Stereoselective synthesis of cis-2,6-disubstituted piperidines from 1,2-cyclic sulfamidates

Diastereoselective synthesis of cis-2,6-disubstituted piperidines from 1,2-cyclic sulfamidates is described. Regioselective ring-opening reactions of 1,2-cyclic sulfamidates derived from L-phenylalanine, alanine, valine, norvaline with the ketal protected acetylide with a phenyl substituent proceed smoothly to form the N-sulfamate intermediates which on acidic hydrolysis give alkynylated amines with the ketal group intact. Hydrogenation of the alkynylated amines, debenzylation, ketal deprotection, subsequent cyclization (of aminoketones) and stereoselective hydrogenation of the cyclic iminium ion intermediates afford the corresponding cis-2,6-disubstituted piperidines in high diastereoselectivity (98%?≥?d.e.) with good chemical yields (68–86%). The present approach provides a novel route for the stereoselective synthesis of cis-2,6-disubstituted piperidines.     

Generation of Nucleophilic Chromium Acetylides from gem-Trichloroalkanes and Chromium Chloride: Synthesis of Propargyl Alcohols

Nucleophilic mixed chromium(II) and chromium(III) acetylides are generated from the smooth reduction of primary 1,1,1-trichloroalkanes with chromium(II) chloride in the presence of an excess amount of triethylamine at room temperature. These species arise from chromium(III) vinylidene carbenoids. It has been demonstrated that uncommon low-valent Cr(II) acetylides are formed by C-H insertion of Cr(II)Cl(2) into terminal alkynes, formed in situ through the Fritsch- Buttenberg-Wiechell (FBW) rearrangement, whereas Cr(III) acetylides are concomitantly generated by HCl elimination from the chromium(III) vinylidene carbenoid. Both divergent pathways result, overall, in the formation of nucleophilic acetylides. In situ trapping with electrophilic aldehydes afforded propargyl alcohols. Furthermore, deuteration experiments and the use of deuterium labeled 1,1,1-trichloroalkane substrates demonstrated the prevalence of low-valent Cr(II) acetylides, potentially useful, yet highly elusive synthetic intermediates.     

Synthesis of chiral quaternary fluorinated cyclic sulfamidates via palladium-catalyzed arylation with arylboronic acids

An enantioselective palladium-catalyzed arylation of fluorinated cyclic N-sulfonyl ketimines with arylboronic acids is described. This methodology provides an efficient and convenient route to chiral quaternary fluorinated cyclic sulfamidates in high yields with up to 99% ee.     

Aziridines from intramolecular alkene aziridination of sulfamates: reactivity toward carbon nucleophiles. application to the synthesis of spisulosine and its fluoro analogue

Catalytic intramolecular alkene aziridination of sulfamate is an emerging methodology for the asymmetric synthesis of chiral functionalized amines involving the formation of bicyclic aziridines. This study demonstrates the ability of the latter to undergo ring-opening with various carbon nucleophiles: Grignard reagents, lithium salts of terminal alkynes, dithiane, malonate. These S(N)2-type reactions occur with high levels of regio- and chemoselectivity to generally afford seven-membered cyclic sulfamidates in good yields. Carbon nucleophiles have also been found to react with these sulfamidates provided that the sulfamate ester has been previously activated by introduction of a tosyl substituent on the NH group. The versatility of this strategy has been illustrated with the syntheses of spisulosine and its fluoro analogue.     

Ring opening of cyclic sulfamidates with bromophenyl metal reagents: complementarity of sulfamidates and aziridines

Bromophenyl magnesium reagents generated via a Knochel type magnesium-halogen exchange of aryl iodides undergo regioselective ring opening of cyclic primary and secondary N-Boc sulfamidates in good to excellent yields. With secondary sulfamidates the reaction proceeds with clean inversion of the stereochemistry. This protocol complements the ring opening of aziridines with bromophenyl metal reagents and extends its scope to secondary substrates.     

Direct synthesis of 1,5-disubstituted-4-magnesio-1,2,3-triazoles, revisited

After revisiting earlier works reporting the regioselective synthesis of 1,5-disubstituted-1,2,3-triazoles via the addition of bromomagnesium acetylides to azides, much improved yields of the products were obtained for a wide array of azides and alkynes. The intermediates of that reaction can be trapped with different electrophiles to regioselectively form 1,4,5-trisubstituted 1,2,3-triazoles. [reaction: see text]     

Anti-Markovnikov stereoselective hydroamination and hydrothiolation of (hetero)aromatic alkynes using a metal-free cyclic trimeric phosphazene base

Hydroamination and hydrothiolation are the most efficient and completely atom-economical process to construct important enamine and vinyl sulfide intermediates in pharmaceutical and organic chemistry. The cyclic trimeric phosphazene base (CTPB) showed great catalytic activity for the anti-Markovnikov stereoselective hydroamination and hydrothiolation of alkynes in good to excellent yields. A broad substrate scope of alkynes and nucleophiles was demonstrated, including aryl and heteroaryl alkynes, terminal and internal alkynes, different N-heterocycles, thiols and thiophenols. This versatile and cost-efficient approach with good stereoselectivity and excellent functional group tolerance provided new opportunity for the organocatalyzed hydrofunctionalization of alkynes.     

