Azide based routes to tetrazolo and oxadiazolo derivatives of pyrrolobenzodiazepines and pyrrolobenzothiadiazepines

N-Alkylation and Aminohydroxylation of 2-Azidobenzenesulfonamide Gives a Pyrrolobenzothiadiazepine Precursor Whereas Attempted N-Alkylation of 2-Azidobenzamide Gives Benzotriazinones and Quinazolinones

“…10,24 2-Azidobenzenesulfonamide 9 was synthesized by reacting the sulfonyl chloride 10 with ammonia or from the diazotization and azidation of 2-aminobenzenesulfonamide 15 , which was produced from 2-nitrobenzenesulfonyl chloride 13 via the sulfonamide 14 . 10,24…”

“…2−4 PBD derivatives have entered phase II clinical trials as antitumor compounds 5 and have also attracted attention as antibiotics with a novel mode of action. 6 Pyrrolo[1,2- b ][1,2,5]benzothiadiazepines (PBTDs) 2 are attracting interest as PBD analogues, 7 non-nucleosidic reverse transcriptase inhibitors, 8 antischistosomals, 9 and Glut-1 transporter inhibitors (compound 3 ) 10 and are emerging as a potential treatment for chronic leukemia (compound 4 ). 11−13 …”

An Update on the Synthesis of Pyrrolo[1,4]benzodiazepines

“…In the same year, Hemming et al [70] reported the synthesis of azido-oxime 167 in order to study the potential of the azide to oxime intramolecular cycloaddition (Scheme 28). Acyl substitution of 2-azidobenzoyl chloride 163 by ( S )-prolinol 164 afforded amide 165 that was subjected to Swern oxidation to yield azido-aldehyde 166 .…”

Intramolecular Azide to Alkene Cycloadditions for the Construction of Pyrrolobenzodiazepines and Azetidino-Benzodiazepines

“…The reaction was diluted with water (20 mL), the ethereal layer was separated and the aqueous phase was extracted with ether (3 × 10 mL). The combined organics were dried (MgSO4), filtered, concentrated under reduced pressure and purified by silica chromatography Pyrrolobenzodiazepine (25) and aziridinopyrrolobenzodiazepine (16). The alkene 14 (78.0 mg, 0.32 mmol) was dissolved in CHCl3 (10 mL) and heated at reflux under an inert atmosphere of nitrogen for 16 h whilst being monitored by TLC (EtOAc/Hex; 3:2).…”

“…The replacement of the PBD tertiary amide with a sulfonamide leads to the pyrrolobenzothiadiazepines (PBTDs) which are synthetic analogues of the PBDs [22]. The PBTDs have received much less attention than the PBDs, but it is known that PBTDs 7-9 are useful as non-nucleosidic reverse transcriptase inhibitors [23], potent leukemia cell-line inhibitors [24] and Glut-1 transporter inhibitors with chemotherapeutic potential [25], respectively. We reported previously [26] that the 1,2,3-triazolo-fused PBDs and PBTDs 11 ( Figure 2) are available via intramolecular azide to alkyne 1,3-dipolar cycloaddition of 1-(azidoaryl)-2-alkynyl pyrroles 10, and have recently shown [25] that the 1-(azidoaryl)-2-cyano pyrroles 12 give the 1,2,3,4-tetrazolo-fused PBD and PBTD systems 13.…”