Tandem cyclization-cycloaddition behavior of rhodium carbenoids with carbonyl compounds: stereoselective studies on the construction of novel epoxy-bridged tetrahydropyranone frameworks

Investigations and stereoselective studies on the tandem reactions of carbonyl ylides generated from alpha-diazo ketones in the presence of carbonyl compounds are presented in this paper. Intramolecular cyclization of rhodium carbenoids generated the transient five- or six-membered-ring carbonyl ylide dipoles, which efficiently underwent 1,3-dipolar cycloaddition reactions with various dipolarophiles such as aromatic aldehydes 15, alpha,beta-unsaturated aldehydes 18/24, alpha,beta-unsaturated ketones 27/28/31, and dienone 34. The transient carbonyl ylides underwent cycloadditions with various aromatic aldehydes to furnish diverse epoxy-bridged tetrahydropyranone ring systems in a diastereoselective manner. The cycloaddition of carbonyl ylides with alpha,beta-unsaturated aldehydes 18/24 or dienone 34 afforded C=O addition products in a chemoselective manner despite the presence of C=C bonds in the above dipolarophiles. Alternatively, the cycloaddition of carbonyl ylides with alpha,beta-unsaturated ketones 27/28 provided both the C=O and C=C cycloaddition products. The cycloaddition of carbonyl ylides with carbonyl compounds occurred in good yields and was found to be highly regio- and stereoselective. Single-crystal X-ray analyses were performed to unambiguously establish the structure and stereochemistry of the novel epoxy-bridged tetrahydropyranone ring systems 35a/38. Compound 35a exhibited both intermolecular C-H...O and intramolecular C-H...pi interaction motifs in the solid-state architecture. The regio-, chemo-, and stereoselectivity observed in these reactions have been investigated by semiempirical AM1 MO calculations. FMO analyses and transition state calculations have been performed for the cycloaddition of carbonyl ylides with alpha,beta-unsaturated carbonyl compounds such as tetracyclone (34) and cyclopentenone (27a). Both FMO and transition state calculations correctly predicted the regio- and stereochemistry of the cycloadducts. The calculations further revealed that a severe steric interaction caused by the phenyl rings present in dipolarophile 34 with dipole 14a increases the activation barrier of the transition state during the cycloaddition process.     

Synthesis of novel dispiro-oxindoles via 1,3-dipolar cycloaddition reactions of azomethine ylides

The 1,3-dipolar cycloaddition of 1-allyl-5-haloisatin derivatives as dipolarophiles with the azomethine ylides generated in situ from N-allylisatin and l-proline to furnish novel dispiro-oxindoles has been investigated. The structures and relative stereochemistry of both types of cycloadducts were confirmed by single crystal X-ray diffraction, ¹H and ¹³C NMR spectroscopy and mass spectrometry.     

Direct construction of novel dispiro heterocycles through 1,3-dipolar cycloaddition of azomethine ylides

The 1,3-dipolar cycloaddition of 2-oxo-(2H)-acenaphthylen-1-ylidene-malononitrile and 2-fluoren-9-ylidene-malononitrile as dipolarophiles have been investigated for the first time with the azomethine ylides generated in situ from N-substituted isatin and sarcosine to furnish novel dispiro heterocycles. The structure and relative stereochemistry of both types of cycloadducts were confirmed by single crystal X-ray diffraction, as well as with the help of ¹H, ¹³C, and HMBC spectroscopic methods.     

