Catalytic Decomposition of Diazo Compounds as a Method for Generating Carbonyl‐Ylide Dipoles

The transition metal catalyzed reaction of α‐diazo carbonyl compounds has found numerous applications in organic synthesis, and its use in either heterocyclic or carbocyclic ring formation is well‐precedented. In contrast to other catalysts that are suitable for carbenoid reactions of diazo compounds, those constructed with the dirhodium(II) framework are most amenable to ligand modification that, in turn, can influence reaction selectivity. The reaction of rhodium carbenoids with carbonyl groups represents a very efficient method for generating carbonyl ylide dipoles. Rhodium‐mediated carbenoid–carbonyl cyclization reactions have been extensively utilized as a powerful method for the construction of a variety of novel polycyclic ring systems. This article will emphasize some of the more recent synthetic applications of the tandem cyclization/cycloaddition cascade for natural product synthesis. Discussion centers on the chemical behavior of the rhodium metal–carbenoid complex that is often affected by the nature of the ligand groups attached to the metal center.     

Ligand Effects on the Chemoselectivity of Transition Metal Catalyzed Reactions of α-Diazo Carbonyl Compounds

The transition metal catalyzed reaction of α-diazo carbonyl compounds has found numerous applications in organic synthesis, and its use in either heterocyclic or carbocyclic ring formation is well precedented. Early work in this area made use of insoluble copper catalysts. Although these catalysts are still employed today, their use has decreased significantly with the advent of homogeneous copper catalysts and catalysts based on other metals. The discovery that Rh^II carboxylates facilitate nitrogen loss from diazo compounds rekindled significant interest in the field of diazo/carbenoid chemistry. Since the realization that Rh^II carboxylates are superior catalysts for the generation of transient electrophilic metal carbenoids from α-diazo carbonyl compounds, intramolecular carbenoid addition and insertion reactions have assumed strategic importance in C? C bond-forming reactions in organic synthesis. In contrast to other catalysts that are suitable for carbenoid reactions of diazo compounds, those constructed with the dirhodium(II ) framework are most amenable to ligand modifications that, in turn, can influence reaction selectivity. This article will emphasize the chemical behavior of transition metal carbenoid complexes that are greatly affected by the nature of the ligand groups attached to the metal center. Much of the discussion will center on the ability of the dirhodium(II ) ligands to determine reaction preference toward different functional groups on the same molecule.     

Rhodium(II) mediated cyclizations of diazo alkynyl ketones

The rhodium(II)-catalyzed reaction of -diazo ketones bearing tethered alkyne units represents a new and useful method for the construction of a variety of substituted cyclopentenones. The process proceeds by addition of the rhodium-stabilized carbenoid onto the acetylenic π-bond to give a vinyl carbenoid intermediate. The resulting rhodium complex undergoes a wide assortment of reactions including cyclopropanation, 1,2-hydrogen migration, CH-insertion, addition to tethered alkynes and ylide formation. The exact pathway followed is dependent on the specific metal/ligand employed and is also influenced by the nature of the solvent. Sulfonium ylide formation occurred both intra and intermolecularly when the reaction was carried out in the presence of a sulfide. In the case where an ether oxygen was present on the backbone of the vinyl carbenoid, cyclization afforded an oxonium ylide which underwent a [1,2] or [2,3]-sigmatropic shift to give a rearranged product. These cyclic metallocarbenoids were also found to interact with a neighboring carbonyl π-bond to produce carbonyl ylide dipoles that could be trapped with added dipolarophiles. The domino transformation was also performed intramolecularly by attaching an alkene directly to the carbonyl group. When 2-alkynyl-2-diazo-3-oxobutanoates were treated with a Rh(II)-catalyst, furo[3,4-c]furans were formed in excellent yield. The 1,5-electrocyclization process involved in furan formation has also been utilized to produce indeno[1,2-c]furans. Rotamer population was found to play a significant role in the cyclization of -diazo amide systems containing tethered alkynes. In this account, an overview of our work in this area is presented.     

Synthesis of furo[3,4-c]furans using a rhodium(II)-catalyzed cyclization/Diels-Alder cycloaddition sequence

