Catalytic,three-component assembly reaction for the synthesis of pyrrolidines

[reaction: see text] Copper(I) salts catalyze the three-component assembly reaction between an alpha-diazo ester, an imine, and various alkenes and alkynes to form substituted pyrrolidines with excellent to good diastereoselectivities in high yields. The transition metal-catalyzed decomposition of the alpha-diazo compound in the presence of the imine likely generates a transient azomethine ylid that undergoes addition with various dipolarophiles in a highly convergent manner.     

Regioselective nucleophilic addition to carbonyl ylide intermediates: a novel diastereoselective synthesis of cycloalkyl fused furan-3-ones

[structures: see text] A range of cis-fused hexahydro-1-benzofuran-3(2H)-one or tetrahydro-2H-cyclopenta[b]furan-3(3aH)-one ring systems was synthesized by the rhodium(II) acetate catalyzed reaction of alpha-diazo carbonyl compounds in the presence of various oxygen, nitrogen, and sulfur nucleophiles. A double-nucleophilic addition was possible by using an excess of alpha-diazo ketone. These reactions proceeded with complete diastereoselectivity, and the stereochemistry was confirmed by the single-crystal X-ray analysis. This process discloses the first example of tandem cyclization-nucleophilic addition reaction.     

1,2-vinyl and 1,2-acetylenyl migration in Rh(II) carbene reaction: remarkable bystander effect

A series of beta-(trichloroacetyl)amino alpha-diazo carbonyl compounds have been synthesized, and their Rh(II)-catalyzed reaction was investigated. 1,2-Migration was the predominant reaction pathway, and the migratory aptitude was found to be dramatically affected by the beta-substituents. The 1,2-vinyl and 1,2-acetylenyl group migration occurs preferentially in the presence of beta-hydrogen in Rh(2)(OAc)(4)-catalyzed reaction of beta-(trichloroacetyl)amino alpha-diazo carbonyl compounds. A possible reaction mechanism is discussed.     

Unusual reaction of beta-hydroxy alpha-diazo carbonyl compounds with Cl3CCN/NaH and Rh(II)-catalyzed reaction of beta-trichloroacetylamino alpha-diazo carbonyl compounds

The hydroxyl group was directly converted into the trichloroacetylamino group by reacting beta-hydroxy alpha-diazo carbonyl compounds with Cl(3)CCN and NaH. Rh(II)-catalyzed reactions of the beta-amino alpha-diazo carbonyl compounds were discussed. [reaction: see text]     

Stereoselective intramolecular 1,3 C-H insertion in Rh(II) carbene reactions

[reaction: see text] 1,3 C-H insertion has been found to be a predominant reaction pathway in the Rh(II)-mediated reaction of beta-tosyl alpha-diazo carbonyl compounds.     

Total syntheses of zaragozic acids A and C by a carbonyl ylide cycloaddition strategy

A carbonyl ylide cycloaddition approach to the squalene synthase inhibitors zaragozic acids A and C is described. The carbonyl ylide precursor 8 was synthesized starting from di-tert-butyl D-tartrate (47) via an eleven-step sequence involving the regioselective reduction of the mono-MPM (MPM=4-methoxybenzyl) ether 48 with LiBH4 and the diastereoselective addition of sodium tert-butyl diazoacetate to alpha-keto ester 10. The reaction of alpha-diazo ester 8 with 3-butyn-2-one (40) in the presence of a catalytic amount of [Rh2(OAc)4] gave the desired cycloadduct 59 as a single diastereomer. The dihydroxylation of enone 59 followed by sequential transformations permitted the construction of the fully functionalized 2,8-dioxabicyclo[3.2.1]octane core 5. Alkene 79 derived from 5 serves as a common precursor to zaragozic acids A (1) and C (2), since the elongation of the C1 alkyl side chain can be attained by olefin cross-metathesis, especially under the influence of Blechert's catalyst (85).     

Stereoselective synthesis of functionalized pyrrolidines by ruthenium porphyrin-catalyzed decomposition of alpha-diazo esters and cascade azomethine ylide formation/1,3-dipolar cycloaddition reactions

[reaction: see text] Ruthenium porphyrins catalyze three-component coupling reaction of alpha-diazo esters with a series of N-benzylidene imines and alkenes to form functionalized pyrrolidines in excellent diastereoselectivities. The reaction proceeds via a reactive ruthenium-carbene intermediate and its subsequent reaction with imine to generate azomethine ylide, which reacts with alkenes via 1,3-diploar cycloaddition.     

