C-C bond-forming reductive elimination from a zirconium(IV) redox-active ligand complex

Carbon-carbon bond-forming reductive elimination of biphenyl is observed upon two-electron oxidation of the [ZrIVPh2(ap)2]2- dianion. Crossover experiments confirm that the C-C bond-forming step occurs at a single zirconium metal center. The reactivity is enabled by the participation of a redox-active amidophenolate ligand set.     

Organocatalytic asymmetric deconjugative Michael additions

The organocatalytic allylic C-C bond-forming addition of activated alkylidenes to acrolein has been achieved with good yield and regio- and enantioselectivity. Chiral tertiary amines in the form of cinchona alkaloid catalysts are used to give allyl intermediates that exhibit unusual alpha-selectivity in the C-C bond-forming step. The products are transformed into a large range of intermediates that are difficult to access via alternative methods, using different oxidative and reductive protocols.     

Pd(II)-catalyzed intramolecular amidoarylation of alkenes with molecular oxygen as sole oxidant

Stereoselective palladium-catalyzed synthesis of structurally versatile indoline derivatives, using molecular oxygen as the sole oxidant, is described. New C-N and C-C bonds form across an alkene in an intramolecular manner. The C-N bond-forming step proceeds via a syn-amidopalladation pathway. The moderate kinetic isotope effects (intramolecular KIE = 3.56) suggest that electrophilic aromatic substitution occurs in the arylation step.     

A kinetic and mechanistic study of the amino acid catalyzed aldol condensation of acetaldehyde in aqueous and salt solutions

The amino acid catalyzed aldol condensation is of great interest in organic synthesis and natural environments such as atmospheric particles. However, kinetic and mechanistic information on these reactions is limited. In this work the kinetics of the aldol condensation of acetaldehyde in water and aqueous salt solutions (NaCl, CaCl2, Na2SO4, MgSO4) catalyzed by five amino acids (glycine, alanine, serine, arginine, and proline) at room temperature (295 +/- 2 K) has been studied. Monitoring the formation of three products, crotonaldehyde, 2,4-hexadienal, and 2,4,6-octatrienal, by UV-vis absorption over 200-1100 nm revealed two distinct kinetic regimes: at low amino acid concentrations (in all cases, below 0.1 M), the overall reaction was first-order with respect to acetaldehyde and kinetically limited by the formation of the enamine intermediate. At larger amino acid concentrations (at least 0.3 M), the kinetics was second order and controlled by the C-C bond-forming step. The first-order rate constants increased linearly with amino acid concentration consistent with the enamine formation. Inorganic salts further accelerated the enamine formation according to their pKb plausibly by facilitating the iminium or enamine formation. The rate constant of the C-C bond-forming step varied with the square of amino acid concentration suggesting the involvement of two amino acid molecules. Thus, the reaction proceeded via a Mannich pathway. However, the contribution of an aldol pathway, first-order in amino acid, could not be excluded. Our results show that the rate constant for the self-condensation of acetaldehyde in aqueous atmospheric aerosols (up to 10 mM of amino acids) is identical to that in sulfuric acid 10-15 M (kI approximately 10-7-10-6 s-1) clearly illustrating the potential importance of amino acid catalysis in natural environments. This work also demonstrates that under usual laboratory conditions and in natural environments aldol condensation is likely to be kinetically controlled by the enamine formation. Notably, kinetic investigations of the C-C bond-forming addition step would only be possible with high concentrations of amino acids.     

A coupling reaction between tetrahydrofuran and olefins by Rh-catalyzed/Lewis acid-promoted C-H activation

A novel coupling reaction between tetrahydrofuran and olefins is discovered, in which the consecutive C-C and C-Cl bond-forming process takes place via Rh-catalyzed/lewis acid-promoted C-H activation. This reaction could be developed into a straightforward and effective method for rapid access to 2-(2-chloro-2-arylethyl)-tetrahydrofuran compounds.     

Toward a protecting-group-free halogen-metal exchange reaction: practical, chemoselective metalation of functionalized aromatic halides using dianion-type zincate, tBu4ZnLi2

A versatile preparation method for aromatic zincate compounds through a halogen-zinc exchange reaction using dilithium tetra-tert-butylzincate (tBu4ZnLi2) has been developed. This reagent permits efficient preparation of highly functionalized aromatic zincates, particularly, those with electrophilic functional groups, such as ester, amide, alcohol, and phenol. Halogen-zinc exchange reactions followed by electrophilic trapping (with allyl bromide or benzaldehyde) proved to be a powerful tool for C-C bond formation on functionalized aromatic rings. The functionalized aromatic zincate intermediate was also found to undergo copper- and palladium-catalyzed C-C bond-forming reactions with good yields and high chemoselectivity.     