A series of 2-alkynyl 2-diazo-3-oxobutanoates, when treated with a catalytic quantity of rhodium(II) acetate, afforded furo[3,4-c]furans in good yield. The reaction proceeds by addition of a rhodium-stabilized carbenoid onto the acetylenic pi-bond to give a vinyl carbenoid that subsequently cyclizes onto the neighboring carbonyl group to produce the furan ring. These furo[3,4-c]furans react with various dienophiles, furnishing anisole derivatives derived by loss of water from the initially formed Diels-Alder cycloadducts. The Rh(II)-catalyzed cyclization reaction was quite versatile with regard to the nature of the interacting carbonyl group. The methodology was applied to the synthesis of several oxa-polyheterocyclic systems by first generating a 2-alkoxy-substituted furan and then allowing it to undergo a subsequent intramolecular Diels-Alder cycloaddition. Ring opening of the resulting cycloadduct is followed by deprotonation to furnish a rearranged keto lactone. The potential use of this method for the synthesis of the alkaloid strychnine was probed using suitable model diazo compounds. To establish the viability of this approach, the Rh(II)-catalyzed cyclization/cycloaddition sequence of alpha-diazo amides 64 and 68 were studied. Both compounds underwent the sequential process in good overall yield, leading to novel pentacyclic products. The structural features of the resultant products present numerous opportunities for postcycloaddition manipulations that could be exploited to synthetic advantage.     

Ligand effects in the Rh(II) catalyzed reaction of α-diazo ketoamides

The rhodium(II) catalyzed decomposition of several α-diazo ketoamides resulted in either formation of a push-pull carbonyl ylide intermediate followed by intramolecular [3+2]-cycloaddition across the tethered π-bond or C-H insertion of the initially formed rhodium carbenoid into the C₅-position of the lactam ring followed by a carboethoxy-decarboxylation reaction. The chemoselectivity exhibited by the rhodium carbenoid intermediate was found to be markedly dependent on the metal ligands employed.     

Synthetic Applications of Carbonyl Ylides Generated via the Tandem Cyclization Cycloaddition Reaction of Rhodium Carbenoids

The author's chemical studies dealing with the generation of carbonyl ylides via the rhodium(II) induced cyclization of α-diazo alkanediones are summarized, Dipole formation occurs by reaction of a transient rhodium carbenoid intermediate with a neighboring carbonyl group. These cyclizations are performed under extremely mild conditions, typically at room temperature in a neutral organic solvent. Since these cycloadditions involve carbonyl ylides, the resulting products are oxabicycles of varying ring size. When the dipolarophile is intramolecularly tethered to the dipole, the subsequent cycloaddition affords complex oxapolycyclic systems with three (or more) component rings.     

Rhodium(II)-catalyzed cyclization of amido diazo carbonyl compounds

A series of acyclic diazo ketoamides were prepared from N-benzoyl-N-alkylaminopropanoic acids and were treated with a catalytic amount of rhodium(II) acetate. The resultant carbenoids underwent facile cyclization onto the neighboring amide carbonyl oxygen atom to generate seven-membered carbonyl ylide dipoles. Subsequent collapse of the dipoles with charge dissipation produce bicyclic epoxides which undergo further reorganization to give substituted 5-hydroxydihydropyridones in good yield. Depending on the nature of the substituent groups, it was possible to trap some of the initially formed carbonyl ylide dipoles with a reactive dipolarophile such as DMAD. In other cases, cyclization of the dipole to the epoxide is much faster than bimolecular trapping. A related cyclization/rearrangement sequence occurred when diazo ketoamides derived from the cyclic pyrrolidone and piperidone ring systems were subjected to catalytic quantities of Rh(II) acetate. With these systems, exclusive O-cyclization of the amido group onto the carbenoid center occurs to generate a seven-ring carbonyl ylide dipole. Starting materials are easily prepared, and the cascade sequence proceeds in good yield and does not require special precautions. The overall procedure represents an efficient one-pot approach toward the synthesis of various indolizidine and quinolizidine ring systems.     

A Rh(II)-catalyzed cycloaddition approach toward the synthesis of komaroviquinone

Using a rhodium(II)-catalyzed cyclization/cycloaddition sequence as the key reaction step, the icetexane core of komaroviquinone was constructed by an intramolecular dipolar-cycloaddition of a carbonyl ylide dipole across a tethered π-bond. The ylide was arrived at by cyclization of a rhodium carbenoid intermediate onto a proximal ester group. Efforts toward the preparation of the required precursor for elaboration to the natural product are discussed.     

A ring expansion-annulation strategy for the synthesis of substituted azulenes. Preparation and Suzuki coupling reactions of 1-azulenyl triflates

[structure: see text]. A new strategy for the synthesis of substituted azulenes is reported, based on the reaction of beta'-bromo-alpha-diazo ketones with rhodium carboxylates. The key transformation involves intramolecular addition of a rhodium carbenoid to an arene pi-bond, electrocyclic ring opening, beta-elimination, tautomerization, and trapping to produce 1-hydroxyazulene derivatives. The synthetic utility of the method is enhanced by the ability of the triflate derivatives to participate in Suzuki coupling reactions, as illustrated in a synthesis of the antiulcer drug egualen sodium (KT1-32).     

