Intramolecular cyclizations applications

While esters do not usually react with enamines and can, in fact, be substituents in the azeotropic preparation of enamines, they can be used in acylation reactions when these involve intramolecular cyclizations. Such reactions have been observed even at room temperature when they lead to the formation of five- and six-membered vinylogous lactams (362). Applications to precursors for azasteroids (40S) and alkaloids (309,406) are key steps in synthetic sequences. 

Intramolecular cyclization of sulfonyl radicals is almost absent from literature. The fact that free radical cyclization has been the subject of a large number of studies and applications in the last decade in organic chemistry48 and that sulfonyl radicals add quickly to multiple bonds (vide infra) makes cyclization of sulfonyl radicals a rather attractive area. Recently, Johnson and Derenne49 studied the reaction of 6-methylhept-5-en-2-ylcobaloxime(III) with sulfur dioxide and, based on the product analysis, they suggested reaction 15 to be an intermediate step. 

The mechanism of palladium-catalyzed intramolecular cyclization of o-bromo(aminoalkyl)benzenes has been discussed earlier (see Scheme 50 in Section IV,A,4). This approach is illustrated by the preparation of 1,2,3,4-tetrahydroisoquinolin-l-ones in Scheme 146,86 and examples of applications in benzazepinone synthesis are given later (see Scheme 173 in Section VI,B). 

Malonic acid allylic esters undergo intramolecular cyclization reaction under solid-liquid phase transfer catalytic conditions in the presence of Aliquat 336, potassium carbonate, and iodine (Eq. 60) [84]. Application of microwave irradiation to this procedure enabled 2-3-fold reduction in the reaction time compared with conventional conditions. It was found that use of microwaves affected the exo/endo diastereoi-somers ratio - a linear correlation between microwave power and exo isomer concentration was observed [85]. 

Most of the work on the C-N bond-forming crosscoupling reactions has concentrated on the formation of aromatic C-N bonds. Recent studies show that the application of cross-coupling reactions to alkenyl halides or triflates furnished enamines (Scheme 19) (for palladium-catalyzed reaction, see 28,28a-28d, and for copper-catalyzed reaction, see 28e-28g). Brookhart et al. studied the palladium-catalyzed amination of 2-triflatotropone 109 for the synthesis of 2-anilinotropone 110.28 It was found that the reaction of 109 proceeded effectively in the presence of racemic BINAP and a base. As a simple method for the synthesis of enamines, the palladium-catalyzed reactions of alkenyl bromide 111 with secondary amine were achieved under similar conditions.2841 The water-sensitive enamine 112 was isolated as pure compound after dilution with hexane and filtration through Celite. The intramolecular cyclization of /3-lactam 113, having a vinyl bromide moiety, was investigated by Mori s... 

Applications of the aforementioned methodology are also found in the total synthesis of plagiochin D to link a 16-membered biaryl system [47], as well as to the intramolecular cyclization of di-benzyl halides [45, 48]. Additional examples include dithienothiophene (40) from dithienyl bromide 39 [49] and carbazole 42 from diarylbromide 41 [50]. 

The present volume contains 13 chapters written by experts from 11 countries, and treats topics that were not covered, or that are complementary to topics covered in Volume 1. They include chapters on mass spectra and NMR, two chapters on photochemistry complementing an earlier chapter on synthetic application of the photochemistry of dienes and polyenes. Two chapters deal with intermolecular cyclization and with cycloadditions, and complement a chapter in Volume 1 on intramolecular cyclization, while the chapter on reactions of dienes in water and hydrogen-bonding environments deals partially with cycloaddition in unusual media and complements the earlier chapter on reactions under pressure. The chapters on nucleophiliic and electrophilic additions complements the earlier chapter on radical addition. The chapter on reduction complements the earlier ones on oxidation. Chapters on organometallic complexes, synthetic applications and rearrangement of dienes and polyenes are additional topics discussed. 

