[4+2] Cycloaddition reactions of 4-sulfur-substituted 2-pyridones with electron-deficient dienophiles

[4+2] Cycloaddition reactions of 4-(phenylthio)-1-tosyl-2-pyridone (6a) and 4-(phenylsulfonyl)-1-tosyl-2-pyridone (6b) with electron-deficient dienophiles 7 (N-methylmaleimide, N-phenylmaleimide, and methyl acrylate) gave new isoquinuclidine products 8-10. The N-tosyl group of 6a and 6b was also efficiently converted to N-alkyl derivatives 6c-f, which showed different stereoselectivity toward reactions with dienophiles 7. Several other dienophiles 15 (dimethyl acetylenedicarboxylate, methyl vinyl ketone, ethyl vinyl ether, and methyl methacrylate) were found not to react with 6a or 6b, but led to the formation of tosyl migration products 4-(phenylthio)-O-tosyl-pyridinol (16a) and 4-(phenylsulfonyl)-O-tosyl-2-pyridinol (16b), respectively. The reactivity, regioselectivity, and stereoselectivity of the cycloaddition reactions were also compared with semi-empirical calculations.     

Efficient synthesis of isoxazoles and isoxazolines from aldoximes using Magtrieve (CrO2)

Treatment of aldoximes 1 with Magtrieve^™ (CrO₂) in presence of dipolarophile 3 or 4, furnished a variety of isoxazolines 5a-u and isoxazoles 6a-q as 1,3-dipolar cycloaddition (1,3-DC) products (38 examples; 63-90% isolated yields). In situ formation of a nitrile oxide intermediate was confirmed through isolation of the dimerization product furoxane 2a in absence of any dipolarophile. The methodology has been extended to intramolecular nitrile oxide cycloaddition (INOC) reactions to access highly useful chromane derivatives 7-8 (75-80% isolated yields). Magtrieve^™, as a new reagent for 1,3-DC reactions, has offered excellent substrate generality and at the same time demonstrated tolerance toward sensitive protecting groups and electron-rich functional groups.     

Experimental and theoretical studies of Diels-Alder dimerization of 1,2,3,4,5-pentachlorocyclopentadiene and of Diels-Alder cycloaddition of polychlorinated cyclopentadienes to norbornadiene

Diels-Alder cyclodimerization of 1,2,3,4,5-pentachlorocyclopentadiene (1) affords 2a as the exclusive reaction product. Diels-Alder cycloaddition of 1 to norbornadiene also proceeds stereoselectively to produce a single [4+2] cycloadduct, 4c. The structures of 2a and 4c were established unequivocally via application of single crystal X-ray crystallographic techniques. The origins of the observed diastereofacial selectivity in each of these cycloaddition processes have been investigated by application of semiempirical (AM1 Hamiltonian) and ab initio (Hartree-Fock 3-21G*) calculations. The computational results thereby obtained, which are based upon consideration of the kinetically favored transition state for each of the two cycloaddition reactions studied, are consistent with experiment. These semiempirical and ab initio methods also have been used to investigate the mechanisms of the Diels-Alder reactions that have been used to prepare aldrin and isodrin (7 and 8, respectively). The results thereby obtained suggest that isodrin formation via Diels-Alder cycloaddition of cyclopentadiene to 1,2,3,4,7,7-hexachloronorbornadiene proceeds with kinetic control of product stereochemistry.     

Cycloaddition reactions of 3-fluorobutenone

3-Fluorobutenone (8) reacted as a dienophile with several dienes 9, 11, 13, 15, 17 to give cycloaddition products in moderate yields. The regio- and stereoselectivity of the reactions are given. Compound 8 is slightly less reactive than methyl vinyl ketone.     

Synthesis and highly selective Diels-Alder cycloadditions of the new dienes N-substituted 2,3,5,6-tetrahydrobenzoxazol-2-ones

The synthesis of the new dienes N-substituted 2,3,4,5-tetrahydrobenzoxazol-2-ones 8a-8c is described, through a one-step convergent process from 1,2-cyclohexanedione (7a) and the corresponding isocyanates 2a-2c. The presence of electron-donor substituents in the aryl ring of the isocyanate gave rise to the exclusive formation of the captodative olefins 10. Diene 8a proved to be reactive and stereoselective in Diels-Alder additions with a cyclic olefin. The reaction with acetylenic dienophiles yielded the 2,3-dihydrobenzoxazol-2-ones 21 and 24, as the products of sequential [4+2] cycloaddition and retro-Diels-Alder reactions. Methyl vinyl ketone (22) underwent regio- and stereoselective tandem Diels-Alder and Michael additions to give propellane 29a. Evidence of an endo π-pyramidalization of the central double bond of adduct 19 would rationalize the exo stereoselection in the formation of 29a. The regioselectivity in these reactions has been rationalized in terms of FMO theory by ab initio calculations.     

