Single Cycloadduct Research Articles

A Molecular Electron Density Theory Study of the Polar Diels-Alder Reaction of Naphtoquinone:Cr(CO)3 Complex with Cyclic Dienes

The role of the Cr(CO)3 coordination to the aromatic ring of naphtoquinone (NQ) in the polar Diels-Alder (P-DA) reactions with cyclic dienes, cyclopentadiene (Cp), cyclohexadiene (Ch), and 1-methoxy-cyclohexadiene (ChOMe), has been studied within Molecular Electron Density Theory (MEDT). Electron Localization Function (ELF) of the NQ:Cr(CO)3 complex indicates that Cr(CO)3 does not cause any remarkable change in the electronic structure of NQ. While the NQ:Cr(CO)3 complex is categorized as a strong electrophile, the cyclic dienes are categorized as strong nucleophiles, suggesting P-DA reactions. Formation of the NQ:Cr(CO)3 complex reduces the activation energy by only 0.7 kcal·mol−1. While Ch shows a lower reactivity than Cp, ChOMe presents the highest reactivity of this series of cyclic dienes. Analysis of the activation Gibbs free energies of the P-DA reaction with Cp indicates that the reaction is completely endo and anti stereoselective. The present MEDT study shows that the Cr(CO)3 complex has no effective catalytic activity in the P-DA reactions of NQ with cyclic dienes, but only permits the reaction to take place experimentally with a total endo and anti facial stereoselectivity, yielding a single cycloadduct.

STUDY BASED ON ELECTRONIC DESCRIPTORS OF THE DIASTEREOSELECTIVE AZA-DIELS-ALDER CYCLOADDITION OF [(1R)-10-(N,N-DIETHYLSULFAMOYL)ISOBORNYL] 2H-AZIRINE-3-CARBOXYLATE TO E,E-1,4-DIACETOXY-1,3-BUTADIENE

ABSTRACT Cycloaddition of chiral [(1 R )-10-( N , N -diethylsulfamoyl)isobornyl] 2 H -azirine-3-carboxylate to E , E -1,4-diacetoxy-1,3-butadiene shows complete diatereoselectivity giving a single cycloadduct (-)-(2 S ,5 R ,6 R )-6-[(1 R )-10-( N , N -diethylsulfamoyl)isobornyloxycarbonyl]-1-azabicyclo[4.1.0]hept-3-ene-2,5-diyldiacetate. Our main objective is to identify electronic/steric parameters capable of describing the observed tendencies of this reaction. The results of the calculations conclude that: even though the steric factors can play an important role at the initial steps of the reaction, at the transition states the behavior of several electronic parameters; like hardness, polarizability, aromaticity, charge transfer, etc is decisive enough to justify the obtained product. Finally, this work summarizes an exhaustive analysis of electronic descriptors and empirical reactivity principles, reaching a definitive and comprehensive explanation to the observed experimental result.

The 1,3-dipolar cycloaddition reaction of chiral carbohydrate-derived nitrone and olefin: towards long-chain sugars

The thermal and microwave-activated 1,3-dipolar cycloadditions of several α,β-unsaturated esters derived from d-mannose and chiral nitrones derived from threitol have been studied as a model reaction en route to eleven carbon long chain carbohydrates. Very high facial selectivity is observed for the chiral nitrones whereas the olefin facial selectivity varies with the substrate. The presence of a dioxolane ring α to the olefinic bond is beneficial to the facial selectivity of the olefin whereas a pyranose ring is not. The combination of a d-mannose derivative and a l-threitol-derived nitrone is a matched pair suitable for the synthesis of long chain sugars with nine contiguous chiral centres. Finally complete facial selectivity was observed with exo-glycals which gave a single cycloadduct.

Fast Hetero-Diels−Alder Reactions Using 4-Phenyl-1,2,4-triazoline-3,5-dione (PTAD) as the Dienophile

A hetero-Diels−Alder reaction that proceeds rapidly and only requires a simple filtration to purify the product is presented. The dienophile, 4-phenyl-1,2,4-triazoline-3,5-dione (PTAD), is prepared by the heterogeneous oxidation of 4-phenylurazole by the bromenium ion, Br+, generated in situ by the oxidation of potassium bromide by Oxone. PTAD is reacted with both cyclopentadiene and 1,3,5-cycloheptatriene, and the resulting products are analyzed by NMR spectroscopy. PTAD reacts with cyclopentadiene in the expected fashion; however, it reacts exclusively with the norcaradiene valence tautomer of 1,3,5-cycloheptatriene to form a single cycloadduct. The speed of these reactions allows for more of a three-hour laboratory period to be devoted to spectral characterization and data analysis than in similar experiments. This laboratory experiment is suitable for second- or third-year organic chemistry courses.

