Lithiated 5,6‐Dihydro‐4H‐1,2‐oxazines: Synthesis, Highly Diastereoselective Reactions with Electrophiles, and Subsequent Transformations

Abstract

The 6-(trimethylsilyl)methyl-substituted 1,Zoxazine 1 can smoothly be deprotonated with n-butyllithium at C-4 to give a lithiated species which reacts with a variety of electrophiles to provide the new 1,2-oxazines 5 -16 in good yields. Besides the preparative aspect of these transformations, the high stereoselectivity of many reactions is also interesting from a mechanistic point of view. By deprotonation of the 4-deuterated compound 5a it has been proven that n-butyllithium removes exclusively the proton (or deuteron) cis to the 6-CH2SiMe3 group. Also, in most cases the reaction of lithiated 1 with electrophiles occurs with overall retention of configuration to afford preferentially cis-1,2-oxazines (series a). A mechanistic proposal for this highly stereoselective deprotonation process, which seems to be governed by the 1,2-oxazine oxygen, is discussed including a comparison with a recently reported ab initio calculation dealing with oxime ethers. Similar deprotonation/substitution reactions are described for l,2-oxazines 14, 2, 3, and 4. Possibly due to a differing carbanion structure a deviating behavior is observed in some cases. Several acidinduced and reductive ring-opening reactions of 1,6a, Ea, and 14a demonstrate the potential of 4-substituted 1,Zoxazines for the stereoselective synthesis of polyfunctionalized compounds.5,6-Dihydro-4H-l ,Zoxazines A (herein abbreviated as 1,2-oxazines) are heterocycles with a promising potential for the synthesis of polyfunctional compounds2). They can easily be prepared by the hetero-Diels-Alder reaction of electronrich olefins with nitroso alkenes as developed by Gilchrist and coworkers3). By use of silylated dienophiles we were able to extend the scope of this [4 + 21 cycloaddition considerably'). In this contribution we will include our results on the substitution of 1,2-oxazines A proceeding via the carbanion B to give heterocycles C which incorporate an electrophile El at C-4 and are not easily available otherwise.The analogous sequence is well-known for oxime ethers D5) or the related isoxazolines Eq. However, for the sixmembered heterocyclic system A we are only aware of Shatzmiller's reports dealing with compound F and the regioselectivity of its deprotonation'). We have examined the feasibility of the sequence A-+B-+C using the monocyclic 1,2-oxazines 1 and 2, and after having discovered the surprisingly high stereoselectivity we have extended our investigation to the bicyclic compounds 3 and 4. R = H4 R -SiMq

Oxime ethers as versatile precursors in organic synthesis: a review

“…Deprotonation of oxime ethers by using a strong base such as butyl lithium, and subsequent reaction with a range of electrophiles elaborated the desired product in good yields. [47][48][49][50][51][52][53][54][55] One of the beautiful examples of a-alkylation of oxime ethers has been reported by Caille et al They showed that treatment of (+)-nopinone oxime methyl ether 31 with a wide range of electrophiles in the presence of s-BuLi in THF at À80 C for 10 min gave the corresponding stereoselectively a-alkylated oxime ether 32 in good to high yields. As shown in Scheme 17, due to the stabilization of the carbanion intermediate with the oxygen lone pair of the oxime function, only the E-isomer of 31 able to react through a syn-alkylation process.…”

Ligand-Induced Selectivity in the Rhodium(II)-Catalyzed Reactions of α-Diazo Carbonyl Compounds

“…Preparation of 4-Benzoyl-1-diazo-2-oxo-7-octene (20). A solution of 75.8 mL (37.9 mmol) of 0.5 M potassium hexamethyldisilazide in toluene and 45 mL of THF was cooled to −78 °C, and 6.0 g (34.4 mmol) of 1-phenyl-5-hexen-1-one was added. The solution was stirred at −78 °C for 1 h followed by the dropwise addition of 3.91 g (41.3 mmol) of methyl bromoacetate.…”

Chemistry of Six-Membered Cyclic Oxime Ethers. Application in the Synthesis of Bioactive Compounds

“…As has been already noted, the reaction 3 + 4 → 1 opens the excess predominantly to dihydrooxazines 1 unsubstituted at position C-4 (R 1 = H in Scheme ). However, lithiation of dihydrooxazines 1g (R 1 = H) and subsequent treatment of the resulting anionic species with electrophilic reagent led to various 4-substituted dihydrooxazines 29 in good yields and high stereoselectivity (Scheme , eq 1). − …”