Cyclization Products

Regioselectivity becomes important, if unsymmetric difunctional nitrogen components are used. In such cases two different reactions of the nitrogen nucleophile with the open-chain educt may be possible, one of which must be faster than the other. Hydrazone formation, for example, occurs more readily than hydrazinoLysis of an ester. In the second example, on the other hand, the amide is formed very rapidly from the acyl chloride, and only one cyclization product is observed. 

Other interesting regioselective reactions are carried out within the synthesis of nitrofurantoin. Benzaidehyde semicarbazone substitutes chlorine in chloroacetic ester with the most nucleophilic hydrazone nitrogen atom. Transamidation of the ester occurs with the di-protic outer nitrogen atom. Only one nucleophilic nitrogen atom remains in the cyclization product and reacts exclusively with carbonyl compounds. 

The cyclized products 393 can be prepared by the intramolecular coupling of diphenyl ether or diphenylamine(333,334]. The reaction has been applied to the synthesis of an alkaloid 394[335]. The intramolecular coupling of benzoyl-A-methylindole affords 5-methyl-5,10-dihydroindenol[l,2-b]indol-10-one (395) in 60% yield in AcOH[336]. Staurosporine aglycone (396) was prepared by the intramolecular coupling of an indole ring[337]. 

An efficient carboannulation proceeds by the reaction of vinylcyclopropane (135) or vinylcyclobutane with aryl halides. The multi-step reaction is explained by insertion of alkene, ring opening, diene formation, formation of the TT-allylpalladium 136 by the readdition of H—Pd—I, and its intramolecular reaction with the nucleophile to give the cyclized product 137[I08]. 

In the reaction of aryl and alkenyl halides with 1,3-pentadiene (248), amine and alcohol capture the 7r-allylpalladium intermediate to form 249. In the reactions of o-iodoaniline (250) and o-iodobenzyl alcohol (253) with 1,3-dienes, the amine and benzyl alcohol capture the Tr-allylpalladium intermediates 251 and 254 to give 252 and 255[173-175]. The reaction of o-iodoaniline (250) with 1,4-pen tadiene (256) affords the cyclized product 260 via arylpalladiuni formation, addition to the diene 256 to form 257. palladium migration (elimination of Pd—H and readdition to give 258) to form the Tr-allylpalladium 259, and intramolecular displacement of Tr-allylpalladium with the amine to form 260[176], o-Iodophenol reacts similarly. 

In the alkylative cyclization of the 1,6-enyne 372 with vinyl bromide, formation of both the five-membered ring 373 by exn mode carbopalladation and isomerization of the double bonds and the six-membered ring 374 by endo mode carbopalladation are observed[269]. Their ratio depends on the catalytic species. Also, the cyclization of the 1,6-enyne 375 with /i-bromostyrene (376) affords the endo product 377. The exo mode cyclization is commonly observed in many cases, and there are two possible mechanistic explanations for that observed in these examples. One is direct endo mode carbopalladation. The other is the exo mode carbopalladation to give 378 followed by cyclopropana-tion to form 379, and the subsequent cyclopropylcarbinyl-homoallyl rearrangement affords the six-membered ring 380. Careful determination of the E or Z structure of the double bond in the cyclized product 380 is crucial for the mechanistic discussion. 

Alkynyl)oxiranes also react with carbon nucleophiles to afford furan derivatives. Furanes of different types are obtained depending on the structure of the substrates. 7-Methyl-2-ethynyloxirane (95) reacts with acetoacetate to give the furan 97 by the elimination of formaldehyde from the cyclized product 96. The hydroxy ester of the alkylidenefuran 98 and the corresponding lactone 99 are obtained by the reaction of i-methyl-2-(2-propynyI)oxirane[40, 42]. 

Gassman and co-workers developed a synthetic route from anilines to indoles and oxindoles which involves [2.3]-sigmatropic rearrangement of anilinosul-fonium ylides. These can be prepared from Ai-chloroanilines and ot-thiomcthyl-ketones or from an aniline and a chlorosulfonium salt[l]. The latter sequence is preferable for anilines with ER substituents. Rearrangement and cyclizalion occurs on treatment of the anilinosulfonium salts with EtjN. The initial cyclization product is a 3-(methylthio)indole and these can be desulfurized with Raney nickel. Use of 2-(methylthio)acetaldehyde generates 2,3-unsubstituled indoles after desulfurization[2]. Treatment of 3-methylthioindoles with tri-fiuoroacetic acid/thiosalieylie acid is a possible alternative to Raney nickel for desulfurization[3]. 