Multicomponent reactions of diazoamides: diastereoselective synthesis of mono- and bis-spirofurooxindoles

This paper describes the intermolecular generation of carbonyl ylides by dirhodium(II) tetraacetate-catalyzed reaction of 3-diazoindol-2-ones in the presence of aryl aldehydes and heteroaryl aldehydes. These carbonyl ylides were subsequently trapped with dipolarophiles such as dimethyl acetylenedicarboxylate, maleic anhydride, and ethyl acrylate to afford spirofurooxindoles. Consequently, diastereoselective synthesis of spirodihydrofurooxindoles through the multicomponent reactions of cyclic diazoamides was successfully achieved for the first time. The stereochemistry of the spirofurooxindole is unequivocally corroborated by the single-crystal X-ray analysis of the representative product 4o. Interestingly, these reactions were extended to double multicomponent reactions of bis-cyclic diazoamides to afford the respective complex polycycles in a tandem manner, which led to the construction of four carbon-carbon bonds, two carbon-oxygen bonds, and four chiral centers in a single synthetic step.     

The first example of the generation of azomethine ylides from a fluorocarbene: 1,3-cyclization and 1,3-dipolar cycloaddition

The reaction of Schiff bases with fluorocarbene, generated by reduction of dibromofluoromethane with active lead in the presence of Bu₄NBr under ultrasound irradiation, involves the formation of fluoro-substituted azomethine ylides which undergo cyclization into aziridines. 1,3-Cyclization of ylides, generated from N-arylimines of benzaldehyde, proceeds stereoselectively. When carrying out the reaction of Schiff bases with fluorocarbene in the presence of dimethyl maleate or dimethyl acetylenedicarboxylate, the products of dehydrofluorination of the primary adducts of the 1,3-dipolar cycloaddition of fluoro-substituted azomethine ylides to multiple bonds of dipolarophiles were obtained. In the case of the reaction of N-alkylimines of benzaldehyde the cycloaddition of ylides to dimethyl maleate completely suppressed the cyclization to aziridines.     

Origins of the Reactivity in 1,3-Dipolar Cycloadditions of Acyl Isocyanide Ylides

1,3-Dipolar cycloadditions are the preferred method to generate five-membered heterocyclic rings. Surprisingly, cycloadditions based on acyl-isocyanide ylides have remained underexplored by the chemical community. Acyl-isocyanide ylides readily react with dipolarophiles, such as substituted alkenes, to yield Δ¹-pyrroline derivatives. As an explanation for the observed reactivity of this reaction is lacking, extensive density functional theory calculations were performed to scrutinize the mechanistic features of the transformation. Herein we explain the experimental outcome of the reaction using a variety of reactivity theories and predict opposed regioselectivity for electron-poor and electron-rich dipolarophiles. With the insights obtained, we hope to incentivize the design of new cycloaddition reactions based on the acyl-isocyanide ylides motif.     

Regioselective synthesis of mono- and bis-decahydrobenzocarbazoles via tandem reactions of α-diazo ketones

Regioselective intermolecular 1,3-dipolar cycloaddition reactions of rhodium generated carbonyl ylides with indoles are reported in this paper. Intermolecular 1,3-dipolar cycloaddition reactions of five-membered-ring cyclic carbonyl ylides with indole and substituted indoles afforded hexahydro-2H-carbazol-2-ones in a regioselective manner. Similarly, reactions of cyclic carbonyl ylides were carried out to afford decahydrobenzo[c]carbazoles or decahydrocyclopenta[c]carbazoles with high regioselectivity. Interestingly, the other possible regioisomer decahydrobenzo[a]carbazoles were also obtained by the reaction of cyclic carbonyl ylides and indoles having electron withdrawing substituents. The structure and stereochemistry of regioisomers 6,11c-epoxy-1,2,3,4,4a,5,6,6a,11b,11c-decahydro-4a-methyl-5-oxo-7H-benzo[c]carbazole and 11-benzenesulfonyl-6,11b-epoxy-2,3,4,4a,5,6,6a,11,11a,11b-decahydro-4a-methyl-5-oxo-1H-benzo[a]carbazole were unequivocally corroborated by single-crystal X-ray analyses. To advance this study, regioselective double 1,3-dipolar cycloaddition reaction of five-membered-ring cyclic carbonyl ylides has been demonstrated for the first time with biindoles having various aryl and alkyl spacers. This process constructed up to eight stereocenters, four carbon-carbon and two carbon-oxygen bonds in a single step with an excellent molecular complexity and stereoselectivity.     

