New One-Pot Synthesis of Polysubstituted Benzofurans and Benzo-1,4-dioxines

It has been revealed that the copper(II) triflate catalyzed reaction of ethyl-2-diazo-3-oxobutanoate with phenols followed by cyclization of the intermediate enol in the presence of polyphosphoric acid is a simple and efficient method of synthesis of polysubstituted benzofurans. The use of pyrocatechol leads to the corresponding substituted 1,4-benzodioxine-2-carboxylates as major products.     

Catalytic asymmetric Mannich-type reactions of fluorinated ketoesters with N-Boc aldimines in the presence of chiral palladium complexes

The catalytic enantioselective Mannich reaction promoted by chiral palladium complexes is described. The treatment of α-fluoro-β-ketoesters with N-Boc-aldimines under mild reaction conditions afforded the corresponding β-aminated α-fluoro-β-ketoesters with excellent enantioselectivities (up to 99% ee).     

Unusual Reaction of Diazo Compounds with Enamines

Transition metal catalyzed decomposition of diazo compounds and consequent transformations constitute various synthetic useful reactions in the past decades. The catalytic addition of diazo compounds to olefins generally provides cyclopropanes in high yield. However the reaction of electron-rich enamines with diazo compounds gave variable results. Wenkert et al. reported the reaction of enamines with ethyl diazoacetae (EDA) in the presence of cuprous chloride or silver oxide unexpectedly gave…     

Chemoselective aromatic C-H insertion of α-diazo-β-ketoesters catalyzed by dirhodium(II) carboxylates

The ability of α-diazo-β-ketoesters bearing a substituent on the benzylic position to undergo aromatic C-H insertion is described. Good to excellent yields of the aromatic C-H insertion products were observed with Rh(2)(tpa)(4) or Rh(2)(esp)(2) catalysts. This is an attractive strategy to prepare tetralins carrying a methyl group on the benzylic position, a structural motif found in several types of natural products.     

A mild, efficient method for the oxidation of α-diazo-β-hydroxyesters to α-diazo-β-ketoesters

A wide variety of α-diazo-β-ketoesters can be prepared in good overall yields via a two-step sequence involving addition of ethyl lithiodiazoacetate to aliphatic, aromatic, and conjugated aldehydes followed by mild oxidation with the Dess-Martin periodinane.     

Construction of α-phosphonolactams via rhodium (II)-catalyzed intramolecular C?H insertion reactions

The Rh(II)-catalyzed intramolecular C H insertion reactions of N,N-dialkyl-α-diazo-α-(diethylphosphono)acetamides 2a , f–j in CHCl₃ or ClCH₂CH₂Cl were found to give monocyclic and bicyclic α-phosphono-β-lactams, 3a and 3f–j , in 43–67% yields via regiospecific α-C H insertion of the N-alkyl groups. Similar treatment of N-benzyl-N-isopropyl-α-diazo-α-(diethylphosphono)acetamide ( 2b ) and the corresponding N-isobutyl-N-methylacetamide 2d in ClCH₂CH₂Cl afforded mixtures of β-lactams 3b (35%) and and 3b ′ (16%), β-lactam 3d (47%), and γ-lactam 4d (10%), respectively, each of which is formed by the competitive C H insertion reaction between benzylic and isopropyl α-C H bonds and between methyl α-C H and methine β-C H bonds, respectively. For the formation of β-lactams, the selectivity in the rhodium-mediated C H insertion in ClCH₂CH₂Cl follows the order methyl > methine > benzylic α-C H bond on N-substituents. The N,N-dibutyl-α-diazo homologue 2c and Nα[α-diazo-α-(diethylphosphono)acetyl]-2-methylindoline ( 2k ) exclusively produced γ-lactams 4c (67%) and 4k (81%) via insertion into the methylene β-C H and methyl β-C H bonds. tert-Butyl N-[α-diazo-α-(dibenzylphosphono)acetyl]-piperidine-2-carboxylate ( 2m ) on similar treatment, followed by deprotection of the benzyl ester afforded the 7-phosphono carbacepham 6 in 32% overall yield. Similar Rh(II)-catalyzed cyclization of N-methyl-N[4-benzyloxy-α-(diethylphosphono)-phenyl(diethyl-phosphono)methyl]-α-diazo-acetamide ( 2n ) led to 1-[4′-benzylphenyl(diethylphosphono)methyl] -3-(diethyl-phosphono)azetidin-2-one ( 3n ) in 78% yicld. The phosphono group at C-7 of 3f was converted into the acetylamino group via a four-step reaction. Application of chiral rhodium(II) carboxylates 12a–c to the insertion reactions of 2b , c produced α-phosphono-β-and γ-lactams, 3b and 4c , in 6–24% ee and 25–29% ee, respectively.     

