Carbonyl Ylide Dipoles Research Articles

Facile Synthesis of Oxatricyclic Systems with Various Ring Sizes and Substituents

A series of α-diazo carbonyl compounds having cyclopentanone, cyclohexanone and substituted cyclohexanone units with different tether lengths have been synthesized using diazomethane solution or methanesulphonyl azide. The above synthesized α-diazo carbonyl compounds with rhodium(II) acetate dimer furnish cyclic five- or six-ring carbonyl ylide dipoles, which undergo facile 1,3-dipolar cycloaddition with different dipolarophiles to furnish the substituted and functionalized oxatricyclic systems having various ring sizes. Two X-ray crystallographic analyses of compounds 8b and 15a are reported to firmly establish the stereochemistry of the cycloadducts.

Rhodium(II)-Catalyzed Equilibration of Push-Pull Carbonyl and Ammonium Ylides. A Computationally Based Understanding of the Reaction Pathway

α-Diazo esters containing an amido group in the γ-position have been found to undergo a rhodium(II)-catalyzed transformation, producing five-membered ammonium or carbonyl ylides depending on the reaction conditions used. In the absence of an external dipolarophile, ammonium ylides are the exclusive products formed. In most cases these ylides cannot be isolated as they readily undergo sigmatropic rearrangement or fragmentation reactions. In the presence of typical dipolarophiles such as DMAD or N-phenylmaleimide, cycloaddition products derived from cyclic carbonyl ylide dipoles are formed as the major products. The rhodium carbenoid intermediate generated in these reactions can either attack the lone pair of electrons on the amide nitrogen (ammonium ylide formation) or the lone pair of electrons on the carbonyl oxygen (carbonyl ylide formation). The experimental observations reflect a catalyst-promoted system of equilibria with a clear-cut thermodynamic bias. To examine the underlying mechanism in detail, ...

Model Studies Directed toward the Total Synthesis of (±)-Ribasine. A Tandem Cyclization−Cycloaddition Route Leading to the Core Skeleton

A series of α-diazo-β-(o-carbomethoxy)-substituted aryl ketones were prepared and employed as model systems for a synthetic approach toward the alkaloid ribasine. Six-membered ring carbonyl ylide dipoles were generated by treating the diazoketones with a rhodium(II) catalyst. The initially formed dipole was trapped using a variety of dipolarophiles including N-benzylidene methylamine. The Rh(II)-catalyzed behavior of ethyl 2-diazo-3-(2-formylphenyl)-3-oxo-propionate was also studied to probe the chemoselectivity of the reaction. The major products isolated are derived from bimolecular trapping of the carbonyl ylide dipole, as well as intramolecular C−H insertion of the rhodium carbenoid into the aldehydic hydrogen. Changing the catalyst from Rh(II) trifluoroacetate to Rh(II) acetate caused a significant alteration in product distribution. A study of the tandem cyclization−cycloaddition reaction of an o-allyl phenyl substituted diazoketone was also carried out. An unexpected low-temperature intramolecular dipolar cycloaddition of the diazo group across the neighboring π-bond first occurred, followed by nitrogen extrusion to give products derived from a 1,3-biradical intermediate. By subjecting the diazoketone to the Rh(II) catalyst at 110 °C, it was possible to prepare the carbonyl ylide derived cycloadduct in high yield. This result provides good precedent for the future implementation of the cycloaddition strategy toward the synthesis of ribasine.

Synthesis of the Pentacyclic Skeleton of the Aspidosperma Alkaloids Using Rhodium Carbenoids as Reactive Intermediates.

A series of diazo amido keto esters prepared from N-alkenyl-substituted 3-carbalkoxy-2-piperidone derivatives was treated with rhodium(II) acetate. Attack of the amido carbonyl oxygen at the resultant rhodium carbenoid center produced a transient push-pull carbonyl ylide dipole which underwent an intramolecular dipolar cycloaddition reaction. A related annulation sequence was used to prepare the pentacyclic skeleton of the aspidosperma family of alkaloids. Synthesis of the required diazo imide was carried out from 3-carboxy-3-ethyl-2-piperidone and N-methyl-3-indoleacetic acid. Treatment of the diazo imide with rhodium(II) acetate afforded a transient 1,3-dipole which subsequently underwent cycloaddition across the indole pi-bond. The resulting cycloadduct is the consequence of endo cycloaddition with respect to the dipole which is fully in accord with the lowest energy transition state. The cycloadduct was converted in three steps into desacetoxy-4-oxo-6,7-dihydrovindorosine. The stereochemistry of the final product was established by a X-ray crystallographic study.