Synthesis of conjugated enynes from ketones and aldehydes by 1,2-CC insertion and 1,2-CH insertion of carbenoids as the key reactions

The addition reactions of 1-chlorovinyl p-tolyl sulfoxides, which were derived from ketones and chloromethyl p-tolyl sulfoxide, with lithium acetylides gave adducts in moderate to good yields. Treatment of the adducts with Grignard reagents resulted in the formation of conjugated enynes in good to high yields via the 1,2-carbon-carbon insertion (1,2-CC insertion) reaction of the generated magnesium carbenoid intermediates. On the other hand, the addition reactions of 1-chlorovinyl p-tolyl sulfoxides derived from aldehydes with lithium acetylides directly gave conjugated enynes bearing a p-tolyl sulfinyl group at the 1-position through the 1,2-carbon-hydrogen insertion (1,2-CH insertion) reaction of the generated lithium carbenoid intermediates. These procedures provide a good way for the synthesis of multi-substituted conjugated enynes from ketones and aldehydes.     

Silyl triflate-accelerated additions of catalytically generated zinc acetylides to N-phenyl nitrones

Terminal alkynes readily form zinc acetylides in the presence of iPr₂NEt and 20 mol % ZnBr₂, then attack N-phenyl nitrones activated by trimethylsilyl trifluoromethanesulfonate. Deprotection with aqueous acid yields N-hydroxyl propargylamine. Yields are generally high for nitrones derived from aromatic aldehydes. Control experiments suggest that silyl triflate has a significant accelerating effect upon the reaction.     

Zirconium-promoted epoxide rearrangement-alkynylation sequence

Additions of terminal alkynes to electrophiles are important transformations in organic chemistry. Generally, activated terminal alkynes react with epoxides in an S(N)2 fashion to form homopropargylic alcohols. We have developed a new synthetic method to form propargylic alcohols from epoxides and terminal alkynes via 1,2-shifts. This method involves cationic zirconium acetylides as both the activator of epoxides and nucleophiles. Due to the mild conditions to pre-activate alkynes with silver nitrate, this synthetic method is useful for both electron-rich and electron-deficient alkynes with other acid- and base-sensitive functional groups.     

Facile and efficient addition of terminal alkynes to benzotriazole esters: synthesis of d-erythro-sphingosine using ynones as the key intermediate

From the perspective of synthesis, ynones are compounds of considerable interest because of their occurrence in a wide variety of biologically active molecules and as key synthetic intermediates. In this context, a facile and highly efficient synthesis of ynones was developed based on the high reactivity of benzotriazole esters formed in situ. Lithium acetylides can alkylate various carboxylic acids in yields ranging from 60% to 92%. To determine whether our methodology is useful for synthesising complex and biologically relevant molecules, we synthesise d-erythro-sphingosine in four steps and with 33% overall yield from l-serine.     

New routes to N-alkylated cyclic sulfamidates

BOC- and dibenzosuberyl-protected chiral and hindered cyclic sulfamidates ([1,2,3]-oxathiazolidine-2,2-dioxides) were synthesized and subsequently deprotected using trifluoroacetic acid. The resulting crystalline sulfamidates were then used in several alkylation reactions involving benzyl bromide and alcohols in a versatile route to cyclic sulfamidates with differing N-alkyl substituents.     

Microwave-assisted synthesis of pyridylpyrroles from N-acylated amino acids

A small library of 3- and 4-pyridyl-substituted pyrroles was prepared from N-acylated amino acids. Nicotinoyl or isonicotinoyl chloride was used for the N-acylation of benzyl esters of amino acids. Debenzylation by palladium-catalyzed hydrogenation gave N-acylated amino acids. Dehydration of the acylated amino acids gave cyclic intermediates, münchnones or azlactones, which were treated in situ with alkynes in 1,3-dipolar cycloadditions. The starting materials were prepared in a parallel fashion, and microwave irradiation was used to facilitate the cycloaddition reactions. The regiochemistry of the cycloaddition was studied.     

An unprecedented highly efficient solvent-free oxidation of alkynes to α,β-acetylenic ketones with tert-butyl hydroperoxide catalyzed by water-soluble copper complex

The catalytic system composed of CuCl₂ and 2,2′-biquinoline-4,4′-dicarboxylic acid dipotassium salt (BQC) was found to be highly efficient for the selective α-oxidation of internal alkynes to the corresponding α,β-acetylenic ketones, with aqueous tert-butyl hydroperoxide under mild conditions. For the first time, full conversions of alkynes were reached with excellent selectivities, and propargylic tert-butylperoxy ethers were observed and suggested as the reaction intermediates. In the case of terminal alkynes, the oxidations are sluggish and low yields ranging from 32% to 40% were obtained.     

