β‐Nitroacrylates as Starting Materials of Thiophene‐2‐Carboxylates Under Continuous Flow Conditions

Abstract

We report herein a general and efficient continuous flow‐based protocol for synthesizing thiophene‐2‐carboxylates starting from ketal‐functionalized β‐nitroacrylates. The protocol involves (i) a promoter‐free conjugate addition of thioacetic acid to β‐nitroacrylates, (ii) a base‐induced elimination of nitrous acid, and (iii) a final acid‐promoted domino cyclization‐aromatization process to afford the title targets. Thanks to the means of the flow chemistry and the use of solid supported systems, the three steps were combined in a whole flow chemical process, by which the products were isolated in good to excellent overall yields (38–88%).magnified image

β-Nitroacrylates: New Key Precursors of Indole-2-Carboxylates via Fischer Indole Synthesis

“…Among them, α-ketoesters are of particular interest since they are key precursors of alkyl indole-2-carboxylates, a very important class of indole that is widely investigated for its activities and is exploited as a strategic intermediate of biologically active targets, such as the NNRTI Delavirdine and its analogues [12][13][14][15][16][17]. Recently, following our study concerning the use of β-nitroacrylates 1 as a useful building block of heterocyclic systems [18][19][20][21], we reported a new protocol for synthesizing 5, starting from 1 and o-bromoanilines, based on a palladium catalyzed Heck coupling [22] (Scheme 3, Way b). Now, in continuing this study with the aim of avoiding the use of precious metal (Pd), we found 1 to be a valuable alternative of α-ketoesters for the Fischer indole synthesis (Scheme 3, Way a).…”

A New Valuable Synthesis of Polyfunctionalized Furans Starting from β-Nitroenones and Active Methylene Compounds

“…Herein, following our studies on the preparation of heteroaromatic systems starting from aliphatic nitro compounds [14][15][16][17], we found β-nitroenones 1 and α-functionalized ketones 2 to be precious and practical building blocks of 3-alkylidene furans 3. In particular, this study complements our previous research concerning the reaction of α-functionalized ketones 2 with β-nitroacrylates 4 [18] to produce, by a different reaction mechanism, the tetrasubstituted furans 5 (Figure 1).…”