A Facile Synthesis of Cyclopenta[d][1,2]oxazines through [6+4] Cycloaddition Reaction

Abstract

Functionalized 1,2-oxzines are known to exhibit various pharmacological properties, such as antibacterial activity, acetylcholinesterase inhibitory activity, protein tyrosine phosphatase inhibitory activity. They also occur as a key structural subunit in biologically active natural products. However, there have been only limited methods for the synthesis of cyclopenta[d][1,2]oxazines and their derivatives. Linn and Sharkey reported the first practical synthesis of cyclopenta[d][1,2]oxazine by use of benzoylated cyclopentadiene. Lloyd and co-workers also reported the synthesis of cyclopenta[d][1,2]oxazine by reaction of diaroylcyclopentadienes with hydroxylamine. The reaction of benzonitrile oxide with fulvene was known to yield both 1 : 1 and 2 : 1 adducts. Herein, we report the first example of a facile and convenient synthesis of various cyclopenta[d][1,2]oxazines starting from chlorooxime and fulvene through [6+4] cycloaddition. In an effort to pursue of PTP1B inhibitors, a convenient synthesis of functionalized cyclopenta[d][1,2]oxazine derivatives was required. Fulvenes were obtained from the reaction of dimethyl sulfate salt of dimethylamides 3 and cyclopentadienyl sodium as cited. Howe and co-workers reported a convenient synthesis of chlorooximes by the use of N-chlorosuccinimide in DMF in place of chlorine, avoiding the use of hazardous chlorine and ring chlorination as side reactions with benzaldoximes that contain electron-donating substituents. Based on this efficient synthetic methodology for chlorooximes 2, we could achieve a facile synthesis of various cyclopenta[d][1,2]oxazines 5 by the cyclocondensation of 2 with fulvene 4 in the presence of triethylamine (eq. 1). The introduction of alkyl or aromatic substituents at 1-position could be accomplished by the use of substituted fulvenes or chlorooximes as given in Table 1. Diethyl ether was the solvent of choice over dichloromethane (41% yield, 5a) for cycloaddition and all of the reaction afforded the corresponding cyclopenta[d][1,2]oxazines in moderate yields. The relatively low yields for 5c, 5i, and 5l were presumably due to the deprotection of protective group, t-butyl or acetyl group. Cycloadditions of chlorooxime with fulvene are affected by the steric factor of the substituents (5o-5r), as the introduction of substituent (R) lowered the reaction yield. This method was then applied to substituted fulvenes 6, in situ generated from the corresponding cyclopentadiene, and 10 as shown in Scheme 1. As can be seen, carbometh-