4,5-Dihydrooxazole

5-Dihydrooxazole was previously known as A -oxazoline or 2-oxazoline. It follows from mi-crowave spectra that the ring is planar. 

On the basis of this reaction, 4,5-dihydrooxazoles can be regarded as carboxylic acid dervatives, i.e. as cyclic imido esters [74]. 

5-Dihydrooxazoles are prepared from y0-amino alcohols (from oxiranes and ammonia, see p 18) and carboxylic acids or carboxylic esters [75]. A -(2-Hydroxyalkyl)carboxylic acid amides can be isolated as intermediates and subsequently subjected to thermal cyclodehydration or to the action of H2SO4, SOCI2 or to other dehydrating agents  

5-Dihydrooxazoles are widely used as building blocks and auxiliaries in organic synthesis because of their accessibility and the mild hydrolytic conditions for ring-opening. The CH-acidity of 2-alkyl-4,5-dihydrooxazoles, the electrophilic reactivity at C-2 in A -alkyl-4,5-dihydrooxazolium salts and the activation of 2-aryl substituents in the 4,5-dihydrooxazole system in metalation reactions have all been synthetically exploited as shown in the following examples  

A chiral 2-alkyl-4,5-dihydrooxazole 7 is obtained by the use of (+)-( 5, 2 S)-1-phenyl-2-aminopropane-1,3-diol, available from the chiral pool (see p 115). From this, the methyl ether 8 is prepared using sodium hydride and iodomethane. As a result of internal asymmetric induction, the alkylation of its lithium derivative occurs diastereoselectively. In the case of = Me, = Et, hydrolysis yields the (+)-( S)-enantiomer of 2-methylbutanoic acid 9, with ee = 67 %, as the main product  

As a mechanistic rationale for this two electron/two proton transfer, formation of an iodine (Ill)-educt complex 18 can be envisaged, which undergoes redox disproportionation by loss of Ph-I and HOAc leading to the benzoxazole system via intermediate 19. 

Oxazole formation can be interpreted as Cu-mediated O-arylation of the amide function ( 21) followed by NH-deprotonation. 

Benzoxazole forms colorless crystals of mp 31 °C. Some benzoxazole derivatives are used I p I as pharmaceuticals, for example, 2-amino-5-chlorobenzoxazole as a sedative. ---  

5- Dihydrooxazoles are weak bases and form salts with strong acids. They undergo a stepwise hydrolysis in aqueous acid medium to give salts of fS-amino alcohols and carboxylic acids. The nucleophile attacks at the 2-position, as in oxazohum salts  

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A different approach to chiral oc-hydroxy acids 4 is the nucleophilic addition of organometallic reagents to chiral oc-oxo 4,5-dihydrooxazoles 2, which can be synthesized by oxidation of the corresponding 2-alkyl-4,5-dihydrooxazoles l17,19. 

Results of nucleophilic addition reactions to various a-oxo 4,5-dihydrooxazoles are summarized in Table 24. In general, the diastereoselectivity of these reactions is low to moderate, although an increased selectivity is found in the presence of triethylamine or N,N,N, N -te-tramethylethylenediamine, which slow down the rate of reaction. Nevertheless, enantiomerical-ly pure 2-hydroxy carboxylic acids can be prepared by this method, since the diastereomeric addition products are separable either by recrystallization or HPLC21. 

Under inversion of the configuration at sulfur, enantiomerically pure 4,5-dihydro-2-[(7 )-sulfinylmethyl)]oxazoles (e.g 2) are obtained from metalaled 4,5-dihydrooxazoles and (-)-menthyl (5,)-4-methylbenzenesulfinate31. 

Reaction of the corresponding lithiated 2-ethyl-4,5-dihydrooxazole 8 with 2-methylpropanal affords a 82 18 mixture of the anti- and. yw-adducts from which 75% of the pure (Y S,2 S)-anti-enantiomer can be isolated by chromatography19. 

Enhanced anti selectivity is observed in reactions of lithiated 4.5-dihydrooxazoles bearing an additional substituent which facilitates the formation of rigid azaenolates by internal chelation of lithium13. Thus, reaction of 2-ethyl-4,5-dihydro-4,4-dimethyloxazole (10) with 2-methylpropanal gives a 56 44 mixture of adducts while (R)-2-ethyl-4,5-dihydro-4-(methoxymethyl)-oxazolc (12) reacts with the same aldehyde to yield a 90 10 mixture of adducts 1313. 

