Microwave-assisted solid-phase synthesis of hydantoin derivatives

A microwave-assisted synthesis of 3,5- and 1,3,5-substituted hydantoins starting from various resins for solid-phase combinatorial chemistry has been developed. The hydantoins were synthesized from pre-loaded resins with amino acids via treatment with isocyanate or phenylisocyanate and subsequent intramolecular cyclization. Both reactions were performed under microwave irradiation. We studied the cyclative cleavage leading to hydantoin compounds dependent on the nature of the amino acid and the nucleofuge properties of the resin.     

Traceless solid-phase synthesis of 1,4-disubstituted-6-nitro-3,4-dihydro-1H-quinoline-2-ones

A traceless solid-phase route to 1,4-disubstituted-6-nitro-3,4-dihydro-1H-quinazolin-2-ones is described. N-Alloc-3-amino-3-(2-fluoro-5-nitrophenyl)propionic acid was tethered to Rink resin via its carboxylic group. The protected amine was coupled with an organic acid after Alloc-deprotection and the arylfluorine was displaced with a primary amine to generate a resin-bound aniline with two diversity points. The aniline was released via cleavage to produce the desired products in high yield and purity.     

Facile solid-phase synthesis of 2,3-disubstituted 6H-pyrano[2,3-f]benzimidazole-6-ones

We report herein the facile solid-phase synthesis of 2,3-disubstituted 6H-pyrano[2,3-f]benzimidazole-6-ones using 7-fluoro-4-methyl-6-nitro-2-oxo-2H-1-benzopyran-3-carboxylic acid as the scaffold. The fluorine of the resin-bound scaffold was first replaced by a primary amine. Reduction of the nitro group with tin(II) chloride afforded an o-dianilino intermediate that was treated with an aldehyde followed by the addition of 2,3-dichloro-5,6-dicyanoquinone (DDQ). 2,3-Disubstituted 6H-pyrano[2,3-f]benzimidazole-6-ones were obtained in high purity and good yield after cleavage.     

A cyclative cleavage approach to solid-phase synthesis of annulated pyrimidinones using Baylis-Hillman derivatives

An efficient and robust solid-phase synthesis of 6-substituted-2,5,6,8-tetrahydro-3H-imidazo[1,2-a]pyrimidin-7-ones, 3-substituted-1,3,4,6,7,8-hexahydro-pyrimido[1,2-a]pyrimidin-2-ones and 3-substituted-3,4,6,7,8,9-hexahydro-1H-pyrimido[1,2-a][1,3] diazepin-2-ones from the acetates of Baylis-Hillman adducts employing Michael addition of diamines followed by intramolecular cyclization with cyanogen bromide and, finally, base promoted cyclative cleavage has been developed. The procedure is validated through an automated parallel synthesis of a small library of fourteen compounds of the 3H-imidazo[1,2-a]pyrimidin-7-one series.     

Cyclopropanation of 3,4-dihydro-1 H-benzo[e][1,4]diazepine-2,5-diones

A two step parallel synthesis protocol for the preparation of 1N-substituted spirobenzodiazepineones is described. Treatment of 4-methyl-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione with a series of alkyl halides using a microwave-assisted heating protocol provided N-derivatized compounds, which were transformed to the corresponding cyclopropylamines employing modified Kulinkovich-type reaction conditions. X-ray structural analysis gave conclusive evidence of the newly created spiro centre and revealed a significant flattening of the seven-membered ring system compared with the benzodiazepinedione system providing a characteristically different pattern of bond exit vectors. The physicochemical parameters log D, pK_a, solubility and membrane permeability of both cyclopropanated and precursor compounds were assessed.     

Synthesis of 1H-pyrazolo[3,4-d]pyrimidines via solid-phase Aza-Wittig/electrocyclic ring closure reaction

An elegant solid-phase synthetic route of pyrazolo[3,4-d]pyrimidine derivatives via Aza-Wittig/electrocyclic ring closure reaction was developed and validated. By manipulating the R group from the primary amine building block, one can easily prepare the library of pyrazolo[3,4-d]pyrimidine derivatives.     

