Three-component one-pot process to propargylic amines and related amide and sulfonamide compounds: application to the construction of 2-(aminomethyl)benzofurans and indoles

An efficient palladium-copper-catalyzed three-component assembling of propargyl halides, aryl or heteroaryl halides, and secondary amines is described. A wide variety of tertiary propargylic amines were synthesized in good to excellent yields from easily accessible starting materials. This three-component assembling was also effective when using potassium phthalimide or di-tert-butyliminodicarbonate instead of secondary amines. Consequently, it provides a quick entry to N-protected propargylic amines suitable intermediates for the synthesis of primary and secondary propargylic amines. In a similar way, related compounds including propargylic amide, carbamate and sulfonamide derivatives were efficiently obtained. This catalytic domino three-component process has been applied successfully to the construction of functionalized 2-(aminomethyl)benzo[b]furan or indole derivatives of biological interest.     

tert‐Butyldimethylsilyl‐Directed Highly Enantioselective Approach to Axially Chiral α‐Allenols

A highly efficient and enantioselective synthesis of axially chiral α‐allenols was realized in practical yields with 96–99 % ee or de from TBS‐protected propargylic alcohols, aldehydes, and a commercially available, inexpensive, chiral, secondary amine (S)‐α,α‐diphenylprolinol or its enantiomer followed by desilylation. The easily removable TBS group not only acts as a protecting group, but also as a possible sterically directing group for the excellent enantioselectivity and in situ prevention of possible allene racemization.     

Synthesis and Functionalization of Allenes by Direct Pd‐Catalyzed Organolithium Cross‐Coupling

A palladium‐catalyzed cross‐coupling between in situ generated allenyl/propargyl‐lithium species and aryl bromides to yield highly functionalized allenes is reported. The direct and selective formation of allenic products preventing the corresponding isomeric propargylic product is accomplished by the choice of SPhos or XPhos based Pd catalysts. The methodology avoids the prior transmetalation to other transition metals or reverse approaches that required prefunctionalization of substrates with leaving groups, resulting in a fast and efficient approach for the synthesis of tri‐ and tetrasubstituted allenes. Experimental and theoretical studies on the mechanism show catalyst control of selectivity in this allene formation.     

Synthesis of Highly Substituted γ‐Butyrolactones by a Gold‐Catalyzed Cascade Reaction of Benzyl Esters

Easily accessible benzylic esters of 3‐butynoic acids in a gold‐catalyzed cyclization/rearrangement cascade reaction provided 3‐propargyl γ‐butyrolactones with the alkene and the carbonyl group not being conjugated. Crossover experiments showed that the formation of the new C?C bond is an intermolecular process. Initially propargylic–benzylic esters were used, but alkyl‐substituted benzylic esters worked equally well. In the case of the propargylic–benzylic products, a simple treatment of the products with aluminum oxide initiated a twofold tautomerization to the allenyl‐substituted γ‐butyrolactones with conjugation of the carbonyl group, the olefin, and the allene. The synthetic sequence can be conducted stepwise or as a one‐pot cascade reaction with similar yields. Even in the presence of the gold catalyst the new allene remains intact.     

Ene reaction of arynes with alkynes

Arynes, generated in situ from ortho-silylaryl triflates, undergo ene reaction with alkynes possessing propargylic hydrogen in the presence of KF/18-crown-6 in THF at room temperature to give substituted phenylallenes. Various terminal and internal alkynes as well as different arynes can be used to give the corresponding phenylallenes in good to moderate yields. The reaction of alkyne without propargylic hydrogen gave an acetylenic C-H addition product (a phenylalkyne) and a dehydro Diels-Alder product (a phenanthrene).     

Electronic effects in the pt-catalyzed cycloisomerization of propargylic esters: synthesis of 2,3-disubstituted indolizines as a mechanistic probe

The initial 5-exo versus 6-endo cyclization of the acyl group onto the activated alkyne of propargylic esters has been found to be dependent on electronic effects of the acyl, alkyne, and propargylic carbon substituents. These electronic effects control the ratio of 2,3-disubstituted versus 1,3-disubstituted indolizine products formed when substrates bearing pyridines at the alkyne terminus are used.     

Palladium catalysed 3-component cascade synthesis of bis(2-arylallyl) tertiary amines from aryl iodides,allene and primary amines

A 3-component cascade synthesis of bis(2-arylallyl) tertiary amines from aryl iodide, allene and primary aliphatic amines is described; chiral amines give analogous products with no detectable racemisation; mixtures of two different aryl iodides can be utilised to give the mixed tertiary amines as the sole, or major, product; the reaction is sensitive to stereoelectronic effects which lead to mono(2-arylallyl) secondary amines.     

