Aryl-substituted amidines

Amidines and related systems such as guanidines react with a-halogenoketones to form imidazoles. a-Hydroxyketones also take part in this reaction to form imidazoles, and a variety of substituents can be introduced into the imidazole nucleus by these procedures. Reaction of the a-halogenoketone (73) with an alkyl- or aryl-substituted carboxamidine (76) readily gave the imidazole (77) (01CB637, 48JCS1960). Variation of the reaction components that successfully take part in this reaction process is described in Chapter 4.08. 

The preparation of biologically active [l,2,4]triazolo[l,5- ]pyrazines has been reported recently. The reaction routes are shown in Scheme 50. Dowling et al. reported <2005BML4809> the synthesis of aryl-substituted derivatives 411. The first step was the transformation of the 2-aminopyrazine compound 409 to an amidine 410, which was subjected... 

Addition of aryl isocyanates to N-substituted amidines at elevated temperatures [89]. 

IV,N,N -Tris(trimethylsilyl)amidines have been used recently as precursors for a number of inorganic heterocycles and metallacycles,1 some of which are being studied in light of their unusual solid state properties2. Boere et al. reported the synthesis of several aryl-substituted persilylated benzamidines and the related compound /V,N,N, N",N",Ar" -hexakis(trimethylsilyl)-l,4-benezenedicarboximidamide (hereafter referred to as HBDA) 3 the present syntheses, which are generally based on the same reaction of an aryl-substituted carbonitrile with lithium bis(trimethylsilyl)amide, offer more facile routes to representative mono- and polyfunctional carboximidamides (i.e., amidines) as well as the prototypal derivative N,N,N -tris(trimethyl-silyl)formimidamide.4 As before, the crystalline diethyl ether adduct of lithium bis(trimethylsilyl)amide5 is favored over the nonsolvated amide in these syntheses the preparation of the diethyl ether adduct is also described here. 

Certain nitriles add amines to form N-substituted amidines. This reaction has been modified and extended through the use of ammonia and alkyl- or aryl-ammonium salts of sulfonic acids. Many amidines have been prepared in yields ranging from 13% to 86%. Some amidines are obtained in better yields by heating a cyanide with ammonium thiocyanate or an alkylammonium thiocyanate."... 

Thiadiazoles.—Synthesis. The reaction between benzoyl isothiocyanate and alkyl azides RN3 gives a mixture of the 1,2,4-thiadiazole (203 R = NRCOPh, R = SCOPh) and the 1,2,4-dithiazole (204). The oxidation of the aryl thioamides ArCSNH2 with nitrous acid gives a mixture of (203 R = R = Ar) and ArCN, but, when Ar was 2,6-dichlorophenyl, the aryl isothiocyanate was isolated.Oxidation of the substituted amidines, e.g. PhC(S)N=CPhNHPr,... 

The influence of the aryl substitution for derivatives bearing the aryl group at the functional carbon depends on the electronic nature of the aryl substituent. Smaller basicity is measured than for acetamidines. Bicychc amidines show larger basicity, compared to the most of simple alkyl derivatives, with the gas phase basicities in the following order DBU > DBD > PMDBD > DBN > 74. DBU has the largest gas phase basicity value of 243.4kcalmol . Five-membered ring amidines display smaller basicity than six- and seven-membered cyclic amidines. 

Amidine addition to a,p-unsaturated carbonyl derivatives is another popular method to construct pyrimidine rings. 2,4,6-Tri(hetero)aryl-substituted pyrimidines can be readily synthesized in a three-component, one-pot process based upon a coupling-isomerization sequence of an... 

Intramolecular N-arylations of amidines 83 led to benzimidazoles 84 mediated by potassium hydroxide (140L536). Multi-substituted benzimidazoles 86 were obtained from amidines 85 via iodine(III)-promoted oxidative C(sp )-C(sp ) and C(sp )-N bond formation (140L2822). Direct... 

An analogous reaction sequence can be used to generate benzimidazoles and aminobenzimidazoles, involving the palladium-catalyzed intramolecular cyclization of aryl bromide-substituted amidines and guanidines, respectively (e.g.. Scheme 6.37) [48]. With aryl bromides, simple Pd(PPh3)4 or Pd2dba3/PPh3 catalysts are sufficient to mediate cyclization. This same approach is equally applicable to indazoles and polycyclic benzimidazoles [49]. 

P) and silanes undergo Si-H abstraction. Pentacoordinate dihydridosilicates are very good reducing agents while aryl substituted derivatives reduce carbodiimides to the N-acyl formamides and amidines. ... 

Scheme 60 Synthesis of 2-substituted quinazolinones and quinazolines via Cul-catalyzed N-arylation of amidines...

Oxidative attack on a carbon-hydrogen bond of an alkyl group a to a nitrogen atom is not restricted to saturated aliphatic amines. In fact X in an X-N-CH- structural subunit can be virtually any common atomic grouping that can be found in stable organic molecules. For example, w-carbon hydrogens of Aralkyl-substituted aromatic cyclic amines (119), aryl amines (120), amides (121), amidines (122), A-nitrosodialkylamines (123), etc. are all subject to oxidative attack, carbinolamine formation, and in most cases release of an aldehyde or ketone depending on the substitution pattern (1° or 2°)... 

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>. 

Substituted malondialdehydes form pyrimidines substituted in the 5-position with an alkyl, aryl, halo, or hetero substituent. The pyrimidine is unsubstituted in the 4- and 6-positions. /3-Dialdehyde equivalents are frequently used in these reactions, for example, 3-alkoxy- or 3-aminoacroleins. With aldehydo ketones, the pyrimidine carries a substituent in the 4- or 6-position. The formyl group in the ketone is normally masked as an alkoxymethylene ketone or as an aminomethylene ketone. A commonly used procedure involves the preparation of a dimethylaminomethyl-ene ketone 645 by reaction of a methyl ketone 644 with DMF dimethylacetal and subsequent reaction with an amidine or guanidine to form the target pyrimidine 646 <2003MI237, 2004JHC461>. 

Alkyl(or aryl)amino-3-substituted-l,2,4-thiadiazoles (115) are synthesized129 without difficulty from A-substituted-iV -acetimidoyl-(or benzimidoyl)thioureas (114), obtained by condensing amidines and isothiocyanates. 

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