Regioselective transformation of alkynes into cyclic acetals and thioacetals with a gold(I) catalyst: comparison with Brønsted acid catalysts

Au(I) catalyzes the transformation of alkynes into cyclic acetals and thioacetals at much higher rate than Brønsted acids. The reaction appears to be general for a range of alkynes and diols or dithiols, which are efficiently transformed with high selectivities. One of the salient features of this reaction process is the high reactivity of the enol ether or enol thioether intermediates, which undergo a rapid isomerization reaction to afford the cyclic acetals or thioacetals, so that isolation or subsequent activation processes are not required. This type of reactions allows us to synthesize a series of fragrances.     

Highly diastereoselective synthesis of α-trifluoromethylated α-propargylamines by acetylide addition to chiral CF3-substituted N-tert-butanesulfinyl ketimines

A convenient and practical method for the preparation of enantiomerically pure α-trifluoromethylated α-propargylamines is described. A range of enantiopure α-trifluoromethylated α-propargyl sulfinamides were obtained by the addition of lithium acetylides generated in situ with n-BuLi and terminal alkynes to diverse chiral CF₃-substituted (S)-N-tert-butanesulfinyl ketimines in moderate to excellent yields (56–97%) and with uniformly excellent diastereoselectivities (>99:1) by using Ti(OⁱPr)₄ as the catalyst and THF as the polar solvent. Enantiomerically pure α-trifluoromethylated α,α-dibranched propargyl amines were then readily obtained in excellent yields (87–97%) by acidic cleavage of the tert-butanesulfinyl group.     

Kukhtin–Ramirez-Reaction-Inspired Deprotection of Sulfamidates for the Synthesis of Amino Sugars

Herein, we present a mild strategy for deprotecting cyclic sulfamidates via the Kukhtin–Ramirez reaction to access amino sugars. The method features the removal of the sulfonic group of cyclic sulfamidates, which occurs through an N-H insertion reaction that implicates the Kukhtin–Ramirez adducts, followed by a base-promoted reductive N-S bond cleavage. The mild reaction conditions of the protocol enable the formation of amino alcohols including analogs that bear multiple functional groups.     

A catalytic multicomponent protocol to dihydropyridine-3-carboxylate from terminal alkynes,isocyanates, and malonates

Monatshefte für Chemie - Chemical Monthly - A domino catalytic reaction between terminal alkynes, isocyanates, and malonates has been developed. Copper acetylides attack on isocyanates to form...     

Heavier alkaline earth catalysts for the intermolecular hydroamination of vinylarenes, dienes, and alkynes

The heavier group 2 complexes [M{N(SiMe(3))(2)}(2)](2)(1, M = Ca; 2, M = Sr) and [M{CH(SiMe(3))(2)}(2)(THF)(2)] (3, M = Ca; 4, M = Sr) are shown to be effective precatalysts for the intermolecular hydroamination of vinyl arenes and dienes under mild conditions. Initial studies revealed that the amide precatalysts, 1 and 2, while compromised in terms of absolute activity by a tendency toward transaminative behavior, offer greater stability toward polymerization/oligomerization side reactions. In every case the strontium species, 2 and 4, were found to outperform their calcium congeners. Reactions of piperidine with para-substituted styrenes are indicative of rate-determining alkene insertion in the catalytic cycle while the ease of addition of secondary cyclic amines was found to be dependent on ring size and reasoned to be a consequence of varying amine nucleophilicity. Hydroamination of conjugated dienes yielded isomeric products via η(3)-allyl intermediates and their relative distributions were explained through stereoelectronic considerations. The ability to carry out the hydroamination of internal alkynes was found to be dramatically dependent upon the identity of the alkyne substituents while reactions employing terminal alkynes resulted in the precipitation of insoluble and unreactive group 2 acetylides. The rate law for styrene hydroamination with piperidine catalyzed by [Sr{N(SiMe(3))(2)}(2)](2) was deduced to be first order in [amine] and [alkene] and second order in [catalyst], while large kinetic isotope effects and group 2 element-dependent ΔS(++) values implicated the formation of an amine-assisted rate-determining alkene insertion transition state in which there is a considerable entropic advantage associated with use of the larger strontium center.     

Palladium-catalysed coupling of terminal alkynes with aryl halides aided by catalytic zinc

The palladium-catalysed coupling of aryl halides with terminal alkynes can be performed using base, zinc chloride and sodium iodide. This protocol represents a convenient method for the generation of nucleophilic acetylides in situ.