Diels-Alder reactions of acyclic α-cyano α,β-alkenones: a new approach to highly substituted cyclohexene system

The Diels-Alder reactions of a variety of acyclic α-cyano α,β-unsaturated ketones 8 have been investigated. With the assistance of boron trichloride, these compounds were found to undergo the cycloaddition readily with dienes to give the corresponding adducts 9 in good to high yields. In addition, some of 9 could be further subjected to the reductive alkylation reactions using lithium naphthalenide (LN) and an appropriate alkylating agent, thus allowing for the generation of highly substituted cyclohexenes 10 with the replacement of the cyano group with an alkyl substituent.     

A novel mesoionic ring system: unusual cyclization of thio- and amino-acid derivatives of 6-azauracil

Novel mesoionic heterocyclic structures 8 have been obtained via the internal cyclization of thio- and amino-acid derivatives of 6-azauracil 7b-d. These compounds undergo ring-opening reactions with amines to yield the respective 6-azauracil amides (9) in good yields under microwave irradiation.     

Domino routes to substituted benzoindolizines: tandem reorganization of 1,3-dipolar cycloadducts of nitrones with allenic esters/ketones and alternative cycloaddition-palladium catalyzed cyclization pathway

Reactions of C-(4-oxo-4H[1]benzopyran-3-yl)-N-phenyl nitrones (7) with allenic esters (8a-c) and allenic ketones (18a-d) furnish benzoindolizines (9a-k, 19a-d) in good yields. The formation of benzoindolizines is postulated to involve regioselective addition of 1,3-dipole to C2-C3 π bond of allenic esters/ketones followed by domino transformation of the cycloadducts, which involve an intramolecular aza Diels-Alder reaction in the intermediate C. DFT calculations of various parameters for diene and dienophile components in the proposed intermediate C have revealed that conformational constraints imposed by the alkyl groups (R=Me, Et) favor intramolecular aza-Diels-Alder cycloaddition. An alternative domino route to benzoindolizines (9a,d,g) involving sequential one-pot cycloaddition of azadienes (22a-c) with silyl-enol ether (23) followed by palladium(0)-catalyzed Heck coupling reaction has also been developed. Both these approaches represent novel domino routes for the synthesis of benzoindolizines.     

Reactions of (E)-1,2-di(3-guaiazulenyl)ethylene and 2-(3-guaiazulenyl)-1,1-bis(4-methoxyphenyl)ethylene with tetracyanoethylene (TCNE) in benzene: comparative studies on the products and their spectroscopic properties

Reactions of the title ethylene derivatives, (E)-1,2-di(3-guaiazulenyl)ethylene (1) and 2-(3-guaiazulenyl)-1,1-bis(4-methoxyphenyl)ethylene (2), with a 2 M amount of TCNE in benzene at 25 °C for 24 h under argon give new cycloaddition compounds, 1,1,2,2,11,11,12,12-octacyano-3-(3-guaiazulenyl)-8-isopropyl-5,10-dimethyl-1,2,3,6,9,10a-hexahydro-6,9-ethanobenz[a]azulene (3) from 1 and 1,1,2,2,11,11,12,12-octacyano-8-isopropyl-3,3-bis(4-methoxyphenyl)-5,10-dimethyl-1,2,3,6,9,10a-hexahydro-6,9-ethanobenz[a]-azulene (4) from 2, respectively, in 66 and 87% isolated yields. Comparative studies on the above reactions as well as the spectroscopic properties of the unique products 3 and 4, possessing interesting molecular structures, are reported and, further, a plausible reaction pathway for the formation of these products is described.     

(4+2) Cycloaddition to tricarbonyl[(1-4-η)-2-methoxy-5-methylene-cyclohexa-1,3-diene]iron for the rapid construction of a spiro[5.5]undecane system

Diels-Alder reactions of tricarbonyl[(1-4-η)-2-methoxy-5-methylene-cyclohexa-1,3-diene]iron 1 with 1,2,4,5-tetrazine-3,6-disubstituted derivatives 2a,b,d and 2,3,4,5-tetrabromothiophene-1,1-dioxide 5 are reported. The (4+2) cycloaddition reactions took place exclusively with highly electron deficient dienes to form spiro[5.5]undecane system in good yield. The more electron rich nature of the 1,2,4,5-tetrazine-3,6-disubstituted derivatives 2b did not react. The reaction also took place stereospecifically exo to the Fe(CO)₃ moiety.     

