Solid-Phase Synthesis of Trisubstituted Benzo[1,4]-Diazepin-5-one Derivatives

Solid-phase synthesis of 3,4-dihydro-benzo­[e]­[1,4]­diazepin-5-ones with three diversity positions is described. Various primary amines were used as the starting material and immobilized on the polystyrene resin equipped with different acid-labile linkers. Polymer-supported amines were converted to α-aminoketones with the use of their sulfonylation with the 4-nitrobenzensulfonylchoride (4-Nos-Cl) and subsequent alkylation with α-bromoketones. After the cleavage of the 4-Nos group, the corresponding α-aminoketones were acylated with various <i>o</i>-nitrobenzoic acids. Reduction of the nitro group followed by spontaneous on-resin ring closure gave the target immobilized benzodiazepines. After acid-mediated cleavage the products were obtained in very good crude purity and satisfactory yields, which makes the developed method applicable for simple library synthesis of the corresponding derivatives in a combinatorial fashion

Ring Contraction of 2,5-Dihydrobenzo[<i>f</i>][1,2,5]thiadiazepine 1,1-Dioxides: Access to 4<i>H</i>‑Benzo[<i>b</i>][1,4]thiazine 1,1-Dioxides

We report an efficient synthesis of 4<i>H</i>-benzo­[<i>b</i>]­[1,4]­thiazine 1,1-dioxides via unprecedented ring contraction of 2,5-dihydrobenzo­[<i>f</i>]­[1,2,5]­thiadiazepine 1,1-dioxides under mild conditions involving carbon–sulfur bond formation. 2,5-Dihydrobenzo­[<i>f</i>]­[1,2,5]­thiadiazepine 1,1-dioxides are easily accessible from commercially available building blocks, including Fmoc-protected amino acids, 2-nitrobenzenesulfonyl chlorides, and bromo ketones. Benzothiazine 1,1-dioxides represent pharmacologically relevant derivatives with biological, medicinal, and industrial applications

Solid-Phase Synthesis of Anagrelide Sulfonyl Analogues

Simple solid-phase synthesis of 3,10-dihydro-2<i>H</i>-benzo­[e]­imidazo­[1,2-<i>b</i>]­[1,2,4]­thiadiazin-2-one 5,5-dioxides is described, with Fmoc-α-amino acids and 2-nitrobenzenesulfonyl chlorides (2-NosCls) being the key building blocks. Fmoc-α-amino acids were immobilized on Wang resin and transformed to the corresponding 2-nitrobenzenesulfonamides in two steps. After reduction of the nitro group, Fmoc-thioureas were synthesized followed by cyclization of the 1,2,4-benzothiadiazine-1,1-dioxide scaffold with diisopropylcarbodiimide (DIC). Cleavage of the Fmoc protecting group followed by spontaneous cyclative cleavage gave the target products in excellent crude purity

Traceless Solid-Phase Synthesis of Trisubstituted Quinazolines

A traceless polymer-supported synthesis of 4-benzoylquinazolines was developed using the following commercially available building blocks: Fmoc-α-amino acids, 2-nitrobenzensulfonyl chlorides and α-bromoacetophenones. The acyclic intermediates underwent base-catalyzed rearrangement involving C–C and N–N bond formation followed by ring expansion and yielded resin-bound dihydroquinazoline-2-carboxylic acids. After they were released from the resin by treatment with trifluoroacetic acid, base-mediated decarboxylation produced the target quinazolines in moderate-to-high yields and purities

Stereoselective Polymer-Supported Synthesis of Morpholine- and Thiomorpholine-3-carboxylic Acid Derivatives

Herein we report the polymer-supported synthesis of 3,4-dihydro-2<i>H</i>-1,4-oxazine-3-carboxylic acid derivatives using immobilized Fmoc-Ser­(<i>t</i>Bu)-OH and Fmoc-Thr­(<i>t</i>Bu)-OH as the starting materials. After the solid-phase-synthesis of <i>N</i>-alkyl-<i>N</i>-sulfonyl/acyl intermediates, the target dihydrooxazines were obtained using trifluoroacetic acid-mediated cleavage from the resin. This approach was also studied for the preparation of dihydrothiazines from immobilized Fmoc-Cys­(Trt)-OH. Inclusion of triethylsilane in the cleavage cocktail resulted in the stereoselective formation of the corresponding morpholine/thiomorpholine-3-carboxylic acids. Stereochemical studies revealed the specific configuration of the newly formed stereocenter and also the formation of stable <i>N</i>-acylmorpholine rotamers