Protecting group directed cyclization: asymmetric synthesis of both cis- and trans-dihydrexidine from a common precursor

Protection group of amino- and tethered o-arene functionality of 1,4-aryl-2-amino-1-butanol derived from l-serine dictates the cyclization mode under acidic conditions leading to reverse diastereoselectivity. N-Boc and acetal protected amino alcohol undergo cascade cyclization providing exclusively cis-dihydrexidine via reduction, where formation of C-ring (isoquinoline unit) prior to Friedel–Crafts cyclization control the cis-stereochemistry of the B-ring. N-Cbz and O-benzyl protection direct first F–C cyclization yielding the trans-1-aryl-2-aminotetralin and subsequent deprotection-cyclization forming the C-ring afforded dihydrexidine.     

Regioselective radical cyclization initiated by the reaction of allylic hydroperoxides with iron(II) sulfate

Treatment of 1-methyl-2-methylene-1-cyclohexyl hydroperoxide with a mixture of FeSO₄/CuCl₂ yielded 1-(1-chlorocyclohexyl)ethanone as the major product consistent with 6-endo-trig cyclization of the intermediate 5-acetylhex-5-enyl radical. This strategy was extended to the ring enlargement of a series of 1-isopropenylcycloalkyl hydroperoxides. Regioselective 7- or 8-endo-trig cyclization reactions could be achieved by treatment of the corresponding cyclopentyl or cyclohexyl hydroperoxides with either a mixture of FeSO₄/CuCl₂ or with FeSO₄ only. The influence of substituents on the efficiency of the 8-endo-trig cyclization process was also explored.     

Synthesis of fused polycyclic nitrogen-containing heterocycles via cascade cyclization

A novel strategy for the synthesis of fused polycyclic-nitrogen containing heterocycles via cascade cyclization is described. The methodology involves condensation of 1-(2-aminophenyl)-9H-β-carboline-3-carboxylic acid amide with isothiocyanates followed by in situ treatment of the resulting thioureas with HgCl₂ for 1 h at rt. The one-pot cascade cyclization leads to interesting changes in molecular structure and an increase in molecular complexity. A mechanistic rationale for the cascade cyclization is discussed.     

Efficient and rapid synthesis of N-substituted isoquinolin-1-ones under mild conditions: Facile access to doryanine derivatives

We describe the simple and efficient synthesis of N-substituted isoquinolin-1-one derivatives. Initiating with the coupling of benzoic acids containing vinyl ethers with different amines, followed by rapid intramolecular cyclization under acidic conditions at room temperature, N-substituted isoquinolin-1-ones were furnished in high yields. The utility of this simple and mild cyclization method was demonstrated through the practical synthesis of natural product doryanine and its analogues.     

Palladium-catalyzed expedient Heck annulations in 1-bromo-1,5-dien-3-ols: Exceptional formation of fused bicycles

An unprecedented Pd-catalyzed intramolecular Heck cyclization has been investigated on halogenated diene scaffolds undergoing various mode of cyclization and termination leading to the formation of structurally differing fused cyclopenta(e)none and aromatic analogue. The discrimination in the fate of palladium intermediates formed in situ undergoing Heck cyclization preferentially arises out of the difference in reaction temperature as well as substrate architecture. Sequential Heck reaction of 1-Bromo-5-methyl-1-aryl-hexa-1,5-dien-3-ol derivatives followed by oxidation or termination via sp² CH activation in aromatic ring led to the formation of fused cyclopentanes. However, the similar reaction at elevated temperature showed predominance towards the formation of aromatic analogues via one pot cyclization and dehydroxylation. The mechanism for the formation of cyclopentanone fused with cyclopropane ring system is supported by density functional theory based calculations.     

Synthesis of spiro[4.5]decane and bicyclo[4.3.0]nonane ring systems by self-cyclization of (Z)- and (E)-2-(trimethylsilylmethyl)pentadienal derivative

The two title carbon frameworks were synthesized utilizing a new type of iron-induced cyclization reaction of 2-(trimethylsilylmethyl)pentadienal. 2-Methylspiro[4.5]dec-2-en-1-one was obtained from (Z)- and (E)-4-cyclohexylidene-2-(trimethylsilylmethyl)but-2-enal. It was found that the (Z)-substrate isomerized to (E)-intermediate followed by cyclization to afford the initial product, 2-methylenespiro[4.5]dec-3-en-1-ol, which was isomerized to the above product. The cyclization of 4-(4-alkyl)cyclohexylidene-2-(trimethylsilylmethyl)but-2-enal proceeded stereoselectively. While, (E)-3-(cyclohex-1-en-1-yl)-2-(trimethylsilylmethyl)prop-2-en-1-al cyclized immediately affording 8-methylenebicyclo[4.3.0]non-9-en-7-ol. The corresponding (Z)-isomer gave several cyclization products as a complex mixture.     

