Unusual reaction of aryldiazoacetates with enamines: highly effective synthesis of γ-ketoesters

The reaction of aryldiazoacetates with enamines catalyzed by copper and rhodium complexes provided γ-ketoesters in good yields. Careful analysis of the crude reaction mixture revealed a substituted enamine as the primary product, which was hydrolyzed over silica gel to give a γ-ketoester as the final product. A reaction mechanism involving nucleophilic addition of an enamine to a metal carbene and subsequent hydrogen transfer was proposed.     

New reaction of enamines with aryldiazoacetates catalyzed by transition metal complexes

The reaction of aryldiazoacetates with enamines catalyzed by copper and rhodium complexes provided γ-keto esters in good yields. A full investigation of the effects of solvents, catalysts, enamines and aryldiazoacetates on the reaction was carried out. Careful analysis of the crude reaction mixture revealed a substituted enamine as the primary product, which was hydrolyzed over silica gel to give a γ-keto ester as the final product. A reaction mechanism involving nucleophilic addition of an enamine to a metal carbene and subsequent hydrogen transfer was proposed. Chiral dirhodium and copper catalysts were examined and found to provide γ-keto esters with no enantioselectivity. The result could be rationalized based on the proposed reaction mechanism. Attempts to trap the enamine intermediate with several electrophilic reagents were not successful.     

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.     

Efficient Synthesis of γ‐Keto Esters from Enamines and EDA

Abstract

The reaction of enamines with ethyl diazoacetate (EDA) catalyzed by dirhodium and copper complexes provided γ‐keto esters in good yields. The influences of catalyst, reaction solvent, temperature, and structure of enamines on this transformation were investigated.     

1,3-Dipolar Addition of Methyl α-Diazoacetoacetate to Enamines： A New Synthetic Route to 5-Amino-4,5-dihydrofurans

The reaction of methyl α-diazoacetoacetate with enamines catalyzed by dirhodium and copper complexes underwent formal 1,3-dipolar addition to give 5-amino-4,5-dihydrofurans in moderate yields. The reaction was suggested to proceed via a nucleophilic addition of enamines to rnetal-carbenes and a subsequent intramolecular cyclization of the resulting zwitterionic intermediates.     

Gold‐Catalyzed Formal C−C Bond Insertion Reaction of 2‐Aryl‐2‐diazoesters with 1,3‐Diketones

The transition‐metal‐catalyzed formal C−C bond insertion reaction of diazo compounds with monocarbonyl compounds is well established, but the related reaction of 1,3‐diketones instead gives C−H bond insertion products. Herein, we report a protocol for a gold‐catalyzed formal C−C bond insertion reaction of 2‐aryl‐2‐diazoesters with 1,3‐diketones, which provides efficient access to polycarbonyl compounds with an all‐carbon quaternary center. The aryl ester moiety plays a crucial role in the unusual chemoselectivity, and the addition of a Brønsted acid to the reaction mixture improves the yield of the C−C bond insertion product. A reaction mechanism involving cyclopropanation of a gold carbenoid with an enolate and ring‐opening of the resulting donor–acceptor‐type cyclopropane intermediate is proposed. This mechanism differs from that of the traditional Lewis‐acid‐catalyzed C−C bond insertion reaction of diazo compounds with monocarbonyl compounds, which involves a rearrangement of a zwitterion intermediate as a key step.     

Acid catalyzed reactions of α,β-unsaturated aldehydes and ethyl diazoacetate

The formation of cyclopropanes from α,β-unsaturated aldehydes and diazo compounds has been a rather challenging goal due to the extremely reactive aldehyde starter. Herein, our group reports the first formation of ethyl 2-formyl-1-cyclopropanecarboxylate in 100% yield from the acid catalyzed reaction between acrolein and ethyl diazoacetate (EDA).     

Copper carbene complexes: advanced catalysts,new insights

Controlling the selectivity of reactive intermediates is a major goal of organic chemists. Carbenes generated by thermal or photochemical extrusion of nitrogen from diazo compounds defy external control and tend to give complex product mixtures. However, the catalyzed decomposition of diazo compounds gives rise to highly selective "carbenoids" which have found extensive application in synthesis although little is known of their precise nature. On the other hand, a large variety of carbene metal complexes have been prepared and characterized which more or less lack carbenoid reactivity. Structural evidence for the transients of catalyzed diazo decomposition is becoming available through experiment and computation. Although the present report focuses on copper complexes, outstanding results with other metals are also covered.     

