Amide intramolecular cyclization

In contrast to the above additions A-allyl- and substituted A-allyl-amides, -urethanes, -ureas and -thioureas undergo intramolecular cyclization only in 6(3-96% sulfuric acid to give the corresponding oxazolinium and thiazolinium salts. Treatment of these cations with base yields 2-oxazolines and 2-thiazolines in moderate to good yields. The reaction is illustrated by the conversion of A-2-phenylallylacetamide (342) into 2,5-dimethyl-5-phenyl-2-oxazoline (343) in 70% yield 70JOC3768) (see also Chapter 4.19). 

A series of amides has been prepared as protective groups that are cleaved by intramolecular cyclization after activation, by reduction of a nitro group, or by activation by other chemical means. These groups have not found much use since the first edition of this volume and are therefore only listed for completeness. The concept is generalized in the following scheme ... 

Particularly interesting are the results obtained with the phosphonium ylides including an acyl rest derived from aminoacid if the N-H bond reactivity is blocked by an amide protection, the alkyne formation takes place [25,27], but if the N-H bond is not deactivated, an intramolecular cyclization occurs to give a new stabilized ylide [27,28]. 

There are two important rhodium-catalyzed transformations that are broadly used in domino processes as the primary step. The first route is the formation of keto carbenoids by treatment of diazo keto compounds with Rh11 salts. This is then followed by the generation of a 1,3-dipole by an intramolecular cyclization of the keto carbenoid onto an oxygen atom of a neighboring keto group and an inter- or intramolecular 1,3-dipolar cycloaddition. A noteworthy point here is that the insertion can also take place onto carbonyl groups of aldehydes, esters, and amides. Moreover, cycloadditions of Rh-carbenes and ring chain isomerizations will also be discussed in this section. 

A series of new pyrazoloindolizinium salts has been prepared for their interest as dyestuffs. The amide 278 undergoes an intramolecular cyclization to the tricycle 279 upon heating in an ethanol/piperidine mixture. The methylene group of this can then react with different electrophiles, for example, aldehydes, to extend the chromo-phore <2002JCCS571> (Scheme 76). 

Ketal 219 undergoes intramolecular cyclization to intermediate imidazopyridine 220 which is a precursor to amide 221 (Scheme 9) <2004TL553>. 

Cyclisation of an NH amide toward a cyclic thionium ion was described for the synthesis of a tetrahydropyrrolo-[l,2-tf]pyrimidine-2,6(l//,7//)-dione 351. Compound 349 was transformed to 351 in two steps. The first one is the formation of a transient alkylthio-substituted lactam 350 from amidothioacetal 349 in the presence of dimethyl-(methylthio)sulfonium tetrafluoborate (DMTSF) followed by intramolecular cyclization <2000JOC235>. 

Azetidones (p-lactams) are generally obtained in high yield from (3-halopropion-amides (Table 5.18) and the low yield from the reaction of N-phenyl (3-chloropropi-onamide can be reconciled with the isolation of A-phenyl acrylamide in 58% yield [34]. The unwanted elimination reaction can be obviated by conducting the cyclization in a soliddiquid system under high dilution [35, 36]. Azetidones are also formed by a predominant intramolecular cyclization of intermolecular dimerization to yield piperazine-2,5-diones, or intramolecular alkylation to yield aziridones. Aone-pot formation of azetidones in 45-58% yield from the amine and P-bromocarboxylic acid chloride has also been reported [38]. 

Sames et al. have reported the intramolecular cyclization of alkene-amide substrates catalyzed by [Ir(COE)2Cl]2 and the A-heterocyclic carbene ligand, N, A -bis-(2,6-diisopropylphenyl)-imidazolyl, via olefin insertion following oxidative addition of an sp C-H bond (Scheme 11) [117]. 

Likewise, aryllithiums generated by lithium-iodine exchange undergo intramolecular cyclization to give pyrrolo-azepine 72. The best results were obtained when Weinreb (R = Me, = OMe) or morpholine amides were used as internal electrophiles, resulting in 66 and 70% yields, respectively (Equation (7) (2005T331D). 

The proposed reaction pathway invokes initial formation of carbonyl ylide 100 by intramolecular cyclization of the intermediate keto carbenoid onto the oxygen atom of the amide. Subsequent isomerization to the azomethine ylide is followed by 1,3-dipolar cycloaddition to DMAD to furnish the intermediate cycloadduct 101, which undergoes in situ alkoxy 1,3-shift to the final drhydropyrrolizine 102 (Scheme 3.28). 

Ring opening of a 4-(hydroxyalkyl)-substituted oxazolone using dimethylamine gives an amide 245 that can be used as an intermediate in a subsequent intramolecular cyclization to prepare lactones 247 (Scheme 1.19) ... 

Radical cyclizations are often used in ring formations and are an effective methodology in the synthesis of piperidines. The intramolecular cyclization of an oxime ether, such as 63 onto an aldehyde or ketone gives a new entry into cyclic amino alcohols <99JOC2003, 99H(51)2711>. Similarly, reaction of a terminal acetylene with BujSnH generates a vinyl radical, which will cyclize with an imine moiety to give 3-methylenepiperidine <99TL1515>. The indolizidine alkaloid ipalbidine was prepared by a sulfur-controlled 6-exo-selective radical cyclization of an a/p/ia-phenylthio amide <99H(50)31>. 