ChemInform Abstract: X=Y-ZH Systems as Potential 1,3-Dipoles. Part 32. Generation of Nitrones from Oximes. Tandem Michael Addition-1,3-Dipolar Cycloaddition Reactions. Background and Class 1 Processes.

Abstract Intermolecular Michael addition of aldoximes and ketoximes to electronegative olefins generates nitrones. The keto nitrones can be trapped in regiospecific intermolecular cycloaddition reactions giving single cycloadducts in good yield. Chemospecific 1:1:1 cycloadducts are obtained from ketoximes, monosubstituted electronegative olefins (Michael acceptor) and N-methylmaleimide (dipolarophile), whilst the chemoselectivity of the corresponding reactions with aldoximes is dependent on the oxime stereochemistry. Z-Aldoximes show high chemospecificity whilst E-aldoximes are much less chemoselective.

One-pot enyne metathesis/Diels–Alder reaction for the construction of highly functionalized novel polycyclic aza-compounds

Various tricyclic dienes were synthesized via enyne metathesis using the first generation Grubbs catalyst. The enyne metathesis proceeded smoothly in refluxing CH 2Cl 2 with a low catalyst loading (3.0 mol %), giving good yields (72–89%) of the tricyclic products 6 and 16. The resulting 1,3-dienes are suitable precursors of polycyclic structures via a Diels–Alder process. One-pot RCM/Diels–Alder reactions of the enyne products with dienophiles proceeded smoothly to afford polycyclic compounds as a single cycloadduct. The structures of the Diels–Alder adducts were determined by 1H NMR spectra and X-ray analysis. The cycloadducts were formed via the approach of the dienophiles towards the diene in endo mode.

Preparation and Diels−Alder Chemistry of 4-Vinylimidazoles

Various 4-vinylimidazole derivatives have been prepared from the corresponding 4-iodoimidazoles or from urocanic acid. Several methods for the elaboration of these vinylimidazoles and their Diels-Alder reactions are reported. All of the vinylimidazoles prepared in the course of this study react with N-phenylmaleimide quite readily with mild thermal activation providing a single cycloadduct, in most cases the initial, nonaromatic adduct. With more electron rich substrates, there is a tendency for these initial cycloadducts to undergo aromatization, ene reaction, and oxidation although this can be circumvented to a large extent by the choice of reaction conditions. Limited reactions were observed with other dienophiles, providing the expected cycloadducts in most cases, although an abnormal adduct was obtained in one case with dimethyl acetylene dicarboxylate. These substrates also participate in regioselective Diels-Alder reactions with monoactivated dienophiles, but require fairly forcing conditions, thus only providing the aromatized cycloadducts in modest yields. An investigation of substituent effects at the 2-position of the imidazole moiety was undertaken, in which electron-donating and weakly electron-withdrawing substituents are tolerated. In addition, several substrates with terminally substituted vinyl moieties have been investigated.

Stereoselective Aza Diels−Alder Reaction on Solid Phase: A Facile Synthesis of Hexahydrocinnoline Derivatives

As part of our continuing studies of polymer-supported pericyclic reactions for preparing biologically interesting heterocyclic compounds, we have introduced a traceless solid-phase synthesis of hexahydrocinnolines. We developed a method in which mild reaction conditions can be used for the hetero-Diels-Alder reactions on a polymeric support. The dienoic 3-vinyl-2-cyclohexenol attached to a Wang resin through an ether linkage undergoes [4 + 2] cycloaddition reaction with several azadienophiles. The highly stereoselective Diels-Alder reaction showed preferential formation of a single cycloadduct resulting from an anti attack of the dienophile on the polymer-bound diene. Trifluoroacetic acid-mediated cleavage of the polymer-bound cycloadducts yields fused nonaromatic hexahydrocinnolines in moderate yields in three steps.

X [dbnd]Y–ZH compounds as potential 1,3-dipoles. Part 63: Silver catalysed azomethine ylide cycloaddition—the synthesis of spiro homoserine lactone analogues

A range of room temperature 1,3-dipolar cycloaddition reactions of imines of 2-amino-γ-lactone and thiolactone, catalysed by a combination of AgOAc or Ag 2O with NEt 3 or DBU, are described. The spiro lactones/thiolactones are formed regio- and stereoselectively as single cycloadducts in good yield via the syn dipoles and an endo-transition states.