Synthesis, structural characterization, and anion binding ability of sterically congested adamantane-calix[4]pyrroles and adamantane-calixphyrins

Novel adamantane derivatives of calix[4]pyrroles 4-8 and calixphyrin 9 have been synthesized. The structure of 8 has been characterized by X-ray powder diffraction and the structure of 9 by single crystal X-ray analysis. Whereas calixphyrin 9 does not bind anions, analogous calyx[4]pyrrole 8 forms a complex with Cl⁻ in the DMSO solution and in the solid state. The solid state complexation has been accomplished on grinding in a mill, which is the first example of complex formation with an anion in the solid state.     

An unexpected reaction of pyridine with acetyl chloride to give dihydropyridine and piperidine derivatives

An unexpected reaction of pyridine with acetyl chloride to give N-acetyl-1,2 and 1,4-dihydropyridyl acetic acid (1, 2) in high yield and regioselectivity has been reported. The key step is the formation of a zwitterionic pyridinium ketene enolate. The effect of different activating agents on the reaction yield and selectivity has been studied. Platinum(IV) mediated hydrogenation of the corresponding methyl esters (7, 8) gave piperidine derivatives (9, 10).     

Photochemistry of benzene and quinoxaline fused Δ-1,2,3-triazolines and their trapping products

The benzene and quinoxaline fused Δ²-1,2,3-triazolines 1a and 1b were synthesized in good yields using Knoevenagel condensation and intramolecular 1,3-dipolar cycloaddition as two of the key reactions. Photolysis (254 nm) of Δ²-1,2,3-triazoline 1a or 1b in acetonitrile led to the homolytic cleavage of nitrogen that generated diethyl diazomalonate 7, highly reactive intermediates aziridines 8a,b, and isoindoles B. The latter two species subsequently underwent rearrangement to give the nitrogen extrusion products 9a,b, and polymers. Furthermore, the reactive intermediates were trapped by dienophiles to give the corresponding cycloadducts. Subsequent rearrangement of the N-bridged cycloadducts gave N-substituted pyrrolo[3,4-b]quinoxalines 12b and 15b in 6% and 9% yields, respectively. Irradiation of 1a in the presence of fumaronitrile led to the isolation of cycloadduct 16a with retention of stereochemistry. Thermal reaction of 1b gave more nitrogen extruded product 9b (58-63% yield) than that by photolysis (5-23% yield), which implied that zwitterionic intermediate might be involved in the former.     

Solid-state photocycloaddition of 6,6′-dimethyl-4,4′-[bis(methylenoxy)phenylene]-di-2-pyrones with benzophenone

Photocycloaddition reactions of 6,6′-dimethyl-4,4′-[bis(methylenoxy)phenylene]-di-2-pyrones (4a-c) with benzophenone (2a) by mixing in the solid state (solid solution) afforded the corresponding oxetane derivatives (5a-c; 1:2 adducts) with high site- and regioselectivity across the C5-C6 and C5′-C6′ double bonds in 4 via the triplet excited state of benzophenone. The oxetane formation proceeded more effectively in the solid state than in solution. The reaction mechanism was inferred by MO methods to be initiated by electrostatic interaction between the C6 position of 4a-c and the carbonyl oxygen of 2a in their ground states. The solid-state interaction may be enhanced by the electron density at the carbonyl oxygen of the triplet 2a. The transition state (TS) analysis of the [2+2] cycloaddition reactions also suggested some triplet complexes and high regioselectivity. The hydrogen-bonding interaction between 2a and 4a-c and the triplet reaction mechanism were also explained by the IR analyses and the quenching experiments, respectively.     

Reactions of acceptor substituted thiophene-1,1-dioxides with cyclopentadiene: control of selectivity by substitution

Diels-Alder reactions of thiophene-1,1-dioxides with strong electron withdrawing groups (EWG) were studied experimentally and theoretically. Thiophene-1,1-dioxides with two strong EWG behave as dienophiles and regio- and stereoselectively react with cyclopentadiene to give [2+4] cycloadducts 2a-c, which are derivatives of benzothiophene. In contrast, thiophene-1,1-dioxides with one EWG behave as dienes in the inverse electron demand Diels-Alder reaction yielding dihydro-1H-indenes derivatives. Cope [3,3]-sigmatropic rearrangement of adducts 2a-c was also demonstrated. MP2 calculations successfully rationalize the contrasting regioselectivities of these cycloaddition reactions.     

