Combinatorial Liquid-Phase Synthesis of [1,4]Oxazepine-7-ones via the Baylis−Hillman Reaction

Abstract

A new method for the synthesis of [1,4]oxazepin-7-ones from readily available aldehydes and alpha-amino alcohols was developed using the Baylis-Hillman reaction as the key step. To determine the scope and limitations of the method, a mixture library was synthesized from six aldehydes and six alpha-amino alcohols on the soluble polymer support poly(ethylene glycol) 5000 monomethyl ether (MeOPEG) via split synthesis and analyzed by GC-EIMS. Those oxazepines that were formed predominantly were resynthesized in a parallel synthesis and fully characterized. Thus, we have shown that split synthesis on MeOPEG can be an efficient method to rapidly screen the substrate spectrum of a newly developed reaction sequence.

Synthesis of Poly(Ethylene Glycol)–Supported (R)-BINOL Derivatives and Their First Application in Enantioselective Mukaiyama Aldol Reactions

“…Starting materials 1, [24] 2, [35] 5, [25] (R)-4, [26] and (R)-7 [27] were prepared by literature procedures. All other chemicals were commercially available and were used as received.…”

“…We choose this position to avoid the connection of the polymer moiety in close proximity of the 2-and 2 0 -positions, which bind the titanium counterpart in the active catalyst species. The preparation of the desired polymer-supported BINOL ligands (R)-6 and (R)-8 was easily achieved by a Heck coupling reaction of MPEG-supported acrylate 5 [25] with the corresponding 6-bromo-and 6,6 0 -dibromo-substituted precursors (R)-4 [26] and (R)-7, [27] respectively (Scheme 1). The expected coupling products were formed in good yields and with a fairly low degree of racemization.…”

Triethylamine‐Catalyzed Synthesis of Oxazepine from Maleamic Acids

“…A considerable number of methods toward the formation of oxazepine ring have been reported in recent years via the Baylis–Hillman reaction , by the cyclization of propenamides with 2‐aminophenol , by the reaction of nitrosonaphthol with TNT , a phosphine‐mediated tandem reaction of ynones with 2‐azido alcohols , intermolecular amidoalkylation reaction , using the benzotriazole methodology , scandium‐ or copper‐triflate‐catalyzed acylaminoalkylation of α ‐methoxyisoindolones , from imines by their acylation and further cyclization , and one‐pot multicomponent reaction of 2‐aminophenols, Meldrum's acid and isocyanides . The use of microwave irradiation has also been employed .…”

The dipolar route to naphtho[2,1‐c]isoxazoles from the baylis‐hillman adducts of 2‐alkynylbenzaldehydes

“…We and other groups have demonstrated applications of this reaction in the synthesis of benzannulated or other heterocyclic systems. These include indolizines [10], quinolines [11], chromenes [12], thiochromenes [13], indenes [14], pyridopyrimidones [15], 1,4-oxazepin-7ones [16], coumarins [17], isobenzofurans [18], 3-oxo-2,3-dihydro-1H-isoindoles [19], 1H-indoles [20], and 2benzazepines [21]. Also, we described facile syntheses of 4H-tetrazolo[1,5-a] [1]benzazepines [22] and 5H-1,2,3triazolo[4,3-a] [2]benzazepines [23] from the Baylis-Hillman adducts of 2-azidobenzaldehyde and 2-alkynylbenzaldehydes using intramolecular 1,3-dipolar cycloaddition reaction, respectively.…”