Two Novel 1,2,4,5-Tetrazines that Participate in Inverse Electron Demand Diels−Alder Reactions with an Unexpected Regioselectivity

[reaction: see text] Two new unsymmetrical 1,2,4,5-tetrazines, 3-methylsulfinyl-6-methylthio-1,2,4,5-tetrazine (4) and 3-(benzyloxycarbonyl)amino-6-methylsulfinyl-1,2,4,5-tetrazine (5), were prepared, and the scope of their participation in intermolecular inverse electron demand Diels-Alder reactions was defined. As anticipated, sulfoxides 4 and 5 (4 > 5) display a reactivity that is substantially greater than that of their corresponding sulfides (2 and 3), being derived from their enhanced electron-deficient character and resulting in a wider range of potential dienophile choices or the use of milder reaction conditions. The cycloaddition reactions were expectedly regioselective, typically producing a single cycloadduct, ensuring their synthetic utility, but both were found to proceed with a regioselectivity opposite what would be anticipated and complementary to that observed with 2 and 3.

Diastereoselective Synthesis of 2,3,4,5‐Tetrasubstituted Isoxazolidines via 1,3‐Dipolar Cycloaddition.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Diastereoselective synthesis of 2,3,4,5-tetrasubstituted isoxazolidines via 1,3-dipolar cycloaddition

The 1,3-dipolar cycloaddition reactions of α-2-methoxyaryl nitrones with nitrostyrenes and chalcones have been investigated. The regiochemistry and stereochemistry of the resultant cycloadducts have been determined with the help of NMR spectroscopy and X-ray analysis. β-Nitrostyrenes add to nitrones to give two geometrical isomers, while the β-methyl-β-nitrostyrene gives a single isomer in relatively low yield. The chalcones give a single cycloadduct upon 1,3-dipolar addition.

Synthesis of Chiral Oxacyclic Dienes via Ruthenium‐Catalyzed Enyne Metathesis: Useful Building Blocks for Chiral Tricyclic Oxygen Derivatives.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Intermolecular Diels-Alder reactions of brominated masked o-benzoquinones with electron-deficient dienophiles. A detour method to synthesize bicyclo[2.2.2]octenones from 2-methoxyphenols.

Intermolecular Diels-Alder reactions of masked o-benzoquinones, i.e., 6,6-dimethoxy-2,4-cyclohexadienones 5-7 and 21-24 generated from 2-methoxyphenols 1-3 and 17-20, respectively, with electron-deficient dienophiles leading to highly functionalized bicyclo[2.2.2]octenones are described. The masked o-benzoquinones (MOBs) 5-7 underwent Diels-Alder cycloadditions with methyl acrylate, methyl methacrylate, and methyl vinyl ketone to provide bicyclo[2.2.2]octenones 13a-c to 15a-c (direct method) in low to moderate yields with the concomitant formation of considerable amounts of dimers 9-11. To retard dimerization and to improve the yields of the requisite bicyclo[2.2.2]octenones, a detour method comprised of sequential bromination of 2-methoxyphenols 1-4, oxidation and Diels-Alder reaction, and debromination has been developed. The oxidation of bromophenols 17-20 produced MOBs 21-24 which are stable enough to be isolated. The MOBs 21-24 underwent cycloaddition with electron-deficient dienophiles in a very efficient manner to afford the corresponding cycloadducts 25a-c to 28a-c in good to high yields without self-dimerization. When the cycloadducts 25a-c to 28a-c were treated with either Bu(3)SnH/AIBN or tributylammonium formate-palladium reagent, the corresponding debrominated products 13a-cto 16a-c were obtained in high to excellent yields. In general, the cycloadducts 13a-c to 15a-c were obtained in 20-40% higher yields via the detour method than those via the direct method. In both routes, the Diels-Alder reactions proceeded in a highly regio- and stereoselective manner to furnish a single cycloadduct in each case.

Synthesis of chiral oxacyclic dienes via ruthenium-catalyzed enyne metathesis: useful building blocks for chiral tricyclic oxygen derivatives

Various chiral oxacyclic dienes were synthesized via enyne metathesis using Grubbs catalyst (PCy 3) 2Cl 2RuCHPh. A series of substrates bearing a 1,2-diol skeleton was prepared from (2 S)-(benzyloxy)-propanal. The enyne metathesis proceeds smoothly in CH 2Cl 2 at 23°C with a low loading of catalyst (2.0 mol%) under ethylene gas (1–2.5 atm), giving good yields of products without epimerization at any stereogenic carbon. Heating compound 5 comprising a disubstituted alkyne in benzene (80°C) under nitrogen resulted in formation of two diastereomers via epimerization of the primary product. The epimerization occurs at the oxacyclic carbon rather than the benzyl carbon. Diels–Alder reactions of chiral oxacyclic dienes 19 and 22 with maleic anhydride, maleimide and benzoquinone proceeded with high diastereoselectivities, yielding a single cycloadduct efficiently at ambient conditions. The structures of Diels–Alder adducts were determined by 1H NOE NMR spectra. The cycloadducts were formed via the approach of dienophiles to the diene in endo mode and opposite the substituent of the stereogenic center. The cycloadducts 29 and 31 were transformed into enantiopure tricyclic furans 35 and 38 after transformation of the (2 S)-(silyloxy)ethyl group into an acetate group.

