Solid-Phase Parallel Synthesis of N‑Substituted-2-aminothiazolo[4,5‑<i>b</i>]pyrazine Derivatives via Tandem Reaction of Isothiocyanate Terminated Resin with <i>o</i>‑Bromo-2-Aminopyrazines

A novel solid-phase synthesis methodology of N-substituted-2-aminothiazolo­[4,5-<i>b</i>]­pyrazine derivatives was developed. The key step in this synthesis strategy is the tandem reaction of isothiocyanate terminated resin <b>2</b> with <i>o</i>-bromo-2-aminopyrazine, affording cyclized 2-aminothiazolo­[4,5-<i>b</i>]­pyrazine resin <b>4</b>. To increase the diversity of our library, Suzuki coupling reaction was performed at the position C6. Further functionalization of 2-aminothiazolo­[4,5-<i>b</i>]­pyrazine core skeleton with various electrophiles such as alkyl halides, acyl chlorides, and sulfonyl chlorides and cleavage from the resin with TFA in DCM generated <i>N</i>-alkyl-, <i>N</i>-acyl-, and <i>N</i>-sulfonyl-2-aminothiazolo­[4,5-<i>b</i>]­pyrazine derivatives. The physicochemical properties and the polar surface areas of synthesized compounds were evaluated

Application of Thio-Ugi Adducts for the Preparation of Benzo[<i>b</i>]thiophene and S‑Heterocycle Library via Copper Catalyzed Intramolecular C–S Bond Formation

Fused heterocycles, such as benzo­[<i>b</i>]­thiophene, thiochroman, benzo­[<i>b</i>]­[1,4]­thiazine, and 1,4-benzothiazepine were generated from thio-Ugi adducts containing a thioamide group through copper-catalyzed intramolecular C–S bond formation under microwave irradiation

Construction of 1,3,4-Oxadiazole and 1,3,4-Thiadiazole Library with a High Level of Skeletal Diversity Based on Branching Diversity-Oriented Synthesis on Solid-Phase Supports

An efficient solid-phase synthetic route for the construction of 1,3,4-oxadiazole and 1,3,4-thiadiazole libraries based on branching diversity-oriented synthesis (DOS) has been developed in this study. The core skeleton resins, 1,3,4-oxadiazole and 1,3,4-thiadiazole, were obtained through desulfurative and dehydrative cyclizations of thiosemicarbazide resin, respectively. Various functional groups have been introduced to the core skeleton resins, such as aryl, amine, amide, urea, thiourea, and an amino acid. Most of the libraries were purified by simple trituration without extraction or column chromatography after cleavage of the products from the solid-supported resin. As a result, we obtained high yields of pure 1,3,4-oxadiazole and 1,3,4-thiadiazole derivatives (total numbers = 128). Finally, we confirmed the drug-like properties of our library by calculation of physicochemical properties, displays of the skeletal diversities of the library in 3D-space, and occupation of a broad range of areas by their functional groups

Synthesis of 2‑Alkoxy/Thioalkoxy Benzo[<i>d</i>]imidazoles and 2‑Thione Benzo[<i>d</i>]imidazoles via a Phase-Based, Chemoselective Reaction

2-Alkoxy/thioalkoxy benzo-[<i>d</i>]-imidazole and 2-thione benzo-[<i>d</i>]-imidazole libraries were constructed in solution phase and on solid phase, respectively. The key step in this work is the phase-based chemoselective reaction of the 2-mercaptobenzo-[<i>d</i>]-imidazole intermediate with benzyl chloride (solution phase) and Merrifield resin (solid phase). In the solution-phase case, benzyl chloride reacted with the thiol group of 2-mercaptobenzo-[<i>d</i>]-imidazole, whereas in the solid-phase case, Merrifield resin was introduced at an internal amine group of benzo-[<i>d</i>]-imidazole. To afford the desired 2-alkoxy/thioalkoxy benzo-[<i>d</i>]-imidazole analogues, we used various alkyl halides, alcohols, and thiols in solution phase, and to obtain 2-thione benzo-[<i>d</i>]-imidazole derivatives on solid phase, we used diverse alkyl halides and boronic acids. Finally, to measure the drug potential to be orally active and the molecular diversity in three-dimensional (3D) space, we calculated physicochemical properties and displayed energy-minimized 3D structures. As a result, the libraries from solution phase and solid phase show distinct features in physicochemical properties and skeletal diversities in 3D space

Solid-Phase Synthesis of 1,3,4-Thiadiazole Derivatives via Desulfurative Cyclization of Thiosemicarbazide Intermediate Resin

A 1,3,4-thiadiazole library was constructed by solid-phase organic synthesis. The key step of this solid-phase synthesis involves the preparation of polymer-bound 2-amido-5-amino-1,3,4-thiadiazole resin by the cyclization of thiosemicarbazide resin using <i>p</i>-TsCl as the desulfurative agent, followed by the functionalization of the resin by alkylation, acylation, alkylation/acylation, and Suzuki coupling reactions. Both the alkylation and acylation reactions chemoselectively occurred at the 2-amide position of 2-amido-5-amino-1,3,4-thiadiazole resin and the 5-amine position of 2-amido-5-amino-1,3,4-thiadiazole resin, respectively. Finally, these functionalized 1,3,4-thiadiazole resins were treated with trifluoroacetic acid in dichloromethane, affording diverse 1,3,4-thiadiazole analogs in high yields and purities. The 1,3,4-thiadiazole analogs show a different distribution of physicochemical and biological properties compared with our previously constructed 1,3,4-oxadiazole and 1,3,4-thiadiazole libraries in a range of orally available drug properties