Asymmetric synthesis of cis-5-substituted pyrrolidine 2-phosphonates using metal carbenoid NH insertion and delta-amino beta-ketophosphonates

Cis-5-substituted pyrrolidine phosphonates, proline surrogates, are prepared by a highly stereoselective intramolecular metal carbenoid N-H insertion from a sulfinimine-derived delta-amino alpha-diazo beta-ketophosphonate. [reaction: see text]     

Copper-catalyzed [4 + 1] cycloadditions of alpha,beta-acetylenic ketones with diazoacetates to form trisubstituted furans

Copper-catalyzed [4 + 1] cycloaddition reaction of alpha,beta-acetylenic ketones with alpha-diazo esters offers an efficient, direct route to highly substituted furans. The reaction conditions and the scope of the process are examined, and a possible mechanism is proposed.     

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.     

Direct catalytic asymmetric aldol-type reaction of aldehydes with ethyl diazoacetate

The direct aldol-type condensation of aldehydes with ethyl diazoacetate catalyzed by the chiral complex of BINOL derivatives-Zr(O(t)Bu)(4) gave beta-hydroxy alpha-diazo carbonyl compounds with moderate enantioselectivities (53-87% ee). [reaction: see text]     

Cu(I)-carbenoid- and Ag(I)-Lewis acid-catalyzed asymmetric intermolecular insertion of alpha-diazo compounds into N-H bonds

Chiral Cu(I)-bisoxazoline- and Cu(I)-PN-complexes were found to catalyze the intermolecular insertion of alpha-diazo compounds into N-H bonds. The insertion reactions proceed with enantioselectivities of up to 28% ee for the different alpha-diazo acetates into one of the N-H bonds of different amines. Analogous chiral Ag(I) complexes were found to give higher enantioselectivities of up to 48% ee, however, lower yields were obtained. There are indications, that the Ag(I)-mediated reactions follow a different reaction mechanism compared to the Cu(I)-catalyzed insertions. It is demonstrated that different alpha-amino acid derivatives can be obtained via this approach in good yields and with low to moderate enantioselectivities. However, the results obtained are the highest asymmetric inductions obtained for an intermolecular N-H insertion via chiral carbene complexes or chiral Lewis acid catalysis.     

Photochemical patterning of a self-assembled monolayer of 7-diazomethylcarbonyl-2,4,9-trithiaadmantane on gold films via Wolff rearrangement

Photolithographic attachment of functional organic molecules via ester or amide linkages to self-assembled monolayers (SAMs) on gold thin films was achieved by employing a novel photoreactive surface anchor, 7-diazomethylcarbonyl-2,4,9-trithiaadmantane. The photoreactive SAM was prepared by the spontaneous physical adsorption of the photoreactive surface anchor onto gold surfaces. The alpha-diazo ketone moiety of the SAM was found to display the classical Wolff rearrangement reactivity to produce a ketene intermediate on the exposed area. Organic molecules such as alcohols and amines can thus be attached to the gold surfaces selectively by the facile in situ formation of ester or amide linkages. The structure and reactivity of the photoreactive surface anchor were characterized by real-time FT-IR, fluorescence, and polarization modulation infrared reflectance absorption spectroscopy (PM-IRRAS). The Wolff rearrangement reactivity of the SAM suggested that a "surface-isolated" carbonylcarbene may be generated when the SAM was exposed to 255-nm irradiation.     

An approach toward isoindolobenzazepines using the ammonium ylide/Stevens

Ammonium ylides derived from the Cu(II)-catalyzed decomposition of alpha-diazo carbonyls tethered to tertiary amines underwent a benzylic Stevens [1,2]-rearrangement to give tetrahydroisoquinolines or benzazepines containing fused five-membered rings, a feature found in the cephalotaxus alkaloids. Model studies were also carried out toward the synthesis of lennoxamine, a member of the isoindolobenzazepine family of alkaloids. The approach utilized is based on the Rh(II)-catalyzed reaction of an alpha-diazo carbonyl compound containing an amido group in the gamma-position. Treatment of several N,N-dialkyl-substituted amido diazo-esters with Rh2(OAc)4 in benzene at 80 degrees C in the presence of several dienophiles gave [4 + 2]-cycloadducts derived from the Diels-Alder reaction of a transient alpha-amino isobenzofuran intermediate. In the absence of an external trapping agent, no rearranged product derived from an ammonium ylide intermediate could be detected in the crude reaction mixture. In contrast to this result, reaction of the related diazo dihydroisoquinoline amide 46 with Rh2(OAc)4 afforded the isoindolobenzazepine ring system in high yield. Formation of the 5,7-fused skeleton was rationalized in terms of a spirocyclic ammonium ylide that underwent a preferential Stevens [1,2]-shift of the benzylic carbon atom. While we were ultimately thwarted in using the ammonium ylide/rearrangement cascade for a lennoxamine synthesis by an uncooperative diazo transfer reaction, the cascade sequence was shown to be useful for the preparation of various isoindolobenzazepines.     

