Trig Cyclization Research Articles

Tandem radical cyclization-based strategy for the synthesis of oxa- and aza-cages: a case of fragmentation versus cyclization

Tandem radical cyclizations involving two successive radical cyclizations result in the formation of the oxa- and aza-cage compounds. Cyclization with the ketones or olefins without stabilizing groups led to oxa-cages via a fragmentation reaction. A new strategy for the synthesis of oxa- and aza-cage compounds based on tandem radical cyclizations is described. The iodides 1 lead to oxa-cages 3 after two tandem radical cyclizations. The ester 10aa on reaction with n -Bu 3 SnH and AIBN gives rise to the oxa-cage 12aa after two tandem 5- exo - trig cyclizations. On the other hand, reaction of the ketones 17aa and 21 under similar conditions furnished the oxa-cages 20aa and 23 , respectively, via a double 5- exo - trig tandem radical cyclization followed by fragmentation.

Manganese(III)-mediated facile synthesis of 3,4-dihydro-2(1 H)-quinolinones: selectivity of the 6- endo and 5- exo cyclization

The 4,4-bis(ethoxycarbonyl)-3,4-dihydro-2(1 H)-quinolinones 2 were easily synthesized by the oxidative 6- endo- trig cyclization of 2-[2-( N-arylamino)-2-oxoethyl]malonates 1 with manganese(III) acetate in good to excellent yields. The same reaction of N-(2,4-dimethoxyphenyl)-substituted malonate 1t exclusively produced the 5- exo-cyclized 4,4-bis(ethoxycarbonyl)-1-azaspiro[4,5]deca-6,9-diene-2,8-dione 5t instead of the corresponding dihydroquinolinone. The regioselectivity during the cyclization could be explained by the difference in the activation energy of the transition state of the 6- endo/5- exo cyclization.

Synthesis of substituted 2-aroyl-3-methylchromen-4-ones from isovanillin via 2-aroyl-3-methylchroman intermediates

The synthesis of substituted 2-aroyl-3-methylchromen-4-one from isovanillin is described. O-Allylphenol ( 2) prepared from isovanillin ( 1) was allowed to react with various α-bromoacetophenone ( 3) to produce 2-(2-allyl-3,4-dimethoxy)phenoxy-1-aroylethanones ( 4). The resultant 4 were treated with 2 equiv of potassium tert-butoxide to afford the substituted 2-aroyl-3-methylchromans ( 5) through an isomerization of an allylic double bond and a carbanion–olefin intramolecular 6- endo- trig cyclization reaction. Subsequently, resultant 5 were oxidized with DDQ to yield the title compound 6, in good over-all yields.

Synthesis of aryl ring-fused benzimidazolequinones using 6- exo- trig radical cyclizations

The preparation of alicyclic ring-fused tetracyclic and pentacyclic benzimidazoles containing one and two fused aryl rings, respectively, is achieved conveniently in three steps, including Bu 3SnH-mediated 6- exo- trig cyclization of σ-aryl radicals generated from 1-allyl-2-(ω-bromoaryl)benzimidazoles. Inclusion of 4,7-dimethoxy substituents on the radical precursors allows access to aryl ring-fused benzimidazolequinones, a unique family of potential bioreductive anti-cancer agents.

Novel synthesis of fused indoles and 2-substituted indoles by the palladium-catalyzed cyclization of N-cycloalkenyl- o-haloanilines

A new palladium-catalyzed cyclization of N-alkenyl- o-haloanilines with selective isomerization of a double bond followed by formal 5- endo- trig cyclization was developed. A variety of fused and 2-substituted indoles were synthesized from enaminoesters prepared by condensation of β-ketoesters and o-iodoaniline.

Novel Synthesis of Oxathiocine Derivatives by Wittig Olefination and Intramolecular Heck Reaction via an 8-endo-trig Cyclization

Syntheses of hitherto unreported heterocycles, such as oxathiocine derivatives, in excellent yields, and a doubly cyclized oxathiocine derivative, through a Wittig olefination and intramolecular Heck reaction sequence via an unusual 8-endo-trig cyclization, are reported.

