A K₂CO₃‐Mediated Regioselective Synthesis of Indole/Pyrrole‐Fused 1,4‐Oxazines: An Unexpected Indole‐Fused Azlactone Synthesis

Abstract

A highly regioselective and efficient base‐catalyzed intramolecular hydroalkoxylation of primary and secondary alkynyl alcohols was developed to afford 1,4‐oxaza heterocycles. Although the rates of cyclization for terminal alkynyl alcohols were significantly greater than those for internal ones, our method tolerated both terminal and internal alkynes. In addition, an unprecedented one‐pot hydroamination reaction was found to proceed with high chemo‐ and regioselectivity to form indole‐fused azlactones in the presence of base.

s-Block cooperative catalysis: alkali metal magnesiate-catalysed cyclisation of alkynols

“…Utilising similar reaction conditions, Wang employed potassium carbonate to prepare indole/pyrrole-fused 1,4-oxazines. 64 Baire has also recently reported that cycloisomerisation of cis-6hydroxy-and cis-6-acyloxyhex-2-en-4-ynals to 2-acylfurans and 2-(1-acyloxyalkenyl)furans is achievable using calcium catalysis. 65 In contrast, magnesium-based reagents have not followed suit by showing very little promise to catalyse these types of transformations; whereas the catalytic properties of s-block bimetallic complexes remain unexplored in this context.…”

Base‐Promoted Formation of an Annelated Pyrrolo‐1,4‐oxazine Ensemble from 1H‐pyrrol‐2‐ylmethanol and Propargyl Chloride: A Theoretical and Experimental Study

“…According to the present experimental results, the reaction of 1H-pyrrol-2-ylmethanol with propargyl chloride in the system KOH/DMSO yields three products: N-allenylpyrrol-2-ylmethanol (9), N-allenyl-2-[(propargyloxy)methyl]-1H-pyrrole (15) and 3-Me-1H-pyrrolo [2,1-c] [1,4]oxazine (27).…”

“…The low activation barrier of acetylene-allene isomerization of N-propargylpyrrol-2-ylmethanol indicates its complete transition to the experimentally observed N-allenylpyrrol-2-ylmethanol (9). The latter, in turn, is a precursor of the following products: the most thermodynamically stable N-allenyl-2-[(propargyloxy)methyl]-1H-pyrrole (15) and the target 3-Me-1H-pyrrolo[2,1-c] [1,4] oxazine (27). Compound 27 is formed as a result of the intramolecular cyclization of 9, upon the attack of an alcohol group at the allene internal atom, while product 15 is produced through the S N 2 reaction of 9 with the second molecule of propargyl chloride.…”

“…[71] Compounds of a similar structure, namely, propargyl ethers of N-propargylindolinic acids were previously used as intermediates in the assembly of highly effective cytotoxic drugs with anticancer, antibacterial, and DNA-cleavage activities. [72] To obtain the target pyrrolyloxazine (27), high basicity is required (for activation of the OH-group) at high dilution (in order to prevent addition at the OH-group of the second molecule of propargyl chloride) (Scheme 8).…”

“…[26] At present, there are only two approaches to the preparation of pyrrolo-and indoloxazines that do not contain the keto group. Chen and Wang proposed assembling from N-propargyl-2-hydroxymethylpyrroles/indoles under the action of K 2 CO 3 , [27] while Abbiati and co-workers employ a domino assembling from N-propargylindole-2-carbaldehydes and alcohols (through the corresponding hemiacetals) under the action of metallic sodium (Scheme 1). [28] The A.E.…”