Harnessing sulfur and nitrogen in the cobalt(iii)-catalyzed unsymmetrical double annulation of thioamides: probing the origin of chemo- and regio-selectivity

Abstract

An unconventional cobalt(III)-catalyzed one-pot domino double annulation of aryl thioamides with unactivated alkynes is presented. Sulfur (S), nitrogen (N), and o,o'-C-H bonds of aryl thioamides are involved in this reaction,...

Sulfur and Nitrogen Modulated One-Pot Double Annulation of Arenes

“…Motivated from the undisputed challenges involved in the annulation of arylthioamides and alkynes, the investigation was initiated executing a reaction between N -[4-methyl­benzothioyl]- S -methyl- S -phenyl­sulfoximine ( 1a ) and 3-hexyne ( 2a ) with an air stable Ru-catalyst (Table ). , Interestingly, the desired 6,6-fused thiopyrano-isoquinoline ( 3a ) was formed in 29% yield under the catalytic conditions {[RuCl 2 ( p -cymene)] 2 (5.0 mol %), Cu­(OAc) 2 ·H 2 O (1.0 equiv), and AgSbF 6 (20 mol %) in 1,2-dichloroethane (DCE) at 120 °C for 24 h} (entry 1, Table ). Screening of acetate sources [NaOAc, KOAc, CsOAc, Mn­(OAc) 2 ·3H 2 O, Zn­(OAc) 2 ·2H 2 O, AgOAc, and anhydrous Cu­(OAc) 2 ] revealed that Cu­(OAc) 2 was most effective (entries 2–8), providing 3a in 34% yield (entry 8). , …”

“…A recent study on the one-pot double annulation of MPS-enabled arylamide with 1,2-diaryl alkynes was reported to yield linearly and angularly fused heterocycles (Figure ). , Hence, double annulation of aryl thioamides with a 1,2-diaryl alkyne was expected to afford linearly fused polycyclic thioamides (A; forming 2-C–C and 2-C–N bonds) and a polycyclic amide (B; via the in situ hydrolysis of A or the annulation of hydrolyzed precursor 1 with an alkyne) along with the expected angularly fused thiopyrano-isoquinoline derivative (C; forming 2-C–C, 1-C–N, and 1-C–S bonds) and pyranoisoquinoline skeleton (D; forming 2-C–C, 1-C–N, and 1-C–O bonds), as shown in Figure . However, the annulation preference of S with the alkyne over N (observed in the synthesis of 3l – o , Scheme ) could inhibit the formation of A, B, and D. Hence, we attempted to explore this important double annulation of 1 with 1,2-diaryl alkynes for the synthesis of thiopyrano-isoquinoline systems, which is undoubtedly challenging. , …”

“…On the basis of the above mechanistic studies, the plausible mechanism is proposed (Figure ). − The ligand exchange between [RuCl 2 ( p -cymene)] 2 , AgSbF 6 , and Cu­(OAc) 2 at first produces the active Ru­(II) catalyst. The coordination of the “S” moiety to the active catalyst and the activation of the proximal C–H bond of aryl thioamides forms a five-membered Ru-intermediate I .…”

“…Owing to the high atom and step economy, the directing group (DG)-assisted TM-catalyzed oxidative annulation of (hetero)­arenes with alkynes has emerged as the most efficient route to access novel complex heterocycles from readily available precursors . Despite the widespread popularity of this method, most of the annulations are confined to the construction of oxygen- and nitrogen-containing polycyclic heteroarenes. − In this regard, amide, imine, nitrile, hydroxyl, and carbonyl DGs are extensively uncovered for the direct annulation of inert C–H bonds. , On the other hand, thioamide-directed activation and functionalization of inert C–H bonds are rare . This is probably because the strong binding ability of S to the TM, high lability of S to oxidation, and competition between S and N coordination to the metal catalyst make this process difficult (Figure A) …”

Efficient synthesis of benzo[h]carbazol[3,2‐b][1,6]naphthyridines

“…The molecular mechanism of ellipticine to act as an anticancer drug molecule was initially involved through DNA binding to inhibit topoisomerases‐II [3]. Therefore, ellipticine has been established to be an attractive synthesis candidate, with numerous methods having been discovered [4]. Not only ellipticine, but also hetero‐annulated carbazoles, which are structurally similar, have received a lot of attention in the laboratory, and these congeners have a superior pharmacological profile than the others [5].…”