Alkylation of oxazolines

Table 6. Enantioselective Alkylation of Oxazolines (182), derived from (S)-Aspartic Acid...

Electrophilic substitution. A number of chiral nucleophilic species have been described that result in optically active a-alkyl aldehydes, ketones, acids, and acid derivatives upon alkylation and (usually) subsequent hydrolytic cleavage. Enders provides a number of examples (Figure 3) one of which results in the ant alarm pheromone, 4-methyl 3-heptanone (26 2 7). Studies by A. I. Meyers of the chemistry of anions of chiral oxazolines (Figure 4) were the first of the genre, however ( 8 ). Related reactions of chiral anions of metalloenamines and hydrazones (29, 30, 31) have in common with the alkylation of oxazolines metallated azaenolate intermediates that predispose one face of an azaenolate double bond to reaction with the electrophile. 

Based on the study of the thermal 3-aza-Cope rearrangement of iV-allylketene Af,0-acetals, Kurth and coworkers have developed a similar methodology to the asymmetric synthesis of C(a)- and C( )-substituted-4-pentenoic acids by using a chiral auxiliary. Prepared from the alkylation of oxazolines 179 with tosylate esters 180, followed by neutralization with n-butyllithium in THF, iV-allylketene. /V,0-acetals of 182 rearrange without isolation at 180 °C to 2-butenylisoxazolines (183) with 79-92% diastereoselectivity (d.e,). Enantiomeric excess (e.e.%) reaches as high as 98%. In... 

Quaternization of the nitrogen atom in a heterocyclic system can activate the ring towards addition reactions. An oxazoline moiety was converted to an aldehyde in 97% overall yield by alkylation of oxazoline with MeOTf, reduction with sodium boro-hydride, and hydrolysis of the resulting aminal (eq 10). Alternatively, treatment of an TV-methylated oxazolium triflate with a Grignard reagent followed by aqueous acid produced a ketone. Reaction of alkenyl oxazoles with MeOTf induced spontaneous intramolecular [4 -i- 2] cycloaddition at room temperature leading to a hydroindole or a hydroisoquinoline after reduction by sodium borohydride (eq 11). ... 

The Meyers oxazoline auxiliary provides an efficient means of performing Michael addition to prochiral alkenes with excellent diastereofacial selectivity.shown below this allows convenient access to chiral -alkylated acids (83). Note, however, that the facial selectivity is opposite to that observed in the alkylation of oxazoline anions (section 5.3.1). 

General Synthesis.—One of the more significant publications of 1976 is a full report 1 from Meyer s group on the preparation of chiral a-alkylalkanoic acids (2) in up to 80% optical yield, by alkylation of chiral 2-oxazolines (1) (Scheme 1). The thorough study has revealed that alkyl iodides or activated halides afford maximum yields, and that no racemization occurs on hydrolysis thus the propanediol derivative (3) can be recycled. In addition, it is possible to predict which enantiomer of acid (2) will be obtained on double alkylation of oxazoline (4) by due consideration of the order of alkylation. The carbanion from (4) has also been found to be capable of chiral recognition of racemic secondary alkyl iodides to afford 3-alkylalkanoic acids in ca. 40% optical purity. In similar studies, oxazoline... 

Scheme 12.6 Asymmetric phase-transfer catalytic alkylation of oxazoline, thiazoline, imidazoline and other relative derivatives.

Methylene thiirane is obtained by thermolysis of several spirothiirane derivatives which are formally Diels-Alder adducts of methylenethiirane and cyclopentadiene or anthracene <78JA7436). They were prepared via lithio-2-(methylthio)-l,3-oxazolines (c/. Scheme 121). A novel synthesis of the allene episulfide derivatives, 2-isopropylidene-3,3- dimethylthiirane (good yield) or its 5-oxide (poor yield), involves irradiation of 2,2,3,3-tetramethyl-cyclopropanethione or its 5-oxide (81AG293). Substituents on the thiirane ring may be modified to give new thiiranes (Section 5.06.3.9). The synthesis of thiirane 1-oxides and thiirane 1,1-dioxides by oxidation is discussed in Section 5.06.3.3.8 and the synthesis of 5-alkylthiiranium salts by alkylation of thiiranes is discussed in Section 5.06.3.3.4. Thiirene 1-oxides and 1,1-dioxides may be obtained by dehydrohalogenation of 2-halothiirane 1-oxides and 1,1-dioxides (Section 5.06.4.1.2). 