Stereospecific and Stereoselective Rhodium(I)‐Catalyzed Intramolecular [2+2+2] Cycloaddition of Allene‐Ene‐Ynes: Construction of Bicyclo[4.1.0]heptenes

Treatment of the allene‐ene‐yne substrates with [{RhCl(CO)₂}₂] effected the intramolecular [2+2+2]‐type ring‐closing reaction to produce various of tri‐ and tetracyclic derivatives containing a cyclopropane ring. The reaction is highly stereoselective as well as stereospecific with good to excellent yields.     

Lewis and Brønsted Acid Cocatalyzed Reductive Deoxyallenylation of Propargylic Alcohols with 2‐Nitrobenzenesulfonylhydrazide

Reductive deoxyallenylation of sterically hindered tertiary propargylic alcohols was realized on reaction with 2‐nitrobenzenesulfonylhydrazide (NBSH) by the combined use of Lewis and Brønsted acid catalysts. This method features a broad substrate scope, mild reaction conditions, and good functional‐group tolerance, and affords various mono‐, di‐, and trisubstituted allenes in good‐to‐excellent yields. The synthetic utility of this method was demonstrated by the synthesis of 2H‐chromenes and 1,2‐dihydroquinolines.     

Dehydrogenative Meyer–Schuster‐Like Rearrangement: A Gold‐Catalyzed Reaction Generating an Alkyne

Easily accessible propargylic esters are converted to the inverted alkynyl ketones in an oxidative gold‐catalyzed reaction. Gagosz’s catalyst in combination with PhI(OAc)₂ is the best system for this conversion and 18 examples with yields up to 80 % are reported. The results indicate that the triple bond in the product is formed by elimination from a vinylgold intermediate. In a formal sense the new conversion overall is a dehydrogenative Meyer–Schuster rearrangement.     

Regio- and diastereoselective reactions of chiral secondary alkylcopper reagents with propargylic phosphates: preparation of chiral allenes

The diastereoselective S_N2′-substitution of secondary alkylcopper reagents with propargylic phosphates enables the preparation of stereodefined alkylallenes. By using enantiomerically enriched alkylcopper reagents and enantioenriched propargylic phosphates as electrophiles anti-S_N2′-substitutions were performend leading to α-chiral allenes in good yields with excellent regioselectivity and retention of configuration. DFT-calculations were performed to rationalize the structure of these alkylcopper reagents in various solvents, emphasizing their configurational stability in THF.

The diastereoselective S_N2′-substitution of secondary alkylcopper reagents with propargylic phosphates enables the preparation of stereodefined alkylallenes.     

Complementary Iron(II)‐Catalyzed Oxidative Transformations of Allenes with Different Oxidants

Substituent‐ and oxidant‐dependent transformations of allenes are described. Given the profound influence of the substituent on the reactivity of allenes, the subtle differences in allene structures are manifested in the formation of diverse products when reacted with different electrophiles/oxidants. In general, reactions of nonsilylated allenes involve an allylic cation intermediate by forming a C?O bond, at the sp‐hybridized C2, with either DDQ (2,3‐dichloro‐5,6‐dicyano‐p‐benzoquinone) or TBHP (tert‐butyl hydroperoxide), along with FeCl₂?4 H₂O (10 mol %). In contrast, silylated allenes favor the formation of propargylic cation intermediates by transferring the allenic hydride to the oxidant, thus generating 1,3‐enynes (E1 product) or propargylic THBP ethers (S_N1 product). The formation of these different putative cationic intermediates from nonsilylated and silylated allenes is strongly supported by DFT calculations.     

Gold Redox Catalysis with a Selenium Cation as a Mild Oxidant

Gold-catalyzed alkyne and allene diselenations were developed. Excellent regioselectivity (trans) and good to excellent yields were achieved (up to 98 % with 2 % catalyst loading) with a wide range of substrates. Mechanistic investigation revealed the formation of a vinyl gold(I) intermediate followed by an intermolecular selenium cation migration, suggesting that a gold(I/III) redox process was successfully implemented under mild conditions.     