Asymmetric 1,3-dipolar cycloadditions of a chiral nonracemic glyoxylic azomethine imine

The reactivity of a chiral nonracemic glyoxylic azomethine imine has been investigated. This species reacts with a wide range of dipolarophiles, with a complete regio- and facial stereoselectivity. The introduction of an electron-withdrawing substituent on the ylide leads to a lower endo selectivity with electron-withdrawing dipolarophiles, but to an improved exo selectivity with styrene derivatives when compared to the reactivity of aliphatic- or aromatic-substituted ylides.     

A facile regioselective 1,3-dipolar cycloaddition protocol for the synthesis of new class of quinolinyl dispiro heterocycles

The 1,3-dipolar cycloaddition reaction of azomethine ylides generated in situ from isatin and secondary amino acids with quinolinyl dipolarophiles in refluxing methanol afforded new class of quinolinyl dispiro heterocycles with multi hetero core units. The regio and stereochemistry of the product was unambiguously assigned by ¹H, ¹³C, 2D NMR techniques and single crystal X-ray analysis. The structures of the compounds are stabilized through the presence of intermolecular hydrogen bonding and intramolecular non-covalent interactions.     

A facile entry into a novel class of dispiroheterocyclic framework through 1,3-dipolarcycloaddition of azomethine ylides with 3-arylidene-4-chromanones as dipolarophiles

The cycloaddition reaction of azomethine ylides, generated through decarboxylation, with (E)-3-arylidene-4-chromanones as dipolarophiles has been investigated. A high degree of regioselectivity has been observed in the synthesis of a new class of functionalized dispiroheterocyclic compounds bearing chromanone and acenaphthenequinone framework. The structures were established by spectroscopic techniques as well as single crystal X-ray analysis.     

Sequential Pd/Ru-catalysed allenylation/olefin metathesis/1,3-dipolar cycloaddition route to novel heterocycles

A novel sequential palladium/ruthenium-catalysed four component process is described involving carbonylation of an aryl/heteroaryl iodide followed by allenylation to generate (π-allyl) palladium species which are intercepted by nitrogen nucleophiles to afford 1,6-dienes. Subsequent Ring-Closing Metathesis (RCM) affords C-acyl-N-heterocycles in good yield. These heterocycles proved to be active dipolarophiles in sequential and cascade 1,3-dipolar cycloaddition reactions (1,3-DC) as exemplified by reactions with nitrones and azomethine ylides.     

Cu-Fesulphos complexes: efficient chiral catalysts for asymmetric 1,3-dipolar cycloaddition of azomethine ylides

The Cu^I-Fesulphos catalyst system (≤3 mol %) shows an excellent performance in the asymmetric 1,3-dipolar cycloaddition of azomethine ylides. High to very high levels of reactivity, endo/exo selectivity, and enantioselectivity (69->99% ee) are generally achieved with a very wide range of azomethine ylides and dipolarophiles. Based on experimental and computational studies data, a model that accounts for this high enantiocontrol is proposed.     

1,3-Dipolar cycloadditions with azomethine ylide species generated from aminocyclopropanes

Two types of bicyclic N-cyclopropyl glycine ester derivatives have been prepared and put under scrutiny as possible precursors of azomethine ylides. The results demonstrate that they can indeed participate in 1,3-dipolar cycloaddition reactions with dipolarophiles, as illustrated in the cases of phenyl vinyl sulfone, N-phenylmaleimide, diethyl fumarate and diethyl maleate. The relative configurations of the major diastereoisomers produced are consistent with the predicted generation of azomethine ylide species, reacting in concerted cycloaddition processes. This unprecedented way of generating such 1,3-dipoles provides access to functionalised pyrrolizidine and pyrrolidine derivatives, that would be difficult to make directly by more classic methods. It was also found that using phenyl vinyl sulfone or N-phenylmaleimide as the dipolarophile reactant, a domino nucleophilic conjugate addition/1,3-dipolar cycloaddition process may operate competitively.     

