A Rapid One‐Pot Five Component Sequential Access to Novel Imidazo[2,1‐b]thiazinyl‐α‐aminophosphonates

Abstract

A facile and rapid entry towards assembly of novel imidazo[2,1b][1,3]thiazinyl-a-aminophosphonate scaffolds through a onepot, sequential reaction of 2-amino-4H-1,3-thiazine-3-one, dialdehydes, isocyanides, aromatic amines and dialkyl/aryl phosphites is demonstrated. Successive sequencing of Groebke-Blackburn-Bienaymé (GBB) reaction with Kabachnik Field's reaction results in the efficient formation of novel bis-heterocyclic frameworks. The highlights of the present protocol include survival of the aldehydic group post GBB without any protection. Additionally, simplicity of execution excluding both solvent and catalyst, cheap reagents, excellent functional group tolerance under minutes of microwave irradiation justify it to be a green protocol.

Assembly of New Heterocycles through an Effective Use of Bisaldehydes by Using a Sequential GBB/Ugi Reaction

“…In our previous work, the reaction of alkyl propiolate with thiourea generated 2‐amino‐4 H ‐1,3‐thiazin‐4‐one ( 1 a ), which was utilized as a starting substrate in our current approach. Thus, we began our investigation by developing optimized reaction conditions for the six‐component sequential reaction by using compound 1 a , 1,4‐phthalaldehyde ( 2 a ), N ‐ tert ‐butylisonitrile ( 3 a ), aniline ( 5 a ), and benzoic acid ( 6 a ) as model substrates.…”

“…In our previousw ork, [4,15] the reactiono fa lkyl propiolate with thiourea generated 2-amino-4H-1,3-thiazin-4-one( 1a), which was utilized as as tartings ubstrate in our currenta pproach. Thus, we began our investigation by developingo ptimized reaction conditions for the six-components equential reactionb y using compound 1a, 1,4-phthalaldehyde (2a), N-tert-butylisonitrile (3a), aniline (5a), and benzoic acid (6a)a sm odel substrates.F or as equential synthesis, first, we reacted compounds 1a, 2a,a nd 3a at 80 8Cu nder microwave irradiation for 10 min to generate intermediate 4a;h owever,d isappointingly, under Ugi reactionc onditions in MeOH at room temperature for 5h,t he reactionr esulted in ac omplex reactionp rofile (Scheme2).…”

“…Thus, we decided to isolate intermediate 4a after the first GBB reaction, which would then act as as tarting substrate for the second IMCR. To verify our new plan, the reaction between compounds 1a, 2a,a nd 3a was screened at 80 8Cu nder microwavei rradiationf or 10 min in various solvents, that is, THF, EtOH,w ater,a nd N,N-dimethylformamide (DMF);h owever, ac omplex reactionp rofile was obtainedi na ll cases ( Table 1, entries [1][2][3][4]. Next, the reactionw as screened withouta ny solvent at various operating temperatures (80, 100, 120,1 40, and 160 8C) under microwave irradiationf or 10 min and the desired product (4a)w as isolatedi n5 5%,6 0%,6 2%,7 5%,a nd 50 % yield, respectively ( Table 1, entries [5][6][7][8][9].…”

“…MCRs convert simple and flexible building blocks into complex molecular architectures in a one‐pot, high bond‐forming index (BFI) synthetic transformation. Over the past few decades, MCRs have heralded a new epoch in the design of molecular architectures of high structural diversity through the combination of two or more isocyanide‐based multicomponent reactions (IMCRs) . Two notable IMCRs are the Groebke–Blackburn–Bienaymé (GBB) reaction and the Ugi reaction .…”

“…[1,2] MCRs convert simple and flexible buildingb locks into complex molecular architectures in ao ne-pot, high bond-formingi ndex (BFI) synthetic transformation.O ver the past few decades, MCRs have heralded an ew epoch in the design of molecular architectureso fh ighs tructural diversity through the combination of two or more isocyanide-based multicomponent reactions (IMCRs). [3,4] Twon otable IMCRs are the Groebke-Blackburn-BienaymØ (GBB) reaction and the Ugi reaction. [5,6] The GBB reaction-typically an acid-catalyzed reaction between ah eterocyclic amidine, an aldehyde, and an isocyanide that proceeds through imine formation ands ubsequent [4+ +1] cycloaddition, provides access to fused bicyclic heterocycles, such as imidazo[2, 1-b]azines.…”