Organocatalytic asymmetric allylic carbon-carbon bond formation

Organocatalytic allylic C-C bond-forming addition of activated alkylidenes to alkyl and aryl nitroalkenes has been achieved with high diastereo- and enantioselectivity. Chiral tertiary amine catalysts are used to give allyl intermediates which exhibit gamma-selectivity in the C-C bond forming step. The reactions proceed with up to >99:1 syn:anti ratio for both the alkyl- and aryl nitroalkenes with up 96% and 98% ee, respectively. The products of this conjugate addition are transformed into a range of intermediates, such as optically active conjugated dienes and 1-substituted tetralones, which are difficult to access via alternative methods.     

Nickel-catalyzed coupling reactions of alkyl electrophiles, including unactivated tertiary halides, to generate carbon-boron bonds

Through the use of a catalyst formed in situ from NiBr(2)·diglyme and a pybox ligand (both of which are commercially available), we have achieved our first examples of coupling reactions of unactivated tertiary alkyl electrophiles, as well as our first success with nickel-catalyzed couplings that generate bonds other than C-C bonds. Specifically, we have determined that this catalyst accomplishes Miyaura-type borylations of unactivated tertiary, secondary, and primary alkyl halides with diboron reagents to furnish alkylboronates, a family of compounds with substantial (and expanding) utility, under mild conditions; indeed, the umpolung borylation of a tertiary alkyl bromide can be achieved at a temperature as low as -10 °C. The method exhibits good functional-group compatibility and is regiospecific, both of which can be issues with traditional approaches to the synthesis of alkylboronates. In contrast to seemingly related nickel-catalyzed C-C bond-forming processes, tertiary halides are more reactive than secondary or primary halides in this nickel-catalyzed C-B bond-forming reaction; this divergence is particularly noteworthy in view of the likelihood that both transformations follow an inner-sphere electron-transfer pathway for oxidative addition.     

Transition-metal-catalyzed carbon-heteroatom three-component cross-coupling reactions: a new concept for carbothiolation of alkynes

The deep-seated understanding of flexible ligand behavior of thiolate on transition-metals has paved the way to achieve metal-catalyzed carbothiolations of terminal alkynes. The strategy of the reaction is quite simple: 1) generation of the complex with C-Pt-S fragments formed after the Pd-catalyzed C-S bond-forming cross-coupling reaction, 2) insertion of an alkyne into Pt-S bond to form the complex with a C-Pt-C fragment, and 3) C-C bond-forming reductive elimination.     

A solid-supported,enantioselective synthesis suitable for the rapid preparation of large numbers of diverse structural analogues of (-)-saframycin A

A 10-step solid-supported, enantioselective synthesis suitable for the rapid preparation of large numbers of diverse structural analogues of saframycin A is described. The synthetic route, which bears analogy to solid-phase peptide synthesis, involves the directed condensation of N-protected alpha-amino aldehyde reactants. A novel dual linker was developed for attachment of intermediates to the solid support via a C-protective group, a substituted morpholino nitrile derivative. The route employs a novel diastereospecific cyclorelease mechanism, supports structural variation at multiple sites in the saframycin core, and obviates the need for chromatographic purification of the products or any intermediate. To demonstrate the feasibility of structural variation at multiple sites, a matrix of 16 saframycin A analogues was prepared by parallel synthesis with simultaneous variation of two sites. This work is notable not only as a preliminary step toward large-scale library construction but also as an example of the use of sequential stereoselective C-C bond-forming reactions on the solid phase for the preparation of natural product analogues.     

Copper-catalyzed intramolecular alkene carboetherification: synthesis of fused-ring and bridged-ring tetrahydrofurans

Fused-ring and bridged-ring tetrahydrofuran scaffolds are found in a number of natural products and biologically active compounds. A new copper-catalyzed intramolecular carboetherification of alkenes for the synthesis of bicyclic tetrahydrofurans is reported herein. The reaction involves Cu-catalyzed intramolecular addition of alcohols to unactivated alkenes and subsequent aryl C-H functionalization provides the C-C bond. Mechanistic studies indicate a primary carbon radical intermediate is involved and radical addition to the aryl ring is the likely C-C bond-forming mechanism. Preliminary catalytic enantioselective reactions are promising (up to 75% ee) and provide evidence that copper is involved in the alkene addition step, likely through a cis-oxycupration mechanism. Catalytic enantioselective alkene carboetherification reactions are rare and future development of this new method into a highly enantioselective process is promising. During the course of the mechanistic studies a protocol for alkene hydroetherification was also developed.     

Solid-Phase Combinatorial Synthesis of Polyisoxazolines: A Two-Reaction Iterative Protocol

Starting from a polymer-bound olefin, iterative application of nitrile oxide 1,3-dipolar cycloaddition and selenide oxidation/elimination steps were employed to deliver a polymer-bound triisoxazoline that can be liberated from the resin by transesterification. When four nitroseleno ethers (2-5) and four capping nitroalkanes (6-9) were employed, a triisoxazoline library (V) of 64 positional isomers was obtained by three iterative applications of these two reactions. The tactical flexibility of this strategy for preparing small polyfunctional oligomers is particularly attractive in that each subunit addition proceeds via a C-C bond-forming step.     