A Highly Efficient Diversification of 2‑Amino/Amido-1,3,4-oxadiazole and 1,3,4-Thiadiazole Derivatives via Reagent-Based Cyclization of Thiosemicarbazide Intermediate on Solid-Phase

A 2-amino/amido-1,3,4-oxadiazole and 1,3,4-thiadiazole library has been constructed on solid-phase organic synthesis. The key step on this solid-phase synthesis involves the preparation of polymer-bound 2-amino-1,3,4-oxadiazole and 1,3,4-thiadiazole core skeleton resin by cyclization of thiosemicarbazide with EDC·HCl and <i>p</i>-TsCl, respectively. The resulting core skeleton undergoes functionalization reaction with various electrophiles such as alkyl halides, and acid chlorides to generate <i>N</i>-alkylamino and <i>N</i>-acylamino-1,3,4-oxadiazole, and 1,3,4-thiadiazole resin, respectively. Finally, the 2-amino and 2-amido-1,3,4-oxadiazole and 1,3,4-thiadiazole library was then generated in good yields and high purities by cleavage of the respective resin under trifluoroacetic acid­(TFA) in dichloromethane­(DCM). The constructed library shows reasonable, oral bioavailability drug properties as determine by using the Lipinski’s Rule and similar parameters

Regioselective Synthesis of 2‑Amino-Substituted 1,3,4-Oxadiazole and 1,3,4-Thiadiazole Derivatives via Reagent-Based Cyclization of Thiosemicarbazide Intermediate

A regioselective, reagent-based method for the cyclization reaction of 2-amino-1,3,4-oxadiazole and 2-amino-1,3,4-thiadiazole core skeletons is described. The thiosemicarbazide intermediate <b>3</b> was reacted with EDC·HCl in DMSO or <i>p</i>-TsCl, triethylamine in <i>N</i>-methyl-2-pyrrolidone to give the corresponding 2-amino-1,3,4-oxadiazoles <b>4</b> and 2-amino-1,3,4-thiadiazoles <b>5</b> through regioselcective cyclization processes. The regioselectivity was affected by both R¹ and R² in <i>p</i>-TsCl mediated cyclization. It is shown in select sets of thiosemicarbazide <b>3</b> with R¹(benzyl) and R²(phenyl). 2-Amino-1,3,4-oxadiazole <b>4</b> was also shown in the reaction of <i>p</i>-TsCl mediated cyclization. The resulting 2-amino-1,3,4-oxadiazole and 2-amino-1,3,4-thiadiazole core skeleton are functionalized with various electrophiles such as alkyl halide, acid halides, and sulfornyl chloride in high yields

Novel Solid-Phase Parallel Synthesis of <i>N</i>‑Substituted-2-aminobenzo [<i>d</i>]thiazole Derivatives via Cyclization Reactions of 2‑Iodophenyl Thiourea Intermediate Resin

A novel solid-phase methodology has been developed for the synthesis of <i>N</i>-alkyl, <i>N</i>-acyl, and <i>N</i>-sulfonyl-2-aminobenzo­[<i>d</i>]­thiazole derivatives. The key step in this procedure involves the preparation of polymer-bound 2-aminobenzo­[<i>d</i>]­thiazole resins <b>5</b> by cyclization reaction of 2-iodophenyl thiourea resin <b>3</b>. The resin-bound 2-iodophenyl thiourea <b>3</b> is produced by addition of 2-iodophenyl isothiocyanate <b>2</b> to the amine-terminated linker amide resin <b>1</b>. These core skeleton 2-aminobenzo­[<i>d</i>]­thiazole resins <b>5</b> undergo functionalization reactions with various electrophiles, such as alkyl halides, acid chlorides, and sulfonyl chlorides to generate <i>N</i>-alkyl, <i>N</i>-acyl, and <i>N</i>-sulfonyl-2-aminobenzo­[<i>d</i>]­thiazole resins <b>6</b>, <b>7</b>, and <b>8</b>, respectively. Finally, <i>N</i>-alkyl, <i>N</i>-acyl, and <i>N</i>-sulfonyl-2-aminobenzo­[<i>d</i>]­thiazole derivatives <b>9</b>, <b>10</b>, and <b>11</b> are then generated in good yields and purities by cleavage of the respective resins <b>6</b>, <b>7</b>, and <b>8</b> using trifluoroacetic acid (TFA) in dichloromethane (DCM)

Construction of Druglike 2‑Amido Benzo[<i>d</i>]imidazole Analogues via Desulfurative Cyclization of Thiourea Intermediate Resin on Solid-Phase

A 2-amido benzo­[<i>d</i>]­imidazole library has been constructed by solid-phase synthesis. The key step of this solid-phase synthesis involves the preparation of polymer-bound 2-amino benzo­[<i>d</i>]­imidazole resin through desulfurative cyclization of thiourea resin using 2-chloro-1,3-dimethylimidazolinium chloride and <i>N</i>,<i>N</i>-diisopropylethylamine in dichloromethane (DCM), and the resin is then functionalized by acylation at the 2-amine position to afford 2-amidobenzo­[<i>d</i>]­imidazole resin. In the case of 2-amidobenzo­[<i>d</i>]­imidazole resin having a <i>p</i>-I or <i>m</i>-NO₂, the resin was further functionalized by Suzuki/Sonogashira-coupling (<i>p</i>-I) and reduction to the primary amine (<i>m</i>-NO₂) followed by acylation. Finally, the functionalized 2-amido-benzo­[<i>d</i>]­imidazole resin was cleaved from the polymer support by treatment with a cocktail of trifluoroacetic acid and DCM. As a result, we obtained 2-amidobenzo­[<i>d</i>]­imidazole analogues in high yield and good purities