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. ... 

The first use of chiral oxazolines as activating groups for nucleophilic additions to arenes was described by Meyers in 1984. " Reaction of naphthyloxazoline 3 with phenyllithium followed by alkylation of the resulting anion with iodomethane afforded dihydronaphthalene 10 in 99% yield as an 83 17 mixture of separable diastereomers. Reductive cleavage of 10 by sequential treatment with methyl fluorosulfonate, NaBKi, and aqueous oxalic acid afforded the corresponding enantiopure aldehyde 11 in 88% yield. 

The mechanism of the asymmetric alkylation of chiral oxazolines is believed to occur through initial metalation of the oxazoline to afford a rapidly interconverting mixture of 12 and 13 with the methoxy group forming a chelate with the lithium cation." Alkylation of the lithiooxazoline occurs on the less hindered face of the oxazoline 13 (opposite the bulky phenyl substituent) to provide 14 the alkylation may proceed via complexation of the halide to the lithium cation. The fact that decreased enantioselectivity is observed with chiral oxazoline derivatives bearing substituents smaller than the phenyl group of 3 is consistent with this hypothesis. Intermediate 13 is believed to react faster than 12 because the approach of the electrophile is impeded by the alkyl group in 12. 

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... 

P-amino acid products. Treatment of oxazoline 53 with 7V-lithiopiperidine followed by alkylation with iodomethane affords aniline derivative 54 in 94% yield and 99% de. Hydrolysis of the oxazoline group provided amino acid 55 in 92% yield and >99% ee. 

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... 

The C2-symmetric bifunctional tridentate bis(thiazoline) 222 has been shown to promote the zinc(II)-catalyzed asymmetric Michael addition of nitroalkanes to nitroalkenes in high enantioselectivity <06JA7418>. The corresponding bis(oxazoline) ligand provides comparable enantioselectivity but higher product yield. The same bis(thiazoline) ligand has also been evaluated in the enantioselective Friedel-Crafts alkylation of indoles, but the enantioselectivity is moderate <06OL2115>. 

Addition of 2-Alkyl-2-Oxazolines All of the above mentioned reactions of nucleophilic addition of nitrones give the corresponding hydroxylamines. In this chapter, the reactions of nitrones and nucleophiles and their conversions to compounds of other structures are considered. 

The reaction of lithiated 2-alkyl-2-oxazolines with nitrones enables stereoselective and enantioselective syntheses of 5-isoxazolidinones, which are used as precursors of 3-amino acids. Highly enantiomerically enriched 5-izoxazolido-nones and 3-amino acids of inverse configuration can be generated by simply changing the chirality of the initial 2- . sopropyl-2-oxazoline (600). 

Scheme 2-25. Alkylation of chiral oxazolines to carbonyl acids 44.

TABLE 2-7. Alkylation of Chiral Oxazolines to Carbonyl Acids 4446... 

In a study published concurrently with the Evans bis(oxazoline) results, Jacobsen and co-workers (82) demonstrated that diimine complexes of Cu(I) are effective catalysts for the asymmetric aziridination of cis alkenes, Eq. 66. These authors found that salen-Cu [salen = bis(salicylidene)ethylenediamine] complexes such as 88b Cu are ineffective in the aziridination reaction, in spite of the success of these ligands in oxo-transfer reactions. Alkylation of the aryloxides provided catalysts that exhibit good selectivities but no turnover. The optimal catalyst was found to involve ligands that were capable only of bidentate coordination to copper. 

Carbonyl alkylation and condensation reactions are always of great value in synthesis, and the formation of o-ANIS ALDEHYDE via 4,4-dimethyl-2-oxazoline, 2,2-DIMETHYL-3-PHENYLPROPION-ALDEHYDE via alkylation of the magnesio-enamine salt and threo-4-HYDROXY-3-PHENYL-2-HEPTANONE via a directed aldol... 

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. 

