Stereospecific alkyl and alkynyl substitution reactions of epoxy sulfides with organoaluminums with double inversion of the configuration

A regioselective and stereospecific substitution reaction of 1-(phenylthio)-2,3-epoxyalkanes was achieved by using organoaluminum reagents as a nucleophile. Under the influence of trimethyl- or triethylaluminum, a 1-(phenylthio)-2,3-epoxyalkane underwent substitution at the C2 position to give a product with retention of the configuration. The reaction proceeds through an episulfonium ion intermediate, which gives rise to the C2-substitution products with double inversion of the configuration. Introduction of an alkynyl group was also accomplished by the reaction with dimethyl[2-(trimethylsilyl)ethynyl]aluminum in dichloromethane.     

C-H activation of terminal alkynes by tris-(3,5-dimethylpyrazolyl)boraterhodiumneopentylisocyanide: new metal-carbon bond strengths

C-H bond activation of terminal alkynes by [Tp'Rh(CNneopentyl)] (Tp' = hydridotris-(3,5-dimethylpyrazolyl)borate) resulted in the formation of terminal C-H bond activation products Tp'Rh(CNneopentyl)(C≡CR)H (R = t-Bu, SiMe(3), hexyl, CF(3), p-MeOC(6)H(4), Ph, and p-CF(3)C(6)H(4)). A combination of kinetic selectivity determined in competition reactions and activation energy for reductive elimination has allowed for the calculation of relative Rh-C(alkynyl) bond strengths. The bond strengths of Rh-C(alkynyl) products are noticeably higher than those of Rh-C(aryl) and Rh-C(alkyl) analogues. The relationship between M-C and C-H bond strengths showed a linear correlation (slope R(M-C/H-C) = 1.32), and follows energy correlations previously established for unsubstituted sp(2) and sp(3) C-H bonds in aliphatic and aromatic hydrocarbons.     

Rhodium(I)‐Catalyzed Sequential C(sp)C(sp3) and C(sp3)C(sp3) Bond Formation through Migratory Carbene Insertion

A Rh^I‐catalyzed three‐component reaction of tert‐propargyl alcohol, diazoester, and alkyl halide has been developed. This reaction can be considered as a carbene‐involving sequential alkyl and alkynyl coupling, in which C(sp)? C(sp³) and C(sp³)? C(sp³) bonds are built successively on the carbenic carbon atom. The Rh^I‐carbene migratory insertion of an alkynyl moiety and subsequent alkylation are proposed to account for the two separate C? C bond formations. This reaction provides an efficient and tunable method for the construction of all‐carbon quaternary center.     

Rhodium(I)‐Catalyzed Sequential C(sp)?C(sp3) and C(sp3)?C(sp3) Bond Formation through Migratory Carbene Insertion

A Rh^I‐catalyzed three‐component reaction of tert‐propargyl alcohol, diazoester, and alkyl halide has been developed. This reaction can be considered as a carbene‐involving sequential alkyl and alkynyl coupling, in which C(sp) C(sp³) and C(sp³) C(sp³) bonds are built successively on the carbenic carbon atom. The Rh^I‐carbene migratory insertion of an alkynyl moiety and subsequent alkylation are proposed to account for the two separate C C bond formations. This reaction provides an efficient and tunable method for the construction of all‐carbon quaternary center.     

Nucleophilic vinylic substitutions on unactivated substrates. : The behaviour of styryl alkyl sulphides and selenides towards sulphur and selenium nucleophiles.

Sodium alkanethiolates or lithium methyl selenide react with styryl alkyl sulphides and selenides, in DMF at 100°C, to give the products of vinylic or aliphatic substitution. The two nucleophilic reagents are extremely selective. In the case of RSNa the attack at the vinylic carbon atom is much faster than that at the aliphatic carbon atom and the (Z)- or (E)- styryl alkyl sulphides are obtained as the result of a stereospecific vinylic substitution which occurs with retention of configuration. On the contrary, in the case of MeSeLi, under the same experimental conditions, the only reaction occurring is the aliphatic substitution which affords the vinyl thiolate anions, as an equilibrium mixture of the (E)- and (Z)- isomers, or the vinyl selenide anions which retain the configuration of the starting styryl alkyl selenides.     