Solid-phase synthesis of 4H-2-(3-hydroxy-4-methoxyphenyl)-naphtho[1,2-b]pyran-1-one

An effective solid-phase preparation of the pharmaceutically interesting 4H-2-(3-hydroxy-4-methoxyphenyl)-naphtho[1,2-b]pyran-1-one system from an anchored bisarylacetylene is described.     

A convenient semicarbazide resin for the solid-phase synthesis of peptide ketones and aldehydes

Use of a semicarbazide resin for the solid-phase preparation of peptide ketones and aldehyde led to optimal results in terms of both purity of the final product and overall yield. This resin was prepared without complication by activation of the commercial available aminomethyl polystyrene with CDI at room temperature, followed by treatment with tert-butyl carbazate. Furthermore, the TNBSA colorimetric assay has been adapted for checking the incorporation of the carbonyl moiety onto hydrazine-based resins.     

Solid-phase synthesis of 2-cyanoquinazolin-4(3H)-one and 2,3-dihydrooxazolo[2,3-b]quinazolin-5-one derivatives utilizing resin-bound anthranilic acid derivatives

We were able to obtain 2-cyanoquinazolin-4(3H)-ones 11 in 35-60% four-step overall isolated yields and 2,3-dihydrooxazolo[2,3-b]quinazolin-5-ones 12 in 20-71% four-step overall isolated yields utilizing polymer-bound anthranilic acid derivatives 1, and 6-amino-2-cyanoquinazolin-4(3H)-ones 19 in 30-44% six-step overall isolated yields making use of anthranilic acid derivative resin 2 via dithiazole resins 10 and 17. The reactions on solid phase were monitored by single bead ATR-FTIR spectroscopic method.     

A new enlargement methodology for the preparation of 2H-1- and 2H-3-benzazepin-2-one derivatives

An investigation of the one-carbon homologation of some 1-tribromomethyl-isoquinoline and 2-tribromomethyl-quinoline derivatives was conducted. Under the influence of an aqueous solution of silver nitrate in the presence of a nucleophilic species (MeOH, H₂O, EtNH₂), these derivatives led to the respective expanded heterocycles, 2H-1- and 2H-3-benzazepin-2-one derivatives. A mechanism for this novel ring enlargement involving initial formation of an aziridinium, and its subsequent opening to form a stabilized benzylic carbocation, is proposed to explain the results.     

A new efficient method for the synthesis of 3,4-dihydro-2H-1,4-benzoxazines via iodocyclization

An efficient approach for the synthesis of 3,4-dihydro-2H-1,4-benzoxazine derivatives is described by molecular iodine- mediated cyclization. The reaction condition is very simple, offers easy isolation, and affords good to excellent yields of the products.     

Synthesis of substituted 4-(3-alkyl-1,2,4-oxadiazol-5-ylmethyl)-3,4-dihydro-2H-1,4-benzoxazines and 4-(1H-benzimidazol-2-ylmethyl)-3,4-dihydro-2H-1,4-benzoxazines

Substituted 2H-1,4-benzoxazines were synthesized from substituted 2-amino phenols and 1,2-dibromoethane using K₂CO₃ in good to excellent yields. The cyclized products were further reacted with alkyl bromides to obtain the desired N-substituted 3,4-dihydro-2H-1,4-benzoxazines.     

A Visual Tagging Process for Mix and Sort Combinatorial Chemistry

Colored glass beads and caps provide a simple color-coding strategy adapted to porous plastic containers and allow visual identification of the individual constituents of combinatorial libraries.     

