Regioselective cyclizations

The mechanism of formation of pyridines from a,P-unsatuiated nitriles and active cyano compounds has been investigated. These processes proceed through a Michael adduct which undergoes a regioselective cyclization to the corresponding pyridine <96H(43)33>. 

The intramolecular Pummerer reaction has been applied to the synthesis of simple quinolizidine alkaloids like lupinine <2000JOC2368>, and also to arenoquinolizine alkaloids. Thus, the 2-(2-piperidyl)indole 284 was converted to indolo[2,3- ]quinolizidine 287 following a protocol that has as the key step the regioselective cyclization onto the indole 3-position of a thionium ion generated by Pummerer reaction from the appropriately substituted compound... 

This reaction is applied to the intramolecular regioselective cyclization of the 3-alkoxybenzoeyelobutenedione 60 to 61, a precursor of nanaomycin A 62 [33], (Scheme 23)... 

Phenylthio)carbenoids 26 possessing different chain lengths (Scheme 12, n = 1,2, 3), namely, 4-, 5-, and 6-oxidoalkyl(phenylthio)carbenes (Table 6, entries 1, 7 and 8), undergo similar regioselective cyclization reactions to give 2-(phenylthio)cycloalkanols 27. 

A)-5,5-Dimethyl-thiazoline-4-carboxylic acid reacted efficiently with alkyl and aryl isothiocyanates to give bicyclic thiohydantoins 418. A similar diastereo- and regioselective cyclization of chiral l,3-thiazolidine-2,4-dicarboxylic acids was also reported (Equation 191) <1996JHC1099, 1998HCA744>. 

Heravi and co-workers have reported the solvent-free regioselective cyclization of 3-allylmercapto-l,2,4-triazoles to thiazolo[3,2,- ][l,2,4]triazoles over sulfuric acid adsorbed in silica gel <2006PS(181)377>, or over HZSM-5 zeolite using microwave irradiation <2006MI6, 2006IJH411>. 

Theoretical calculations were carried out for the rationalization of the ring closure reactions yielding thiazolo[2,3-7][l,2,4]triazinones 47 <2003PS1143>. PM3 and AMI methods were applied which revealed that the observed regioselective cyclization is in accordance of the charge control of the reaction. 

Indolylaminomethylenemalonates (681) were regioselectively cyclized on the action of acetic anhydride or trifluoroacetic anhydride in carbon tetrachloride at 10-20°C for 3 hr, to give 8-carbolines (682) in 22-75% yields (85ZOR432). 

Regioselective cyclization of /V-(4-benzoyl-5-benzimidazolyl)amino-methylenemalonates (969, R = H, Me) was observed. When the cyclization was carried out in polyphosphoric acid, then 4-phenylimidazo-[4,5-/]quinoline-5-carboxylates (970) were obtained, while the thermal cyclization in diphenyl ether at 200°C, or the cyclization in a mixture of phosphoryl chloride and polyphosphoric acid afforded 4-benzoyl-8-hydroxyimidazo[5,4-g]quinoline-7-carboxylates (971) (89KFZ692). 

Highly regioselective cyclizations of 3,4-, 4,5- and 5,6-unsaturated alcohols to yield tetrahydrofuranols and tetrahydropyranols have been carried out with the TS-I-H2O2 system (this is a titanium silicate molecular sieve-H202 complex.) The reactions involve the intermediate formation of epoxides and their Ni ring opening. 

Zimmerman and Hoffacker also observed a regioselective reaction subjecting various aryl-substituted 1,4-pentadienes to photoinduced electron transfer using DCN and DCA. The radical cations produced underwent a regioselective cyclization wherein one electron-deficient aryl group of one diarylvinyl moiety bonds to the (3-carbon of the second diarylvinyl group (Scheme 30) [41]. 

The a-enynyl complex Ru(Tp)[PhC=C(Ph)C=CPh](PMe Pr2) 10 efEciently catalyzed the regioselective cyclization of a,(D-alkynoic acids involving an anti-Markovnikov intramolecular addition to give unsaturated lactones [29] (Equation 10.5). 

Acid-catalyzed intramolecular attack of nucleophilic hydroperoxide function on an oxirane ring results in formation of 3-(l-hydroxyalkyl)endoperoxides. For example, epoxidation of unsaturated hydroperoxide 320 affords oxirane-hydroperoxide 321 (66%), which through acid-catalyzed regioselective cyclization gives 1,2-dioxolane 322 (70%) (Scheme 79) . This type of reaction is applicable also to a more complex epoxide-hydroperoxide such as 323, which cyclizes to polyfunctionalized 5-membered cyclic... 

The reactions of ethyl hippurate 352 with l,2-diimidoyl-l,2-dichloroethanes 353 afforded 6-imino-6//-l,3-oxazines 354 by regioselective cyclization via the carbon and oxygen atoms of the dianion formed by the dilithiation of 352... 

The orthogonal reactivities exhibited by IBr (2.5equiv at —78°C) and Au(PPh3)BF4 (5mol% at 0°C) in the activation of the alkene and alkyne groups of trichloroacetimidate 440 could be utilized in regioselective cyclizations toward 5,6-dihydro-4//-l,3-oxazine derivatives 441 or 442, respectively (Scheme 84) <2006OL3537>. 

