Solid-phase synthesis of substituted alkynes using the Nicholas reaction

The first example of a Nicholas reaction on solid phase is reported, involving the reaction of cobalt complexes of polymer-bound alkynols with different nucleophiles in the presence of a Lewis acid, to form carbon-oxygen or carbon-carbon bonds.     

Cobalt-mediated solid phase synthesis of 3-O-alkynylbenzyl galactosides and their evaluation as galectin inhibitors

Methyl β-d-galactoside was converted to the corresponding 3,4-O-stannylene acetal, which was selectively benzylated with 3-iodobenzyl bromide and coupled to a polymer-bound propargylic ether via a Sonogashira reaction. The polymer-bound carbohydrate substrate was cleaved from the resin with different carbon nucleophiles in a cobalt-mediated Nicholas reaction. The product 3-O-alkynylbenzyl galactosides were screened towards galectin-1, -3, -7, -8N and -9N in a competitive fluorescence polarisation assay. Particularly potent inhibitors were identified against galectin-7 with affinity enhancements up to one order of magnitude due to the 3-O-alkynylbenzyl moiety.     

Carbonylative Sonogashira annulation sequence: One-pot synthesis of 4-quinolone and 4H-chromen-4-one derivatives

Carbonylative Sonogashira annulation sequence for one pot synthesis of 4-quinolone and 4H-chromen-4-one has been developed in presence of Pd-NHC catalyst. Substituted 2-iodoaniline and 2-iodophenol independently underwent in the carbonylative Sonogashira annulation reaction with a variety of acetylenes to result in 4-quinolone and flavone derivatives respectively in good to excellent yield. Moreover, this protocol does not require toxic CO gas, high catalyst loading and any expensive salt/additive. Herein we, for the first time, are using Mo(CO)₆, as solid CO source for the one pot synthesis of flavone derivatives via carbonylative Sonogashira annulation reaction.     

Biology‐Oriented Combined Solid‐ and Solution‐Phase Synthesis of a Macroline‐Like Compound Collection

Macrolines constitute a class of natural products that has more than 100 members and displays diverse biological activities. These compounds feature a cycloocta[b]indole scaffold that represents an interesting target structure for biology‐oriented synthesis (BIOS). We have presented a solid‐phase synthesis of isomerically pure cycloocta[b]indoles by employing the Pictet–Spengler reaction and the Dieckmann cyclization as key steps. The scope of this reaction sequence was investigated in more detail by using various additional diversification procedures, such as Pd‐catalyzed Sonogashira or Suzuki couplings on a solid phase, thus allowing, for example, the generation of 10‐substituted cycloocta[b]indole derivatives. Finally, solution‐phase decoration of the cycloocta[b]indole skeleton by reduction and saponification was evaluated, thereby further extending the scope of the solid‐phase synthesis.     

Transition‐Metal‐Free Formal Sonogashira Coupling and α‐Carbonyl Arylation Reactions

Transition‐metal‐free formal Sonogashira coupling and α‐carbonyl arylation reactions have been developed. These transformations are based on the nucleophilic aromatic substitution (S_NAr) of β‐carbonyl sulfones to electron‐deficient aryl fluorides, producing a key intermediate that, depending on the reaction conditions, gives the aromatic alkynes or α‐aryl carbonyl compounds. The development of these reactions is presented and, based on investigations under basic and acidic conditions, mechanisms have been proposed. To develop the formal Sonogashira coupling further, a milder, two‐step protocol is also disclosed that expands the reaction concept. The scope of these reactions is demonstrated for the synthesis of Sonogashira and α‐carbonyl arylated products from a range of electron‐deficient aryl fluorides with a variety of functional groups and aryl‐, heteroaryl‐, alkyl‐, and alkoxy‐substituted sulfone nucleophiles. These transition‐metal‐free reactions complement the metal‐catalyzed versions in terms of substitution patterns, simplicity, and reaction conditions.     

Cobalt-mediated approach for the synthesis of terpene-based hybrids

[structure: see text] Dicobalt-beta-pinene hybrids of types I and II have been prepared using a Nicholas reaction between propargyl derivatives, obtained from commercial (1R)-(-)-myrtenal, and different aromatic nucleophiles. The method is suitable for the preparation of densely functionalized bio-organometallic natural product-based hybrids, as demonstrated by the preparation of a beta-pinene-neoclerodane hybrid.     