Both Friedel-Crafts acetylation and Vilsmeier formylation of the 2,3-dihydrooxazole 5 occur at C-5, indicating that the A-acyliminium ion is more stable than the oxonium ion17. This is corroborated by ab initio calculations, which show that 3-formyl-2,5-dihydro-3-oxazolium 7 is ca. 46 kJ mol 1 more stable than 3-formyl-2,4-dihydro-l-oxazolium 817. 

Formation of C-C Bonds by Addition to Olefinic Double Bonds Enimines, Nitroalkenes, 4,5-Dihydrooxazoles, a,/MJnsaturated Sulfones, Sulfoxides and Sulfoximines... 

I.5.3.3. Addition to 2-Vinyl or 2-Aryl-4,5-dihydrooxazoles I.5.3.3.I. Diastereofacial Selectivity Chiral 4,5-Dihydrooxazoles... 

The addition of various alkyllithium reagents to ( )-2-(l-alkenyl)-4,5-dihydrooxazoles in THF at —78 °C followed by acid hydrolysis gave nonracemic chiral / ,/>-disubstituted carboxylic acids in high enantiomeric purity (>91% ee). 

In some cases the yields were poor due to competing deprotonation of the substrate by the organolithium reagent. Deprotonation was the predominant reaction with methyllithium or when (Z)-2-(l-alkenyl)-4,5-dihydrooxazoles were employed. The stereochemical outcome has been rationalized as occurring from a chelated transition state. The starting chiral amino alcohol auxiliary can also be recovered without racemization for reuse. 

More recently, 4-/m-hutyl- and 4-isopropyl-substituted 4,5-dihydrooxazoles were found to be superior to the original 4-methoxymethyl-5-phenyloxazolines9. Thus, addition of butyl-lithium to 2-(1 - or 2-naphthyl)-substituted 4-ter/-butyl-4,5-dihydrooxazole followed by addition of iodomethane gave adducts in 99 1 and 98.5 1.5 diastereoselection, respectively. The 4-isopropyl analog was less diastereoselective, although the diastereoselection was superior to that of the original 4,5-dihydro-4-methoxymethyl-5-phenyloxazole. 

A flame-dried flask under argon containing a 0.08 M THF solution of 317 mg (1.0 mmol) of the 2-(l- or 2-naphthyl)-substituted 4,5-dihydrooxazole is cooled to a temperature of between — 80 and 0 CC (see ref 7) and is treated with 1.5-2.0 equiv of the alkyllithium. The solution becomes deep red over 2-4 h and is quenched by the dropwise addition of 1.5 equiv of the electrophile (either neat or as a THF solution). The temperature is maintained for 1 h and then the solution is warmed gradually to 0 JC. The solution is diluted with 100 mL of diethyl ether and washed with 5 mL of sat. NH4C1, followed by 3 mL of sat. aq NaCI. The combined aqueous layers are back-extracted with 10 mL of CII2C12, and the combined extracts are dried over Na2S04. Concentration of the filtrate in vacuo provides a yellow oil, which is flash chromatographed over silica gel (1 -10% ethyl acetate in hexane) to yield the desired adducts. The diastereomeric ratios are determined by HPLC (Zorbax Sil column, Du Pont). 

In contrast, the reaction of 147 with 1, in the absence of catalyst, affords traces of adduct after 3 days. The activation by I2 is due to the formation of cationic iodolactonization intermediate 148 (Scheme 4.28) which reacts easily with the diene, affording the dihydrooxazole 149 which is then treated with Bu N to give the final adduct. With some substrates, this method of activation was proved to be more effective than the use of Lewis acids. 

Using the above procedures, allyl a-azido alkyl ethers of type 281 were prepared by employing an unsaturated alcohol such as allyl alcohol [76] (Scheme 32). The reaction of an aldehyde with allyl alcohol and HN3 in a ratio of 1 3 9 carried out in the presence of TiCl4 as catalyst provided azido ethers 281, 283, and 285 in 70-90% yield. The ratio of reagents is critical to ensure a high yield of azido ether and to prevent formation of acetal and diazide side products [75]. Thermolysis of azido alkenes 281, 283, and 285 in benzene (the solvent of choice) for 6-20 h led to 2,5-dihydrooxazoles 282,284, and 286, respectively, in 66-90% yield. 

