Alkylations oxazoline system

A reasonable reaction mechanism may start with formation of a bromonium ion 3 by attack of NBS at the olefin, followed by oprening of 3 by the nitrile ( 4) and addition of water to the nitriUum ion 4. This sequence leads to bromoamides 5, which finally undergo Lewis acid-mediated ring-closure via SN2-type intramolecular O-alkylation of the amide function to render stereoselectively the oxazoline system of 2. 

Jew, Park, and coworkers extended the substrate scope of phase-transfer catalytic alkylation to the oxazoline system in order to synthesize chiral a-alkyl serine derivatives. The authors chose phenyl oxazoline derivative 74 [106] as the substrate (Scheme 12.6). In the presence of Cj-symmetric chiral quaternary ammonium bromide (S,S)-31c, the asymmetric phase-transfer alkylation of 74 with alkyl halides, followed by acidic hydrolysis, provided chiral a-alkyl serines in very high yields and enantioselecti vities. 

The mechanism of organolithium addition to naphthyl oxazolines is believed to occur via initial complexation of the alkyllithium reagent to the oxazoline nitrogen atom and the methyl ether to form chelated intermediate 17. Addition of the alkyl group to the arena 7t-system affords azaenolate 18, which undergoes reaction with an electrophile on the opposite face of the alkyl group to provide the observed product 4. The chelating methyl... 

An alternative protocol for treating alkylzinc bromides with primary and secondary alkyl bromides and iodides was described by Zhou and Fu.409 In the study, a combination of Ni(cod)2 and a chiral oxazoline ligand 306 was used as a catalytic system providing 62-88% yield of product 307 A,A-dimethylacetamide (DMA) was the reaction solvent (Scheme 156). 

C-Alkylation of 2-oxazolin-5-ones under catalysed mildly basic conditions provides a convenient route to a-branched a-amino acids (50-80%) [126]. Similarly, A-alkyloxindoles are mono- and di-alkylated at the 3-position [127], For other examples of the alkylation of heteroaryl systems, see Chapter 5. 

The constrained bis(oxazolines) 9a and 9b can be constructed beginning with malononitrile 32 as shown by Ghosh and co-workers. Thus, treatment of 32 with anhydrous hydrochloric acid in dioxane, as shown by Lehn and co-workers, yielded imidate salt 33 (Fig. 9.9). Condensation of the imidate salt with commercially available (15,2/ )-l-aminoindan-2-ol afforded the conformationally constrained bis(oxazoline) inda-box 9a. Alkylation at the bridging methylene of 9a was carried out by Davies and co-workers.Treatment of 9a with lithium diisopropylamide followed by alkylation with methyl iodide afforded 9b. Alternatively, alkylation with diiodoalkanes incorporated ring systems at the bridging position (structures 34a-d). 

The above system failed entirely when nonstabilized carbanions such as ketone or ester enolates or Grignard reagents were used as carbon nucleophiles, leading to reductive coupling of the anions rather than alkylation of the alkene. However, the fortuitous observation that the addition of HMPA to the reaction mixture prior to addition of the carbanion prevented this side reaction1 extended the range of useful carbanions substantially to include ketone and ester enolates, oxazoline anions, protected cyanohydrin anions, nitrile-stabilized anions3 and even phenyllithium (Scheme 3).s... 

The next phase of the synthesis was installation of the dimethylamino-oxazoline ring system. This was constructed from the oxazolidinone precursor 19. Oxazolidinone formation occurred when 25 was reacted with thionyl chloride. The more nucleophilic carbonyl of 19 was then O-alkylated with the Meerwein reagent to give an iminium ion that readily participated in a nucleophilic addition/elimination reaction with dime-thylamine to give 26. The final step of the synthesis was O-deacetylation of 26 with sodium methoxide to provide (—)-allosamizoline hydrochloride in 98% yield after acidification. 

It is clear, nonetheless, that successful dearomatising cyclisations are not confined to systems which can undergo electrocyclic ring closure 456 for example cyclises to 457, which may be protonated or alkylated stereoselectively.201 Without the oxazoline substituent, similar reactions lead to rearomatisation. 

A Pd(ll) catalyst system with an oxazoline ligand 44 has been described that allows the desymmetrization of meso-Z-alkyl-2-propargylcyclohexane-l,3-diols in an asymmetric cyclization-carbonylation reaction. The products which contain a chiral quaternary carbon were obtained in excellent yields with high ee s (Scheme 56) <2006T9988>. 7-Hydroxy terminal <2005JOC3099> and internal <2006TL2793> alkenes can be converted to tetrahydrofurans by Pd(0)-catalyzed carboetherification reactions combined with a coupling of aryl or vinyl halides. 

There s no way -CH3 I can cover the complete naming system for organic compounds here but maybe what I ve presented will take the edge off when you see a molecule called 2-alkyl-4 4-dimethyl-2-oxazoline. Of course scientists never make things easy so you ll still see compounds called by their prefix naming convention. For example, we don t use the lUPAC system in naming isopropyl alcohol. 

The asymmetric aldol-type addition of tosylmethyl isocyanide (99) to aldehydes can also be catalyzed by the chiral silver(I) complex, giving almost exclusively trans-S-alkyl-4-tosyl-2-oxazolines 98 [E = S02(p-Tol)] with up to 86 % ee as shown in Sch. 26 [52]. The slow addition method described above is not necessary for this reaction system. 

There is another important feature of these systems to keep in mind the effect of alkylation temperature on the diastereomer ratio. The selectivity observed in the alkylation of the tetrahydroisoquinoline formamidine illustrated in Figure 4(a) (with methyl iodide) increases from 9 1 to 99 1 when the temperature is lowered from -78 to -100 Similarly, the selectivity with the oxazoline illustrated in Figure... 

The group of Park and Jew developed the efficient reaction systems for the preparation of optically active a-alkylserine and a-alkylcysteine derivatives (Scheme 6.15) [40], The group developed the oxazoline-based substrate for serines 52a and the thiazoline-based substrate 52b for cysteines, respectively. The oxazoline and thiazoline moieties fulfilled a dual function the activation of the a-proton and the protection of both the amino and the side chain hydroxy groups. The ortho-biphenyl derivatives 52a and 52b were specifically designed for the cinchona PTC 54, and solid cesium hydroxide monohydrate was chosen as an optimal base. The PTC 29 was also found to be as effective as the PTC 54 for the asymmetric alkylation of 52a. 

Two types of substrate have been most thoroughly examined. The first are substrates bearing three aryl groups (two at Cl and one at C3) in which case the alkylation can occur at the less substituted carbon but can still generate a stereocenter, Scheme 31. Bosnich reported some useful results with this system in 1985 where ees up to 86% were obtained with chiraphos as the ligand [110]. More recently, Williams showed that an oxazoline-phosphine ligand 29 produced better results (up to 97% ee) [73,74, 111, 112]. 

Alkyl/alkyl ketones are challenging substrates for rhodium-catalysed asymmetric hydrosilylation and are generally reduced with low enantioselectivities using oxazoline-based hgands. However a number of alternative ligand systems have been used successfidly in the rhodium-catalysed hydrosilylation of alkyl/alkyl ketones. For example, the 8-keto ester (3.158) undergoes enantioselective... 

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