Synthesis of (+/-)-3H-epivincamine via a Rh(II)-triggered cyclization/cycloaddition cascade

A synthesis of (+/-)-3H-epivincamine is reported. Important steps include (1) a Rh(II)-catalyzed intramolecular [3+2]-cycloaddition of an alpha-diazo indolo amide, (2) a reductive ring opening of the cycloadduct, (3) a decarboethoxylation reaction, and (4) a base-induced keto-amide ring contraction.     

Electronic effects in migratory groups. [1,4]-versus[1,2]-rearrangement in rhodium carbenoid generated bicyclic oxonium ylides

The variety of alpha-diazo beta-keto esters (3a-f, 8a-f) with varying substituents (ED/EW) on the phenyl ring of the O-benzyl group were prepared. The rhodium(II) acetate catalyzed decomposition of diazo compounds in benzene reflux conditions. The ratio of 1,4 versus 1,2 migration product was determined. It was found that an increase in electron density on the benzylic carbon of the migrating group prefers 1,4 migration products (4, 9) while a decrease in electron density leads to a preponderance of 1,2 migration products (5, 10). The results obtained were correlated to the mechanistic aspect of the product selectivity. The intermediacy of the intramolecular oxonium ylide formation was demonstrated by crossover experiments. The preference for the formation of 2,3 sigmatropic rearrangement product over 1,2 and 1,4 was demonstrated by performing the reaction with alpha-diazo beta-keto esters (13a, 13b) with O-allyl and O-propargyl at C3. The effect of solvent, temperature, and mole percentage of rhodium(II) acetate was also studied.     

High enantiocontrol in the intramolecular cyclopropanation of diazo ketones catalyzed by dirhodium(II) complexes with ortho-metalated aryl phosphine ligands

[reaction: see text]. Chiral dirhodium(II) complexes, Rh2(O2CCF3)2(PC)2, [PCH = (p-CH3C6H4)3P, (m-CH3C6H4)3P], provide an excellent yield and a high enantiocontrol in the cyclopropanation of alpha-diazo ketones with gamma and delta double bonds. The ee values are significantly dependent on the solvent used; the best results are obtained using pentane.     

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.     

2-Diazoacetoacetic acid, an efficient and convenient reagent for the synthesis of alpha-diazo-beta-ketoesters

The formation of various alpha-diazo acetoacetic esters can be obtained in a single transformation with good to excellent yields using readily available 2-diazoacetoacetic acid.     

Synthesis and relative stability of 3,5-diacyl-4,5-dihydro-1H-pyrazoles prepared by dipolar cycloaddition of enones and alpha-diazoketones

An unusual reaction process that produced unexpected heterocyclic systems by a fragmentation-recombination mechanism is described. Thus treatment of the triketone, 3-acetyl-2,6-heptanedione, 1, with methanesulfonyl azide gave, in addition to the expected alpha-diazo ketone 3a, the dihydropyrazole 3c and its oxidation product, the pyrazole 3d. We propose that the initially formed alpha-diazo ketone 3a fragments into the simple alpha-diazomethyl ketone and methyl vinyl ketone which then undergo an intermolecular [2,3]-dipolar cycloaddition. Analogous treatment of the trifluoromethyl trione 2 again afforded a pyrazole 4c. Further experiments were carried out to lend evidence to our mechanistic hypothesis. Thus alpha-diazoacetophenone 5 and MVK underwent a [2,3]-dipolar cycloaddition under mild conditions to give the two regioisomeric dihydropyrazoles 6a and 6b. Interestingly these were formed in a 2:1 ratio, which suggested that 6a was more stable than 6b. The structures of 6a and 6b were optimized by using the B3LYP density functional method and the 6-31G* basis set and isomer 6a was predicted to be 1.5 kcal/mol more stable than isomer 6b. This energy difference could be rationalized by the greater capacity of the acetyl group than the benzoyl group to conjugate with the hydrazone. This difference in conjugation is reflected by key bond length differences. Thus we have discovered a novel fragmentation-cycloaddition process. We have also presented evidence for the mechanism of the formation of the dihydropyrazoles and carried out calculations to support these findings.