Carbon-carbon and carbon-heteroatom bond formation on solid phase using cationic iron carbonyl complexes

Iron-mediated methodology for the formation of carbon-carbon and carbon-heteroatom sp(3) bonds on solid phase has been developed. Treatment of a polymer-bound cationic iron cyclohexadienyl complex with carbon, oxygen, nitrogen, and phosphorus nucleophiles, followed by cleavage with amines and subsequent decomplexation, yielded 18 different cyclohexadienoic acid amides of high purity. [reaction: see text]     

Solid phase palladium-catalysed CC bond formation in the pyridine series: access to aryl and alkynyl pyridylpiperazines

The underdeveloped topic of solid phase CC bond formation in pyridine series has been investigated. Stille, Negishi, Suzuki and Sonogashira cross-couplings have been performed leading to aryl and alkynyl pyridylpiperazines in acceptable to good yields.     

Synthesis,spectroscopic characterization and chemical reactions of stable o-QM on solid phase

A novel approach towards quinone methides stabilization has been achieved by anchoring the reactive o-QM intermediate on solid phase (RTHP). The reactivity and selectivity of supported o-QM towards N and S centered nucleophiles have been explored.     

Divergent synthesis and optoelectronic properties of oligodiacetylene building blocks

A new and divergent synthetic route to oligodiacetylene (ODA) building blocks has been developed via Sonogashira reactions under a reductive atmosphere. These central building blocks provide a new way for rapid preparation of long ODAs. In addition, we report on their optoelectronic properties which are dependent on their end cap. Finally, the formation of their radical cations, and their optical properties and reactivity towards nucleophiles are investigated.     

Pd-Cu bimetallic catalyzed domino cyclization of alpha-allenols followed by a coupling reaction: new sequence leading to functionalized spirolactams

A novel regioselective metal-catalyzed spirocyclization of alpha-allenols-cross coupling (Heck, Sonogashira, and Suzuki) reaction sequence, leading to potentially bioactive spirocyclic lactam derivatives has been developed. Precursors for the tandem spirocyclization-coupling reaction, alpha-allenols 2 a-d were obtained starting from alpha-oxolactams 1 a-c via indium-mediated Barbier-type carbonyl-allenylation reaction in aqueous media by using our previously described methodologies.     

Nicholas reactions with carboxylic acids for the synthesis of macrocyclic diolides

[reaction: see text] We have developed a new strategy for the preparation of diolides using a cascade of Nicholas reactions. The carboxylic acid nucleophiles in these reactions are virtually unstudied participants in transformations of this type. Using this methodology, a 16-membered cobalt-complexed cyclic diyne is available in 28% yield over eight steps (an average of 85% per step). We can also easily access the uncomplexed diolide in one additional step.     

Immobilization of Pd Catalysts on Mesoporous Silica for Amine- and Copper-Free Sonogashira Coupling Reactions

Immobilization of catalysts on solid supports is a promising approach to combine the advantages of heterogeneous and homogeneous catalysts. Pd(PPh₃)₂Cl₂, known as an extremely active homogeneous catalyst for the Sonogashira coupling reaction, has been immobilized on high-surface-area MCF (mesocellular foams)–type mesoporous silica powder modified with 3-aminopropyltriethoxysilane and subsequently with diphenylphosphine. The functionalized MCF-type silica and supported catalysts have been characterized by x-ray photoelectron spectroscopy (XPS), fourier transform infrared spectroscopy (FTIR), elemental analysis, nitrogen sorption porosimetry, and scanning electron microscopy (SEM). Such supported Pd catalysts have proven to be useful recyclable reagents for copper- and amine-free Sonogashira coupling reactions of haloaromatic compounds with terminal alkynes.     

原位生成的水溶性Salen-Pd配合物催化微波促进水中的C-C偶联反应

将一种水溶性Salen,N,N’-双[（5-磺酸基-2-羟基）苄基]缩N,N’-二甲基-1,2-乙二胺（L）与醋酸钯原位生成水溶性Salen-Pd配合物,该水溶性钯配合物应用于催化微波加热的水中的Heck和Sonogashira碳-碳偶联反应.在优化反应条件之后,对溴苯衍生物与乙烯衍生物的Heck偶联反应以及溴苯衍生物与苯乙炔及其衍生物之间的Sonogashira偶联反应进行了考察.发现,在优化的反应条件下,无论是Heck反应,还是Sonogashira偶联反应,都能得到很好的收率.在有机物分离之后,水相继续循环使用4次,在水相的前3次循环使用时,都获得了不错的收率.     

Bartoli indole synthesis on solid supports

[reaction: see text] Bartoli indole synthesis has been performed for the first time on solid supports. Starting from Merrifield resin, immobilization of five nitro benzoic acids was performed. Addition of four different alkenyl Grignard reagents and basic cleavage leads to substituted methyl indole carboxylates in excellent purities. Features of this reaction are the stability of halide groups, ester moieties, and tolerance of o,o'-unsubstituted nitro resins. Heck and Sonogashira reactions are also possible with immobilized indoles.     

