Amidines intramolecular cyclization

Reaction of 7V-(phenylsulfonyl)benzhydrazidoyl chloride, which fails to yield a 1,3-dipole, with N-substituted benzamidines is postulated to proceed via an intermediate formed by nucleophilic attack of the hydrazidoyl carbon by the more basic imino nitrogen of the amidine. Intramolecular cyclization of the intermediate yields a triazoline loss of amino or phenyl-sulfonyl moieties from the latter leads to triazoles as final reaction products (Scheme 24A) (77BCJ2969). 

Presumably an amidine intermediate is involved which undergoes intramolecular cyclization by nucleophilic attack on the carbonyl function to yield the pyrimidine. 

Intramolecular cyclization of the amidine (203) using a strong base (LDA) gives compound (204) (Equation (26)) <91JHC1441>. Cyclization of the esters (205) gives the derivatives (206) which upon... 

Imidazoles can also be made by heating 4-tosyloxazolines in saturated methanolic ammonia or monoalkylamines. These reactions proceed through intermolecular condensation of a-aminoketones and amidines and intramolecular cyclization of a-ainidinoketones, respectively [49] (see Section 4.2). When A -unsubstituted 4-oxazolin-2-ones are added to isocyanates, the 2-oxo-4-oxazoline-3-carboxamide products cleave under the influence of strong acids and heat. Subsequent ring closure gives 4-imidazolin-... 

Amidines 1170 substituted with electron-rich aromatic rings undergo an oxidative intramolecular cyclization process to give A-substituted benzimidazoles 1172. The reaction proceeds well in MeCN with CAN or electrochemical oxidation and probably involves the cationic intermediate 1171 (Scheme 285) <1996JOC3902>. 

There is an increasing amount of evidence that the amidine groups are present in the semicyclic form resulting either from intramolecular cyclization of the terminal amine hydrochloride [202, 204, 206, 210], viz. 

Formation of imidazo[4,5-e]-1,2,4-triazines 119 has been observed to occur when 6-ethylamino-5-methylamino-1,2,4-triazines 118 react with benzamidine. However, in this case only the methylamino group at C-5 is substituted by the amidine, while the ethylamino group at C-6 participates itself as a nucleophile in an intramolecular cyclization reaction (Scheme 68) (78CPB3154). 

Comparative results have been obtained in the synthesis of 3H-quinazolin-4-one [100]. The fusion of anthranilic acid with formamide led to the formation of an o-amidine intermediate and usually proceeded by intramolecular cyclization (Eq. 15) ... 

Amination of azaheteroaryl bromides and chlorides has also been reported to be smoothly executed within 10 min by use of standard reaction conditions and microwave irradiation [118]. Benzimidazoles have been prepared by Brain and Steer via intramolecular cyclization using an amidine moiety as the N-nucleophile [119]. The reaction was rapid and high yielding, and in combination with a catch and release strategy featuring capture of the benzimidazole on an acidic resin in the... 

Kumagai, N., Matsunaga, S. and Shibasaki, M. (2004) An efficient synthesis of bicyclic amidines by intramolecular cyclization. Angewandte Chemie - International Edition, 43, 478-482. 

Oximes can react with triflic anhydride to afford amidines or enamines after a nucleophUic capture of the iminocarhocation formed (111). The activated oxime can also eliminate to form the corresponding nitrile in the presence of imidazole or he converted into henzisoxazoles through an intramolecular cyclization process. ... 

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]. 