Environment-friendly organic synthesis using bismuth compounds. Bismuth triflate catalyzed synthesis of substituted 3,4-dihydro-2H-1-benzopyrans

A highly catalytic method for the synthesis of dihydrobenzopyrans from salicylaldehydes has been developed. An extension of this method to the synthesis of a pyrano[2,3,b]benzopyran has also been achieved. Bi(OTf)₃·xH₂O (1 < x < 4) (0.1 mol%) smoothly catalyzes the condensation of substituted salicylaldehydes with 2,2-dimethoxypropane to give the corresponding substituted 3,4-dihydro-2H-1-benzopyrans as a mixture of diastereomers (9:1) in moderate yields. The relative configuration of the methoxy groups in the two diastereomers was established by NOE experiments. The advantages of this method include the use of an easy to handle, inexpensive and relatively non-toxic catalyst.     

1,2-Dihydro-2-thioxo-4H-3,1-benzothiazin-4-one: formation from carbon disulfide and isatoic anhydride

The reaction of isatoic anhydride (1) with carbon disulfide at room temperature unexpectedly afforded 1,2-dihydro-2-thioxo-4H-3,1-benzothiazin-4-one (2). The use of ¹³C-labeled carbon disulfide elucidated that CS₂ was entirely incorporated into the product.     

New 2-functionalized 2H-3,4-dihydro-1,4-benzothiazin-3-ones and their application in the synthesis of spiro heterocycles

The reaction of 2-chloro-3,4-dihydro-2H-1,4-benzothiazin-3-ones 1 with enamines is an efficient synthetic method to produce 2-substituted derivatives. The resulting bifunctional compounds such as 6a,b, 7c,d and 8b react with hydrazines to furnish the spiro derivatives of N-aminopyrrole or 3-pyridazinone depending on the direction of the primary nucleophilic attack and the nature of the nucleophile. Under the reaction conditions, spiro pyridazinones 13 are converted into the 3-pyridazinone-4-carboxylic acid derivatives 9 via the 1,4-thiazine ring opening.     

Synthesis of 4-N-alkyl and ribose-modified AICAR analogues on solid support

Herein, we report the solid-phase synthesis of several 5-aminoimidazole-4-(N-alkyl)carboxamide-1-ribosides (4-N-alkyl AICARs) and the corresponding 2′,3′-secoriboside derivatives. The method uses the N-1-dinitrophenyl-inosine 5′-bonded to a solid support. This inosine derivative has the C-2 of the purine base strongly activated towards the attack of N-nucleophiles thus allowing the preparation of several N-1 alkylated inosine supports from which a small library of 4-N-alkyl AICAR derivatives has been synthesized. A set of new 4-N-alkyl AICA-2′,3′-secoriboside derivatives have also been obtained in high yields by solid-phase cleavage of the 2′,3′-ribose bond.     

Suzuki coupling reaction for the solid-phase preparation of 5-substituted nicotinic acid derivatives

The application of the Suzuki coupling reaction to the preparation of small combinatorial libraries using 5-bromonicotinic acid as a scaffold onto three different types of solid support (Wang, Rink, and BAL resin) is described.     

Novel synthesis of 2,2-dialkyl-3-dialkylamino-2,3-dihydro-1H-naphtho[2,1-b]pyrans

2,2-Dialkyl-3-dialkylamino-2,3-dihydro-1H-naphtho[2,1-b]pyrans were prepared from 2-naphthol, a secondary amine, and 3-hydroxy-2,2-dialkylpropanal in the presence of a catalytic amount of p-toluenesulfonic acid. This one-pot reaction involves retro-aldol disintegration of 3-hydroxy-2,2-dialkylpropanal followed by formation of a Mannich base intermediate from 2-naphthol, a secondary amine, and formaldehyde (retro-aldol product). This Mannich base then disproportionates into a quinone methide intermediate and the secondary amine is regenerated. It then forms an enamine intermediate with 2,2-dialkylacetaldehyde (another retro-aldol product). Finally, the quinone methide intermediate undergoes electrocyclic ring closure with enamines to produce the title compounds.