SmI 2-promoted intra- and intermolecular C–C bond formation with chiral N-acyl oxazolidinones

The suitability of chiral oxazolidinones in the SmI 2-mediated C–C bond generation between the imide functionality of an N-acyl oxazolidinone unit and an olefinic radical acceptor, in both inter- and intramolecular reactions, was investigated. It was shown that the products from an Evans asymmetric alkylation can undergo direct carbon–carbon bond formation with an acrylamide providing chiral acyclic ketones in reasonable yields. These examples represent the first transformation of such N-acyl oxazolidinones where this chiral auxiliary is removed under the conditions for ketone formation. 5- exo- trig Cyclization studies were also undertaken with the same type of substrates, providing trans-2,5-disubstituted cyclopentanones in yields of approx. 50%. However, attempts to cyclize heteroatom-containing equivalents were less rewarding.

Synthetic studies toward paraherquamides E and F and related 13C-labeled putative biosynthetic intermediates: stereocontrolled synthesis of the α-alkyl-β-methylproline ring system

A substituted 2 R-allyl-3 S-methylproline ethyl ester suitable for elaboration to paraherquamides E, F and related 13 C-labeled putative biosynthesis intermediates have been prepared efficiently in six steps and 24% overall yield. The key steps are a 5- exo- trig cyclization of a zinc enolate on an unactivated alkene and a stereocontrolled alkylation of the enolate formed from 3 S-methyl-pyrrolidine-1,2 R-dicarboxylic acid 1- tert-butyl ester 2-ethyl ester.

ChemInform Abstract: Novel Synthesis of Oxocine Derivatives by Wittig Olefination and Intramolecular Heck Reaction via 8‐endo trig Cyclization.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

A computational study and valence bond approach to the intramolecular electrophilic aromatic substitution mechanism of ortho-allyl- N-benzylanilines

Ab initio computational studies were performed for the intramolecular Friedel–Crafts alkylation of ortho-allyl- N-benzylanilines catalyzed by sulfuric acid, which results in the formation of both dihydrodibenz[ b, e]azepine and tetrahydrodibenz[ b, f]azocine isomers. This intramolecular reaction occurs through the rearrangement of the cationic species generated from the allyl moiety and falls into the type of electrophilic aromatic substitution rearrangements. Due to this fact, we discuss the reactivity trends of the intermediate species participated in this competitive 7- exo- trig versus 8- exo- trig cyclization process. The valence bond configuration mixing is used for this purpose and with this model the reduced potential energy surface and the reaction profile are constructed. The expected patterns such as single step or stepwise mechanism, and the trends in the reaction barriers for the electrophilic attack effects of the aryl substituents are discussed.

Rapid stereoselective access to the tetracyclic core of puupehenone and related sponge metabolites using metal-free radical cyclisations of cyclohexenyl-substituted 3-bromochroman-4-ones

The tetracyclic nucleus of puupehenone, 15-oxopuupehenol and other sesquiterpene–phenol natural products can be assembled stereoselectively in three steps, the last of these being the 6- endo- trig cyclisation of an alpha-keto radical generated from a substituted 2-(2-cyclohexenyl)ethyl 3-bromo-4-chromanone under metal-free conditions.

Synthesis of Angularly Fused Carbocycles via Tandem Radical Cyclization of α‐Carbonyl Radicals

AbstractAn α‐carbonyl radical cyclization approach towards the synthesis of angularly fused tricyclic systems is described. On reduction with tributyltin hydride, bromo ketones yield a α‐carbonyl radical that undergoes successive 5‐exo‐dig/trig cyclizations, resulting in two or four contiguous stereocenters. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)

A New Class of Substrates for Nucleophilic 5‐endo‐trig Cyclization, 2‐Trifluoromethyl‐1‐alkenes: Synthesis of Five‐Membered Hetero‐ and Carbocycles That Bear Fluorinated One‐Carbon Units

Disfavored 5-endo-trig cyclizations were achieved in 2-trifluoromethyl-1-alkenes with a nucleophilic nitrogen, oxygen, sulfur, or carbon atom through 1) intramolecular S(N)2' reaction with loss of a fluoride ion or 2) intramolecular nucleophilic addition to the vinylic group. This reaction manifold provides a versatile method for the synthesis of indolines, indoles, pyrrolidines, tetrahydrofurans, 2,3-dihydrobenzo[b]thiophenes, tetrahydrothiophenes, and cyclopentanes that bear a fluorinated one-carbon unit such as a difluoromethylene, difluoromethyl, or trifluoromethyl group.

Novel synthesis of oxocine derivatives by Wittig olefination and intramolecular Heck reaction via 8- endo trig cyclization

A concise and efficient method for the preparation of oxocine derivatives is described via sequential Wittig and intramolecular Heck reactions. The method is highly regioselective and affords high yields of the products.