Lewis and protic acid mediated Nicholas reactions of 3-acetoxycyclohept-1-en-4-ynedicobalt hexacarbonyl: site selectivity of nucleophile incorporation

Nicholas reactions on the cation derived from the cyclic allylic acetate alkynedicobalt complex 1 favour the γ-site kinetically for most nucleophiles, with increasing amounts of α-products in cases with greater nucleophilicity. Some regiocontrol in introduction of a specific nucleophilic fragment is possible by using different nucleophiles. Under conditions where reversibility is possible, the thermodynamically favoured site is exclusively γ-.     

Synthesis and reactions of 7-fluoro-4-methyl-6-nitro-2-oxo-2H-1-benzopyran-3-carboxylic acid: a novel scaffold for combinatorial synthesis of coumarins

7-Fluoro-4-methyl-6-nitro-2-oxo-2H-1-benzopyran-3-carboxylic acid has been prepared as a novel scaffold for combinatorial synthesis of coumarins. The scaffold has three points of diversity. The optimal conditions for its reactions with different nucleophiles in solid phase were obtained. Sixteen coumarin derivatives with different structures were designed and synthesized in solid phase to demonstrate its application as a scaffold for combinatorial synthesis of coumarins. Thirteen of these derivatives were obtained in high yields. Many of these model compounds fluoresce. Combinatorial libraries constructed with this novel scaffold may have interesting biological or physical properties.     

Ruthenium-catalyzed propargylic substitution reactions of propargylic alcohols with oxygen-, nitrogen-, and phosphorus-centered nucleophiles

The scope and limitations of the ruthenium-catalyzed propargylic substitution reaction of propargylic alcohols with heteroatom-centered nucleophiles are presented. Oxygen-, nitrogen-, and phosphorus-centered nucleophiles such as alcohols, amines, amides, and phosphine oxide are available for this catalytic reaction. Only the thiolate-bridged diruthenium complexes can work as catalysts for this reaction. Results of some stoichiometric and catalytic reactions indicate that the catalytic propargylic substitution reaction proceeds via an allenylidene complex formed in situ, whereby the attack of nucleophiles to the allenylidene C(gamma) atom is a key step. Investigation of the relative rate constants for the reaction of propargylic alcohols with several para-substituted anilines reveals that the attack of anilines on the allenylidene C(gamma) atom is not involved in the rate-determining step and rather the acidity of conjugated anilines of an alkynyl complex, which is formed after the attack of aniline on the C(gamma) atom, is considered to be the most important factor to determine the rate of this catalytic reaction. The key point to promote this catalytic reaction by using the thiolate-bridged diruthenium complexes is considered to be the ease of the ligand exchange step between a vinylidene ligand on the diruthenium complexes and another propargylic alcohol in the catalytic cycle. The reason why only the thiolate-bridged diruthenium complexes promote the ligand exchange step more easily with respect to other monoruthenium complexes in this catalytic reaction should be that one Ru moiety, which is not involved in the allenylidene formation, works as an electron pool or a mobile ligand to another Ru site. The catalytic procedure presented here provides a versatile, direct, and one-step method for propargylic substitution of propargylic alcohols in contrast to the so far well-known stoichiometric and stepwise Nicholas reaction.     

Parallel Synthesis of Alkyl Tetrazole Derivatives Using Solid Support Chemistry

The synthesis of several omega-chloroalkyl tetrazoles and their subsequent attachment to a solid support is described. Using an in situ Finkelstein reaction, a variety of nucleophiles were alkylated and then cleaved from the resin to give pure alkyl tetrazole derivatives. A sample library of 5 x 6 demonstrates the general utility of this sequence.     

Solid‐Phase Synthesis of Structurally Diverse Heterocycles by an Amide–Ketone Condensation/N‐Acyliminium Pictet–Spengler Sequence

An efficient approach for the solid‐phase synthesis of structurally diverse heterocyclic compounds is presented. Under acidic reaction conditions, peptidic levulinamides undergo intramolecular ketone–amide condensation reactions to form cyclic N‐acyliminium intermediates. In the presence of a tethered nucleophile, a second cyclization reaction results in the formation of a fused bicyclic ring system. The scope of the methodology was demonstrated by several combinations of substituted ketones and nucleophiles, the latter conveniently originating from amino acids with functionalized side chains, such as tryptophan, substituted phenylalanines, and cysteine. The cyclization sequence provides diastereomerically pure products in high yields. In one extension of the methodology, the resulting relative stereochemistry of the products enables the formation of bridged ring systems by a unique cyclative release mechanism.