Acid-promoted cyclization

An interesting case of ipso intramolecular alkylation has been observed in the case of the acid-promoted cyclization of the amino alcohols (61). With trifluoroacetic acid the major product was the rearranged thienopyridine (62), whereas with polyphosphoric acid the product formed exclusively was the non-rearranged thienopyridine (63) (82CC793). 

No oxidizing agent is required for the sulfuric acid promoted cyclization of iV,iV-diphenyl-hydroxylamine to carbazole (13CB3304). The parallel conversion of diphenyl sulfoxide and diphenyl selenoxide to dibenzothiophene (23CB2275) and dibenzoselenophene (39CR(199)53l) is effected by treatment with sodamide. 

The acid promoted cyclization of AT-(2-chloroallyl)enaminones (Scheme 35a) provides the expected 3-methyltetrahydroindoles, whereas similar treatment of iV-(2-chloroallyl)anilines yields unexpectedly 2-, rather than 3-, methylindoles (Scheme 35b) (75JCS(Pl)U46). The course of the latter cyclization is not resolved although various intermediates, such as those shown, have been considered. The ring closure in the furan synthesis shown in Scheme 35c is catalyzed by mercury(II) ion (79JCs(Pl)316l). 

B. Lewis or Protic Acid Promoted Cyclizations 1. Synthesis of IndoloquinoUzines... 

The isoindolobenzazepine 380 obtained readily from prechilenine (139), 13-hydroxyoxyberberine (134), or oxybisberberine (130) (223), was recently isolated and named as chilenine (225). On reduction with zinc in hydrochloric acid-acetic acid 380 gave chilenamine (458) along with the hydroxylated product 459 (Scheme 94). Reduction of 380 followed by methylation and elimination of methanol gave pictonamine (460). On treatment with sodium hydroxide in aqueous methanol, 380 was converted to the isoindole 461, exposure of which to trifluoroacetic acid promoted cyclization and decarboxylation to afford the isoindoloisoquinoline neuvanine (462) (226). Its structure was revised (227) from the one originally proposed 463 (228). 

Van Muijlwijk-Koezen and co-workers utilized the reaction sequence beginning with the deprotonation of aminonitrile 139, which when trapped with various nitriles produced aminoquinazolines 140 upon acid-promoted cyclization, in their preparation of numerous aminoquinazoline as antagonists for the human adenosine A3 receptor <00JMC2227>. 

Once this process is explored with the model system to assess the level of enantioselectivity, we will then prepare alkyl zinc reagent 48 from 44 using standard methods - - and cross couple 48 to aryl bromide 18 using the appropriate chiral catalysts (Scheme 7). Although the acetonide stereocenter in 48 is somewhat remote from the coupling site, the stereocenter may serve to enhance the stereoselectivity of the cross-coupling process because the two possible products are diastereomers, not simply enantiomers. This reaction will produce 49 from (S)-48 and 30 from (R)-48 that can then be converted to epoxides 31 and 32 using standard methods. Epoxide 31 leads to heliannuol D 4 after base-promoted epoxide cyclization and deprotonation. Similarly, epoxide 32 leads to heliannuol A 1 after acid-promoted cyclization. 

An alternative focus based on known antitumor activity of adriamycin-type systems stimulated the synthesis of the aza-anthraquinones 599 and 600 (Scheme 177) (84CC897). Thus, synergistic chloro-oxazoline directed metalation of 597 with methyllithium followed by treatment with 2,5-dimethoxybenzaldehyde and acid-promoted cyclization provided the lactone 598. Radical bromination and base-induced hydrolysis gave an intermediate keto acid which, upon Friedel-Crafts cyclization with methanesulfonic acid, led to the aza-anthraquinone 599 in modest yield. The azanaphthacene dione 600 was prepared by an analogous series of reactions starting with 597. 

The unusual condensation between alloxan and o-amino-N,N-dimethylaniline yields the tetrahydroquinoxaline spiran 21.28 A possible mechanism for spiran formation involves the acid-promoted cyclization... 

Ipso intramolecular alkylation to (93) occurs in the acid-promoted cyclization of the amino alcohols (92) with trifluoroacetic acid. Polyphosphoric acid gave the non-rearranged thieno-pyridine (94)... 