Ammonium ylide versus carbonyl ylide formation in the rhodium(II)-catalyzed decomposition of diazoacetylureas. Generation and X-ray structure of a stable five-membered N-acyl ammonium ylide

The Rh(II)-catalyzed decomposition of diazoacetylurea 5 gives rise to carbenoid intermediate 7 which can either cyclize to ammonium ylide 6 or to the isomeric carbonyl ylide dipole 8. In the presence of a rhodium catalyst, ammonium ylide 6 rearranges to carbonyl ylide 8 which undergoes 1,3-dipolar cycloaddition reaction with DMAD to give furan 12.

Cyclization of rhodium carbenoids using ester and amido carbonyl groups

Carbonyl ylide dipoles derived from diazoacetyl esters underwent 4π-electrocyclization to furnish bicyclic epoxides. Reaction of related α-diazoketo amides with rhodium(II) carboxylate catalysts resulted in cyclization on both the oxygen and nitrogen atoms of the amido group to give carbonyl and ammonium ylides.

Dipolar Cycloaddition Reactions of Dihydropyrimidine-Fused Mesomeric Betaines. An Approach toward Conformationally Restricted Dihydropyrimidine Derivatives1

The bimolecular and intramolecular cycloaddition potential of various 4-aryldihydropyrimidine-fused mesomeric betaines was investigated. Dihydropyrimidine-fused isothiomünchnones and isomünchnones were found to undergo 1,3-dipolar cycloaddition reactions with electron-deficient dipolarophiles such as DMAD, methyl propiolate, methyl vinyl ketone, or N-methylmaleimide. In contrast, cross-conjugated mesomeric thiazinium betaines underwent 1,4-dipolar cycloaddition reaction with electron-rich dipolarophiles such as ynamines or ketene acetals. In general, these cycloadditions show a high degree of regioselectivity, facial selectivity, and exo/endo diastereoselectivity. Intramolecular variations of the above processes involving o-alkenylaryl-tethered dihydropyrimidine-fused isomünchnones lead to polycyclic dihydropyrimidine analogs that closely mimic the proposed receptor-bound conformation of dihydropyridine calcium channel modulators. These cycloadducts are the result of an endo-addition of the pi-bond to the carbonyl ylide dipole embedded in the isomünchnone system. The relative stereochemistry of these cycloadducts was established by single-crystal X-ray analysis.

Theoretical Insights Regarding the Cycloaddition Behavior of Push-Pull Stabilized Carbonyl Ylides.

A series of diazoamido keto esters were prepared by the reaction of N-substituted 3-carbethoxy-2-piperidone with n-butylmagnesium chloride followed by the addition of ethyl 2-diazomalonyl chloride. Treatment of these diazo amides with rhodium(II) acetate afforded transient push-pull carbonyl ylide dipoles which could be readily trapped with electron deficient dipolarophiles. All attempts to induce the dipolar cycloaddition to occur across tethered alkenyl pi-bonds failed to give internal cycloadducts. However, placing a sp(2) center on the tethered side chain was found to result in the formation of a tricyclic adduct in 95% yield. The stereochemistry of the cycloadduct was firmly established by an X-ray crystallographic study and occurred endo with respect to the amido carbonyl ylide dipole. A detailed computational study was undertaken to provide better insight into the factors that influence the intramolecular cycloaddition process. The calculations indicate that a severe cross-ring 1,3-diaxial interaction caused by the bridgehead methyl group promotes a boat or twist-boat conformation in the piperidine ring fused to the newly forming one. The presence of a carbonyl group in the dipolarophile tether helps to relieve the steric congestion by virtue of favoring a second boat in the latter ring. Without the C=O group, both nascent and piperidine rings are in the chair conformation at lowest energy, and the reaction barrier is disadvantaged by 5.6 kcal/mol, allowing other competing processes to intervene.