Gold‐Catalyzed Cascade Reactions of Furan‐ynes with External Nucleophiles Consisting of a 1,2‐Rearrangement: Straightforward Synthesis of Multi‐Substituted Benzo[b]furans

A gold‐catalyzed cycloisomerization of silyl‐protected 2‐(1‐alkynyl)‐2‐alken‐1‐(2‐furanyl)‐1‐ols with various nucleophiles including water, alcohol, aniline, sulfonamide, and electron‐rich arene has been developed. The method provides a highly efficient access to 5,7‐disubstituted or 2,5,7‐trisubstituted benzo[b]furans with a wide diversity of substituents under mild reaction conditions, which are not easily available by other methods. Remarkably, an interesting rearrangement of the alkyl group from C2 to the C3 position of the furan ring takes place during the cyclization process. The following gold‐assisted allylic substitution enables an elaboration of benzo[b]furans on its side chain of the C5 position with a wide range of functional groups.     

Reactions of some diorganonickel(II) complexes with N-bromosuccinimide

The reactions of some diorganonickel(II) complexes with N-bromosuccinimide (NBS) resulted in facile bromine for hydrogen substitution in aromatic, alkynyl or alkenyl substituents, or in the addition of NBS to CC bonds.     

Gold‐Catalyzed C(sp3)H/C(sp)H Coupling/Cyclization/Oxidative Alkynylation Sequence: A Powerful Strategy for the Synthesis of 3‐Alkynyl Polysubstituted Furans

In sharp contrast to the gold‐catalyzed reactions of alkynes/allenes with nucleophiles, gold‐catalyzed oxidative cross‐couplings and especially C? H/C? H cross‐coupling have been under represented. By taking advantage of the unique redox property and carbophilic π acidity of gold, this work realizes the first gold‐catalyzed direct C(sp³)? H alkynylation of 1,3‐dicarbonyl compounds with terminal alkynes under mild reaction conditions, with subsequent cyclization and in situ oxidative alkynylation. A variety of terminal alkynes including aryl, heteroaryl, alkenyl, alkynyl, alkyl, and cyclopropyl alkynes all successfully participate in the domino reaction. The protocol offers a simple and region‐defined approach to 3‐alkynyl polysubstituted furans.     

Ligand‐Free Copper‐Catalyzed Negishi Coupling of Alkyl‐, Aryl‐, and Alkynylzinc Reagents with Heteroaryl Iodides

Reported herein is an unprecedented ligand‐free copper‐catalyzed cross‐coupling of alkyl‐, aryl‐, and alkynylzinc reagents with heteroaryl iodides. The reaction proceeds at room temperature for the coupling of primary, secondary, and tertiary alkylzinc reagents with heteroaryl iodides without rearrangement. An elevated temperature (100 °C) is required for aryl–heteroaryl and alkynyl–heteroaryl couplings.     

Gold‐Catalyzed C(sp3)?H/C(sp)?H Coupling/Cyclization/Oxidative Alkynylation Sequence: A Powerful Strategy for the Synthesis of 3‐Alkynyl Polysubstituted Furans

In sharp contrast to the gold‐catalyzed reactions of alkynes/allenes with nucleophiles, gold‐catalyzed oxidative cross‐couplings and especially C H/C H cross‐coupling have been under represented. By taking advantage of the unique redox property and carbophilic π acidity of gold, this work realizes the first gold‐catalyzed direct C(sp³) H alkynylation of 1,3‐dicarbonyl compounds with terminal alkynes under mild reaction conditions, with subsequent cyclization and in situ oxidative alkynylation. A variety of terminal alkynes including aryl, heteroaryl, alkenyl, alkynyl, alkyl, and cyclopropyl alkynes all successfully participate in the domino reaction. The protocol offers a simple and region‐defined approach to 3‐alkynyl polysubstituted furans.     

Gold(I)‐Catalyzed Cycloisomerizations and Alkoxycyclizations of ortho‐(Alkynyl)styrenes

Indenes and related polycyclic structures have been efficiently synthesized by gold(I)‐catalyzed cycloisomerizations of appropriate ortho‐(alkynyl)styrenes. Disubstitution at the terminal position of the olefin was demonstrated to be essential to obtain products originating from a formal 5‐endo‐dig cyclization. Interestingly, a complete switch in the selectivity of the cyclization of o‐(alkynyl)‐α‐methylstyrenes from 6‐endo to 5‐endo was observed by adding an alcohol to the reaction media. This allowed the synthesis of interesting indenes bearing an all‐carbon quaternary center at C1. Moreover, dihydrobenzo[a]fluorenes can be obtained from substrates bearing a secondary alkyl group at the β‐position of the styrene moiety by a tandem cycloisomerization/1,2‐hydride migration process. In addition, diverse polycyclic compounds were obtained by an intramolecular gold‐catalyzed alkoxycyclization of o‐(alkynyl)styrenes bearing a nucleophile in their structure. Finally, the use of a chiral gold complex allowed access to elusive chiral 1H‐indenes in good enantioselectivities.     