Synthesis of polycyclic indolizine derivatives via one-pot tandem reactions of N-ylides with dichloro substituted α,β-unsaturated carbonyl compounds

Convenient and regioselective syntheses of 1,2-annulated, and 1,2-, 5,6- and 1,2-, 7,8-bisannulated polycyclic indolizine derivatives have been achieved by one-pot tandem reactions of cyclic N-ylides derived from the corresponding N-substituted pyridinium, quinolinium, and isoquinolinium salts 1-3 with dichloro substituted α,β-unsaturated carbonyl compounds 4-7. The reactions of the N-ylides with 2,3-dichloroindenone 4, 3,4-dichlorocoumarin 5, and 4a,6,7,8a-tetrachloro-1,4-methanonaphthalene-5,8-dione 6 proceed by sequential [3+2] cycloaddition and elimination of hydrogen chlorides from the cycloadducts. On the other hand, reactions of the N-ylides with 2,3-dichloro-1,4-naphthoquinone 7 take place via a novel reaction sequence to give the products 15-17.     

Synthesis of 6-substituted tetrahydropyridinones and cyclization to indolizidine and quinolizidine structures

3-Sulfolenes 1 with various substituents at C-2 underwent [4+2] cycloaddition reactions with p-toluenesulfonyl isocyanate to give the teterahydropyridinones 4. Through N-detosylation and Hg(II)-mediated electrophilic addition/intramolecular cyclization of 4e and 4f, the indolizidine and quinolizidine compounds 7a/7b and 8 were synthesized, respectively.     

Photochemical transformation leading to eupteleogenin—I: Introduction of epoxy-lactone system

Being interested in the photochemical reactions which are potentially applied in the biogenetic-type chemical derivations of natural products, the appropriate photochemical means have been sought to produce the 11α,12α-epoxy-13β,28-lactone moiety in the oleanane skeleton, which is one of the unique functions of eupteleogenin (2). Photooxidation of oleanolic acid (6a) in acidic medium has been undertaken and desired 11α,12α-epoxy-oleanolic lactone (12a) obtained. Erythrodiol (8a) has been submitted to photooxidation and the 11α,12α-epoxy-13β,28-oxide moiety (24a) introduced along with skeletal rearrangement affording the 11α,12α-epoxy-taraxerene derivative (25a). During photooxidation of 8a, it has been noticed that 11ξ-hydroxy-olean-12-ene derivatives (28, 42) are fairly labile, allowing the trans-formation of dihydropriverogenin A(10a) into the thermodynamically less favored isomer priverogenin B(9).     

Diels-Alder cycloaddition of 2-azadienes to methyl 2-(2,6-dichlorophenyl)-2H-azirine-3-carboxylate in the synthesis of methyl 4-oxo-1,3-diazabicyclo[4.1.0]heptane-6-carboxylates

A number of fused 4-oxo-1,3-diazabicyclo[4.1.0]heptane-6-carboxylates, a new type of compound, have been obtained by Diels-Alder cycloaddition between nucleophilic 2-azadienes and an electrophilic 2H-azirine. The reactions are completely endo- and regioselective, the azirine being added by its less hindered face to the diene. There are two isomers 7 and 8 formed from dienes 1 due either to isomerization of the cycloadducts 7 and 8 or by isomerization of the CN bond of the diene during the reaction. The isomer 10 is formed from diene 2e, and a single diastereoisomer structure 4a-i is formed from dienes 11. Some pyrimidones 8a, 7c/8c, 7e, 10, 11d have been hydrolyzed leading to functionalised aziridines 12, 13 and 15.     

Synthesis and phototransformations of novel styryl-substituted furo-benzobicyclo[3.2.1]octadiene derivatives

Novel cis- and trans-(o-H/Me/vinyl) substituted styryl furo-benzobicyclo[3.2.1]octadiene derivatives (7a,b, 8) were prepared and transformed to the novel naphthofuran derivatives of benzobicyclo[3.2.1]octadiene (6a,b) and novel phenanthrene-benzobicyclo[3.2.1]octadiene derivative (11) by photochemical electrocyclic ring closure in the presence of iodine and by intramolecular photoinduced [4+2] cycloaddition, respectively. These novel annelated bicyclo[3.2.1]octadiene derivatives (6a,b, 11) are especially interesting for their rigid methano-bridged junction of two aromatic units at defined geometrical arrangement and thereby as potentials for molecular clips.