Heck-type reactions of allylic alcohols: Part IV: (2-Substituted)-1-indanones via 5- endo- trig cyclizations

Various conditions have been tested to obtain efficiently 2-methyl-1-indanone via the Pd-catalyzed 5- endo- trig cyclization of 1-( o-bromophenyl)-2-methylprop-2-en-1-ol. High yield (97%) was obtained at 120 °C in DMF with Pd(OAc) 2/cinchonine as the catalytic system and NaHCO 3 as the base. Use of this procedure for the synthesis of other substituted indanones led to lower yields but replacing thermal heating by microwave heating improved greatly the results.

Synthesis of 13a-methylphenanthroindolizidines using radical cascade cyclization: synthetic studies toward (±)-hypoestestatin 1

A radical cascade involving 6- endo cyclization of aryl radicals generated from N-acryloyl- N-(1-methylethenyl)-9-bromophenanthren-10-ylmethylamines, followed by 5- endo- trig cyclization of the resulting α-amidoyl radicals afforded phenanthroindolizidines bearing a methyl substituent at the angular C13a position. 2,3,6-Trimethoxy derivative was synthesized by using this method, but its spectral data were not in accord with those of literature values reported for hypoestestatin 1. Further synthetic study toward hypoestestatin 1 is demonstrated.

A copper-catalyzed domino radical cyclization route to benzospiro-indolizidinepyrrolidinones

In this Letter the synthesis of benzospiro-indolizidinepyrrolidinones is described by a domino atom transfer radical cyclization reaction using a copper catalyst. The structure of one of the products was established by single crystal X-ray diffraction. The investigated precursors, bearing a homo allyl substituent on the N-indole, result in a 5- exo- trig, followed by a 6- endo- trig cyclization. When the N-indole is substituted with an allyl group, only the spiro-cyclization occurs.

Reactivity of cyclopropanic δ-oxo-α,β-unsaturated esters towards SmI 2: 3- exo- trig cyclisation versus cyclopropane ring opening

trans-(2′,2′-Diphenyl-bicyclopropyl-2-yl)-4,4-dimethyl-5-oxo-pent-2-enoic acid methyl ester 9, undergoes 3- exo- trig cyclisation in the presence of SmI 2 without competitive ring opening of Newcomb's bicyclopropylic probe next to the carbonyl group. From this result, it may be concluded that the absence of ring opening observed earlier in the case of 5-cyclopropyl-4,4-dimethyl-5-oxo-pent-2-enoate 7 is not due to the potentially reversible character of this process. Meanwhile, as deduced from kinetic considerations based on data of the literature, the absence of ring opening does not necessarily mean that formation of ketyl radicals is not involved in the 3- exo- trig cyclisations of δ-oxo-α,β-unsaturated esters. Compounds 7 and 9 cyclise with total syn selectivity, leading ultimately to lactones. This syn selectivity contrasts with that of other alkylic δ-oxo-α,β-unsaturated esters.

Asymmetric synthesis of pent-3-yl ( R)-6-methyl-cyclohex-1-ene carboxylate

An expeditious asymmetric synthesis of pent-3-yl ( R)-6-methyl-cyclohex-1-enecarboxylate has been achieved in four steps in 42% overall yield employing as the key step a domino reaction initiated by a highly diastereoselective lithium amide 1,4-conjugate addition to a nona-2,7-diendioic diester followed by a 6- exo- trig cyclisation of the thus formed enolate. Cope elimination protocol of the cyclic adduct affords, depending on the lithium amide used, the corresponding nitro-compound or the expected cyclohexene derivative. The methyl group attached to the cyclohexane ring is achieved by selective ester hydrolysis and subsequent Barton decarboxylation.

Heck-type 5- endo- trig cyclizations promoted by vinylic fluorines: Ring-fluorinated indene and 3 H-pyrrole syntheses from 1,1-difluoro-1-alkenes

Arylpalladium or aminopalladium species bearing a 2,2-difluorovinyl group undergo an unusual 5- endo alkene insertion followed by β-fluorine elimination. These processes provide a facile access to ring-fluorinated five-membered carbocyclic and heterocyclic compounds starting from an o-(3,3-difluoroallyl)phenyl trifluoromethanesulfonate and 3,3-difluoroallyl ketone O-pentafluorobenzoyloximes. In both systems, the two vinylic fluorine atoms are essential for Heck-type 5- endo- trig cyclizations.