5- And 6-exocyclic products, cis-2,3,5-trisubstituted tetrahydrofurans, and cis-2,3,6-trisubstituted tetrahydropyrans via Prins-type cyclization

Exocyclic products having cis-2,5 and cis-2,6 substitution were synthesized from terminally substituted alkynyl alcohols with various aldehydes via Prins-type cyclization in good yields. It is of interest that synthesized 5- and 6-exocyclic vinyl cations generated as a result of Prins-type cyclization could be trapped as a vinyl triflate in CH2Cl2 to give 3-furanylidenes and 3-pyranylidenes. Those 3-furanylidenes and 3-pyranylidenes underwent hydrolysis to give the corresponding 3-acyl-substituted products having all-cis-configured isomers, such as 2,3,5-trisubstituted tetrahydrofurans and 2,3,6-trisubstituted tetrahydropyrans.     

Symmetrical and Unsymmetrical Coupling of Alkyl Halides Mediated by Grignard Reaction

A simple method for extending the carbon chain via the coupling of alkyl or aryl halides has been developed. The versatility of this reaction has been demonstrated by symmetrical and unsymmetrical coupling of alkyl, alkenyl or alkynyl halides.     

Gold(I)‐Catalyzed Regiodivergent Rearrangements: 1,2‐ and 1,2′‐Alkyl Migration in Skipped Alkynyl Ketones

A series of 2‐alkynyl carbonyl compounds that contain a cyclopentene ring or a heterocycle can be transformed into various fused dihydrobenzofurans and tetrahydrofuro[2,3‐c]pyridines by means of a 1,2‐alkyl migration process. Both of these reactions proceed with excellent regioselectivity and stereospecificity when using a cationic gold(I) catalyst. Treatment of 4‐styrylcyclopent‐1‐enecarboxylates under different conditions affords a range of highly functionalized dihydrobenzofurans and dihydroisobenzofurans. A divergence in product selectivity, which depends on the anion of the silver salts used, was observed. Interestingly, ring‐fused tetrahydroquinolines undergo only 1,2′‐alkyl migration reaction by means of a C? C cleavage/cyclization sequence to provide tetrahydroazepine derivatives. Mechanistic studies suggest that the gold complexes catalyze 1,2‐alkyl migration reactions through a concerted reaction pathway and 1,2′‐alkyl migration reactions through a stepwise reaction pathway.     

Synthesis of internal alkynes via one-pot palladium-catalyzed and dehydrobromination reactions of 1,1-dibromo-1-alkenes

Tandem palladium-catalyzed cross-coupling of alkyl, alkenyl, alkynyl, aryl, and heteroaryl 2-substituted 1,1-dibromo-1-alkenes with aryl or heteroaryl boronic acids or borate esters and dehydrobromination of the intermediate coupled products afforded internal alkynes in moderate to good yields (up to 89%). The synthesis has been carried out in a one-pot process and in a two-step sequence according to the nature of the starting 1,1-dibromoalkenes. The reported protocol is compatible with the presence in the 1,1-dibromo-1-alkene molecule of additional reactive halogen–carbon bonds, thus allowing to build up more complex alkyne derivatives.     

Asymmetric Substitution by Alkynyl Copper Driven Dearomatization and Rearomatization

Catalytic asymmetric transformations by dearomatization have developed into a widely applicable synthetic strategy, but heavily relied on the use of arenes bearing a heteroatom. In this case, the dearomatization is facilitated by the involvement of a p-orbital electron of the heteroatom. Different from the conventional substrate-dependent model, here we demonstrate that the activation by a d-orbital electron of the transition-metal center can serve as a driving force for dearomatization, and is applied to the development of a novel asymmetric alkynyl copper facilitated remote substitution reaction. A newly modified PyBox chiral ligand enables the construction of valuable diarylmethyl and triarylmethyl skeletons in high enantioselectivities. An unexpected tandem process involving sequential remote substitution/cyclization/1,5-H shift leads to the formation of the enantioenriched C−N axis. A gram-scale reaction and various downstream transformations highlight the robustness of this method and the potential transformations of the products. Preliminary mechanistic studies reveal a mononuclear Cu-catalyzed remote substitution process.     

Electron-donating or -withdrawing nature of substituents revealed by the electrochemistry of metal-free phthalocyanines

The effect of substituents on the electrochemistry of metal-free phthalocyanines was examined for 17 phthalocyanine compounds. This work also provides new information about the electron-donating or -withdrawing nature of various substituents, namely, alkoxy, alkylthio, alkyl, alkynyl, phenyloxy, and phenylthio groups attached to the phthalocyanine system, from the viewpoint of electrochemistry. Most of the effects of peripheral and nonperipheral substitution and changes in the ring (pi-conjugated system) size on the electrochemistry of metal-free phthalocyanines can be reasonably explained by considering the energy levels of frontier molecular orbitals of the corresponding compounds, which were obtained by calculations using the semiempirical PM3 method.     