A reaction by Clough et al. comes close to the direct synthesis shown in Scheme 1 (89TL7469). Here amides (62) react in a radical mechanism to 4-methylene compounds (63) that with 03/PPh3 are converted to tetramic acids (64). (See Fig. 29.) Several authors, however, prepared esters of 4-amino-3-oxo-butanoic acid, which served as precursors for intramolecular cyclization to tetramic acids (82JHC883). Koehler and Gerlach in an initial stage of a synthesis of dysidine, contained in marine sponge... 

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 this synthetic sequence, displacement of the benzylic chloride from o-chlorobenzylchloride 100, with ethyl cyanoacetate anion afforded 3-(2-chlorophenyl)-2-carboethoxypropionitrile 101 in 68% yield after distillation. Saponification of the ethyl ester followed by thermal decarboxylation and fractional vacuum distillation, provided 3-(2-chlorophenyl)propionitrile 102 in 92% yield. Intramolecular cyclization was accomplished with sodium amide in liquid ammonia to afford 1-cyanobenzocyclobutene 103 as a colorless liquid in a... 

Intramolecular cyclization of allylsilanes.4 p-Keto esters (or amides) substituted in the a-position by an allylsilane undergo diastereospecific cyclization in the presence of TiCl4 (chelation controlled). Cyclizations induced by F" or BF3 etherate give mixtures of diastereomers. 

Intramolecular cyclization of a, -enamide esters Reaction of the a,(3-en-amide (1) with either trimethylsilyl triflate (1 equiv.) or t-butyldimethylsilyl triflate (1 equiv.) and N(C2H5)3 at 15° results in the benzo[a]quinolizidine 2 in high yield. 

The formation of compound 175 could be rationalized in terms of an unprecedented domino allene amidation/intramolecular Heck-type reaction. Compound 176 must be the nonisolable intermediate. A likely mechanism for 176 should involve a (ji-allyl)palladium intermediate. The allene-palladium complex 177 is formed initially and suffers a nucleophilic attack by the bromide to produce a cr-allylpalladium intermediate, which rapidly equilibrates to the corresponding (ji-allyl)palladium intermediate 178. Then, an intramolecular amidation reaction on the (ji-allyl)palladium complex must account for intermediate 176 formation. Compound 176 evolves to tricycle 175 via a Heck-type-coupling reaction. The alkenylpalladium intermediate 179, generated in the 7-exo-dig cyclization of bro-moenyne 176, was trapped by the bromide anion to yield the fused tricycle 175 (Scheme 62). Thus, the same catalytic system is able to promote two different, but sequential catalytic cycles. 

Mitsunobu reaction. The Mitsunobu reaction is an intramolecular cyclization of suitable amides (Scheme 4). 

Moeller has more recently contributed a series of reports describing the further use of this reaction in synthesis. Oxidation of the unsaturated amide 71 in methanolic acetonitrile afforded a substance 72 (equation 37) which could subsequently be converted into conformationally restricted peptide mimics99. Further, anodic oxidation of 73 resulted in intramolecular cyclization to afford 74 (equation 38), which could be converted into bicyclic reverse-turn peptidomimetics100. A similar intramolecular anodic cyclization of 75 into 76 (equation 39) was employed as the key step in total syntheses of the natural products (—)-A58365A and (+)-A58365B101. 

The reaction of methyl 10, l l -dihydropyrrolo[ l, Z-b [ l, 2,5]bcnzothiadiazcpinc-l l -acetate 5,5-dioxide 73 or the corresponding ethyl ester 74 with potassium hydroxide in EtOH at 25 °C gave the acid 75 (Scheme 14), which upon treatment with trifluoroacetic anhydride in tetrahydrofuran (THF) underwent intramolecular cyclization to afford 76. The 1,2,5-thiadiazepines 73 and 74 were then heated with an excess of concentrated ammonium hydroxide to give the carboxamide 77. The acid 75 upon reaction with 4-chlorophenol, 4-chlorobenzyl alcohol, or 4-chloroaniline in the presence of iV-(3-dimethylaminopropyl)-iV -ethylcarbodiimide hydrochloride (EDCI) and 4-dimethylaminopyridine (DMAP) afforded the respective esters and amide 78-80 <1996FES425>. 

Intramolecular cyclization of bis(amides) 106 (X = 0 R1, R2 = Me, Ph, 4-BrC6H4) (Scheme 20) on treatment with Ph3PBr2 in the presence of triethylamine gave the corresponding benzoxadiazepines 107 in 52-74% yields <1988M1279>. Similarly, reaction of bis(thioureas) 106 (X = S R1 = R2 = NHBu-/, arylamino) with I2/KI/KOH system in ethanol afforded in 68-79% yields the benzothiadiazepines 107, existing as exocyclic bis(imino) tautomers... 

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