Intramolecular cyclization of 5-trimethylsilyloxy mesylates to produce 6-membered cyclic ethers is catalysed by tetra-n-butylammonium fluoride on a stoichiometric scale [52] and has found particular application in a high yielding (>90%) synthesis of 0-2-isocephams. 

Preparation of diketopiperazine as part of a bicyclic system was developed by a one-pot Ugi-4-center-3-component reaction (U-4C-3CR) [50]. A 3-keto or aldo acid 155 was used as bifunctional educt for an intramolecular Ugi reaction forming a five-membered ring. The application of C-protected amino acids 156 as amine components enables an intramolecular cyclization forming 2,6-piperazinediones 158 (Scheme 26). 

A few synthetic applications of palladium catalysis appeared this year. The palladium-catalyzed cyclization of amino allenes 58 occurs with coupling of aryl iodides or vinyl triflates at the 3-position <990L717, 99SL324>. The cyclization can also proceed by the exo-trig pathway, but under suitable reaction conditions the piperidine 59 is prepared selectively. The intramolecular cyclization of amines onto N-allylbenzotriazoles similarly affords piperidines <99JOC6066>. 

The application of the Friedlander reaction to 3-aminopyridine-2-carbaldehyde (135) gives good yields of the 2,3-disubstituted 1,5-naphthyridines (136) (75CR(C)(280)38l). The intramolecular cyclization of /3- (3-aminopyridinyl)acrylic acid (137) results in the formation of l,5-naphthyridin-2-one (138) (66JHC357), whilst the condensation of 3-aminopyridine-2-carboxylic acid or its esters (139) with active methylene compounds yields 4-oxo (132) and 4-hydroxy-2-oxo compounds (134 R = H) after hydrolysis and decarboxylation of the intermediates (140) and (134 R = C02Et). Reductive cyclization of the 3-nitropyridine derivative (141) gives the 1,5-naphthyridine (142) (71JOC450). 

Iwasawa, N. Funahashi, M. Hayakawa, S. Ikeno, T. Narasaka, K. Synthesis of mediumsized bicyclic compounds by intramolecular cyclization of cyclic /i-keto radicals generated from cyclopropanols using Mn(III) tris(pyri-dine-2-carboxylate) and its application to total synthesis of 10-isothiocyanatoguaia-6-ene. 

Application of the halogenation of y-aminoolefins preceding intramolecular cyclization has been applied to the synthesis of fused piperidines (Equation 33) <2003CC1918>. The presence of chiral substituents (e.g., via the nitrogen protecting group) generates a diastereoselective reaction (Equation 34). 

The exploitation of intramolecular Diels-Alder reactions has included synthetic applications in the thienopyrimidine series as well. Thus, the 1,2,4-triazine with a tethered alkyne (276) participates in an intramolecular cyclization, with concomitant loss of RCN, to produce the thienopyrimidine (277) (Equation (97)) <87JOC4287>. A similar reaction occurs with oxygen analogues. 

The application of the Wurtz coupling for the synthesis of [2.2](2,6)pyridinophane (85) from 2,6-bis(bromomethyl)pyridine (86) was already attempted in the fifties by Baker et al. [68]. Yet, the desired cyclophane could not be found. However, the intramolecular cyclization of 87 with phenyl Uthium or butyl lithium in ether led to in 3 and 28% yield, respectively [68]. The iwteraiolecular cyclization of 86 with phenyl lithium in dioxane gives a 9% yield of 85, too [69]. 

In a similar way, 2-oxazolidinones and tetrahydro-2//-l, 3-oxazin-2-ones have been prepared by the reaction of primary allyl amines and homoallyl amines10, respectively, with carbon dioxide and iodine in methanol via an intramolecular cyclization. Prolonged reaction for a week in the presence of cesium carbonate increases the yield to 70-90%. This reaction has a large applicability and the ease of the method makes it useful in organic synthesis. 

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