A Novel Cycloaddition Reaction of α-Diazo-γ-amido Ketones Catalyzed by Rhodium(II) Acetate. Scope and Mechanistic Details of the Process

α-Diazo ketones containing an amido group in the γ-position have been found to undergo a novel rhodium(II)-catalyzed cycloaddition reaction. Intramolecular cyclization of the keto carbenoid onto the oxygen atom of the amide group generates a carbonyl ylide dipole as a transient species. This highly stabilized dipole does not readily undergo 1,3-dipolar cycloaddition but rather transfers a proton to produce a cyclic ketene N,O-acetal. The ketene acetal is unstable to moisture and upon standing is readily hydrolyzed to a γ-keto δ-lactone and an amine. In the absence of any significant amount of water, the ketene N,O-acetal undergoes conjugate addition with the activated π-bond of the dipolarophile to give a zwitterion intermediate. The anionic portion of the zwitterion adds to the neighboring carbonyl group. This is followed by epoxide ring formation with charge dissipation leading to an amido-substituted spiro cyclopentyl epoxide. In certain cases a hydroxy lactone was also isolated and its formation can be attributed to the competitive hydrolysis of the zwitterionic intermediate. The Rh(II)-catalyzed reaction of the diazo ketoamide derived from N-benzylpiperidone with DMAD afforded two different types of cycloadducts. In addition to the spiro cyclopentyl epoxide, a product derived from trapping of the carbonyl ylide dipole was also obtained, thereby providing additional support for the proposed mechanism.

Stereo and electronic effects in the rhodium(II)-mediated synthesis of polycyclic lactones and lactams from .alpha.-diazo ester and amide precursors

The rhodium(II) carboxylate catalyzed decomposition of several α-diazo esters and amides has been studied. A series of 5-keto-1-diazo acetates were prepared by acylation of α-hydroxy ketones using the (p-toluenesulfonyl)hydrazone of glyoxylic acid chloride. Treatment of these compounds with Rh(II) acetate afforded products derived from carbenoid insertion into solvent. When the hydrogen atom of the diazo carbon was replaced with an electron-withdrawing substituent, smooth cyclization occurred to produce a carbonyl ylide dipole which was subsequently trapped with different dipolarophiles. A series of N-alkyl-2-diazo-π-oxobutylamides, when treated with a catalytic quantity of rhodium(II) acetate, gave furo[3,4-c] furans in good yield. The reaction proceeds via addition of a rhodium stabilized carbenoid onto the acetylenic π-bond to give a vinyl carbenoid which subsequently cyclizes onto the neighboring carbonyl group to produce the furan ring. N-Alkynyl-substituted 2-diazoacetamides were also found to cyclize onto the tethered alkyne unit. The resulting rhodium carbenoid can undergo intramolecular and bimolecular cyclopropanation depending on both electronic and conformational factors. Rotamer population of the starting diazoamide was also found to influence product distribution

Azomethine ylide generation via the dipole cascade

A series of N-acyl 2-diazo-3-oxobutanoates, when treated with a catalytic quantity of a rhodium(II) carboxylate, were found to afford substituted pyrroles derived from an azomethine ylide intermediate. The initial reaction involves generation of the expected carbonyl ylide dipole by intramolecular cyclization of the keto carbenoid onto the oxygen atom of the neighboring amide group. The primary cycloadduct undergoes a subsequent rearrangement-fragmentation reaction to give the pyrrole derivative. When the α-position of the α-diazoketone was blocked with two methyl groups, the rhodium(II)-catalyzed cycloaddition with dimethyl acetylenedicarboxylate led to the carbonyl vlide cycloadduct in high yield. MNDO calculations show that the cyclic carbonyl ylide derived from ethyl 2-diazo-4-dibenzoylamino-3-oxobutyrate is 3.3 kcal lower in its heat of formation than the corresponding azomethine ylide. This thermodynamic difference in stability of dipoles nicely accounts for why the carbonyl ylide cycloadduct is the major product from the rhodium(II) catalyzed reaction of ethyl 2-diazo-4-dibenzoylamino-3-oxobutyrate.

ChemInform Abstract: Tandem Cyclization‐Cycloaddition Reaction of Rhodium Carbenoids. Scope and Mechanistic Details of the Process.

AbstractTreatment of 1‐diazo‐2,5‐pentanediones such as (I) with rhodium(II) carboxylates affords cyclic carbonyl ylide dipoles (III), which undergo 1,3‐dipolar cycloaddition with both electron‐deficient and electron‐rich dipolarophiles as well as with carbonyl compounds to give adducts such as (IV), (VI), (VII), (IX) or (X).