Florencio Zaragoza

Palladium-Catalyzed Trifluoromethylation of (Hetero)Arenes with CF3 Br.

The CF3 group is an omnipresent motif found in many pharmaceuticals, agrochemicals, catalysts, materials, and industrial chemicals. Despite well-established trifluoromethylation methodologies, the straightforward and selective introduction of such groups into (hetero)arenes using available and less expensive sources is still a major challenge. In this regard, the selective synthesis of various trifluoromethyl-substituted (hetero)arenes by palladium-catalyzed C-H functionalization is herein reported. This novel methodology proceeds under comparably mild reaction conditions with good regio- and chemoselectivity. As examples, trifluoromethylations of biologically important molecules, such as melatonin, theophylline, caffeine, and pentoxifylline, are showcased.

Solid-phase synthesis of substituted 1,2,3-triazoles

Abstract Diversely substituted 1,2,3-triazoles have been synthesized on a solid support. A resin-bound 3-oxobutyramide could be effectively condensed with primary aliphatic amines. The resulting 3-amino-2-butenoic acid amides were then cyclized by treatment with tosyl azide in the presence of a tertiary amine. Acidolytic cleavage from the support yielded the corresponding 1,2,3-triazoles in purities up to 82% (HPLC).

Solid-phase synthesis of N-hydroxyindoles and benzo[c]isoxazoles by C-arylation of substituted acetonitriles and 1,3-dicarbonyl compounds with polystyrene-bound aryl fluorides

The reaction of different carbon nucleophiles with resin-bound 4-fluoro-3-nitrobenzoic acid and the chemistry of the resulting products has been investigated. Treatment of Wang resin bound 4-fluoro-3-nitrobenzoic acid with 1,3-dicarbonyl compounds or acceptor-substituted acetonitriles, followed by reduction of the nitro group and cleavage from the support, led to substituted 1-hydroxy-6-indolecarboxylic acids. Treatment of polystyrene-bound 4-fluoro-3-nitrobenzoic acid amides with arylacetonitriles led to 4-aroyl-3-nitrobenzoic acid derivatives, which upon reduction with tin(II) chloride yielded benzo[c]isoxazoles.

SOLID-PHASE SYNTHESIS OF SUBSTITUTED 3-AMINOTHIOPHENES AND 2-METHYLENE-2,3-DIHYDROTHIAZOLES

Abstract Diversely substituted 3-aminothiophenes and 2-methylene-2,3-dihydrothiazoles have been synthesized on a solid support. A resin-bound cyanoacetamide reacted efficiently with aliphatic or aromatic isothiocyanates in DMF/DBU. The resulting intermediates were then alkylated at sulphur with different α-haloketones under acidic conditions. Acidolytic cleavage from the support yielded 2-methylene-2,3-dihydrothiazoles in purities up to 88% (HPLC). Alternatively, treatment of the resin-bound, S-alkylated intermediates with DBU, followed by acidolytic cleavage, yielded 3-aminothiophene derivatives in purities up to 91 % (HPLC).

(Cyanomethyl)trimethylphosphonium iodide as reagent for the intermolecular S-alkylation of thiols with alcohols

Abstract Treatment of mixtures of thiols and primary aliphatic alcohols with (cyanomethyl)trimethylphosphonium iodide leads to the clean formation of unsymmetric thioethers. The required phosphonium iodide is simple to prepare and stable towards air and moisture. This new synthesis of thioethers yields crude products of high purity and should be suitable for parallel solution-phase chemistry.

Generation of rhodium carbenoids on a polystyrene support and their OH-insertion reaction with alcohols

Abstract A rhodium carbenoid attached to a polystyrene resin was generated by treatment of a resinbound diazoacetamide with rhodium(II) acetate in dichloromethane. This immobilized reactive species underwent OH-insertion reactions with alcohols to yield ethers of high purity. A rhodium carbenoid attached to a polystyrene resin was generated and shown to undergo OH-insertion reactions with alcohols to yield ethers of high purity. Download : Download full-size image

Sequential Nucleophilic Substitution: A Powerful Strategy for the Solid-Phase Production of Diverse Compound Libraries.

Polyfunctionalized, unprotected reagents (e.g. amines and thiols) can be used in the production of highly diverse compound libraries by performing sequential nucleophilic substitutions on support-bound polyelectrophiles (see scheme). The procedure reported here enables the efficient preparation of new beta-alanine derivatives which are suitable for lead discovery. E*=polyelectrophile, *=solid support.

Solid phase synthesis of cyanoacetamidines: Fast access to potential bioisosteres of acceptor-substituted guanidines

Abstract A synthesis of cyanoacetamidines has been developed, which can be realized on solid support. Reaction of resin-bound cyanoacetic acid with aromatic isothiocyanates yielded thioamides, which could be condensed with primary or secondary aliphatic or aromatic amines in the presence of EDC to yield ketene aminals. TFA-mediated cleavage from the support with concomitant decarboxylation gave cyanoacetamidine trifluoroacetates in purities up to 83% (HPLC, 254 nm).

Intermolecular N-alkylation of amines under conditions of the Mitsunobu reaction: a new solid-phase synthesis of tertiary benzylamines

Abstract Support-bound secondary aliphatic amines can be N -benzylated with benzyl alcohols under the standard conditions of the Mitsunobu reaction if the amine is converted into the corresponding ammonium iodide salt prior to Mitsunobu reaction.

One-Step Conversion of Methyl Ketones to Acyl Chlorides

Treatment of aromatic and heteroaromatic methyl ketones with sulfur monochloride and catalytic amounts of pyridine in refluxing chlorobenzene leads to the formation of acyl chlorides. Both electron-rich and electron-poor aryl methyl ketones can be used as starting materials. The resulting C1-byproduct depends on the precise reaction conditions chosen.