Metalation of α-diazocarbonyl compounds using Grignard reagents. A convenient synthesis of α-diazo-β-ketoesters and mixed esters of α-diazomalonate

α-Diazocarbonyl compounds react with methylmagnesium bromide at −78 °C generating the corresponding α-diazo-α-bromomagnesio species, which can be intercepted by various electrophilic reagents. For example, with alkyl chloroformates α-diazo-β-ketoesters or mixed esters of α-diazomalonate are obtained in good yields.     

Solid-phase synthesis of oxazolones and other heterocycles via Wang resin-bound diazocarbonyls

The preparation of Wang resin bound α-diazo-β-ketoesters is described. These highly useful intermediates were used for the synthesis of a series of heterocycle libraries, which were obtained from the resin using TFA cleavage. In addition, a novel route for the synthesis of oxazolones using an N-H insertion strategy is disclosed.     

Enantioselective Friedel–Crafts alkylation of indoles with β,γ-unsaturated α-ketoesters catalyzed by new squaramide-linked bisoxazoline–Zn(OTf)2 complexes

Enantioselective Friedel–Crafts alkylation reactions of indoles with β,γ-unsaturated α-ketoesters catalyzed by novel chiral C₂-symmetric squaramide-linked bisoxazoline–Zn(OTf)₂ complexes were investigated. The corresponding indole ketoesters were obtained in good to excellent yields (up to 98%) and with high enantioselectivities (up to 94% ee). This is the first report on the use of chiral squaramide-linked bisoxazoline SQBOX in a catalytic enanitioselective Friedel–Crafts alkylation reaction.     

Asymmetric synthesis of α-fluoro-α-sulfenyl-β-ketoesters using DBFOX-Ph/Ni(II) complex

Enantioselective α-sulfenylation of α-fluoro-β-ketoesters 4 with phenylsulfenyl chloride catalyzed by DBFOX-Ph/Ni(II) complex afforded the corresponding α-fluoro-α-sulfenyl-β-ketoesters 2 in moderate to good yields with excellent enantiomeric excesses up to 93% ee. α-Fluoro-α-sulfenyl-β-ketoesters can be effectively converted to tri-fluorinated α-sulfenylcarboxylates by the use of DAST, which should be useful intermediates for the synthesis of non-racemized fluorinated isosteres of pharmaceutically attractive SM₃₂. The enantioselective α-phenylsulfenylation as well as α-pentafluoro-phenylsulfenylation of non-fluorinated β-ketoesters 5 were also carried out under the same catalyst conditions affording up to 95% ee of the products 6-8.     

Novel synthesis of fused indoles and 2-substituted indoles by the palladium-catalyzed cyclization of N-cycloalkenyl-o-haloanilines

A new palladium-catalyzed cyclization of N-alkenyl-o-haloanilines with selective isomerization of a double bond followed by formal 5-endo-trig cyclization was developed. A variety of fused and 2-substituted indoles were synthesized from enaminoesters prepared by condensation of β-ketoesters and o-iodoaniline.     

Chemical reactivity of 6-diazo-5-oxo-l-norleucine (DON) catalyzed by metalloporphyrins (Fe,Ru)

The transfer of the metallocarbene derived from N- and O-protected 6-diazo-5-oxo-l-norleucine (DON) catalyzed by metalloporphyrins undergoes dimerization, cyclopropanation, N-H and S-H insertion reactions, respectively. An efficient and direct synthesis of 5-oxo-l-pipecolic acid from DON is described from unprotected 6-diazo-5-oxo-l-norleucine.     

Intramolecular asymmetric C–H insertion of N-arylalkyl,N-bis(trimethylsilyl)methyldiazoamides mediated by chiral rhodium(II) catalysts. Synthesis of (R)-β-benzyl-γ-aminobutyric acid

The enantio- and site-selectivity of the intramolecular C–H insertion reactions of acyclic N-arylalkyl, N-bis(trimethylsilyl)methyl α-diazoacetamides, and α-carboalkoxy-α-diazoacetamides 1a–g, catalyzed by chiral Rh(II) carboxamidates and Rh(II) carboxylates were studied. In general, the reaction showed good to excellent chemoselectivity. Regioselectivity for most of the reactions was high, but was also found to be influenced by the structure of the diazo substrate and the chiral Rh(II) catalyst employed. The highest enantioselectivity for the reactions catalyzed by chiral Rh(II) carboxamidates was 69% and Rh₂(4R-MEOX)₄ was found to be the most effective. For the chiral Rh(II) carboxylate catalyzed reactions, the highest ee obtained was 75% and Rh₂(S-PTTL)₄ is the optimal catalyst. The method was applied toward the synthesis of a GABA analogue, (R)-β-benzyl-γ-aminobutyric acid.     

