Diastereoselective α-C-H Oxygenation of Aliphatic Amines: A General Route to Oxazines
Scheme 10: Proposed mechanism 2.8 One pot synthesis of oxazine
Chapter 2
36 treatment with Ag2O furnished o-quinone methide 2.69. Quinonic oxygen is good H- acceptor30 and alpha-hydrogen of tertiary amines is known to intramolecularly migrate to suitably positioned acceptor (tert-amino effect).31 Therefore [1,6]-hydrogen shift lead to produce zwitterionic intermediate 2.70.32 Protonation of 2.70 and subsequent diastereoselective cyclization of the resulting iminium ion 2.71 gave rise to trans (relative to C-Ar and C-O-) oxazine 2.72 (Scheme 10, eq. 23). Alternatively, 2.71 can also be formed via mesomerization of quinone methide 2.69 followed by a proton transfer (Scheme 10, eq. 24).
In a related study, Fülöp and co-workers showed that trans-oxazines are thermodynamically more stable as compared to cis-isomer. 33 Cyclization occurred in a way to selectively position the aryl group at the convex face of the molecule and thus to minimize the steric repulsion with R- and the naphthyl moiety. This was further supported from the observation of lower selectivity in case of oxazine 2.67 when naphthyl was replaced by a phenyl group. The electron-withdrawing group on Ar- and electron donating nature of R- will stabilize the zwiterionic intermediate 2.70. Thus better yields for the substrates (2.67d & 2.67p) with nitro group on Ar- and Ph- as R- are supportive for 2.70. Expected lower yield for morpholine derivative is due to the reduced stability of zwiterionic intermediate 2.70 because of the negative inductive effect of ring oxygen atom (Scheme 10, eq. 23).
Scheme 10: Proposed mechanism
Diastereoselective α-C-H Oxygenation of Aliphatic Amines: A General Route to Oxazines
37 membered oxazine 2.67i (48%) (Scheme 11, eq. 25 and 26).
Scheme 11: One pot syntheses of oxazines 2.9 Synthetic application
Substituted morpholine derivative is an important structural unit of biologically active molecules. Moreover, it is used as chiral reagent for asymmetric synthesis.34,35 Considering oxazine as masked iminium ion,36 oxazine 2.67j was reacted with phenyl magnesium bromide. The hydroxy naphthyl group was subsequently removed by aq. NaOH-MeOH in THF to give α-functionalized amine 2.75 with 61% yield (Scheme 12, eq. 27). However, reported method for the synthesis of α-phenyl morpholine involved multistep synthetic strategy starting from phenyl alanine (Scheme 12, eq. 28).37
Scheme 12: Synthesis of α-phenyl morpholine.
At the same time, similar work was published by Maycock and co-workers for the synthesis of dihydro-1,3-oxazines through Cu+2-mediated C-O bond formation.38 Recently, Hajra group developed a method for redox-neutral [3+2]-cycloadditions using pyrrolidine and benzaldehyde to form the oxazole.39
Chapter 2
38 2.10 Summary
In summary, an unprecedented, operationally simple, versatile and diastereoselective protocol has been developed to access synthetically as well as biologically important oxazines via α-C-H aryloxylation of aliphatic amines. The methodology is very general and thus worked well for wide range of saturated aliphatic amine based substrates, some of them were otherwise difficult to functionalize. Additionally, its synthetic potential is exemplified by a straightforward and elegant synthesis of 3-phenylmorpholine. Therefore, it was believed that the synthetic methodology presented has the promising ability to be utilized widely as the general and practical approach to functionalize aliphatic amines.
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