Another interesting case is afforded by 2-alkyl-N-phenacyl or N-acetonylthiazolium salt (239), which in basic medium gives an intramolecular cyclization product. According to Reid et al. (502), this could... 

Write the structure of the Dieckmann cyclization product formed... 

The starting material in this example is the Dieckmann cyclization product of diethyl heptanedioate (see Problem 21 2a)... 

Insertion Reactions. Isocyanates also may undergo iasertion reactions with C—H bonds. Acidic compounds, such as 1,3-dicarbonyl compounds (6), react readily at room temperature to form carboxyamides. At higher temperatures carboxyamides frequentiy undergo secondary reactions leading to cyclized products (33,34). 

The acid-instabihty of erythromycin makes it susceptible to degradation in the stomach to intramolecular cyclization products lacking antimicrobial activity. Relatively water-insoluble, acid-stable salts, esters, and/or formulations have therefore been employed to protect erythromycin during passage through the stomach, to increase oral bioavakabihty, and to decrease the variabiUty of oral absorption. These various derivatives and formulations also mask the very bitter taste of macroHdes. 

There are reports of an increasing number of palladium-assisted reactions, in some of which the palladium has a catalytic function. Thus furan and thiophene undergo facile palladium-assisted alkenylation giving 2-substituted products. Benzo[6 Jfuran and TV- acetyl-indole yield cyclization products, dibenzofurans and carbazoles respectively, in addition to alkenylated products (8UOC851). The arylation of pyrroles can be effected by treatment with palladium acetate and an arene (Scheme 86) (81CC254). 

Methoxy 6( 2 Chlorobenzoyl)-ben2o(c acid (2).2 3-Metboxy-2(3-cblorobenzoyl)-benzolc acid 1 (1.0 g, 3.4 mmoQ was heated In cone. H2S04 (6 mL) for 1 h at 6S°C. The cooled reaction mixture was poured into ice and neutralized. The cyclized product was filtered off (0 2 g) and the filtrate was acidHIed to give 2, rrp 205°C. 

Deamination of the corresponding amine gives the allylic alcohol resulting from iQ dride shift as the main product and an increased amount of the cyclization product. 

With 4-iodoalkynes, the intermediate radicals can be trapped by activated alkenes and lead to cyclized products. ... 

If selenide additions are carried out in the presence of tri- -butylstannane, the radical generated by addition can be reduced by hydrogen abstraction. The chain is then continued by selenide abstraction by the stannyl radical. This leads to nonselenated addition and cyclization products. 

The cyclization product is thermally unstable relative to Z-stilbene and reverts to starting material unless trapped by an oxidizing agent. The extent of eyclization is solvent-dependent, with nonpolar solvents favoring cyclization more than polar ones. ° Whereas the quantum yield for Z-E isomerization is nearly constant at about 35%, the cyclization... 

Addition to 1,2-dimethyl- -piperideine or 1,2-dimethyl- -pyrroline is followed by intramolecular alkylation by the ester group as a side reaction to give 140 and 141 ( = 1, 2), respectively. Cyclization products 142 and... 

The addition of phenylisocyanate to aldehyde-derived enamines resulted in the formation of aminobutyrolactams (438,439). As aminal derivatives these produets can be hydrolyzed to the linear aldehyde amides and thus furnish a route to derivatives of the synthetically valuable malonaldehyde-acid system. With this class of reactions, a second acylation on nitrogen becomes possible and the six-membered cyclization products have been reported (440). Closely related to the reactions of enamines with isocyanates is the condensation of cyclohexanone with urea in base (441). 

The adaptation of the Bischler-Napieralski reaction to solid-phase synthesis has been described independently by two different groups. Meutermans reported the transformation of Merrifield resin-bound phenylalanine derivatives 32 to dihydroisoquinolines 33 in the presence of POCI3. The products 34 were liberated from the support using mixtures of HF/p-cresol. In contrast, Kunzer conducted solid-phase Bischler-Napieralski reactions on a 2-hydroxyethyl polystyrene support using the aromatic ring of the substrate 35 as a point of attachment to the resin. The cyclized products 36 were cleaved from the support by reaction with i-butylamine or n-pentylamine to afford 37. 

