Acid-mediated cyclization

Skraup proposed a simple mechanism involving imine formation followed by an acid-mediated cyclization. Unfortunately the observed regioselectivity is not consistent with the proposed mechanism when, for example, electron-rich aniline 4 reacts with a, 3-unsaturated aldehyde 5 to give quinoline 6. ... 

Dibenz[c 1c ]azepine (32 a) is obtained by acid-mediated cyclization of 2 -(aminomethyl)bi-phenyl-2-carbaldehyde (31 a), which is generated in situ by reduction of the oxime acetal 30a.85 The acetyl 30 a and benzoyl 30c oximes behave similarly and give the dimethyl and diphenyl derivative 32 b and 32 c, respectively. 

In an analogous manner, the same authors have synthesized the dihydro tricyclic purine derivative 199 via a polyphosphoric acid-mediated cyclization of 198 (Equation 51) <1995CC2041>. 

For a Lewis-acid-mediated cyclization reaction of a tryptamine-derived vinylogous amide that affords the Aspidosperma skeleton, see Huizenga RH, Pandit UK (1991) Tetrahedron 47 4155 1164... 

A Mitsunobu reaction then inverts the C-4 configuration to provide compound 151, and subsequent isomerization provides compound 152, which is ready for Lewis acid-mediated cyclization to construct the eight-membered firing. Using MeiAlOTf as a catalyst, intramolecular cyclization occurs, giving product 153 in which A, B, and C rings have been introduced with the desired stereochemistry (Scheme 7-45). 

Isoquinoline synthesis via acid-mediated cyclization of the appropriate ami-noacetal intermediate. 

This approach is used for the syntheses of fused heterocycles which have a [l,3]-heteroatom juxtaposition in one of the rings <1996CHEC-II(7)49>. The unambiguous synthesis of tetrahydro-3//-benzothieno[2,3- / imidazole 87, as a target for the potential treatment of anxiety disorders, was accomplished starting from commercially available ethyl 2-amino-4,5,6,7-tetrahydro-benzothiophene-3-carboxylate 85 the key formation of the bicyclic heterocycle occurred through a final acid-mediated cyclization of 86 (Scheme 17) <1997SC473>. 

Oxindole 89 was cleanly demethylated upon treatment with boron tribromide. The resulting oxindole 90 was subjected to the prenylation conditions, and the desired alkylated product 91 was obtained in 52% yield. The epoxidation/Lewis acid-mediated cyclization proved to be successful on this substrate. The epoxide product was directly treated with SnCl4 in THF to provided the desired 92. When oxindole 92 was treated with NaBHt (1.6 equivjand BF3 OEt2 (3.5 equiv) in THF, the desired 93 was obtained. The indole 93 was treated with TBDMSC1 and imidazole in DMF, to provide the required O-silylated indole, which was easily converted to the gramine 94 through the well known Mannich procedure. 

A stereoselective, Lewis acid-mediated cyclization of l-substituted-2-naphthols (41) has been reported to produce spirocyclic ketones (43). Evidence has been presented for the involvement of the cyclic aluminium intermediate (42).50... 

The synthesis of the 1,4-oxazepine 179 involved the formation of intermediate 178. The latter has been obtained by the three-component reaction of amine 175, aldehyde 176, and benzotriazole, leading to the intermediate 177, which underwent dehydrative cyclization to generate 178. Lewis acid-mediated cyclization with the loss of benzotriazole anion produced the interesting 1,4-oxazepine 179 (Scheme 29) <2001JOC5590>. A similar scandium or copper triflate-catalyzed reaction has been reported <1996SL871>. 

Pyrrolo-thiazepine 236 was obtained by connecting the a-carbon of the pyrrole moiety with the carbonyl group of 237 using phosphorus pentachloride in anhydrous dichloromethane (Equation 20) <2003MOL678>. A similar procedure was followed by Campiani et al. <1997EJM241>. Petrova et al. reported the synthesis of the related imidazothiazepine by polyphosphoric acid-mediated cyclization <2003SC4355>. 