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.     

Cobalt-catalyzed sequential cyclization/cross-coupling reactions of 6-halo-1-hexene derivatives with Grignard reagents and their application to the synthesis of 1,3-diols

Cobalt/N-heterocyclic carbene system or cobalt/diamine combination effectively catalyzes sequential cyclization/cross-coupling reactions of 6-halo-1-hexene derivatives with trialkylsilylmethyl, 1-alkynyl, and aryl Grignard reagents. The sequential cyclization/cross-coupling reactions are applied to the synthesis of 1,3-diols starting from siloxy-tethered 6-halo-1-hexene derivatives.     

A new regioselective synthesis and ambient light photochemistry of quinazolin-1-oxides

Quinazolin-1-oxides were prepared by the oxidation of tetrahydroquinazolines with H₂O₂-tungstate and their ambient light photochemistry was investigated. Substituent effects on their photochemical cyclization and the reactions of the products 1aH-[1,2]oxazireno[2,3-a]quinazolines under photochemical and thermal conditions are reported. The cyclization of quinazolin-1-oxides and the reactions of 1aH-[1,2]oxazireno[2,3-a]quinazolines show pronounced solvent isotope and solvent effects.     

Synthesis of phthalascidin analogs

We report a new approach to obtain phthalascidin analogs. 6-Phthalimidomethylpyrazino[1,2-b]isoquinoline-1,4-dione (5a) was obtained in a one-pot N-alkylation/cyclization of the corresponding 1-acetyl-3-arylmethyl-2,5-piperazinedione with N-phthalylacetaldehyde dimethyl acetal. Chemoselective reduction of the C(1)-carbonyl group in the 3-arylmethyl-11,11a-dehydroderivative 9a was followed by cyclization of an acyliminium intermediate, to give the 6,15-imino-7-oxo-14,14a-dehydroisoquino[3,2-b]3-benzazocin 11a. Alternatively, the octacyclic compound 13a was obtained through a novel double cyclization of a precursor in which the C(1)-carbonyl and one phthalimide carbonyl group were reduced.     

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

The 4,4-bis(ethoxycarbonyl)-3,4-dihydro-2(1H)-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.     

A solid-phase approach to the synthesis of N-1-alkyl analogues of cyclic inosine-diphosphate-ribose (cIDPR)

We report here an efficient solid-phase synthesis of N-1-alkyl-substituted analogues of cyclic inosine-diphosphate-ribose (cIDPR), a mimic of cyclic ADP-ribose (cADPR). Our synthetic strategy makes use of a polystyrene support to which inosine was bonded through a 2′,3′-acetal linkage. Insertion of a ω-hydroxy-polymethylene chain of variable length on N-1, followed by conversion into N-1-alkylinosine-bis-phosphate derivatives and cyclization, allowed to obtain analogues of cIDPR of various ring size. The cyclization step was carried out both in solid-phase and in solution by pyrophosphate bond formation. The effect of the N-1-polymethylene chain length on the cyclization yields as well as the reaction conditions, which led to the solid-phase pyrophosphate bond formation, were thoroughly investigated.     

Synthetic scope, computational chemistry and mechanism of a base induced 5-endo cyclization of benzyl alkynyl sulfides

We present an experimental and computational study of the reaction of aryl substituted benzyl 1-alkynyl sulfides with potassium alkoxide in acetonitrile, which produces 2-aryl 2,3-dihydrothiophenes in poor to good yields. The cyclization is most efficient with electron withdrawing groups on the aromatic ring. Evidence indicates there is rapid exchange of protons and tautomerism of the alkynyl unit prior to cyclization. Theoretical calculations were also conducted to help rationalize the base induced 5-endo cyclization of benzyl 1-propynyl sulfide (1a). The potential energy surface was calculated for the formation of 2,3-dihydrothiophene in a reaction of benzyl 1-propynyl sulfide (1a) with potassium methoxide. Geometries were optimized with CAM-B3LYP/6-311+G(d,p) in acetonitrile with the CPCM solvent model. It is significant that the benzyl propa-1,2-dien-1-yl sulfane (6) possessed a lower benzylic proton affinity than the benzyl prop-2-yn-1-yl sulfane (8) thus favoring the base induced reaction of the former. From benzyl(propa-1,2-dien-1-yl sulfane (6), 2,3-dihydrothiophene can be formed via a conjugate base that undergoes 5-endo-trig cyclization followed by a protonation step.     