Since ketone R)-16 was prepared in a non-selective way when an achiral imino enolate was alkylated, it was considered whether alkylation of chiral enolates, such as that of oxazoline 18, with benzyl bromide 14, would provide stereoselective access to the corresponding alkylation product 19 with R-configuration at C(8) (Scheme 4). Indeed, alkylation of 18 with 14 gave the biaryl 19 and its diastereoisomer almost quantitatively, in a 14 1 ratio. However, reductive hydrolysis using the sequence 1. MeOTf, 2. NaBH4, and 3. H30", afforded hydroxy aldehyde 20 in 25% yield at best. Furthermore, partial epimerization at C(8) occurred (dr 7.7 1). An alternative route, using chiral hydrazones, was even less successful. 

Gawley and coworkers showed that oxazolines can be used in place of formamidines for asymmetric alkylations of tetrahydroisoquinolines. A number of substituted oxazolines were evaluated as chiral auxiliaries, and one derived from valinol was found to be optimal. Interestingly, the same enantiomer of valinol affords the opposite enantiomers of the substituted tetrahydroisoquinoline when incorporated into formamidine or oxazoline auxiliaries. An example is shown in Scheme 58, as applied to a synthesis of laudanosine and the morphinan 9-7 -0-methylflavinantine. ° ... 

The amide derived from the carboxylic acid in Ugi adducts is in most cases tertiary, and therefore it cannot serve as nucleophilic partner in post-condensation transformations, unless a post-Ugi rearrangement converts it into a free amine [52, 54]. An exception is represented by Ugi adducts derived from ammonia, which give rise to two secondary amides, each of them potentially involved, as nucleophile, in nucleophilic substitution processes. Four competitive pathways are in principle possible (N- or 0-alkylations of the two amides), and the reaction is mainly driven by the stability of the formed rings. In the example shown in Fig. 12, 0-alkylation of the carboxylic-derived amide is favoured as it generates a 5-membered ring (oxazoline 62), while the alternative cyclization modes would have formed 3- or 4-membered rings [49]. When R C02H is phthalic acid, however, acylaziridines are formed instead via Walkylation [49]. In both cases, the intramolecular 8 2 reactions takes place directly under the Ugi conditions. 

Hoogenboom R, Thijs HML, Fijten MWM, Schubert US (2007) Synthesis, characterization, and cross-linking of a library of statistical copolymers based on 2- soy alkyl -2-oxazoline and 2-ethyl-2-oxazoline. J Polym Sci Part A Polym Chem 45 5371-5379... 

The living cationic ring opening polymerization (CROP) of 2-oxazolines was first reported in the 1960s [61, 62]. The polymerization can be initiated by an electrophile such as benzyl halides, acetyl halides, and tosylate or triflate derivatives. The typical polymerization mechanism for 2-alkyl-2-oxazoline initiated by methyl tosylate is shown in Scheme 6. 

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... 

This hl-alkylated heterocycle (2) acts as the actual initiator because it is attacked rapidly under ring-opening by an oxazoline molecule, present in excess. The newly formed dimer (3) contains an ionic ring function, which is subjected to the same attack as the initiator molecule. The molecular weight of the polymers is controlled by the amount of the alkylating agent. Other suitable initiators for the polymerization of oxazolines are Lewis acids, protic acids, and alkyl chloroformates. 

Conversion of 2 to the highly crystalline oxazolidinone 3 with phosgene has been described by Thornton who has employed this substance as a chiral auxiliary in asymmetric aldol reactions of its N-propionyl derivative. Kelly has also used an oxazoline derived from 3 as a chiral auxiliary in asymmetric alkylation of a glycolate enolate. Oxazolidinone 3 has also been prepared from 2 with diethyl carbonate in the presence of potassium carbonate. The conversion of 2 to the oxazolidinone 3 is accomplished using triphosgene in this procedure because of the high toxicity of phosgene. 

The authors applied the same synthetic strategy to racemic 4-alkyl -(iodo-methyl)-2-phenyl-5(4/ )-oxazolones 266 and obtained a diastereomeric mixture of oxazolines 267 and 268 (Scheme 7.86). The diastereoisomers were separated chromatographicaUy and then converted into dipeptides incorporating an a-alkyl-serine residue. ... 

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