The overall pathway for the conversion of the unsaturated azido ether 281 to 2,5-dihydrooxazoles 282 involves first formation of the dipolar cycloaddition product 287, which thermolyzes to oxazoline 282 or is converted by silica gel to oxazolinoaziridine 288. While thermolysis or acid-catalyzed decomposition of triazolines to a mixture of imine and aziridine is well-documented [71,73], this chemoselective decomposition, depending on whether thermolysis or exposure to silica gel is used, is unprecedented. It is postulated that acidic surface sites on silica catalyze the triazoline decomposition via an intermediate resembling 289, which prefers to close to an aziridine 288. On the other hand, thermolysis of 287 may proceed via 290 (or the corresponding diradical) in which hydrogen migration is favored over ring closure. 

Asymmetric synthesis of tricyclic nitro ergoline synthon (up to 70% ee) is accomplished by intramolecular cyclization of nitro compound Pd(0)-catalyzed complexes with classical C2 symmetry diphosphanes.94 Palladium complexes of 4,5-dihydrooxazoles are better chiral ligands to promote asymmetric allylic alkylation than classical catalysts. For example, allylic substitution with nitromethane gives enantioselectivity exceeding 99% ee (Eq. 5.62).95 Phosphi-noxazolines can induce very high enatioselectivity in other transition metal-catalyzed reactions.96 Diastereo- and enantioselective allylation of substituted nitroalkanes has also been reported.9513... 

Cyclization of. V-alkeny lam ides to 2-oxazolines was achieved in very mild conditions with fert-butyl hypoiodite <06OL3335>. The 5-exo-dig gold(I)-catalyzed cyclization of propargylic trichloroacetimidates 129 proceeded with remarkably efficiency under very mild conditions to give 4-methylene-4,5-dihydrooxazoles 130 in good yields. The mildness of the protocol was clearly responsible for the lack of isomerization of the final products to the corresponding, thermodynamically more stable, oxazoles <06OL3537>. 

This regioselectivity is practically not influenced by the nature of subsituent R. 3,5-Disubstituted isoxazolines are the sole or main products in [3 + 2] cycloaddition reactions of nitrile oxides with various monosubstituted ethylenes such as allylbenzene (99), methyl acrylate (105), acrylonitrile (105, 168), vinyl acetate (168) and diethyl vinylphosphonate (169). This is also the case for phenyl vinyl selenide (170), though subsequent oxidation—elimination leads to 3-substituted isoxazoles in a one-pot, two-step transformation. 1,1-Disubstituted ethylenes such as 2-methylene-1 -phenyl-1,3-butanedione, 2-methylene-1,3-diphenyl- 1,3-propa-nedione, 2-methylene-3-oxo-3-phenylpropanoates (171), 2-methylene-1,3-dichlo-ropropane, 2-methylenepropane-l,3-diol (172) and l,l-bis(diethoxyphosphoryl) ethylene (173) give the corresponding 3-R-5,5-disubstituted 4,5-dihydrooxazoles. 

Condensation of 2-bromoethylamine hydrobromide with benzoyl chloride in benzene in the presence of 5 equivalents of EtsN gave 2-phenyl-4,5-dihydrooxazole (1) in 67% yield [1]. Treatment of 1 with 3 equivalents of NBS in boiling CCL in the presence of AIBN led to 5-bromo-2-phenyloxazole (2). Presumably, sequential bromination and dehydrobromination of 1 led to 2-phenyloxazole, which underwent further bromination to afford 2. 

Aromatic pyrrolo[2,l- ]oxazoles are unknown compounds. Dihydro derivatives 228 and 229 have been obtained from the thermal rearrangement of dihydrooxazole 226 through intermediate 227 (Scheme 32) <2003EJ01438>. 

Care must be taken in the choice of organic solvent. Chloroform should never be used under the basic conditions due to the risk of the formation of isocyanides (see Chapter 7) and the use of carbon disulphide can lead to formation of dithiocarba-mates, e.g. dimethyl A -(ethoxycarbonylmethyl)iminodithiocarbonate is formed (35-39%), as the major product in high purity, in the liquiddiquid two-phase methyl-ation of ethyl glycinate in carbon disulphide [15]. The product is useful as an intermediate in the synthesis of thiazoles [15] and dihydrooxazoles [16]. 

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