Highly regioselective Friedel-Crafts alkylation of indoles with α,β-unsaturated N-acylbenzotriazoles

The Friedel-Crafts alkylation rather than acylation of indoles was realized with α,β-unsaturated acylbenzotriazoles catalyzed by samarium(III) iodide under reflux in anhydrous THF. The reaction was highly regioselective, and a series of new 3-substituted indole derivatives were obtained in moderate to good yields with the potential to be further transformed into various indole derivatives due to the presence of active acylbenzotriazole moiety.     

Spirocyclic Amide Acetal Synthesis by [CpRu]-Catalyzed Condensations of α-Diazo-β-Ketoesters with γ-Lactams

The synthesis of spirocyclic amide acetals (33–93 %) has been achieved through Ru(II)-catalyzed condensations of N-carbamate protected pyrrolidinones with metal carbenes derived from α-diazo-β-ketoesters. Thanks to the mildness of the diazo decomposition conditions induced by a 1 : 1 combination of [CpRu(MeCN)₃][BAr_F] and 1,10-phenanthroline, the formation of the sensitive products is possible. Full characterization of this carbonyl-ylide mediated process is provided by DFT calculations.     

New tetracyclic compounds containing the β-carboline moiety

Oxidation of 1-methyl-3-methoxycarbonyl-β-carboline with selenium dioxide gave 1-formyl-3-methoxycarbonyl-β-carboline II . Compound II reacted with acetic or propionic anhydride to give easily the 2-methoxycarbonyl-6H-indolo[3,2,1-d,e][1,5]naphthyridin-6-ones III ; reaction of II with some primary amines led to the formation of the Schiff bases IV , which were reduced to the 1-aminomethyl-3-methoxycarbonyl-β-carbolines V with sodium borohydride. Cyclization of V with aqueous formaldehyde led to the pyrimido[3,4,5-lm]pyrido[3,4-b]indoles VI . Analogously, cyclization with formaldehyde, acetone or 1,1′-carbonyldiimidazole of the 3-aminomethyl- 1,2,3,4-tetrahydro-β-carbolines VIII , obtained by reaction of 3-methoxycarbonyl-1,2,3,4-tetrahydro-β-carboline VII with amines followed by lithium aluminium hydride reduction of the resulting amides, gave the imidazo[1′,5′-1,6]pyrido[3,4-b]indoles IX and X . Dieckmann cyclization of 3-methoxycarbonyl-2-[(3-ethoxycarbonyl)-1-propyl]-1,2,3,4-tetrahydro-β-carboline XI led to a 1:1 mixture of the β-ketoesters XII and XIII , which underwent deethoxycarbonylation to 5,6,8,9,10,11,11a,12-octahydroindolo[3,2-b]quinolizin-11-one XIV . Finally, the polyphosphoric acid (or esters) catalyzed cyclization of the N-acyl derivatives XVI of 3-hydrazinocarbonyl-β-carboline XV led smoothly to the 3-(1,3,4-oxadiazol-2-yl)-β-carbolines XVII .     

One-pot, cis-selective synthesis of α-substituted β-trimethylsilyl-α,β-epoxyesters from α-ketoesters and diazo(trimethylsilyl)methyl magnesium bromide

Reaction of α-ketoesters with diazo(trimethylsilyl)methyl magnesium bromide followed by in situ treatment with pivalic acid gave α-substituted β-trimethylsilyl-α,β-epoxyesters in an efficient and cis-selective manner.     

Three-component reactions based on trapping ammonium ylides with N-sulfonyl aldimines via cooperative catalysis of squaramides and Rh2(OAc)4

Three-component reactions of aryl diazoacetates, arylamines and N-sulfonyl aldimines cooperatively catalyzed by squaramides and dirhodium acetate are reported to afford N-sulfonyl α,β-diamino acid derivatives in moderate to good yields and diastereoselectivity.     

Diverse trifluoromethyl heterocycles from a single precursor

Ethyl 2-diazo-4,4,4-trifluoro-3-oxobutanoate is a highly versatile intermediate for the synthesis of a wide range of trifluoromethyl heterocycles. With the use of rhodium(II) or copper(II) catalyzed carbene X-H insertion reactions as key steps, a diverse set of trifluoromethyl-oxazoles, -thiazoles, -imidazoles, -1,2,4-triazines, and -pyridines are available from the diazoketoester, either directly in a single step or with just one additional step.     

Nájera oxime-derived palladacycles catalyze intermolecular Heck reaction with Morita-Baylis-Hillman adducts. An improved and highly efficient synthesis of α-benzyl-β-ketoesters

An improved and highly efficient synthesis of several α-benzyl-β-ketoesters from Morita-Baylis-Hillman adducts is described. These adducts were used as substrates for an intermolecular Heck reaction catalyzed by a Nájera oxime-derived palladacycles. These efficient catalytic conditions probed to be very selective providing only the corresponding functionalized β-ketoesters in high yield with no decarboxylation product. It seems that the method herein described is one of the most efficient for the synthesis of α-benzyl-β-ketoesters.