A novel one-pot sulfonylation/intramolecular thia-Michael protocol is reported for the synthesis of 1,5,2-dithiazepine 1,1-dioxides. Sulfonylation between cysteine ethyl ester/cysteamine and 2-chloroethanesulfonyl chloride, followed by in situ intramolecular thia-Michael addition, was achieved and afforded the titled 1,5,2-dithiazepine-1,1-dioxide scaffolds. Diversification was demonstrated for future library synthesis.
The synthesis of a library of bicyclic sultams incorporating the 1,5,2-dithiazepine 1,1-dioxide moiety is reported. Following scaffold synthesis via a one-pot sulfonylation/intramolecular thia-Michael protocol, several additional cyclization strategies have been realized enabling access to new bicyclic sultams.
A combination of MACOS scale-out and ROMP-derived oligomeric triazole phosphates (OTPn) have been successfully utilized for the preparation of a 106-member library of triazole containing benzothiaoxazepine-1,1-dioxides. This report demonstrates the utilization of a suite of soluble OTPn reagents for facile (triazolyl)methylation of 10 MACOS-derived sultam scaffolds in purification-free process for parallel synthesis of small molecule collections for HTS.
Dihydro-2H-benzothiaoxazepine-1,1-dioxide; sultams; OTP; MACOS; ROMP; (triazolyl)methylation
The synthesis of a unique isoindoline- and tetrahydroisoquinoline (THIQ)-containing tricyclic sultam library, utilizing a Heck-aza-Michael (HaM) strategy is reported. Both isoindoline and THIQ rings are installed through a Heck reaction on a vinylsulfonamide, followed by one-pot deprotection and intramolecular aza-Michael reaction. Subsequent cyclization with either paraformaldehyde condensation or 1,1'-carbonyldiimidazole coupling generates a variety of tricyclic sultams. Overall, a 160-member library of these sultams, together with their isoindolines/THIQ and secondary sulfonamides precursors, were constructed using this strategy.
In the title compound, C15H14N2O5, the central amide C—C(=O)—N—C unit forms dihedral angles of 28.17 (13) and 26.47 (13)° with the two benzene rings, whereas the two benzene rings are almost coplanar, making a dihedral angle of 4.52 (13)°. The two methoxy and the nitro substituents are almost coplanar with their attached benzene rings, with C—O—C—C torsion angles of −1.3 (4) and −4.6 (4)°, and an O—N—C—C torsion angle of 17.1 (3)°. In the crystal, molecules are linked via C—H⋯O and N—H⋯O interactions, forming a tape running along the b axis.
The development of a ‘click, click, cy-click’ process utilizing a double aza-Michael reaction to generate functionalized 1,2,5-thiadiazepane 1,1-dioxides is reported. Optimization in flow, followed by scale out of the inter-/intramolecular double aza-Michael addition has also been realized using a microwave-assisted, continuous flow organic synthesis platform (MACOS). In addition, a facile one-pot, sequential strategy employing in situ Huisgen cycloaddition post-double aza-Michael has been accomplished, and is applicable to library synthesis.
double-aza-Michael; click; MACOS; flow; 1,2,5-thiadiazepane 1,1-dioxides
The asymmetric unit of the title compound, C7H11N3O5S, contains two independent molecules with virtually identical conformations. The imidazole rings of both molecules are essentially planar (r.m.s. deviations = 0.0019 and 0.0038 Å), with a dihedral angle 9.25 (19)° between them. The nitro groups are oriented at 4.5 (2) and 6.44 (13)° with respect to the imidazole rings. In the crystal, molecules are linked to form a three-dimensional framework by C—H⋯O and C—H⋯N hydrogen bonds.
The utilization of a monomer-on-monomer (MoM) intramolecular Mitsunobu cyclization reaction employing norbornenyl-tagged (Nb-tagged) reagents is reported for the synthesis of benzofused thiadiazepine-dioxides. Facile purification was achieved via ring-opening metathesis (ROM) polymerization initiated by one of three metathesis catalyst methods: (i) free metathesis catalyst, (ii) surface-initiated catalyst-armed silica, or (iii) surface-initiated catalyst-armed Co/C magnetic nanoparticles.
In the title compound, C8H6N4O3, the ketone [C—C(=O)—C] and nitro groups are tilted with respect to the benzene ring by 18.92 (6) and 24.11 (15)°, respectively. In the crystal, molecules are linked into interwoven chains running parallel to the  direction by C—H⋯N hydrogen bonds and weak π–π stacking interactions, with centroid–centroid separations of 3.897 (3) Å.
In the molecule of the title compound, C9H9N3O, the angle formed by the least-squares line through the azide group with the normal to the plane of the benzene plane ring is 46.62 (16)°. The crystal structure features C—H⋯O hydrogen bonds, which link the molecules into zigzag chains running parallel to .
Soluble, high-load ROMP-derived oligomeric triazole phosphates (OTP) are reported for application as efficient triazolating reagents of nucleophilic species. Utilizing a “Click”-capture, ROMP, release protocol, the efficient and purification free, direct triazolation of N-, O- and S-nucleophilic species was successfully achieved. A variety of OTP derivatives were rapidly synthesized as free-flowing solids on multi-gram scale from commercially available materials.
The crystal structure of the title compound, C8H6FN3O, is stabilized by C—H⋯O hydrogen bonds, which link the molecules into chains running parallel to the a axis.
In the title compound, C13H12BrN3O4, the dihedral angle between the benzene and imidazole rings is 30.6 (2)°. In the crystal, molecules are linked into chains parallel to  by C—H⋯O hydrogen bonds. The crystal packing is further consolidated by π–π interactions [centroid–centroid distance = 3.482 (2) Å].
In the title compound, C13H12FN3O4, the dihedral angle between the benzene and imidazole rings is 32.77 (12)°. In the crystal, molecules are linked into a three-dimensional network by C—H⋯O hydrogen bonds.