Computational studies on the copper(II) catalyzed Michael reaction

We report computational results on the mechanism of the copper(II) catalyzed Michael addition of enamines formed from β-diketones and amino acids. The results suggest that the enamine gets deprotonated upon coordination to Cu²⁺, and that it occupies three coordination sites of a square planar geometry. The formation of this coordinated aza-enolate is facilitated by basic co-ligands such as acetate which take over the enamine proton. In this rather rigid structure, the former amino acid side chain assumes an angular position which leads to preferred attack of the Michael acceptor from the non-hindered side of the coordination plane and the formation of a preferred enantiomer if one starts from a prochiral diketone. This discrimination becomes effective because the Michael acceptor, although only loosely bound to the complex before carbon-carbon bond formation, attaches itself to a “free” axial position of the copper centre during the reaction.     

Stereoselective Synthesis of Tetrahydroindolizines through the Catalytic Formation of Pyridinium Ylides from Diazo Compounds

Commercially available iron(III) and copper(I) complexes catalyzed multicomponent cycloaddition reactions between diazo compounds, pyridines, and electrophilic alkenes to give alkaloid‐inspired tetrahydroindolizidines in high yield with high diastereoselectivity. Hitherto, the catalytic formation of versatile pyridinium ylides from metal carbenes has been poorly developed; the broad utility demonstrated herein sets the stage for the invention of further multicomponent reactions in future.     

Intramolecular Reactions of Metal Carbenoids with Allylic Ethers: Is a Free Ylide Involved in Every Case?

Rhodium‐, copper‐ and iridium‐catalyzed reactions of the ¹³C‐labelled diazo carbonyl substrates 18* and 19* were performed. Results obtained from copper‐ and iridium‐catalyzed reactions of the ¹³C‐labelled α‐diazo β‐keto ester 19* indicate that either or both of these reactions do not proceed via a free oxonium ylide but instead follow a competing non‐ylide route that delivers apparent [2,3]‐sigmatropic rearrangement products. In the case of the iridium‐catalyzed reaction of α‐diazo β‐keto ester 19* , results obtained from crossover experiments indicate that the initially formed metal‐bound ylide dissociates to give an iridium enolate and an allyl cation, which recombine to form the C?C bond.     

Generation of quaternary stereocenters by asymmetric Michael reactions: enamine regiochemistry as configuration switch

Regioselective enamine formation from cyclic β‐diketones 1 is obtained by the appropriate choice of activating agent: Brønsted acid catalyzed condensation gives endocyclic enamines 3 as the thermodynamically favored products. Activation with Lewis acid BF₃ ? OEt₂ affords betaines 8 as intermediate products, which can be reacted with L ‐valine diethylamide ( 2 ) to preferentially furnish exocyclic enamines 4 as kinetic products. Derivatives with quaternary stereocenters were accessible from both isomeric enamines by using asymmetric, copper(II )‐catalyzed Michael reactions at ambient temperature. Both regioisomers afford the triketones 7 with the same constitution but bearing the opposite absolute configuration at the quaternary stereocenter. Thus, both enantiomers of the product are prepared by using the same chiral auxiliary derived from L ‐valine.     

Construction of a chiral quaternary carbon center by indium-catalyzed asymmetric alpha-alkenylation of beta-ketoesters

Construction of a nonracemic all-carbon quaternary stereocenter at the alpha-position of beta-ketoesters was achieved by way of an indium(III)-catalyzed diastereoselective alpha-alkenylation reaction of chiral enamines with 1-alkynes. The enamine bearing a chiral auxiliary derived from l-isoleucine was added to the alkyne to give an alpha-alkenylated product in excellent yield and with a stereoselectivity better than 90% ee. One can ascribe the high selectivity to a chelate intermediate involving the auxiliary and the metal atom and the high yield to efficient interactions between the indium(III) atom and the alkyne. The selectivity increased as the reaction temperature was raised to 120 degrees C and decreased at higher temperatures.     

A Theoretical and Experimental Study of the Effects of Silyl Substituents in Enantioselective Reactions Catalyzed by Diphenylprolinol Silyl Ether

The effect of silyl substituents in diphenylprolinol silyl ether catalysts was investigated. Mechanistically, reactions catalyzed by diphenylprolinol silyl ether can be categorized into three types: two that involve an iminium ion intermediate, such as for the Michael‐type reaction (type A) and the cycloaddition reaction (type B), and one that proceeds via an enamine intermediate (type C). In the Michael‐type reaction via iminium ions (type A), excellent enantioselectivity is realized when the catalyst with a bulky silyl moiety is employed, in which efficient shielding of a diastereotopic face of the iminium ion is directed by the bulky silyl moiety. In the cycloaddition reaction of iminium ions (type B) and reactions via enamines (type C), excellent enantioselectivity is obtained even when the silyl group is less bulky and, in this case, too much bulk reduces the reaction rate. In other cases, the yield increases when diphenylprolinol silyl ethers with bulky substituents are employed, presumably by suppressing side reactions between the nucleophilic catalyst and the reagent. The conformational behaviors of the iminium and enamine species have been determined by theoretical calculations. These data explain the effect of the bulkiness of the silyl substituent on the enantioselectivity and reactivity of the catalysts.     