A new approach to indolo[2,3-a]quinolizidines through radical cyclization of 2-acyl-1-phenylthiotetrahydro-β-carbolines bearing pendent α,β-unsaturated esters

A new method is reported for the preparation of indolo[2,3-a]quinolizidines based on radical cyclization of a 2-acyl-1-phenylthiotetrahydro-β-carboline bearing a pendent α,β-unsaturated ester. The required radical cyclization precursor is efficiently assembled from E-5-ethoxycarbonyl-4-pentenoic acid and 3,4-dihydro-β-carboline through a DCC/HOBt-activation/N-acylation and BF₃·Et₂O/PhSH iminium-ion trapping sequence. Tin-mediated radical cyclization of the radical cyclization precursor affords stereoselectively a cis-lactam (dr = 7:1) in good yield (81%), bearing the correct D/E ring fusion stereochemistry for the Tacaman alkaloids. The methodology has been applied to formal syntheses of the indoloquinolizidine alkaloids, (±)-eburnaminol and (±)-larutensine.     

Synthesis of thieno[3,4-b]pyrrole derivatives based on the reaction of 1-methyl-2-nitromethylenepyrrolidine with isothiocyanates

The reaction of 1-methyl-2-nitromethylenepyrrolidine with arylisothiocyanates in the presence of a base was found to proceed at the 3-СН₂ group of the nitroenamine followed by further cyclization to afford 4-R-imino-1-methyl-1,2,3,4-tetrahydro-6H-thieno[3,4-b]pyrrol-6-one oximes. Under analogous conditions, alkylisothiocyanates add to 1-methyl-2-nitromethylenepyrrolidine giving 1-methyl-2-nitromethylenepyrrolidine-3-carbothioic acid amides, and no cyclization was observed. A tentative mechanism for the formation of thieno[3,4-b]pyrrolе derivatives is proposed.     

Convenient access to isoindolinones via carbamoyl radical cyclization. Synthesis of cichorine and 4-hydroxyisoindolin-1-one natural products

An efficient and convenient access to 2-tert-butylisoindolin-1-ones via an oxidative radical cyclization process from stable carbamoylxanthates, derived from secondary tert-butylamines, is described. The proposed mechanism for this transformation involves, the generation of a carbamoyl radical, its cyclization to the aromatic system, and the dilauroyl peroxide (DLP) mediated rearomatization to generate the isoindolinone ring system. Additionally, the syntheses of cichorine and 4-hydroxyisoindolin-1-one natural products were carried out to underscore the synthetic potential of this xanthate-based carbamoyl radical-oxidative cyclization.     

Efficient synthesis of β-C-glucosides via radical cyclization with a silicon tether based on the conformational restriction strategy

An efficient method for preparing β-C-glucosides using radical cyclization with a temporary connecting silicon tether was developed. In this reaction, conformational restriction of the substrates to the unusual ¹C₄-form is essential for the cyclization to occur.     

Radical cyclizations to quinolone and isoquinolone systems under oxidative and reductive conditions

Radical cyclizations to quinolone and isoquinolone systems under Fenton-type and n-Bu₃SnH-mediated conditions are described. For N-iodoalkylquinolones, ca. 3:1 mixtures of oxidative cyclization products at C-2, and unexpectedly at C-8, were obtained under both conditions. Five- or six-membered oxidative cyclization products were obtained from N-iodoalkylisoquinolones under Fenton-type conditions, whereas n-Bu₃SnH-mediated reactions gave products of reductive cyclization in the five, six, and seven-membered series.     

α-Dimethylaminomethylenation-induced Houben-Hoesch-type cyclization of cyanoacetanilides: a practical synthesis of 3-formyl-4-hydroxyquinolin-2(1H)-ones

The tandem reaction of cyanoacetanilides with triflic anhydride in DMF proceeded at room temperature to afford 3-formyl-4-hydroxyquinolin-2(1H)-ones in good to high yields. A detailed mechanistic study revealed that the tandem reaction proceeded via α-dimethylaminomethylenation, which promoted the subsequent Houben-Hoesch-type cyclization. Both α-functionalization and the cyclization steps were optimized, and a multi-gram scale synthesis of 3-formyl-4-hydroxyquinolin-2(1H)-one was achieved.     

Facile ring-closure cyclization of arenes by nucleophilic C-alkylation reaction in ionic liquid

A novel synthetic method using an ionic liquid (IL) for a six-membered ring-closure cyclization is described. The ring-closure cyclization by nucleophilic C-alkylation was achieved with various halo- and alkanesulfonyloxyalkyl aromatic compounds in high yields with minimal byproducts using ILs as the reaction media in the absence of any catalyst. For example, the cyclization of 2-(3-methanesulfonyloxy-propoxy)naphthalene (1a) to 2,3-dihydro-1H-naphtho[2,1-b]pyran (2) in IL [bmim][PF₆] proceeded selectively at 150 °C for 24 h in 85% yield.