A simple synthesis of 3-substituted and 23-disubstituted 4-chloiofuians was accomplished. It involves a CuCl/bipy-catalyzed regioselective cyclization of l-acetoxy-2.22-trichloroethyl allyl ether followed successively by dechloroacetoxylation with Zn dust and tandem dehydro-halogenation-aromatization with tBuOK/18-crown-6 <99CC2267>. 

A regioselective cyclization of pent-4-ynoic acid is catalyzed by a TpRu complex 825. The anti-Markovnikov 3,4-dihydropyran-2-one product is exclusively formed in excellent yield (Equation 339) <2001CC2324>. Similarly, alkynoic esters 826 undergo ICl-promoted iodolactonizations to afford 5-iodo-3,4-dihydropyran-2-ones in moderate yield (Equation 340) <2003JOC10175>. 

The regioselective anti-Markovnikov addition of benzoic acid to phenyl-acetylene has also been carried out with success at 111 °C in the presence of ruthenium complexes containing a tris(pyrazolyl)borate (Tp) ligand [RuCl(Tp)(cod), RuCl(Tp)(pyridine), RuCl(Tp)(N,N,Ar,AT-tetramethylethyl-enediamine )] with a stereoselectivity in favour of the (E)-enol ester isomer [22]. The o-enynyl complex Ru(Tp)[PhC=C(Ph)C=CPh](PMe/-Pr2) (C) efficiently catalyses the regioselective cyclization of a,cu-alkynoic acids to give en-docyclic enol lactones [23] (Eq. 2). 

Despite that the regioselective cyclization of 5-hexenyllithiums could be synthetically useful, in those years there was no real development of this methodology9, probably due to the lack of a convenient and efficient procedure for the preparation of unsaturated alkyllithiums and to the conventional belief that simple alkenes are not thought of as sites of nucleophilic attack. Moreover, this was a period when radical cyclizations and radical cascade reactions came to the fore10, and 5-hexenyl substrates were used as probes for radical intermediates in reactions suspected of proceeding via single-electron transfer (SET). 

Attention was centered on radical precursors in which the 3-pyridyl moiety was attached at the indole-3-position with the aim of directly producing the pyrido[4,3-b]carbazole skeleton of ellipticine by regioselective cyclization upon the 4-position of the pyridine ring. Satisfactorily, A-methyl and A-benzyl selenoesters 52a and 52b led to the ellipticine quinones 53a and 53b in acceptable yields (60 and 42% yield, respectively), after the radical cyclization and the in situ oxidation at the interannular methylene group. The cyclization was clearly less efficient from A-(methoxymethyl) selenoester 52c and no reaction was observed... 

Formation of pentacycle 55 was consistent with the radical addition-quinoline rearomatization-overoxidation sequence depicted below. Thus, the initially formed acyl radical L undergoes regioselective cyclization upon the 4-position of the quinoline ring to give the azacyclohexadienyl radical M, which is probably oxidized by hydrogen abstraction at the hands of the initiator AIBN <04AGE95>. A new hydrogen abstraction at the doubly... 

Regiochemistry of enamide photocyclization in this synthesis can also be controlled by the use of an ortho substituent that acts as an eliminating group on cyclization to the root of the substituent. Thus, the omethoxyl and bromo groups are used for this regioselective cyclization as exemplified by a number of total syntheses of alkaloids (19,20) (Scheme 37). 

The enamide 127 that is substituted in an ortho position of the benzyli-dene group was prepared to investigate regioselective cyclization under nonoxidative conditions. However, irradiation brought about an exclusive cyclization to the unsubstituted position to afford the 2,3,9,12-tetrameth-oxy-substituted protoberberine iodide 128 (Scheme 54). 

From a medicinal chemistry point of view, this approach can provide a wealth of camptothecins diversely substituted both in ring A, owing to the availability of anilines, immediate precursors of isonitriles, and at position 7, working on thepropargyl intermediates. Whereas para- and ortho-substituted isonitriles gave a regioselective cyclization, 3-substituted isonitriles gave a mixture of 9- and... 

A regioselective lithiation was achieved by treatment of 3-substituted benzo[3]furan 121 with -BuLi at 0°C in THE, and the 2-lithiated benzo[ ]furan so generated was allowed to couple with quinone monoketal followed by a regioselective cyclization to give kushecarpin A s analog 122 (Scheme 59) <2005TL7511>. 

Cyclization of fame sol.1 This complex (1) is superior to other Hg(II) reagents for regioselective cyclization of various famesol derivatives. The product (3) obtained in this... 

Chiral cyclopentanones.2 The regioselective cyclization of a-diazo-p-keto esters to cyclopentanones (11, 459) is also enantioselective with substrates derived from chiral alcohols. Preliminary studies show that steric factors affect the diastereoselectivity the highest diastereoselectivity is obtained with esters of the alcohol 1, which is available from camphor,3 and in which both the bomane and the naphthalene rings can exert steric effects on the diastereoselectivity. 

The stereo- and regioselective cyclizations of the allylic urethanes (199) to oxazolidin-2-ones and/or perhydropyrroIo[l,2-c][l,3]oxazin-l-ones by iodonium and bromonium dicollidine perchlorates in dichloromethane via intermediate 203 have been studied. In this same manner, 204 was generated from 200. In the cyclization of 201 in the presence of bromonium dicollidine perchlorate, the only product recovered was 205, while a similar reaction with isomer 202 resulted in a mixture of 206 and 207(1 5 ratio, respectively) (83JA654). 

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