1,3-Oxazoline-4-carboxylic acid

Following the original report that the oxazoline carboxylic acid 7.5.12 can serve as an excellent side chain precursor 281), several syntheses of this compound have been reported. Thus racemic oxazoline was prepared from protected cinnamyl alcohol by addition of phenyl-selenyl triflate and azide ion to give the adduct 7.5.9, which was then converted to oxazoline 7.5.10 and ester 7.5.11 282). A similar but more efficient route used diphenyldiselenide and ammonium persulfate to give the racemic oxazoline 7.5.10 in 95% yield from cinnamyl acetate 283). 

PMMA-f-oxazoline/carboxylic acid-terminated PS TEM/solid-state NMR/static light scattering Holderle et al. 1998... 

Ring-opening reaction Oxazoline Carboxylic acid, MAn, amine, halide ... 

ScHOLLKOPF et al (360) reacted a-metallated isocyanoacetic ester with aldehydes and ketones in aprotic solvents to form formyl-enamino acid esters (24) via intermediate oxazoline carboxylic acid esters. 

A number of 2-acylazetidines have been prepared by reaction of 1,3-dihaloacyl compounds with amino derivatives (Section 5.09.2.3.l(m)). This is illustrated for azetidine 2-carboxylic acid (56), the only known naturally occurring azetidine. Ring expansion of activated aziridines (43) and contraction of 4-oxazolines (55) has also found limited use (Section 5.09.2.3.2(f) and Hi)). 

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. ... 

Scheme 15 Parallel synthesis of 2-oxazolines from carboxylic acids and aminoalcohols using PS-Mukaiyama reagent...

When the reaction is run with potassium fert-butoxide in THF at -5°C, one obtains (after hydrolysis) the normal Knoevenagel product (32), except that the isocyano group has been hydrated (16-65). With the same base but with DME as solvent the product is the nitrile (33). When the ketone is treated with 31 and thallium(I) ethoxide in a 4 1 mixture of absolute ethanol and DME at room temperature, the product is a 4-ethoxy-2-oxazoline (34). Since 33 can be hydrolyzed to a carboxylic acid and 34 to an a-hydroxy aldehyde, this versatile reaction provides a means for achieving the conversion of RCOR to RCHR COOH, RCHR CN, or RCR (OH)CHO. The conversions to RCHR COOH and to RCHR CN have also been carried out with certain aldehydes (R = H). 

Whereas cycHzation of the cu-keto-co -hydroxyamide 1466 in boihng toluene or xylene in the presence of camphorsulfonic acid (CSA) results in decomposition of the starting material 1466, heating of 1466 with excess TMSOTf 20 and N-methyl-morphoHne in 1,2-dichloroethane affords 46% of the desired cycHzation product 1467 [30] (Scheme 9.16). The close relationship of product 1467 to d -oxazolines suggests that reaction of carboxylic acids 11 with free (or C-substituted) ethanola-mines 1468 and HMDS 2/TCS 14 might lead analogously, via the silylated intermediates 1469, to d -oxazolines 1470 and HMDSO 7. As demonstrated in the somewhat related cyclization of 1466 to 1467, combination of TMSOTf 20 with N-... 

To examine if the higher catalytic activity and selectivity of 47a as compared to the COP-X system 46 is mainly caused by the pentaphenyl ferrocenium or by the imidazoline moiety, oxazoline 53-Cl was prepared in diastereomerically pure form starting from carboxylic acid 51 and (5)-valinol via oxazoline 52 (Fig. 27) [73]. 

Carboxylic acids can be protected as oxazolines [96, 105-107, 186, 191] or as ester functions. Alkynic esters such as silyl esters [153, 211], tert-butyl esters [216], and even benzyl esters [153, 211] have been successfully hydrozirconated when the reactive site was a terminal alkyne or vinyl group (Scheme 8-27). 

Because of the easy conversion of A-acylaziridines[471 into oxazolines, this method is also useful for protecting carboxylic acids furthermore, it is a means for resolving chiral carboxylic acids. 

A direct catalytic conversion of esters, lactones, and carboxylic acids to oxazolines was efficiently achieved by treatment with amino alcohols in the presence of the tetranuclear zinc cluster Zn4(0C0CF3)60 as catalyst, essential for condensation and cyclodehydration reactions. For example, the use of (5)-valinol allowed the easy synthesis of oxazolines 125 and 126 in satisfactory yields <06CC2711>. A one-pot direct preparation of various 2-substituted oxazolines (as well as benzoxazoles and oxadiazoles) was also performed from carboxylic acids and amino alcohols (or aminophenols or benzhydrazide) using Deoxo-Fluor reagent <06TL6497>. 

Oxazoline Systems. The 2-oxazoline system has long been known42 and can readily be prepared43 from 2-aminoethanol derivatives and carboxylic acids. This compound has served as a potential precursor for elaborated car-... 

The oxazoline methodology can be applied in the total synthesis of natural products. For example, in the course of the total synthesis of European pine-saw fly pheromone 47, the key intermediate, chiral a-methyl carboxylic acid 46, was prepared via the reaction of a-lithioethyloxazoline with n-octyl iodide. The product 2-methyl decanoic acid 46 was obtained, after hydrolysis, in 72% ee (Scheme 2-26).51... 

In addition to the reactions discussed above, a,//-unsaturated oxazolines can also act as chiral electrophiles to undergo conjugated addition of organolithium reagent to give optically active / ,/ -disubstituted carboxylic acids.52 The vinyl oxazolines 48 are prepared using the two methods outlined in Scheme 2-27. 

The reactivity of oxiranes with lithium enoiates and related compounds has been widely explored and reviewed . Dianions derived from carboxylic acids react readily with oxiranes, but the reaction can be slowed by steric hindrance . The reaction of oxiranes with dianions of acetoacetates is greatly accelerated by the addition of BF3 Et20 " . Oxiranes react readily with lithium salts derived from nitriles , malonates and analogues , lithiated oxazolines and lithio enamines . 

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. 

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... 

First of all a 2-substituted oxazoline (1) is formed by cyclocondensation of a carboxylic acid ester with 2-aminoethanol and a small amount of (1) is converted with an alkylating agent (e.g., methyl tosylate) to the activated, ionic form (2). 

The conceptually simple cyclodehydration of a carboxylic acid and a (3-amino alcohol to an oxazoline requires harsh conditions of high temperature with azeotropic water removal (e.g., boric acid in refluxing xylene). Nonetheless, good yields of the oxazoline can be obtained if sensitive functionalities are absent. " A much milder approach has been developed by Vorbriiggen where the reaction of carboxylic acids with (3-amino alcohols is carried out in the... 

Oxazolines have been extensively used as masking groups for either amino alcohols or carboxylic acids. This application has been thoroughly reviewed in Greene s popular monograph and is evident throughout this chapter. Therefore, it is not repeated further here. 

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