Amidine reactions

For most purposes, this amidine synthesis is preferable to the formamide and the ortho ester alternatives it occurs at a lower temperature than the former, and it is free from the intrusion of intermediates characteristic of the latter. It is particularly useful when an alkyl or chloroalkyl group is required in the 2-position of the product, this pathway being much less explored in the formamide and the ortho ester methods. The amidine reaction is suitable for both 7t-deficient and 7t-excessive nuclei. 

A modification of the direct process has recentiy been reported usiag a ckculating reactor of the Buss Loop design (11). In addition to employing lower temperatures, this process is claimed to have lower steam and electricity utihty requirements than a more traditional reactor (12) for the direct carbonylation, although cooling water requirements are higher. The reaction can also be performed ia the presence of an amidine catalyst (13). Related processes have been reported that utilize a mixture of methylamines as the feed, but require transition-metal catalysts (14). 

The reaction of ethyleneimine with nittiles in the presence of HBF gives A -imidazolines (229). If trichloroacetonitrile [545-06-2] (R = Cl) is used as the nitrile component, the intermediate amidine can be isolated (230). 

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... 

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). 

The other main reaction in this class is the Dieckmann-type cyclization of the intermediates (163) from 4(6)-halo-5-ethoxycarbonylpyrimidines with AC-substituted /3-alanine esters and nitriles, and related compounds, to give 5,6,7,8-tetrahydro-5-oxopyrido[2,3-[Pg.221]

The simplest [3 + 3] reactions in the pyridine series involve reaction of o-chloropyridinecarboxylic acid derivatives with three-atom fragments such as urea, thiourea(s), amidines and guanidines, e.g. (240) (241). Examples are known mainly in... 

Another approach uses the reaction of 6-chloro-5-nitropyrimidines with a-phenyl-substituted amidines followed by base-catalyzed cyclization to pteridine 5-oxides, which can be reduced further by sodium dithionite to the heteroaromatic analogues (equation 97) (79JOC1700). Acylation of 6-amino-5-nitropyrimidines with cyanoacetyl chloride yields 6-(2-cyanoacetamino)-5-nitropyrimidines (276), which can be cyclized by base to 5-hydroxypteridine-6,7-diones (27S) or 6-cyano-7-oxo-7,8-dihydropteridine 5-oxides (277), precursors of pteridine-6,7-diones (278 equation 98) (75CC819). 

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. 

Numerous examples of N—S bond formation using oxidative conditions have been described in the literature. A convenient synthesis of isothiazoles involves the direct oxidation of -y-iminothiols and numerous variations have been studied (see Chapter 4.17), The oxidation of the amidine (248) to give the 3-aminoisothiazole (249) illustrates the reaction scheme (65AHC(4)107, 72AHC(14)1), which has been extended to the synthetically useful 5-amino-4-cyano-3-methylisothiazole (251) obtained by oxidation of (250) with hydrogen peroxide (75JHC883). 

Other amino substituted isoxazoles undergo ring-opening reactions on treatment with base. Thus the amidine derivative (249) gave the triazole (250) (64TL149), while the triazene (251) on reaction with ammonia gave the tetrazole (252) (64X461). 

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,... 

There are differences in the high temperature behavior. While oxaziridines almost always isomerize to acid amides, a similar reaction of diaziridines, which should lead to amidines, has not been observed. Sensitivity towards bases, often encountered in oxaziridines, is observed only in some special substituted diaziridines. The tendency of some classes of oxaziridines to transfer the nitrogen function also lacks in the diaziridine field. On homolytic reactions of diaziridines there are only a few observations. 

A modified amidine structure can be seen in (166), the product of reaction of 1,2-diethyldiaziridine (165) with diphenylketene. A second molecule of diphenylketene may have formed the four-membered ring of (166) (75JAP75117765). 

There are some reports on reactions involving complete N—N cleavage in diazirine reactions such as formation of amidine (205) from chlorophenyldiazirine, or on formation of products containing only one nitrogen atom. Betaine (206) was described as a product from difluorodiazirine and triphenylphosphine. Compound (207) is formed from decomposing (204) and cyclohexane (79AHC(24)63). 

A wide variety of /3-lactams are available by these routes because of the range of substituents possible in either the ketene or its equivalent substituted acetic acid derivative. Considerable diversity in imine structure is also possible. In addition to simple Schiff bases, imino esters and thioethers, amidines, cyclic imines and conjugated imines such as cinnamy-lidineaniline have found wide application in the synthesis of functionalized /3-lactams. A-Acylhydrazones can be used, but phenylhydrazones and O-alkyloximes do not give /3-lactams. These /3-lactam forming reactions give both cis and /raMS-azetidin-2-ones some control over stereochemistry can, however, be exercised by choice of reactants and conditions. 

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