Amides heterocyclic synthesis, intramolecular

The synthesis of (5 5 5) fused heterocycle 62 has been achieved via intramolecular Diels-Alder reaction involving a series of A-alkenyl-substituted furanyl amides 494 (Scheme 112) <2006JOC5432>. 

The synthesis of (6 5 6) fused heterocycles may involve one-pot double intramolecular cyclocondensations. A typical example of this reaction is the formation of amide intermediate 247 from 246, which further cyclizes to give pyridopurine derivative 248 (Scheme 13) <1995TL4249>. 

The intramolecular reaction between carbenoids and amides is clearly emerging as a powerful tool for the synthesis of saturated oxazolo[3,2-tf]pyridine derivatives as shown by the cyclization of simple to extremely functionalized substrates 379 <2003CC440> and 381 <20050L47> (Scheme 100) trapping the intermediate isomtinchnone 1,3-dipoles by external (MeOH) or internal (indole) nucleophiles results in new heterocyclic fused systems with especially high efficiency. 

Removal of the amide function is much easier if the reaction is intramolecular, and —CONEt2 amides (sometimes even —CONPr-i2 amides) may be converted to lactones, lactams and other heterocycles in this way . Addition of an aldehyde or ketone as an electrophile generates a hydroxyl group (in some cases, atroposelectively, as it happens —though this is usually irrelevant to the stereochemistry of the product) which cyclizes to give a lactone via a benzylic cation in acid. This reaction has found wide use in the synthesis of polycyclic aromatics, particularly alkaloids. 

The N-heterocyclic alkenes derived from ring-closing metathesis are useful substrates for further transformation. In a synthesis directed toward the insecticidal cripowellin 12, Dieter Enders of RWTH Aachen has shown (Angew. Chem. Int. Ed. 2005,44, 3766) that the tertiary amide 8 cyclizes efficiently to the nine-membered alkene 9. The vision was that an intramolecular Heck cyclization could then deliver the cripowellin skeleton. Indeed, the Heck did proceed, and, depending on conditions, could be directed toward either 10 or 11. Unfortunately, the conformation of 9 is such that the cyclization proceeded cleanly across the undesired face. Nevertheless, both 10 and 11 appear to be valuable intermediates for further transformation. 

In a recent report, Padwa [64] disclosed a general method of wide applicability for constructing a variety of heterocyclic systems. It involved an amino furan ester as a more reactive four carbon component vis avis a pyrone in intramolecular Diels-Alder addition to an unactivated olefin. This method as applied to the synthesis of anhydrolycorinone consisted of the preparation of the tertiary amide 240 (Scheme 40) and its subsequent thermolysis to the N-o-bromoaroylindoline 241. It is believed that the initially formed cycloadduct 242 opened to the acyl iminium oxyanion 243, which by prototropy and dehydration generated 241. The latter, on photolysis in the presence of bis (tri-n-butyltin), furnished the tetracyclic ester 244, which was hydrolysed and decafboxylated to anhydrolycorinone as in the previous synthesis. 

There have been several reports of the use of intramolecular displacements of nitro groups in the synthesis of heterocyclic compounds. Thus, reaction16 of the intermediate (2) with a strong base in DMF results in the substitution of a nitro group by the amide function to yield a dibenzothiazepinone derivative (3). Nucleophilic addition across the double bond of 2,4,6-trinitrostyrene may occur with thiophenol, aniline, and aliphatic amines. The adducts so formed with primary amines may undergo intramolecular substitution of an o-nitro group to give IV-substituted 4,6-dinitroindoles.17... 

Classical reactions involving nucleophiles such as saponification ("OH as the nucleophile), aminolysis (with amines also ammonia in ammonolysis reactions), transesterification (alkoxides, "OR) and others (hydrazinolysis, hydroxamic acid synthesis, etc.) have been adapted to solid phane and used to obtain, for instance, carboxylic acids, amides and esters. Internal or intramolecular nucleophilic attack has been employed to obtain cyclic products such as lactones, lactams (including cyclic peptides) and a great variety of heterocycles (hydantoins, diketopiperazines, benzodiazepinones, etc.). 

Under strictly anhydrous conditions, the iminophosphorane intermediate that is formed as a result of the Staudinger reaction can react with aldehydes and ketones in an intermolecular fashion (as in the synthesis of imine 36 described above) or intramolecularly with a variety of carbonyl containing functional groups to afford a host of products. Nitrogen containing ring systems such as cyclic imines (44) represent just one of the many products one can prepare and the reaction is particularly well suited for the facile synthesis of five, six, and seven-membered rings. In addition to aldehydes and ketones, carboxylic acids, esters, thio-esters, and amides can also react in an intramolecular fashion to trap an iminophosphorane to afford a variety of heterocycles. Examples from the current literature are described in Section 2.5.5. 

Heterocycles are almost invariably formed by inter- and intramolecular Schiff base or lactam formation. We cite here the classical Knorr pyrrole synthesis (see Scheme 1.3.4) and Baeyer s barbituric acid synthesis, where the amide nitrogen atoms of urea are nucleophilic enough to add to malonic acid esters (Scheme 1.4.2). 

The isoquinoline syntheses, which utilize intramolecular S Ar reactions for building the heterocycle, are of greater preparative importance [116]. For instance, on treatment with strong protic acids (H2SO4, polyphosphoric acid), Lewis acid or POCI3, A-(2-arylethyl)amides 46 cyclize giving 1-substituted 3,4-dihydroisoquinolines 47 Bischler-Napieralski synthesis) ... 

Nitrogen Heterocycles.- Intramolecular Wittig reactions have been used to construct heterocyclic rings in, for example, the synthesis of N-alkyl-3-pyrrolines (193) (Scheme 18) and that of 2-methyl-3-(aryl/alkyl)-l-oxo-l,2-dihydroisoquinolines (195) by a one-pot synthesis from the amides (194) (Scheme 19). ... 

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