The rationale for the predominance of linear cyclization products versus angular cyclization products has been accepted as qualitative." The mechanism of the Combes reaction has been argued. It was initially proposed that cyclization to linear products was due to initial protonation of a more reactive site on the aromatic ring (1-position of 13 corrresponding to the 10-position of 15) thus, blocking cyclization to angular products. Bom showed this not to be the case for the cyclization of 2-naphthyl amino-2-penten-4-one. No 10-deutero material was observed. 

Petrow described the formation of 3-iminoketones from 3-keto-aldehydes and aniline. Cyclization in the presence of aniline hydrochloride and ZnCh smoothly provides the desired quinoline 26. Bis-imine 24 is the proposed intermediate that undergoes cyclization. The aldimine is more reactive than the ketimine toward cyclization thus, cyclization on the aldimine occurs. When the bis-imine is not formed, partial aniline migration can occur which results in mixtures of cyclized products. 

Conditions were also arrived at whereby one could obtain without rearrangement the cyclization product 31 from enamino-ketone 30. ... 

Both steric and electronic factors have been claimed to control the selectivity in the cyclization step. Not only the control of the selectivity on the ring closure but also the lack of activity toward cyclization was observed. In one example of this, methyl substituted aminoindole 96 provided cyclization product 99 while attempted cyclization of methyl ether 98 led to decomposition. ... 

With semicarbazones of lower a-keto acids the reaction proceeds with some difficulty or not at all. Thus, the semicarbazones of pyruvic acid cannot be cyclized and that of glyoxylic acid is predominantly hydrolyzed so that the yield of the cyclization product is only 20-25%. ° This reaction was used in work with a different object, for preparing 6-azauracil, for the first time. 

Decomposition of the diazonium salt of 2-amino-iV-methyl-iV-3 -pyridylaniline (205) in aqueous acid solution with copper powder at room temperature gave overall yields of cyclized products consisting of a mixture of i id-iV-methyl-3-carboline (206) (47.5%) and ind-N-methyl-jS-carboUne (207) (25.5%), in agreement with the proposed homolytic character of the reaction under these conditions. This constituted the first unambiguous synthesis of a simple 3-carboline derivative. 

Because of the extremely low solubility of the cyclized products, only the 8-acetyl-9-X oxo-6,9-dihydrothiazolo[5,4-g]quinoline was isolated. On the other hand, 6-substituted derivatives having the same possibility to produce linearly or angularly annelated thiazoloquinolines cyclize regioselectively. 

The cyclization products can be ethylated using ethyl iodide with K2CO3 in DMF to give in the case of thiazolo[4,5-g]- or [4,5-/i]quinolones a mixture of O- and N-ethylated products, whereas in the case of thiazolo[5,4-g]- or -[5,4-/i] quinolones only A-ethyl products arise. Products of 0-ethylation were prepared by... 

Alkylation of the cyclization product 115 and the following hydrolysis gave 9-alkyl substituted 6-oxo-6,9-dihydroimidazo[4,5-/i]quinoline-7-carboxylic acid derivatives 119, compounds useful as antibacterials (no data) [80JAP(K)1], 4(7)-Aminobenzimidazole can react with 1,3-diketones as a bidentate nucleophile, but with 2,4-pentanedione in glacial acetic acid it gives a Combes product, l//-6,8-dimethylimidazo[4,5-/i]quinoline 120, accompanied by 4(7)-acetamido-benzimidazole (91T7459). 

In cyclization of 6-aminoethylene substituted 1-methylbenzimidazole, an angularly annelated l//-l-methyl-8-ethoxycarbonyl-9-oxo-6,9-dihydroimidazo[5,4-/] quinolone 122 prevails over the sterically less hindered (9-oxo group vs 1-methyl group) linearly annelated imidazo[4,5-g]quinoline 123. Hydrolysis of the cyclization product produced the corresponding acid 124 (Scheme 39) (94CCC1145). 

The 6-methylacetylamino-l,2,3,4-tetrahydroquinoline, after nitration and separation of isomers, following reduction and deprotection, gave the 7-amino-6-methylamino derivative, which cyclized with cyanogen bromide. Alkylation of the cyclization products afforded inhibitors of thymidylate synthase, 5-substituted 2-amino-l//-l-methyl-5,6,7,8-tetrahydroimidazo[4,5-g]quinolines 136, designed for use in iterative protein crystal analysis (Scheme 42) (92JMC847). 

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