Azlactones, addition

In contrast to the saturated azlactones, the Friedel-Crafts reaction of 2-substituted-4-arylidene-5-oxazolones is quite complex and may follow several different courses, often concurrently, depending on both reaction conditions and structural variations in the arylidene ring. This behavior is readily interpreted in terms of the a,)S-unsaturated carbonyl moiety and the cross-conjugated system containing nitrogen, both of which provide potential reaction sites in addition to the lactone carbonyl group. The reaction has been investigated " ... 

In the presence of freshly sublimed aluminum chloride and under anhydrous conditions, compounds such as 7 react with benzene to form 1,4-addition products, the saturated azlactones 18, in 70-75% yield [Eq. (12)]. If moisture is not excluded, fragmentation of... 

In contrast to these ring-opening reactions, it was observed by Horner and Schwahn that 4-arylidene-(isopropylidene and cyclo-hexylidene)-oxazolones react with alkyl Grignard reagents by conjugate addition to give saturated azlactones 29a as the only products [Eq. (18)]. 

Filler et al. noted that the labile geometric isomer of 7 gives saturated azlactones (18) in 35-40% yields, as well as products of 1,2-addition, when treated with several arylmagnesium bromides. This stereoselectivity appears to be the only reported difference in chemical behavior between isomers of this type. 

In the third transition state (TS3), the neutral catalyst is recovered by transferring the proton back from the catalyst to the substrate. In other words, the (former) azlactone ether oxygen atom deprotonates the tertiary ammonium ion. For proton transfer, again an LBHB is formed (N-0 distance 2.479 A, <(0,H,N)=166.2°). In the product complex, the catayst is neutral and the A-acylamino acid ester is bound in its iminol form to the catalyst (Product(iininol)). Finally, an additional 66.6 kJ moF are gained by the subsequent iminol-amide tautomerization (Product(ainide)) (Fig. 1). 

Saturated 2-vinyl-5(47Z)-oxazolones have been widely used as intermediates for the synthesis of polymeric compounds that will be described in Section 7.3.2.9. Apart from these polymerization reactions, the Diels-Alder reactions of 4-sub-stituted-2-vinyl-5(47/)-oxazolones 134 with cyclopentadiene are reported to give norbomenyl oxazolones 135 that are useful to prepare norbornenyl functionalized resins by azlactone ring-opening addition reactions (Scheme 7.39). 

Huisgen s group488 have described a new synthesis of pyrroles (26) from oxazol-5-ones (azlactones) (25) with DMAD and MP. The pyrrole derivatives formed in situ from 2,4-dimethyl- and 4-benzyl-2-methyloxazolone with DMAD underwent nucleophilic addition to a second mole of the acetylenic ester to give the Michael adducts 27 and 28... 

As early as 1977 Pracejus et al. investigated alkaloid-catalyzed addition of thiols to a-phthalimido acrylates, methylene azlactones, and nitroolefins [56a]. In the former approach, protected cysteine derivatives were obtained with up to 54% ee. Mukaiyama and Yamashita found that addition of thiophenol to diisopropyl mal-eate in the presence of cinchonine (10 mol%) proceeds in 95% yield and that the product, (S)-phenylthiosuccinate, was formed with 81% ee [56b]. The latter Michael adduct was used as starting material for preparation of (R)-(+)-3,4-epoxy-1-butanol. In the course of an asymmetric total synthesis of (+)-thienamycin Ike-gami et al. studied the substitution of the phenylsulfonyl substituent in the azetidi-none 69 by thiophenol in the presence of cinchonidine (Scheme 4.34) [56c]. This substitution probably proceeds via the azetinone 70. In this reaction the phenyl-thioazetidinone 71 was obtained in 96% yield and 54% ee. Upon crystallization, the optically pure substitution product 71 was obtained from the mother liquor... 

Additions to prochiral ketenes [13.2] Desymmetrization of meso-diols [13.3] Dynamic kinetic resolution of azlactones rearrangement of O-acyl azlactones, O-acyl oxindoles, O-acyl benzofuranones [13.6]... 

H)-Oxazolones react readily with nucleophiles, C(5) and C(2) be ing possible sites for attack, and, in the case of unsaturated azlactones, C(a) as well (see 199-201). It has been proved by using water labelled with lsO that the acid-catalyzed hydrolysis of unsaturated azlactones proceeds by alkyl-oxygen fission (equation 42). The formation, hydrolysis and reduction of 4-methylene-5(4H)-oxazolones is a well-established method for the synthesis of a-amino acids, e.g. phenylalanine (equation 43). The addition of hydrazoic acid to 5(4H)-oxazolones without methylene groups at C(4) likewise occurs exclusively at C(2) to yield tetrazoles by ring-opening and recyclization (equation 44). 

Treatment of saturated azlactones with aromatic compounds under Friedel-Crafts conditions gives acylamino ketones in high yield (equation 46). 4-Benzyl-2-methyl-5(4H)-oxazolone undergoes an intramolecular reaction to yield an acetamidoindanone (equation 47). Friedel-Crafts reactions of 4-(arylmethylene)-5(4H)-oxazolones are complicated by the presence of an additional electrophilic centre (cf. 201) and may follow three courses. The unsaturated azlactone (189) adds benzene under the influence of aluminum chloride to form the saturated azlactone (207) in inert solvents (189) undergoes an intramolecular acylation to yield a mixture of the indenone (208) and the isoquinoline (209 Scheme 20). 

The outcome of Grignard reactions on 5(4H)-oxazolones likewise depends on the nature of the substituent at C(4). The saturated azlactone (210) is converted by the action of phenylmagnesium bromide into the tertiary acylamino alcohol shown in equation (48) on the other hand, saturated azlactones are obtained by the action of alkyl Grignard reagents on (arylmethylene)oxazolones (equation 49). This type of oxazolone reacts with arylmag-nesium halides at the carbonyl group in the presence of copper chloride, however, the addition is directed to the methylene carbon atom. 

Catalytic Michael additions of a-nitroesters 38 catalyzed by a BINOL (2,2 -dihydroxy-l,r-bi-naphthyl) complex were found to yield the addition products 39 as precursors for a-alkylated amino acids in good yields and with respectable enantioselectivities (8-80%) as shown in Scheme 9 [45]. Asymmetric PTC (phase transfer catalysis) mediated by TADDOL (40) as a chiral catalyst has been used to synthesize enantiomeri-cally enriched a-alkylated amino acids 41 (up to 82 % ee) [46], A similar strategy has been used to access a-amino acids in a stereoselective fashion [47], Using azlactones 42 as nucleophiles in the palladium catalyzed stereoselective allyla-tion addition, compounds 43 were obtained in high yields and almost enantiomerically pure (Scheme 9) [48]. The azlactones 43 can then be converted into the a-alkylated amino acids as shown in Scheme 4. 

The azlactone can be recrystallized from alcohol, carbon tetrachloride, or from ethyl acetate with addition of petroleum ether. Aqueous solvents should be avoided, since the azlactone ring is easily opened by water. When alcohol is used for recrystallization, there is some danger of opening the azlactone ring with the formation of an ester, particularly on prolonged heating of the solution. 

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