Quinazolinones are an important class of fused heterocycles that have been reported with remarkable activities in biology and pharmacology such as anticancer, antiinflammatory, anticonvulsant, antibacterial, antidiabetic, hypolipidemic, and protein tyrosine kinase inhibitors. Alper and Zheng reported a palladium-catalyzed cyclocarbonylation of o-iodoanilines with imidoyl chlorides to produce quinazolin-4(3H)-ones in 2008. A wide variety of substituted quinazolin-4(3H)-ones were prepared in 63-91% yields (Scheme 3.27a). The reaction is believed to proceed via in situ formation of an amidine, followed by oxidative addition, CO insertion, and intramolecular cyclization to give the substituted quinazolin-4(3H)-ones. Later on, a procedure was established based on generating the amidine in situ by a copper-catalyzed reaction of terminal allq nes, sulfonyl azide and o-iodo-anilines. The desired quinazolinones can be produced by carbonylation with Pd(OAc)2-DPPB-NEt3-THF as the reaction system. In the same year, Alper s group developed a procedure for 2,3-dihydro-4(lH)-quinazolinone preparation. The reaction started with the reaction of 2-iodoanilines and N-toluenesulfonyl aldimines followed by palladium-catalyzed intramolecular... 

In 2009, a simple and practical copper-catalyzed method for the synthesis of 1,2,4-benzothiadiazine 1,1-dioxide derivatives was developed. " The reaction proceeded via cascade reactions of substituted 2-halobenzenesulfo-namides with amidines, and the corresponding products were formed in good yields (Scheme 3.75). The reaction was proposed to start with C-N coupling then intramolecular transamination to release ammonia and provide the final product. Later on, a procedure for the synthesis of the same products via intramolecular cyclization of o-bromoarylsulfonylated amidines was developed as well. ... 

Cyclocondensation routes also provide access to pyrimidines. 2,3-Disubstituted pyrido[2,3-/i]-quinazolin-4(3//)-ones are obtained via cyclocondensation of 5-aminoquinoline-6-caiboxylic acid with acid chlorides <02SC235>. 5,6,8-Trialkyl-7-methoxy-2-aminoquinazolines are obtained from 1,3-dimethoxybenzenes via cyclocondensation of intermediate dihydrobenzenes with guanidine carbonate <02TL3295>. Diastereoselective intramolecular hetero Diels-Alder cyclization of a pyrazole carboxaldehyde condensed onto 1,3-dimethylbarbituric acid (101) gave polycyclic heterocycle 102 <02T531>. An efficient one-step synthesis of cyclobutene-annelated pyrimidinones 103 from methyl 2-chloro-2-cyclopropylideneacetate and amidines has been... 

The reactivity of coordinated nitriles towards nucleophiles, and electrophiles when deprotonated, has been of major interest. Addition of OH- to the nitrile carbon occurs readily in alkaline solution, kobs = oh[OH-]) and the rate is increased some 106—107 times by coordination (equation 24).176177 k0H has values of 1-50mol-1 dm3 s 1 for R = alkyl177 [e.g. 3.4 (Me) 35 (CH=CH,)j and varies over a wider range for substituted benzonitriles following a Hammett relationship.For 2-cyanoben-zonitrile addition of one equivalent of OH is followed by intramolecular amidine formation on treatment with further alkali (29), or by rearrangement in acid and hydrolysis to the diamide (31), or cyclization to the alternative amidine isomer (32 Scheme 17).179 The alkaline hydrolysis of the... 

Cyclization of amidines 1 to the corresponding quinoxalin-3-amine 1-oxides 2 can be readily achieved by reaction with bases. This ring closure occurs via deprotonation of the benzyl group and intramolecular nucleophilic addition to the nitro group giving structurally definite compounds, in contrast to the mono-A -oxidation reaction of the parent hcterocycles (sec Section6.3.2.1.4.1.). ... 

Diazabicyclo[4.3.0]nonene-based peptidomimetics with a quaternary chiral centre are prepared via intramolecular condensation of A -aminopropyl-y-lactam [27]. Reductive amination of oxazolidinone aldehydes with A -monoprotected propylenediamine give A -phthalimidopropyl lactams however, trials of cyclization to bicyclic amidines after deprotection under dehydration conditions are unsuccessful. To solve this problem, the phthalimides are converted to thiolactams with Lawesson reagent. Deprotection followed by treatment with mercury (11) chloride (HgCl2) yields desired cyclic amidines (Scheme 3.14). 

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