X=Y=ZH Systems as potential 1,3-dipoles. Part 58: Cycloaddition route to chiral conformationally constrained (R)-pro-(S)-pro peptidomimetics

Imines of (1S,9S)-t-butyl-9-amino-octahydro-6,10-dioxo-6H-pyridazino[1,2-a][1,2]diazepine-1-carboxylate undergo thermal (toluene, 110°C) or LiBr-DBU catalysed (MeCN, room temperature) regio- and stereo-specific cycloaddition to a range of chiral dipolarophiles giving enantiopure spiro-cycloadducts in excellent yield. The reactions proceed via intermediate NH azomethine ylides and litho azomethine ylides, respectively and results in the multiplication of chiral centres from 2 (one of which is lost in the process) to 5.     

Synthesis of new calix[4]pyrrole derivatives via 1,3-dipolar cycloadditions

Octamethylcalix[4]pyrrole-2-carbaldehyde 1 and 3-(octamethylcalix[4]pyrrol-2-yl)propenal 5 were used as precursors of azomethine ylides, which were trapped in situ with a range of dipolarophiles, such as 1,4-benzoquinone, 1,4-naphthoquinone, and fumaronitrile. Aldehyde 1 showed very low reactivity but the azomethine ylide generated from the reaction of aldehyde 5 with N-methylglycine could be trapped with those dipolarophiles to afford new β-substituted octamethylcalix[4]pyrrole derivatives in moderate yields. The resulting cycloadducts show high affinity constants for fluoride and acetate anions; compounds 7 and 8 display sharp changes in color in the presence of these anions.     

Binaphthol-derived bisphosphoric acids serve as efficient organocatalysts for highly enantioselective 1,3-dipolar cycloaddition of azomethine ylides to electron-deficient olefins

A variety of chiral bisphosphoric acids derived from binaphthols have been evaluated for enantioselective 1,3-dipolar cycloaddition reactions, revealing that the feature of the linker in the catalysts exerted great impact on the stereoselectivity. Among them, the oxygen-linked bisphosphoric acid 1a provided the highest level of stereoselectivity for the 1,3-dipolar cycloaddition reaction tolerating a wide range of substrates including azomethine ylides, generated in situ from a broad scope of aldehydes and α-amino esters, and various electron-deficient dipolarophiles such as maleates, fumarates, vinyl ketones, and esters. This reaction actually represents one of the most enantioselective catalytic approaches to access structurally diverse pyrrolidines with excellent optical purity. Theoretical calculations with DFT method on the formation of azomethine ylides and on the transition states of the 1,3-dipolar cycloaddition step showed that the dipole and dipolarophile were simultaneously activated by the bifunctional chiral bisphosphoric acids through the formation of hydrogen bonds. The effect of the bisphosphoric acids on reactivity and stereochemistry of the three-component 1,3-dipolar cycloaddition reaction was also theoretically rationalized. The bisphosphoric acid catalyst 1a may take on a half-moon shape with the two phosphoric acid groups forming two intramolecular hydrogen bonds. In the case of maleates, one phosphate acts as a base to activate the 1,3-dipole, and simultaneously, the two hydroxyl groups in the catalyst 1a may respectively form two hydrogen bonds with the two ester groups of maleate to make it more electronically deficient as a much stronger dipolarophile to participate in a concerted 1,3-dipolar cycloaddition with azomethine ylide. However, in the cases involving acrylate and fumarate dipolarophiles, only one hydroxyl group forms a hydrogen bond with the ester functional group to lower the LUMO of the C-C double bond and another one is remained to adjust the acidity and basicity of two phosphoric acids to activate the dipole and dipolarophile more effectively.     