1,2-Thio group migration in Rh(II) carbene reactions

[reaction: see text] A series of beta-thio group substituted alpha-diazo carbonyl compounds have been prepared by nucleophilic substitution reactions of thiophenol, thionaphthol, or benzyl mercaptan with beta-acetoxy-alpha-diazo carbonyl compounds. The diazo decomposition of these diazo carbonyl compounds with various transition metal catalysts, including Rh(II) carboxylates and Cu(I) and Cu(II) complexes, has been investigated. It was found that the diazo decomposition of these compounds gave 1,2-thio group migration products. No 1,2-hydride or 1,2-aryl migration products were observed in all cases.     

Reaction of nitric oxide at the beta-carbon of enamines. A new method of preparing compounds containing the diazeniumdiolate functional group

The reaction of nitric oxide (NO) with enamines has been investigated. Unlike previously reported reactions of NO as a free radical with alkenes, the electrophilic addition of NO to the beta-carbon of enamines results in the formation of compounds containing the diazeniumdiolate functional group (-[N(O)NO](-)). This reaction between NO and enamines has been shown to be quite general and a variety of enamine-derived diazeniumdiolates have been isolated and characterized. While enamines derived from aldehydes and ketones whose structures allow for sequential multiple electrophilic additions tended to undergo overreaction leading to unstable products, it has been shown that this complication may be overcome by suitable choice of reaction solvent. The products obtained may exist as zwitterionic iminium salts or as neutral species depending upon the structure of the parent enamine. The diazeniumdiolate derived from 1-(N-morpholino)cyclohexene is unique among the new compounds in that it spontaneously releases NO upon dissolution in buffered aqueous solution at pH 7.4 and 37 degrees C. While the total quantity of NO released by this material (ca. 7% of the theoretical 2 moles) is apparently limited by a competing reaction in which it hydrolyzes to an alpha-diazeniumdiolated carbonyl compound and the parent amine, this feature may prove to be of great value in the development of multiaction pharmaceuticals based upon this new type of NO-releasing compound. Reports of enzymatic (oxidative) release of NO from previously known carbon-bound diazeniumdiolates also suggest that analogues of these compounds may be useful as pharmaceutical agents. This new method of introducing the relatively rarely studied diazeniumdiolate functional group into organic compounds should lead to further research into its chemical and biological properties.     

New, general, and practical enamine cyclopropanation using dichloromethane

[reaction: see text] Dichloromethane serves as a novel electrophilic carbene equivalent which adds to an enamine double bond. The presence of other alkene moieties in the enamine partner is well tolerated. Even enamines derived from sterically hindered ketones react readily with dichloromethane promoted by TiCl(4)-Mg.     

How Nucleophilic Are Diazo Compounds?

The kinetics of the reactions of benzhydryl cations with eight diazo compounds 1 a-g were investigated photometrically in dichloromethane. The nucleophilicity parameters N and slope parameters s of these diazo compounds were derived from the equation log k (20 degrees C)=s (E+N) and compared with the nucleophilicities of other pi systems (alkenes, arenes, silyl enol ethers, silyl ketene acetals). It is shown that the nucleophilic reactivities of diazo compounds cover more than ten orders of magnitude, being comparable to that of styrene on the low reactivity end and to that of enamines on the high reactivity end. The rate-determining step of these reactions is the electrophilic attack at the diazo-carbon atom to yield diazonium ions, which rapidly lose nitrogen.     

An effective new synthesis of 2-aminopyrrole-4-carboxylates

Efficient syntheses of 2-aminopyrroles are presented starting from β-dicarbonyl compounds, bromoacetonitrile, and amines. Alkylation of β-dicarbonyl compounds with bromoacetonitrile furnished α-cyanomethyl-β-dicarbonyl compounds. The condensation reaction of α-cyanomethyl-β-dicarbonyl compounds with amines catalyzed by p-TsOH affords the corresponding enamines in good yields. Base catalyzed cyclization via the addition of an amine moiety to the carbon-nitrogen triple bond of nitrile furnished 2-aminopyrroles in high yields.     

Catalytic [2,3]-sigmatropic rearrangement of sulfur ylide derived from metal carbene

This paper reviews the most recent development of [2,3]-sigmatropic rearrangement of sulfur ylide generated from the reaction of sulfide with metal carbene. The metal carbene was formed from decomposition of diazo compounds catalyzed by transition metal complexes such as Cu(I) and Rh(II).