Stereoselective Synthesis of Pyrido- and Pyrrolo[1,2-c][1,3]oxazin-1-ones via a Nucleophilic Addition–Cyclization Process of N,O-Acetal with Ynamides

Abstract

An efficient asymmetric approach to access functionalized pyrido-and pyrrolo[1,2-c][1,3]oxazin-1-ones has been developed through a nucleophilic addition−cyclization process of N,O-acetal with ynamides. A number of substituted ynamides 8a−8o and 3silyloxypyrrolidine or piperidine N,O-acetals 6a, 7 were amenable to this transformation, and the desired products 9a−9o, 10a−10m were obtained with excellent regioselectivities and outstanding diastereoselectivities. Moreover, chiral ynamides 14a−14f could also experience this addition−cyclization process to afford products 15a− 15f in excellent yields. Article pubs.acs.org/joc

Stereoselective Intermolecular [4+2] Process of N,O‐acetals with Terminal Alkynes for Construction of Functional cis‐Pyrido and Pyrrolo[1,2‐c][1,3]oxazin‐1‐ones

“…Then the scope and limitation of N ,O‐acetals 5 b and 5 c with different terminal alkynes 6 a – 6 l were also examined (Scheme ). First, the reaction of N ,O‐acetal 5 b with phenylacetylene 6 a successfully delivered the desired product 8 a in 75% yield.…”

“…Our investigation started with the reaction of N ,O‐acetal 5 a with phenylacetylene 6 a . First, well‐known catalysts SnCl 4 and Bi(OTf) 3 were examined, and the results showed that catalytic amount of Bi(OTf) 3 could give the desired product 7 a in 9% yield, along with excellent diastereoselectivity ( dr >99:1) (Table , entries 1–3).…”

“…For example, SnCl 4 could effectively catalyze the intramolecular addition of N ‐acyloxyiminium ions (Scheme , 1); SnCl 4 or Bi(OTf) 3 could also promote intermolecular carboarylation of alkynylarenes and N , O ‐acetals (Scheme , 2/3) . Enlightened by pioneering results, our group recently achieved an effective approach to access functionalized pyrido and pyrrolo[1,2‐c][1,3]oxazin‐1‐ones through nucleophilic addition‐cyclization process of N ,O‐acetals with ynamides (Scheme , 4) . Unfortunately, further efforts to deliver (+)‐Halofuginone ( 3 ) or (+)‐Febrifugine ( 1 ) failed due to the difficulty in manipulating the amide C−N bond for chain elongation under mild conditions.…”

“…[17c,18] Enlightened by pioneering results, our group recently achieved an effective approach to access functionalized pyrido and pyrrolo [1,2-c] [1,3]oxazin-1-ones through nucleophilic addition-cyclization process of N,O-acetals with ynamides (Scheme 1, 4). [19] Unfortunately, further efforts to deliver (+)-Halofuginone (3) or (+)-Febrifugine (1) failed due to the difficulty in manipulating the amide CÀ N bond for chain elongation under mild conditions.…”

Influence of solvent mixture on nucleophilicity parameters: the case of pyrrolidine in methanol–acetonitrile

“…15 Their intrinsic reactivity has been examined in relation with bioactive compounds of natural or synthetic origin, which incorporate such nucleophilic scaffolds. [16][17][18][19] Recently, Mayr group investigated the kinetics of the reactions of several pyrrolidine derivatives and they integrated the resulting constitutive parameters of pyrrolidines into the socalled Mayr's nucleophilicity scale. 16 On the other hand, thiophenes are heterocycles of industrial interest, 20,21 and substituted thiophenes are scaffold found within pharmaceuticals, conductive polymers, photochromic molecular switches, liquid crystals, etc.…”