Alkylation reactions amidines

The chelated lithium anions 1 and 2, derived from enantiomerically pure tetrahydroisoquino-line-amidines or -oxazolines, exhibit high induced stereoselectivity in alkylation reactions (Section D.l.1.1.1.3.1.). 

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>. 

Amidinium salts (obtainable by various methods, compare Section 2.1.2.5) which are not peralkylated at nitrogen are converted to amidines by treatment with strong bases, e.g. aqueous alkali metal hydroxides, alcoholic alkoxides, tertiary amines etc. As already mentioned it is not difficult to alkylate amidines (see Section 2.7.2.5.4), thus by subsequent alkylation and deprotonation reactions amidines can be synthesized carrying the desired substituents at nitrogen, e.g. (308 Scheme 47). A series of trisubstituted formamidines have been prepared by reaction of anilines with the azavinylogous form-amidinium salt (309). ... 

In addition to the construction of the amidine structure iV-alkylation reactions can occur,ring opening in the case of heterocyclic amines and formylation of acidic methylene or methyl groups. 76i,793 jjjg reaction of formamide with excess /V,N-dialkylformamide acetals deviates from this reaction pattern, here azavinylogous formamide acetals (358 Scheme 62) are formed. A, A -Dialkyl-iV -formylformamidines (359) can be prepared either by action of A, N-dialkylformamide acetals on bis(trimethylsilyl)formamide or by treatment of azavinylogous amide acetds (358) with trimethyl-chlorosilane. ... 

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. 

One of the best methods of synthesis of isothiazoles is by direct oxidation of y- iminothiols (169) or their tautomers. The reaction is capable of many ramifications and is represented by the general equation shown in Scheme 27. The substituents represent a wide range of groups. Thus, iminothioamides (169 R = NH2) are oxidized to give 3-alkyl-5-aminoisothiazoles (170 = NH2), amidines (169 R = NH2) produce 3-amino compounds,... 

Reaction of pyridinium-A -(2-pyridyl)amidine (402) and alkyl haloace-tates in the presence of K2CO3 afforded a mixture of 4-oxo-4/f-pyrido[l, 2-u]pyrimidine-2-carboxylates 407 and 2-aminopyridine derivatives 406 through intermediers 403- 05, as depicted in Scheme 15 (00TL5837). Compound 406 could be cyclized on the action of heat or silica gel into 407. The best yield was achieved in the case of ethyl bromoacetate. 

Interesting new sulfido complexes of tin have been prepared by the reaction of styrene sulfide with the N-alkylated tin(II) amidinate complexes Sn[RC(NCy)2]2 (Cy = cyclohexyl R = Me, Bu ). The products exhibit two very different bonding modes for the sulfido ligands in one case, S = Sn[RC(NCy)2]2/ a terminal Sn = S moiety was found while in the other case the bridging... 

Thus unsubstituted (R=H) and substituted (R = alkyl) non-stabilized diyiides 1 react with phenylisocyanate and dicyclohexylcarbodiimide (R NCX), leading to the formation of new monoylide type intermediates. These last ones react in situ with carbonyl compounds through a Wittig type reaction leading respectively to a,)8-unsaturated amides 2 and amidines 3, with a high E stereoselectivity, the double bond being di- or tri-substituted [48,49]. By a similar reactional pathway, diyiides also react with carbonic acid derivatives, with the synthesis as final products of -a,/l-unsaturated esters 4 and acids 5 [50]. 

Reactions of Alkyl 4-Chloro-3-trimethylsilyloxycrotonates with Amidines to Give Alkyl lmldazole(4,5]-acetates... 

Chang et al. reported a mild tandem intramolecular hydroamination of yne amines to form an endo-adduct intermediate, which reacts with electron-deficient azides to produce cyclic amidines <06JA12366>. Selected examples of an interesting synthetic route to tropene derivatives 165 via a dual hydroamination strategy is shown below. This one-step reaction makes use of a palladium catalyst and takes place by sequential intermolecular hydroamination of cycloheptatriene with aryl, heteroaryl, and primary alkyl amines to generate intermediate 166, followed by transannular intramolecular hydroamination <06JA8134>. 

Hydrolysis of amino-alkylamino-l,2,5-thiadiazole 1-oxides 55 with concentrated aqueous HC1 gave the amidines 56 (Equation 4) <2001JME1231>. The hydrolysis reactions of 2-alkyl-4-amino-2,3-dihydro-l, 2,5-thiadiazol-3-one 1,1-dioxides 57 in the range 24-73 °C in buffered aqueous solutions gave the corresponding 2-amino-2-[(iV-alkyl-substituted-sulfamoyl)imino]acetic acid salts 58 (Equation 5) <1998JP0489>. 

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... 

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>. 

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