A short synthesis of α-allenic alcohols from α,β-unsaturated carbonyl compounds with dichloromethyl p-tolyl sulfoxide

The reaction of the α-sulfinyl carbanion of dichloromethyl p-tolyl sulfoxide with α,β-unsaturated carbonyl compounds gave 1-chlorocyclopropyl p-tolyl sulfoxides having a carbonyl group in good to high yields. The carbonyl groups in the products were reduced or treated with alkylmetals to give alcohols. Finally, the alcohols were treated with Grignard reagent to give α-allenic alcohols via the rearrangement of the cyclopropylmagnesium carbenoid intermediates, which were generated by the sulfoxide-magnesium exchange reaction, in good to high yields. This procedure provides a new method for a short synthesis of various α-allenic alcohols in two or three steps from relatively easily available α,β-unsaturated carbonyl compounds.     

Efficient one-pot synthesis of biologically interesting diverse furo[2,3-b]pyran-6-ones by rhodium(II)-catalyzed cascade reactions of diazo compound with ethynyl compounds

Rhodium(II)-catalyzed reactions of diazo compound and a variety of ethynyl compounds were carried out. These reactions provide a rapid route for preparing a variety of furo[2,3-b]pyran-6-one derivatives in one-pot via cascade reactions of metal carbenoid reaction/ketene formation/[2+2]cycloaddition/ring expansion.     

Cross‐Coupling of α‐Carbonyl Sulfoxonium Ylides with C−H Bonds

The functionalization of carbon–hydrogen bonds in non‐nucleophilic substrates using α‐carbonyl sulfoxonium ylides has not been so far investigated, despite the potential safety advantages that such reagents would provide over either diazo compounds or their in situ precursors. Described herein are the cross‐coupling reactions of sulfoxonium ylides with C(sp²)−H bonds of arenes and heteroarenes in the presence of a rhodium catalyst. The reaction proceeds by a succession of C−H activation, migratory insertion of the ylide into the carbon–metal bond, and protodemetalation, the last step being turnover‐limiting. The method is applied to the synthesis of benz[c]acridines when allied to an iridium‐catalyzed dehydrative cyclization.     

Enantiospecific total synthesis of 15-hydroxy-5-(methoxymethoxy)crinipellin-9-one

Enantiospecific total synthesis of the crinipellin mentioned in the title was accomplished. In the present synthesis cyclopentane ring in campholenaldehyde was identified as the B-ring, two intramolecular rhodium carbenoid CH insertion reactions were employed for the construction of the A and C rings, and an intramolecular Michael addition reaction was utilized for the construction of the D-ring of crinipellin.     

Highly regioselective rhodium(II)-catalysed carbenoid insertion reaction into sp CH bond: a general method for the synthesis of 3,3a-dihydro-2H,5H-pyrrolo[1,2-a]quinoline-1,4-dione ring system

A simple and high yielding general method for the synthesis of 3,3a-dihydro-2H,5H-pyrrolo[1,2-a]quinoline-1,4-dione derivatives through a highly regioselective rhodium(II)-catalysed carbenoid sp² C-H insertion reaction on suitably substituted γ-lactam diazocarbonyl compounds is described.     

Synthesis,including asymmetric synthesis,of 3-oxabicyclo[3.1.0]hexanes and bicyclo[3.1.0]hexanes by the 1,5-CH insertion of cyclopropylmagnesium carbenoids as the key reaction

The addition reactions of α,β-unsaturated carbonyl compounds with dichloromethyl p-tolyl sulfoxide in the presence of NaHMDS or LDA resulted in the formation of adducts, 1-chlorocyclopropyl p-tolyl sulfoxides bearing a carbonyl group at the 2-position, in almost quantitative yields. The carbonyl group of the adducts was transformed to various ether groups to give 1-chlorocyclopropyl p-tolyl sulfoxides bearing an ether functional group at the 2-position in short steps. Treatment of these products with i-PrMgCl at low temperature afforded cyclopropylmagnesium carbenoids via the sulfoxide-magnesium exchange reaction. 1,5-Carbon–hydrogen insertion (1,5-CH insertion) reaction of the generated magnesium carbenoid intermediates took place to give 3-oxabicyclo[3.1.0]hexanes or bicyclo[3.1.0]hexanes bearing an ether group at the 4-position in moderate to good yields. When this procedure was carried out starting with enantiopure dichloromethyl p-tolyl sulfoxide, enantiopure 3-oxabicyclo[3.1.0]hexanes were obtained in good overall yields. These procedures provide a good way for the synthesis, including asymmetric synthesis, of multisubstituted 3-oxabicyclo[3.1.0]hexanes and bicyclo[3.1.0]hexanes from α,β-unsaturated carbonyl compounds and dichloromethyl p-tolyl sulfoxide in short steps.     