Synthesis of 2‐silaoxane via 1,3‐ photocycloaddition

AbstractIrradiation of an aryl group with a silyl tethered alkene yields a tetracyclic 2‐silaoxane with high regiose‐lectivity. The multicyclic structure has been further modified to give an unstable tricyclic diol. Photocycloaddition between cyclopentene and phenylcyclopropane gave a single major cycloadduct without cyclopropyl ring opening, indicating that the putative radical intermediate involved in cycloaddition apparently has a very short lifetime if it exists at all.

π-Facial selectivities and proximal/distal regioselectivities in Diels–Alder reactions of unsymmetrical, cage-annulated 1,3-cyclohexadienes

Diels–Alder cycloaddition of hexacyclo[7.5.1.0 1,6.0 6,13.0 8,12.0 10,14]pentadeca-2,4-diene-7,15-dione ( 1) to ethyl propiolate proceeds with π-facial selectivity to afford two cycloadducts, 4b and 5b (product ratio: 4b/ 5b=80:20). Thermal [4+2] cycloaddition of hexacyclo[7.5.2.0 1,6.0 6,13.0 8,12.0 10,14]hexadeca-2,4-diene-7,16-dione ( 2) to ethyl propiolate affords two isomeric cycloadducts, i.e. 6c and 6d (product ratio: 6c/ 6d=40:60). Cycloadducts 6c and 6d are formed with a high degree of endo π-facial selectivity but with only modest proximal/distal regioselectivity. The corresponding [4+2] cycloaddition of 2 (diene) to dimethyl acetylenedicarboxylate (dienophile) produced a single cycloadduct, 7b. These observations have been further examined by employing Hartree–Fock relative energies of transition states presumably formed enroute to the various products. Interestingly, filled orbital electrostatic repulsion between the incoming dienophile and the CO groups in the diene substrate does not appear to be a significant factor that might influence π-facial selection in this [4+2] cycloaddition. Finally, thermal [4+2] cycloaddition of cyclopentadiene (diene) to dienophile 3 proceeded with a high degree of π-facial selectivity to afford a single cycloadduct, 9b.

Unexpected rearrangement of intramolecular Diels-Alder adducts of citraconic anhydride and secondary furfuryl amines

The intramolecular Diels-Alder reactions of citraconic anhydride with several secondary furfuryl amines have been studied at different temperatures. At high temperatures, only a single cycloadduct was isolated, whilst at room temperature, a mixture of two regioisomeric adducts were formed. One of the regioisomers rearranged to another when heated in a solvent. Some aspects of the mechanism were investigated.

Asymmetric and Doubly Asymmetric 1,3-Dipolar Cycloadditons in the Synthesis of Enantiopure Organophosphorus Compounds

Enantiopure five-membered ring nitrones derived from L-tartaric acid and from L-malic acid undergo highly regio- and stereoselective cycloaddition reactions with an excess of racemic 2,3-dihydro-l-phenyl-1H-phospholes producing two readily separable tricyclic cycloadducts and concomitantly effecting kinetic resolution of the dihydrophosphole derivative. Stereochemistry of the cycloaddition process and scope of the kinetic resolution process have been established in details and adjusted to produce dihydrophosphole derivatives in good yields and in very high optical purity. To effect syntheses of single cycloadducts of 100% ee the techniques of doubly asymmetric synthesis and parallel kinetic resolutions have been employed. The resulting tricyclic cycloadducts feature 2,2'-connection of pyrrolidine and phospholane rings and five to seven contiguous stereogenic centers of which three have been induced and one or two kinetically resolved during the cycloaddition process.

Asymmetric and Doubly Asymmetric 1,3-Dipolar Cycloadditons in the Synthesis of Enantiopure Organophosphorus Compounds

Enantiopure five-membered ring nitrones derived from L-tartaric acid and from L-malic acid undergo highly regio- and stereoselective cycloaddition reactions with an excess of racemic 2,3-dihydro-l-phenyl-1H-phospholes producing two readily separable tricyclic cycloadducts and concomitantly effecting kinetic resolution of the dihydrophosphole derivative. Stereochemistry of the cycloaddition process and scope of the kinetic resolution process have been established in details and adjusted to produce dihydrophosphole derivatives in good yields and in very high optical purity. To effect syntheses of single cycloadducts of 100% ee the techniques of doubly asymmetric synthesis and parallel kinetic resolutions have been employed. The resulting tricyclic cycloadducts feature 2,2'-connection of pyrrolidine and phospholane rings and five to seven contiguous stereogenic centers of which three have been induced and one or two kinetically resolved during the cycloaddition process.