Synthesis from amidines

Synthesis from amidines, isocyanates, aldehydes and ketones 512... 

Pinner imidazolone ring synthesis from amidines and benzils... 

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). 

Scheme 6.247 Synthesis of2,4,6-trisubstituted pyrimidines from amidine and alkyne building blocks.

TABLE 7.9. SYNTHESIS OF 4-(A,A-DIALKYLAMINO)-5(2H)-OXAZOLONES FROM AMIDINES AND CARBON DIOXIDE ... 

In 1954, Goerdeler6 introduced a general synthesis of 1,2,4-thia-diazoles from amidines. This versatile method has since been widely extended and has made a great variety of 1,2,4-thiadiazole derivatives readily accessible. Basically, an amidine is converted into its i T-thio-cyanato derivative, which cyclizes spontaneously to the 5-amino-1,2,4-thiadiazole. 

Azomethine ylids derived from amidines undergo internal [3 + 2]cyclization reactions with a styrenic double bond present in the starting amidine. This strategy has been applied to the synthesis of physostigmine and erythramine. 

It effects a synthesis of amidines from simple carboxylic acids and amines ... 

Nitriles are also the usual products of oxidation of aliphatic amines RCH2NH2 by nickel peroxide and lead(IV) acetate. Aliphatic azo compounds can be prepared from these primary amines by first converting them into ulfamides (6), these then being oxidized with sodium hypochlorite or (better) r butyl hypochlorite (Scheme 9). A few aliphatic azo compounds can be formed in good yield by direct oxidation of r-alkylamines for example, AIBN was formed (86%) by oxidation of the amine Me2C(CN)NH2 with sodium hypochlorite. A special case of azoalkane foimation is the synthesis of chlorodiazirines (7) from amidines RC(= NH)NH2 by oxidation with sodium hypochlorite. ... 

There are standard methods available for synthesis of amidines 10] and guanidines. In particular, reaction of an acylated thiourea with an amine, followed by removal of the acyl group(s) from the acylguanidine intermediate provides a mild and efficient synthesis [11]. When dihydroxyacetonc is treated with formamidine acetate in liquid ammonia, imidazole-4-methanol is isolated in 65-70% yield as its hydrochloride (3) (Scheme 4.3.2). This convenient synthesis is much less tedious than the old approach based on the reaction of fructose with ammonia [16]. 

Scheme 5.6 Three-component synthesis of amidine from a-isocyanoacetate.

As will be discussed in the next section, 1,5-pentanediones are obtained by Michael addition of acetophenones to chalcones. The addition and cyclization may be merged in one step (see Section II,C,2,g). When acetophenone was condensed with chalcone (74) in the presence of BFg-EtaO or of HC104, jS-phenylpropio-phenone (76) was obtained as by-product its formation is due to hydride transfer to the conjugate acid of chalcone (75), which is the acceptor (experimental data and theoretical calculations show that chalcones are protonated at the oxygen atom). Balaban obtained a 72% yield in the conversion 70 -> 37 using as acceptor chalcone and as catalysts perchloric or sulfuric acids (i.e., 75). The formation of j8-phenylpropiophenone (76) in the Chichibabin synthesis of pyridines from chalcones and ketones in the presence of ammonium acetate, and in the pyrimidine synthesis from chalcones and amidines is undoubtedly due to a similar hydride transfer. 

The usual procedure36 is to add a slight excess of a secondary amine to an ethereal solution of ethylmagnesium bromide (50% excess relative to the nitrile) and, when evolution of ethane ceases, to heat the mixture under reflux for about 20 min before adding an ethereal solution of the nitrile the whole is then boiled under reflux for 2-3 h, then decomposed with ice. In many cases this method is superior to the Pinner synthesis of amidines from imidoyl esters. 

Acylation of nitrogen compounds by imidic esters. It was mentioned above that synthesis of amidines from orthoesters proceeds through imidic esters, so that both classes of compound are normally treated together in reviews.819-821 Accordingly, also, it is, of course, possible to use imidic ester hydrochlorides as usually prepared from nitriles and to treat these with ammonia or amines.820 Care must be taken, however, with primary amines lest the imido group be also exchanged for the residue from the amine, particularly at higher temperatures ... 

Activation of thioamides to thioimidates with alkylation is also applied to the synthesis of amidines. Dijkink et al. [28] applied this method to the synthesis of chiral bicyclic amidines from (5)-malic acid as a key step. However, the amidine was found to be unstable due to isomerization of the imine double bond followed by ehmination of the silyloxy group (Scheme 3.15). 

Synthesis of Amidines from Amines and Nitriles. An efficient one-step preparation of Af,Af -disubstituted amidines is possible by direct nucleophilic addition of an amine to a nitrile using catalytic amounts of samarium iodide (eq Alternatively, an... 

The synthesis of amidines from Ai-allyl-Ai-sulfonyl ynamides has been reported involving a Pd(0)-catalysed aza-Claisen rearrangement of IV-allyl ynamides (Scheme 3). " ... 

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