Carbon-13 NMR spectra of chromium pentacarbonyl carbenoid complexes

The carbon-13 NMR spectra of six carbenoid complexes of the type (OC)₅Cr-(CXX′) have been recorded. The carbenoid carbon atoms are all markedly deshielded (chemical shifts vs. TMS in the range ?271 to ?360). With only one minor inversion of uncertain significance, the chemical shifts correlate well with the expected ability of the X and X′ groups to engage in dative π bonding to the carbenoid carbon atom. The longitudinal relaxation times for both carbenoid and carbonyl carbon atoms in (OC)₅Cr[C(CH₃)(OC₂H₅)] are 1 – 2 sec. The chemical shift difference for carbonyl carbon atoms cis and trans to the carbenoid ligand is essentially invariant in the six compounds.     

Cyclization-cycloaddition casade of rhodium carbenoids using different carbonyl groups. Highlighting the position of interaction

A series of 3-diazoalkanediones, when treated with a catalytic quantity of a rhodium(II) carboxylate, were found to afford oxabicyclic dipolar cycloadducts derived by the trapping of a carbonyl ylide intermediate. The reaction involves generation of the 1,3-dipole by intramolecular cyclization of the keto carbenoid onto the oxygen atom of the neighboring keto group. Both five- and six-ring carbonyl ylides are formed with the same efficiency. A study of the tandem cyclization-cycloaddition cascade of several alpha-diazo ketoesters was also carried out, and the cascade sequence proceeded in high yield. When the interacting keto carbonyl group was replaced by an imido group, the rhodium(II)-catalyzed reaction proceeded uneventfully. In contrast, alpha-diazo amidoesters do not undergo nitrogen extrusion on treatment with a Rh(II) catalyst. Instead, the diazo portion of the molecule undergoes 1,3-dipolar cycloaddition with various dipolarophiles to give substituted pyrazoles as the final products.     

A new method for synthesis of α,α-disubstituted carbonyl compounds from carbonyl compounds with one-carbon homologation through β-oxido carbenoid rearrangement as the key reaction

The addition reaction of carbonyl compounds with lithium α-sulfinyl carbanions of 1-chloroalkyl p-tolyl sulfoxides gave adducts, α-chloro β-hydroxy sulfoxides, in high to quantitative yields. The adducts were first treated with a base to give alkoxides, which were treated with i-PrMgCl or t-BuLi to give β-oxido carbenoids via a sulfoxide-metal exchange reaction. The β-oxido carbenoid rearrangement then took place to afford the enolates with one-carbon elongation. The enolate intermediates were found to be able to be trapped with electrophiles such as aldehydes, ethyl chloroformate, benzoyl chloride, haloalkanes to give α,α-disubstituted carbonyl compounds in moderate to good yields. This method provides a new and efficient way for synthesis of α,α-disubstituted carbonyl compounds from carbonyl compounds with one-carbon homologation in only two synthetic operations.     

Rhodium(II)-catalyzed carbocyclization reaction of alpha-diazo carbonyls with tethered unsaturation

o-Alkynyl-substituted alpha-diazoketones undergo internal cyclization to produce indenone derivatives upon treatment with catalytic quantities of Rh(II)-carboxylates. A variety of structural influences were encountered by varying the nature of the substituent group attached to the diazo center. The cyclization reaction involves addition of a rhodium-stabilized carbenoid onto the acetylenic pi-bond to generate a cycloalkenone carbenoid. The cyclized carbenoid was found to undergo both aromatic and aliphatic C-H insertion as well as cyclopropanation across a tethered pi-bond. Subjection of diazo phenyl acetic acid 3-phenylprop-2-ynyl ester to Rh(II) catalysis furnished 8-phenyl-1, 8-dihydro-2-oxacyclopenta[a]indenone in high yield. The formation of this compound involves cyclization of the initially formed carbenoid onto the alkyne to produce a butenolide which then undergoes C-H insertion into the neighboring aromatic system. When a vinyl ether is added, the initially formed rhodium carbenoid intermediate can be intercepted by the electron-rich pi-bond prior to cyclization. Different rhodium catalysts were shown to result in significant variation in the product ratios. The competition between bimolecular cyclopropanation, 1,2-hydrogen migration, and internal cyclization was probed using several enol ethers as well as diazoesters which possess different substituent groups on the ester backbone. The specific path followed was found to depend on electronic, steric, and conformational factors.     

Trapping rhodium vinylcarbenoids with aminochalcones for the synthesis of medium-sized azacycles

A rhodium carbenoid initiated cascade has been developed for the stereoselective synthesis of medium-sized azacycles. The cascade approach utilizes readily accessible N-benzyl protected aminochalcones and vinyldiazo compounds to access 9-membered azacycles through a carbene- nitrogen insertion/aldol/oxy-Cope sequence. The cascade reaction has proven general with a range of N-benzyl protected aminochalcones and vinyldiazos to provide diverse medium-sized azacycles.