Metallacyclopentadienes and related heterocycles via 1,1‐organoboration of alkyn‐1‐ylmetal compounds

Metallacyclopentadienes (metalloles) containing M = Si, Ge, Sn, Pb, Ti, Pt can be prepared by 1,1‐organoboration of alkyn‐1‐ylmetal compounds L_nM CC R¹(R¹ = H, alkyl, aryl, silyl, etc; L depends on M, and can be hydrogen, alkyl, aryl, Cl, Br, amino groups, a chelating diphosphane, and one or more L can be again alkynyl groups). These reactions proceed via activation of the M C bond(s) by an electron‐deficient triorganoborane BR₃ (R = alkyl, aryl; non‐cyclic, monocyclic, bicyclic, and tricyclic boranes), at first intermolecular and then intramolecular. In the course of these reactions, the M C bonds are cleaved, zwitterionic alkynylborate‐like intermediates are formed, in which the metal‐containing fragments are coordinated side‐on to the CC bonds. In most cases, the 1,1‐organoboration reactions tolerate various functional groups at the alkyne as well as at the metal. The characterization of intermediates and final products by X‐ray structural analysis and by multinuclear magnetic resonance spectroscopy (NMR) is documented and described. © 2006 Wiley Periodicals, Inc. Heteroatom Chem 17:188–208, 2006; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/hc.20222     

New flexible synthesis of pyrazoles with different,functionalized substituents at C3 and C5

Syntheses of pyrazoles featuring a functionalized side chain attached to carbon 3 and varying alkyl and aryl substituents attached to carbon 5 are presented. Installation of R = methyl, isopropyl, tert-butyl, adamantyl, or phenyl groups at C5 is reported here, starting by coupling protected alkynols with acid chlorides RCOCl, forming alkynyl ketones, which are reacted with hydrazine to form the pyrazole nucleus. Alcohol deprotection and conversion to a chloride gave 5-substituted 3-(chloromethyl)- or 3-(2-chloroethyl)pyrazoles. This sequence can be done within 2 d on a 30 g scale in excellent overall yield. Through nucleophilic substitution reactions, the chlorides are useful precursors to other polyfunctional pyrazoles. In the work here, derivatives with side chains LCH(2)- and LCH(2)CH(2)- at C3 (L = thioether or phosphine) were made as ligands. The significance of the ligands made here is that by placing a ligating side chain on a ring carbon (C3), rather than on a ring nitrogen, the ring nitrogen not bound to the metal and its attached proton will be available for hydrogen bonding, depending on the steric environment created by R at C5.     

Synthesis of 5-acetyloxazoles and 1,2-diketones from β-alkoxy-β-ketoenamides and their subsequent transformations

Lithiated alkoxyallenes, nitriles, and carboxylic acids have been employed as precursors in a three-component reaction leading to highly substituted β-alkoxy-β-ketoenamides. Upon treatment with trifluoroacetic acid, these enamides could be easily cyclized to 5-acetyloxazole derivatives. The synthesis is very flexible with respect to the substitution pattern at C-2 and C-4 of the oxazole core. A mechanistic suggestion for the oxazole formation is presented on the basis of (18)O-labeled compounds and their mass spectrometric analysis. In several cases, 1,2-diketones are formed as side products or even as major components. The acetyl moiety at C-5 of the oxazole derivatives can efficiently be converted into alkenyl or alkynyl moieties, which allows a multitude of subsequent reactions. Condensation reactions of the acetyl group provided the expected oxime or hydrazone. By applying a Fischer reaction, the phenylhydrazone could be transferred into an indole, which emphasizes the potential of 5-acetyloxazoles for the preparation of highly substituted (poly)heterocyclic systems. The alkynyl group at C-2 is prone to addition reactions, providing an enamine with interesting photophysical properties. Sonogashira couplings were performed with 5-alkynyl-substituted oxazoles, furnishing the expected aryl-substituted products. This alkynyl unit was employed for the preparation of a new, star-shaped trisoxazole derivative. The ability of this multivalent compound to form self-assembled monolayers between the basal plane of highly oriented pyrolytic graphite and 1-phenyloctane was demonstrated by scanning tunneling microscopy (STM). The star-shaped compound seems to prefer the C(3)-symmetric arrangement in this two-dimensional crystal. Two 1,2-diketones were smoothly converted into functionalized quinoxaline derivatives.