isoxazoles, respectively (Scheme 20). 

A catch and release synthesis of tetrazoles and cyclic amidines has been reported making use of solid-supported oximes [94]. When bound sulpho-nyloximes, obtained by reacting polymer supported sulfonyl chloride with oximes, were reacted with nucleophiles, tetrazoles or cychc amidines were obtained (Scheme 19). Alternatively, the use of TMS-CN affords imino nitriles, which have been used as intermediates for the preparation of indoles, 1,2,3,4-tetrahydropyridines, quinoxalines and benzimidazoles. 

Microwave-assisted intramolecular C - N bond formations have also been studied. Substituted benzimidazoles were easily prepared from the corresponding M-(2-bromophenyl)imidoformamides by Brian et al. (Scheme 102) [ 104]. The protocol involved the use of a combination of Pd2 (dba)3 and PPha in a mixture of DME and water using NaOH as the base at 160 °C. It was apphca-ble for electron poor, neutral and rich as well as sterically hindered amidines. The fastest reactions were obtained with an electron withdrawing substituent... 

Historically, the amidinate story begins with the discovery of N,N,N -tris(trimethylsilyl)benzamidine, PhC( = NSiMe3)[N(SiMe3)2], by Sanger. The compound was prepared by the reaction of benzonitrile with LiN(SiMe3)2 followed by treatment with chlorotrimethylsilane. The method was later... 

The general route leading to lithium amidinates can also be adapted to prepare asymmetrically substituted derivatives as illustrated in Scheme 5. ... 

The lithium benzamidinates Li[PhC(NR)2] (R = Cy, Pr ) and Li[2,4,6-(Cp3)3C6H2C(NCy)2] have been prepared analogously. Reaction of FcLi (Fc = ferrocenyl) with 1,3-dicyclohexylcarbodiimide ( = DCC, Scheme 6), followed by addition of water, afforded the ferrocene-substituted amidine Fc(NCy)NHCy in 50% yield. The amidine is readily deprotonated by LLN(SiMe3)2 or NaN(SiMe3)2 to yield the alkali metal amidinates, Li[FcC(NCy)2l and Na[FcC(NCy)2l in high yields. ... 

Amidinate- and guanidinate-substituted boron halides are normally prepared using the two standard synthetic routes, i.e., salt-metathesis between suitable... 

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