Regio- and diastereoselective reductive coupling of vinylepoxides catalyzed by titanocene chloride

[reaction: see text] The Ti(III)-catalyzed reaction of a series of vinylepoxides leads, with regio- and E-diastereoselectivity control, to good-to-excellent yields of the corresponding homocoupling products. This homocoupling reaction, which involves a new C-C bond-forming method, takes place via a S(N)2' process between an allyltitanium species and the starting vinylepoxide. The process can be used for the rapid and efficient formation of highly valuable intermediates for organic synthesis, as well as new interesting homologues of natural products.     

A new synthesis of 2-substituted pyridines via aluminum chloride induced heteroarylation of arenes and heteroarenes

[reaction: see text] We herein report a new synthesis of 2-(hetero)aryl-substituted pyridines via heteroarylation of arenes/heteroarenes through AlCl(3)-induced C-C bond-forming reactions. 2-Halopyridines bearing an electron-withdrawing group were reacted with a number of (hetero)arenes to give 2-aryl/heteroaryl-substituted pyridines in good yields.     

Mechanistic implications of nickel-catalyzed reductive coupling of aldehydes and chiral 1,6-enynes

[reaction: see text]. A study of nickel-catalyzed reductive coupling reactions of aldehydes and chiral 1,6-enynes has provided evidence for three distinct mechanistic pathways that govern regioselectivity in this transformation. In the absence of a phosphine additive, high regioselectivity and high diastereoselectivity are obtained as a direct result of coordination of both the alkyne and the olefin to the metal center during the C-C bond-forming step.     

Borrowing hydrogen: iridium-catalysed reactions for the formation of C-C bonds from alcohols

Alcohols have been employed as substrates for C-C bond-forming reactions which involve initial activation by the temporary removal of hydrogen to form an aldehyde. The intermediate aldehyde is converted into an alkene via a Horner-Wadsworth-Emmons reaction, nitroaldol and aldol reactions. The 'borrowed hydrogen' is then returned to the alkene to form a C-C bond.     

C-C bond formation via C-H bond activation: synthesis of the core of teleocidin B4

The core of teleocidin B4, a complex fragment of a natural product containing two quaternary stereocenters and a penta-substituted benzene ring, was synthesized in four C-C bond-forming steps starting from tert-butyl derivative 1. The first step involved alkenylation of the tert-butyl group with a vinyl boronic acid, followed by the successful annulation of the cyclohexane ring to the benzene nucleus via an intramolecular Friedel-Crafts reaction. The third step required a diastereoselective oxidative carbonylation of the geminal dimethyl group, followed at last by indole assembly via the alkenylation of the phenol nucleus, to afford the teleocidin B4 core. Noteworthy is the fact that steps 1 and 3 critically depended on the directing role of the aniline nitrogen (directed C-H bond functionalization).     

Synthesis of pyridazine-based scaffolds as alpha-helix mimetics

The synthesis of several amphiphilic, nonpeptidic scaffolds that mimic the presentation of i, i + 3 or i + 4, and i + 7 residues of a peptide alpha-helix is described. The approach uses a pyridazine core, and the synthesis involves only a few steps and minimizes the number of C-C bond-forming reactions. The versatility of the synthesis makes it suitable for the preparation of small libraries of low molecular weight alpha-helix mimetics that could be targeted to certain protein/protein interactions.     

FeCl3⋅6H2O-catalyzed intermolecular-cascade cyclization of acetoacetanilide: aldehyde-tuned synthesis to valuable 2-pyridone analogues

The first ever breakthrough toward activation of β-ketoacetanilide and subsequent C-C and C-N bond-forming intermolecular-cascade cyclization processes is demonstrated by development of the unprecedented Lewis acid property of non-toxic FeCl(3)?6H(2)O. Aromatic, aliphatic, α,β-unsaturated, chiral sugar-based and chromone aldehydes were regio- and stereoselectively cyclized with acetoacetanilides toward construction of valuable N-containing highly functionalized 2-pyridones (see scheme for an example).     

Synthesis of multiply functionalized benzenes via ruthenium-catalyzed cycloaddition of diiododiynes

Highly functionalized benzenes were precisely synthesized via multi-step processes consisting of ruthenium-catalyzed [2+2+2] cycloaddition of diiododiynes with an ethynylboronate or terminal alkynes, and subsequent chemo- and regio-selective palladium-catalyzed C-C bond-forming reactions of the resulting cycloadducts. The sequential cycloaddition/coupling process was applied to the synthesis of oligo(p-phenylene ethynylene)s.