Synthesis of tetrasubstituted alkenes through a palladium-catalyzed domino carbopalladation/C-H-activation reaction

Helical tetrasubstituted alkenes (7) were obtained in a highly efficient way through a palladium-catalyzed domino-carbopalladation/CH-activation reaction of propargylic alcohols 6 in good to excellent yields. Electron-withdrawing- and electron-donating substituents can be introduced onto the upper and lower aromatic rings. The substrates (6) for the domino process were synthesized by addition of the lithiated alkyne (20) to various aldehydes (19); moreover, the substrates were accessible enantioselectively (in 95% ee) by reduction of the corresponding ketone using the Noyori procedure.     

Stereoselective synthesis of secondary and tertiary propargylic alcohols induced by a chiral sulfoxide auxiliary

The synthesis of optically active secondary and tertiary propargylic alcohols was accomplished by addition of lithium acetylide to chiral β-sulfinyl enones. Only a stoichiometric amount of the lithium acetylide was required and various substituents were tolerated. This reaction could be applied to substrates consisting of both ketones and aldehydes in high yields and excellent diastereoselectivities.     

Highly chemoselective calcium-catalyzed propargylic deoxygenation

A calcium-catalyzed direct reduction of propargylic alcohols and ethers has been accomplished by using triethylsilane as a nucleophilic hydride source. At room temperature a variety of secondary propargylic alcohols was deoxygenated to the corresponding hydrocarbons in excellent yields. Furthermore, for the first time, a catalytic deoxygenation of tertiary propargylic alcohols was generally applicable. The same protocol was suitable for an efficient reduction of secondary as well as tertiary propargylic methyl, benzyl and allyl ethers. Substrates containing an additional keto-, ester or secondary hydroxyl function were reduced with exceptional chemoselectivity at the propargylic position.     

Regioselective synthesis of phthalans via Cu(OTf)2-catalyzed 5-exo-dig intramolecular hydroalkoxylation of 2-(ethynyl)benzyl alcohols

An efficient, regioselective Cu(OTf)₂-catalyzed 5-exo-dig intramolecular hydroalkoxylation of 2-(ethynyl)benzyl alcohol, which provides a concise access to functionalized phthalan in high yields has been developed. A wide range of substrates possessing terminal, internal, and heteroaromatic alkynes can be efficiently transformed into the targeted phthalans. Substrates with primary, secondary, and tertiary benzyl alcohols also proceed well to produce the corresponding phthalans in good yields. Irrespective of the nature of the substrates, the cyclization follows highly selective 5-exo-dig regiochemistry when regioselectivity is an issue.     

An atom-economic and selective ruthenium-catalyzed redox isomerization of propargylic alcohols. An efficient strategy for the synthesis of leukotrienes

Catalytic ruthenium complexes in conjunction with an indium cocatalyst and Bronsted acid isomerize primary and secondary propargylic alcohols in good yields to provide trans enals and enones exclusively. Readily available indenylbis(triphenylphosphine)ruthenium chloride, in the presence of indium triflate and camphorsulfonic acid, gives the best turnover numbers and reactivity with the broadest range of substrates. Deuterium labeling experiments suggest that the process occurs through propargylic hydride migration followed by protic cleavage of the resultant vinylruthenium intermediate. Application of this method to the synthesis of leukotriene B4 demonstrates its utility and extraordinary selectivity.     

Titanocene-catalyzed metallation of propargylic acetates in homopropargyl alcohol synthesis

The titanium-catalyzed metallation and subsequent carbonyl addition of propargylic acetates enable the direct formation of homopropargylic alcohols in good yields. The corresponding products were obtained as single regioisomers without the corresponding allene adducts observed.     

Trisoxazoline/Cu(II)-promoted Kinugasa reaction. Enantioselective synthesis of beta-lactams

The reactions of nitrones with terminal alkynes, catalyzed by chiral (i)Pr-trisoxazoline 2a/Cu(ClO4)2.6H2O under air atmosphere, afforded beta-lactams in moderate to good yields with up to 85% ee. The diastereoselectivity depends on the alkyne. Propiolate gives the trans-isomer as a major product, while the other alkynes afford cis-disubstituted lactams predominantly. Copper(II) salt proved to be an efficient catalyst precursor for the first time in the Kinugasa reaction, and this allowed the reaction to be performed under a practical and convenient condition. An appropriate base used in this reaction was essential to control both diastereoselectivity and enantioselectivity. Compared with primary and tertiary amines, secondary amines gave higher enantioselectivities. The reaction scope and limitation as well as the mechanism were also studied.