Novel synthesis of naphtho[2,1-b]pyrano pyrrolizidines and indolizidines through intramolecular 1,3-dipolar cycloaddition reaction

A facile synthesis of a series of naphtho[2,1-b]pyrano pyrrolizidines and indolizidines was accomplished in good yields in a one-pot reaction through intramolecular 1,3-dipolar cycloaddition of azomethine ylides with Baylis-Hillman adducts as dipolarophiles. The protocol is applicable to a wide variety of photochromic and biologically active napthopyrano products. The regio and stereochemical outcome of the cycloaddition reaction was ascertained by X-ray crystallographic study of some of the products.     

1,3-Dipolar cycloadditions of azomethine ylides with chiral acrylates derived from methyl (S)- and (R)-lactate: diastereo- and enantioselective synthesis of polysubstituted prolines

The 1,3-dipolar cycloaddition of acrylates derived from methyl (R)- and (S)-lactate, as chiral dipolarophiles, with glycine and alanine derived azomethine ylides is described for the first time. By using the corresponding silver metallo-azomethine ylides polysubstituted endo-prolines were obtained with high diastereo- and enantioselectivity. The process occurs at room temperature in toluene with 10 mol % of AgOAc by using either KOH or Et₃N as bases, also in substoichiometric amounts. Under these mild reaction conditions, enantiomerically enriched polysubstituted prolines resulting from an endo approach were obtained in general in high yields and de (86–99%). The absolute configuration of the resulting prolinates can be determined on the basis of X-ray diffraction analysis.     

Three‐component 1,3‐dipolar cycloaddition reactions in synthesis of spiro[pyrrolidine‐2,3′‐oxindoline] derivatives

Regio‐ and stereospecific syntheses of several spiro[pyrrolidine2,3′‐oxindole] derivatives by cycloaddition trapping of azomethine ylides generated in situ, via decarboxylative condensation of isatin with α‐amino acids or by reaction of secondary amines with isatin, are reported. 2,6‐Dibenzylidenecyclohexanone, 2‐arylidene‐1‐tetralone, and arylidenemalononitrile derivatives have been efficiently used as trapping dipolarophiles. The regio‐ and stereochemistry of the additions are controlled by both frontier orbital and steric interactions. © 2002 Wiley Periodicals, Inc. Heteroatom Chem 13:324–329, 2002; Published online in Wiley Interscience (www.interscience.wiley.com). DOI 10.1002/hc.10038     

1,3-Dipolar cycloadditions of nonstabilized azomethine ylides to planar chalcones via regio- and stereoselective route: A three-component strategy

Simple and efficient strategies toward the synthesis of trisubstituted pyrrolizidines and disubstituted oxazolidine systems by 1,3-dipolar cycloaddition reactions using arylaldehydes and α-amino acids have been developed, followed by a one-pot, three-component strategy. Electron-deficient dipolarophiles, chalcones, were reacted with nonstabilized azomethine ylides derived from arylaldehyde and L-proline in dry dimethyl formamide, leading to substituted pyrrolizidines. The route to substituted oxazolidines involved cycloaddition to the C?O bond of a second molecule of the aldehyde. The structures and stereochemistry of the cycloadducts were established by infrared (IR), NMR spectroscopy, and single-crystal x-ray crystallographic analyses. Condensed Fukui functions and local electrophilicity indices have been computed to characterize the reactive sites and predict the preferred interactions of azomethine ylides to planar chalcones. The softness-matching indices have been evaluated to determine the regioselectivity of the cycloaddition reactions. The theoretical predictions were found to be in complete agreement with the experimental results, implying that the density functional theory (DFT)-based reactivity indices correctly predict the regioselectivities of 1,3-dipolar cycloadditions of azomethine ylides to planar chalcones. The frontier molecular orbital (FMO) energies, electronic chemical potentials, chemical hardness, chemical softness, and global electrophilicity indices of azomethine ylides have been calculated at the DFT/B3LYP/6-31 + G (d, p) level of theory.