Hydrogenolysis of the racemic isoxazolyl alcohol 955 followed by an acid-mediated cyclization of the resulting diketone provides the dihydropyran-4-one 956, an intermediate during a synthesis of C-aryl glycosides (Equation 373) <20020L977>. 

Two short syntheses of P-lapachone from readily available naphthols and 3-methylbut-2-enal via a mild phenyl-boronic acid mediated cyclization to 2//-chromenes have been reported. Catalytic hydrogenation of 2H-chromenes with H /Pd-C in ethyl acetate afforded the corresponding naturally occurring chromanes (72) and (73). Oxidation of the adequate chromane with an excess of cerium ammonium nitrate (CAN) furnished P-lapachone in 62% yield [153]. 

In the laboratory of P.G. Steel, a five-step synthesis of ( )-epiasarinin from piperonal was developed. The key steps in the sequence involved the Darzens condensation, aikenyi epoxide-dihydrofuran rearrangement and a Lewis acid mediated cyclization. The desired vinyl epoxide intermediate was prepared by treating the solution of ( )-methyl-4-bromocrotonate and piperonal with LDA, then quenching the reaction mixture with mild acid (NH4CI). 

Similar acid mediated cyclizations have been reported on a variety of substrates. For example, as shown in Scheme 7.3.2, Casiraghi, etal.,14 treated 2,3,4,6-tetra-O-benzyl-D-glucopyranose with a pyrrole-derived Grignard reagent and a titanium based Lewis acid. As shown, the addition proceeded in 64% yield with the formation of a single diasteriomer. Subsequent exposure to an acidic DOWEX resin provided a 50% yield of the p-C-glycoside and an additional 21% isolated as the corresponding a anomer. 

Ketals are capable of being formed under acidic conditions. Consequently, this technology compliments the acid mediated cyclizations set forth in the... 

A remarkable observation is the cyclization of biscarbamate (194) to y-lactone (195) mediated by methanesulfonic acid (equation 133). No trace of the expected 8-lactone is formed, presumably because of the unfavorable ester geometry in the transition state required for six-membered ring formation. Such problems with 8-lactone formation have been observed also in Diels-Alder chemistry. A nice example related to A-acyliminium chemistry is the thermal hetero Diels-Alder reaction of acylimine precursor (196) to bicyclic -y-lactone (197) in good yield. The corresponding intramolecular cycloaddition of (198) fails. Finally, Lewis acid mediated cyclization of allylsilane (199) is unsuccessful, although lactonization of (200) proceeds very well (equation 135, cf. equation 119). ... 

Table 2. Lewis Acid Mediated Cyclization of 2,6-Dimetbyl-5-heptenal...

The above products can be regarded as examples of 3,6-dihydro-2//-1,3-oxazines. Monocyclic representatives of 5,6-dihydro-4//-l,3-oxazines (339) are readily obtained through the acid-mediated cyclization of 3-amidopropanols (338) (Equation (36)) <82MI 605-0l>. Spirocyclic 2-aryl-5,6-dihydro-4//-1,3-oxazines (341) are available through the oxidative cyclization of 4-(A -aroylamino-ethyl)phenols (340) by treatment with thallium(III) trifluoroacetate in trifluoroacetic acid (Equation... 

Methyl-l,3-oxazine-2,4-dione (359) is obtained by the acid-mediated cyclization of the vinyl ether (358) (Equation (42)) <79CCC269>. 

For reviews and accounts, see (a) Hiemstra H (1998) Allenes in novel palladium-catalyzed and acid-mediated cyclization processes. Curr Trends Org Synth (b) Yamamoto Y, Radhakrishnan U (1999) Chem Soc Rev 28 199 (c) Larock RC (1999) J Organomet Chem 576 111 (d) Grigg R,Sridharan V (1999) J Organomet Chem 576 65 (e) Zimmer... 

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