Oxazolines alkyl halide

Chiral oxazolines developed by Albert I. Meyers and coworkers have been employed as activating groups and/or chiral auxiliaries in nucleophilic addition and substitution reactions that lead to the asymmetric construction of carbon-carbon bonds. For example, metalation of chiral oxazoline 1 followed by alkylation and hydrolysis affords enantioenriched carboxylic acid 2. Enantioenriched dihydronaphthalenes are produced via addition of alkyllithium reagents to 1-naphthyloxazoline 3 followed by alkylation of the resulting anion with an alkyl halide to give 4, which is subjected to reductive cleavage of the oxazoline moiety to yield aldehyde 5. Chiral oxazolines have also found numerous applications as ligands in asymmetric catalysis these applications have been recently reviewed, and are not discussed in this chapter. ... 

Variations and Improvements on Alkylations of Chiral OxazoUnes Metalated chiral oxazolines can be trapped with a variety of different electrophiles including alkyl halides, aldehydes,and epoxides to afford useful products. For example, treatment of oxazoline 20 with -BuLi followed by addition of ethylene oxide and chlorotrimethylsilane yields silyl ether 21. A second metalation/alkylation followed by acidic hydrolysis provides chiral lactone 22 in 54% yield and 86% ee. A similar... 

Optically active, a-branched lactams 30 have been built by means of Meyers chiral auxiliaries [ 10]. The key step included the diastereoselective a-alkylations of the initially formed co-i -sulfonamido oxazolines 26. The R or S configuration in the product 27 was obtained reacting the appropriately configured intermediate aza enolates with alkyl halides, high diastereoselectivities have been reported. Several attempts to achieve a complete ring closure to the lactams 30 (via 29) by an acidic cleavage of the oxazolines 27 failed. Varying mixtures of... 

A procedure for enantioselective synthesis of carboxylic acids is based on sequential alkylation of the oxazoline 8 via its lithium salt. Chelation by the methoxy group leads preferentially to the transition state in which the lithium is located as shown. The lithium acts as a Lewis acid in directing the approach of the alkyl halide. This is reinforced by a steric effect from the phenyl substituent. As a result, alkylation occurs predominantly from the lower face of the anion. The sequence in which the groups R and R are introduced... 

Chiral oxazolines have been used in the chiral-selective assembly of carboxylic acids and lactones. The chiral oxazoline (407) was prepared using a commercially available chiral aminodiol. Metallation at -78 °C gave a lithiooxazoline which was alkylated with a variety of alkyl halides to afford on acid hydrolysis a-alkylalkanoic acids (409) of the (S)-configuration (72-82% e.e.). The methoxyamino alcohol released during the hydrolysis could be recycled to produce again the chiral oxazoline (Scheme 91) (79PAC1255). 

Simple alkylation of the chiral chelate complex leads to formation of chiral dialkylacetic acids (Scheme 109).3S5 388 Simpler chiral enamines can also be used. The formation of chiral propanoic acids results from a resolution of racemic alkyl halides by the interaction of a chiral lithiooxazoline, which recognizes and reacts with one enantiomer at the expense of the other (Scheme 110).389 The above aspects of the asymmetric carbon—carbon bond formation from chiral oxazolines have been reviewed by Meyers.390... 

Alkylation of chiral 2-(aminomethyl)oxazoline (105 Z = CH2PI1) at the exocyclic carbon—using n-butyllithium and an alkyl halide—proceeds with negligible de. However, when the amine reactant is changed to a carbamate, e.g. (105 Z = CO2PI1), the products exhibit up to 92% de.m This is ascribed to a preferred formation of an E-enolate-type intermediate during deprotonation, due to complexation of the lithium by the carbamate carbonyl. 

Coupling of R Br(Cl) with R2SnBu. 2 Alkyl halides couple with 2-(tributyl-stannyl-4,4-dimethyl-2-oxazoline (2) in the presence of this Pd catalyst (equation... 

Figure 3.28 Synthesis of an alkyl halide functionalised chiriil oxazoline.

Hardacre and Doherty described the synthesis and use of OSs supported bis(oxazolines) in various copper catalyzed reactions such as Diels-Alder reaction [97] and Mukaiyama-Aldol reactions [98], Starting from mono methyl substituted box ligand, deprotonation followed by alkylation using an excess of dibromopentane provided the required alkyl halide for quatemarisation. After ion metathesis the imidazolium supported box ligand (L12) is isolated in a good 62% overall yield (Fig. 30). 

