Alkylation of Amidines

Alkylation of amidine 1131 with l-bromo-2-methoxy-2-propene affords regiospecifically N-alkylated product 1132. Treatment of 1132 with pyridinium />-toluenesulfonate in aqueous THF provides imidazole 1133 in good yield. In this reaction, l-bromo-2-methoxy-2-propene is used as a protected form of a-bromoacetone, which itself leads to poor yields when reacted directly with amidines (Scheme 275) <2000J1V1E3168>. 

Because esters 745 a, b of imidazole-acetic acid are unstable when stored for long periods, owing to intramolecular catalysis by the imidazole moiety, the esters should be converted into their salts or free acids and stored as such. Only tert-butyl imidazole-(4,5)acetates derived from tert-butyl 4-chloroacetoacetate seem to be stable [232, 233]. N-alkyl-substituted amidines give rise to a mixture of alkyl N-alkylimidazole-4- and 5-acetates [232, 233]. 

Xylamidine (87) is an amidine which serves as a serotonin inhibitor. This agent is prepared by alkylation of m-methoxyphenol with a-chloropropio-nitrile, KI and potassium carbonate in methylethyl ketone to give 85, which is in turn reduced with... 

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... 

Jordan reported that cationic aluminium alkyl derivatives of amidinates (3) [10] and aminotroponiminates (4) [11] are active in ethene polymerization. The amidinate system was later shown to be more complicated, and the nature of the active species remains unclear [14],... 

The most popular preparations of pyrimido[4, 5 ]pyrimidi nes are based on cyanoethylene or cyanomethylene derivatives. In many of these preparations the appropriate acid chloride (R1 = alkyl, aryl) is reacted with malononitrile to give an enol (250), which is readily alkylated to the enol ether (251). This can be condensed with guanidine or a variety of amidines (R2 = H, alkyl, aryl) to yield the key intermediate 4-amino-5-cyanopyrimidines (252) (81S955). Reaction with a second mole of guanidine or amidine is a convenient preparation of a variety of pyrimido[4,5 ]pyrimidines. Under the appropriate conditions the final ring system can be obtained from the enol ether in one step (68JMC568). 

Amidines and guanidines are slightly more basic than aliphatic amines, and steri-cally crowded amidines (e.g. DBU) or guanidines are often used to mediate dehydro-halogenations. Conditions can, however, sometimes be found which lead to the N-alkylation of these organic bases (Scheme 6.30). Identification of appropriate conditions for such reactions is mostly empirical, because small changes can have important but unforeseeable effects on the selectivity of a reaction (compare, e.g., the first and second reactions in Scheme 6.30). If the reactivity of a given substrate is too low, its nucleophilicity can be enhanced by deprotonation. 

N-Acyl or N-alkoxycarbonyl amidines or guanidines can be deprotonated and then alkylated [120]. The scope and limitations of these reactions are similar to those of the N-alkylation of amides or carbamates. N,N -Bis(tert-butyloxycarbonyl)guan-idine is sufficiently acidic to undergo clean N-alkylation under the conditions of the Mitsunobu reaction [121]. 

The catalytic activation of allylic carbonates for the alkylation of soft car-bonucleophiles was first carried out with ruthenium hydride catalysts such as RuH2(PPh3)4 [108] and Ru(COD)(COT) [109]. The efficiency of the cyclopen-tadienyl ruthenium complexes CpRu(COD)Cl [110] and Cp Ru(amidinate) [111] was recently shown. An important catalyst, [Ru(MeCN)3Cp ]PF6, was revealed to favor the nucleophilic substitution of optically active allycarbonates at the most substituted allyl carbon atom and the reaction took place with retention of configuration [112] (Eq. 85). The introduction of an optically pure chelating cyclopentadienylphosphine ligand with planar chirality leads to the creation of the new C-C bond with very high enantioselectivity from symmetrical carbonates and sodiomalonates [113]. 

N-Methylamino acids. N-Methylation of amino acids can be effected with minimal racemization by alkylation of the amidine ester (8, 191) with methyl triflate. Methylation with dimethyl sulfate replts in extensive racemization. 

Aluminium amidinate complexes 392 are synthesized by addition of aluminum alkyls to aliphatic carbodiimides. Also, alkylation of carbodiimides with MeLi, followed by reaction with AICI3 affords aluminum amidinate complexes... 

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