Sulfuric acid promotes cyclization of (V./V-diphenylhydroxylamine (14) to carbazole (11) (13CB3306). The parallel conversions of diphenyl sulfoxide (15) and diphenyl selenoxide to dibenzothiophene (10) (23CB2275) and dibenzoselenophene (39CR(i99)53i) are effected by sodamide. 

This synthesis of benzo[6]thiophenes is probably the most widely exploited single method for such syntheses since its introduction about 1950 by a variety of workers. It is applicable to a great number of highly substituted benzo[6]thiophenes, and intermediates are generally readily available. In 1949 Werner (49RTC509) reported the synthesis of several 3-alkyl- and 2,3-dialkyl-benzo[( ]thiophenes by cyclodehydration of arylthioacetones (99) with phosphorus pentoxide or anhydrous zinc chloride. Arylthioacetaldehydes (99 R = H, R1=H, R2 = Me, Et or Ph) have been cyclized in 65-80% yields with phosphorus pentoxide. In 1950 Tilak (50PIA(A)(32)390) introduced the polyphosphoric acid-promoted cyclization of... 

There is little doubt, however, that the carbonyl compound which has been used most with o-hydroxyacetophenone in chromanone synthesis is benzaldehyde. This gives rise to a chalcone which cyclizes in acid or basic media to a flavanone (Scheme 227) (70JOC2286). During the acid-promoted cyclization of 5-acetamidochalcones, concomitant deacetylation occurs and 6-aminoflavanones result (56JOC1408). 

A final approach to the c -3a-arylhydroindole skeleton that has resulted in a concise total synthesis of ( )-epielwesine (449) featured the acid-promoted cyclization of (Z)-vinylsilane imines such as 575 (Scheme 53) (2/9). Thus, sequential alkylation of 3,4-(methylenedioxyphenyl)acetonitrile (432) with (Z)-4-bromo-l-butenyltrimethylsilane and l-bromo-2-chloroethane provided... 

Several bicyclic hydrazinium ions have been prepared and two synthetic strategies have emerged as generally useful, i.e., electrochemical oxidation and Lewis or Brpnsted acid-promoted cyclization.93 Oxidation of l,6-diazabicyclo[4.4.4]tetradecane, for example, (194) gives the intermediate radical cation (195) and the bicylic dication (196, eq 50).93a... 

Polymer-supported oxime 12 (see also Scheme 5) may also serve as a nucleophile in SflAr reactions (Scheme 9) [32]. This procedure afforded aryl oxime adducts 22 which were released as 3-aminobenzoisoxazoles by means of an acid-promoted cyclization. 

The acetal 49 undergoes acid promoted cyclization to form a mixture of linear- and angular-fused 2//-chromenes (Equation 27) <1997J(P1)1875>. 

Ethoxybut-3-en-2-ones and (E)-4-(dimethylamino)but-3-en-2-ones react with ethyl perfluoroalkanoates to form intermediate 728. Acid promoted cyclization of the intermediate 728 and subsequent elimination of HR1 affords 2-perfluoroalkyl-pyran-4-ones (Scheme 181) <1998T2819, 2000T7313>. 

Trifluoracetic acid-promoted cyclization/dehydration is used to construct a dihydropyran-4-one ring during the total synthesis of (—)-maurenone, establishing the relative stereochemistry of the natural product <2006JOC117>. A double aldol reaction forms two dihydropyran-4-one rings during the total syntheses of (—)- and (+)-membrenone C <20030L1729>. 

A Lewis-acid-promoted cyclization of ethene tricarboxylate derivatived aromatic compounds 1162 provides a route to isochroman-3-ones 1163 via a Friedel-Crafts intramolecular Michael addition protocol. The substrate must possess two ///f to-positioncd electron donating groups in order for the reaction to proceed (Equation 452) <20040BC3134>. 

Synthesis of imidazole-2-carboxaldehyde has previously been reported by manganese dioxide oxidation of the corresponding car-binol,4 by acid-promoted cyclization of 7V-(2,2-diethoxyethyl)-2,2-... 

Zeolites have also been shown to catalyze a variety of acid-promoted cyclizations. Many of these involve the formation of N-heterocycles via intramolecular amination reactions [75-77]. Some examples are shown in Fig. 2.24. 

Indole alkaloids The ester etiolate 1 undergoes 1,4-addition to the pyridinium salt 2 to afford, after acid-promoted cyclization, the tetracycle 3 as an epimeric mixture. The... 

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