Based on the same idea, of using alkyl halides as initiators for the ring opening polymerization of 2-alkyl oxazolines, Schulz and Dworak partially hydrolyzed... 

ABA and AB block copolymers were synthesized by the initiation of 2-oxazoline polymerization by a polymer containing tosylate (140-143) or alkyl halide end groups (144-147). 

In 1982, Evans reported that the alkylation of oxazolidinone imides appeared to be superior to either oxazolines or prolinol amides from a practical standpoint, since they are significantly easier to cleave [83]. As shown in Scheme 3.17, enolate formation is at least 99% stereoselective for the Z(0)-enolate, which is chelated to the oxazolidinone carbonyl oxygen as shown. From this intermediate, approach of the electrophile is favored from the Si face to give the monoalkylated acyl oxazolidinone as shown. Table 3.6 lists several examples of this process. As can be seen from the last entry in the table, alkylation with unactivated alkyl halides is less efficient, and this low nucleophilicity is the primary weakness of this method. Following alkylation, the chiral auxiliary may be removed by lithium hydroxide or hydroperoxide hydrolysis [84], lithium benzyloxide transesterification, or LAH reduction [85]. Evans has used this methology in several total syntheses. One of the earliest was the Prelog-Djerassi lactone [86] and one of the more recent is ionomycin [87] (Figure 3.8). 

With oxazolines substituted only in the 4-position, the selectivity peaked at about 70% with either R = i-Pr, Ph, or Bn (c.f. entries 3-5. 9. and 10) 32. Note that in all these examples, the aldehyde appears to approach the Grignard from the side opposite R (i.e., )3-face as illustrated, assuming chelation of the magnesium by the oxazolinc nitrogen).This is in contrast to the chirality sense of the reaction of the lithium analog with alkyl halides, where approach of the electrophile is from the cr-face 48. Although this came as a surprise,... 

Under appropriate conditions, mostly using alkyl halides, triflates, or tosylates as initiator, the CROP of 2-oxazolines proceeds via a living mechanism [84, 86]. In such an ideal living polymerization, all polymer chains are initiated at the same time by nucleophilic attack of the imino ether onto an electrophilic initiator. Similar to the previously discussed cationic polymerizations, the CROP... 

The overall conversion of alkyl halides (418) into N-substituted acetamides (420) can be achieved by sequential N-alkylation of 2-methyl-2-oxazoline, ring cleavage of the resulting salt using NaSePh and oxidative elimination to give the... 

Fragmentations of heterocycles have played an important role in the preparation of amide derivatives. Moderate to good yields of a-hydroxy-amides were obtained on reaction of a-hydroxy-acid aceto-nides with primary amines.N-Alkyl-2-methyl-2-oxazolinium salts (obtained by mixing alkyl halides and 2-methyl-2-oxazoline in dichloromethane) were found to react with sodium benzeneselenolate to yield -(2-phenylselenoethyl)-t -alkylacetamides, which after oxidation to ] -vinyl analogues with sodium metaperiodate in methanol, gave secondary amides on sequential treatment with mercuric acetate in aqueous tetrahydrofuran and sodium borohydride/3M... 

Among other reactions, the bis-metallated species (151) derived from nitroalkanes condense with dialkyl carbonates to give comp>ounds (152), in 60—80% yield, which can serve as precursors of both a-amino-acids and a-hydroxyamino-esters as well as a-keto-esters. Oxazolin-5-ones (153) can be alkylated at the 4-position by alkyl halides in hot DMF containing HMPA and ethyldi-isopropylamine. Yields are good (60—90%) for allylic, benzylic, and propargylic halides but otherwise poor (e.g. 32% with EtI) under these conditions acid hydrolysis of the products affords substituted a-amino-acids. Mesoionic l,3-oxazol-5-ones (154), obtained from imidoyl chlorides and acyl-tetracarbonylferrates, react with alcohols to give N-acyl-a-amino-acid esters. ... 

Phenyl-2-oxazolin-5-one undergoes ready 4,4-substitution with activated alkyl halides. " Oxidation of the a,a-dialkylated hippuric acids obtained from hydrolysis of the oxazolinones then yields symmetrical ketones (Scheme 17). 

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