4.5- Disubstituted-2-oxazolidinon

It is possible to distinguish a 4,5-trans-disubstituted oxazolidinone or imidazolidinone from its 4,5-ds-analogue by using H NMR analysis. Indeed, both H4 and H5 protons resonate systematically at lower field for the ds-isomer than for the trans-isomer, and higher /4i5 coupling constants are observed for the ds-oxazolidinones (Table 8). In addition, nuclear Overhauser effect (NOE) enhancement experiments confirm the cis or trans relationship of the H4 and H5 protons. 

This imide system can also be used for the asymmetric synthesis of optically pure a,a-disubstituted amino aldehydes, which can be used in many synthetic applications.31 These optically active a-amino aldehydes were originally obtained from naturally occurring amino acids, which limited their availability. Thus, Wenglowsky and Hegedus32 reported a more practical route to a-amino aldehydes via an oxazolidinone method. As shown in Scheme 2 20, chiral diphenyl oxazolidinone 26 is first converted to allylic oxazolidinone 27 subsequent ozonolysis and imine formation lead to compound 28, which is ready for the a-alkylation using the oxazolidinone method. The results are shown in Table 2-6. 

There are few addition reactions to a,/J-disubstituted enoyl systems 151 that proceed in good yield and are able to control the absolute and relative stereochemistry of both new stereocenters. This is a consequence of problematic A1,3 interactions in either rotamer when traditional templates such as oxazolidinone are used to relieve A1,3 strain the C - C bond of the enoyl group twists, breaking conjugation which results in diminished reactivity and selectivity [111-124], Sibi et al. recently demonstrated that intermolecular radical addition to a,/J-disubstituted substrates followed by hydrogen atom transfer proceeds with high diastereo- and enantioselectivity (151 -> 152 or 153, Scheme 40). 

Chiral 4-Substitutcd and 4,5-Disubstituted 3-Acyl-2-oxazolidinones 11 General Acylation Procedure4,611,23,24 26 31-53. 

Chiral 4,5-Disubstituted and 4-Substituted 3-(2-Alkyl-l-oxoalkyl)-2-oxazolidinones 11/12 General Alkylation Procedure ... 

For the final step involving functionalization at N( ) of 62, anilide deprotonation with lithiated 4-benzyl-2-oxazolidinone as a base and alkylation with benzyl bromides again proved effective. Compared to the results obtained in the benzodiazepine series, the N( 1 )-alkylation reaction was generally found to proceed less smoothly with the 3,4-disubstituted quinox-alinones 62. Good results were obtained only if the resin batches were submitted twice to the alkylation conditions. Figure 3.4 displays a selection of structures (63-65) accessible from this first synthetic approach. In no case was there any evidence for racemization at the a-carbon atom of the amino acid. 

Scheme 2.28 The direct enantioselective a-amination of a,a-disubstituted aldehydes catalyzed by L-proline, and further transformations to optically active oxazolidinones.

The first simple 5(2/f)-oxazolones were the trifluoromethyl derivatives obtained by treating a-amino acids with trifluoroacetic anhydride (equation 156). A general synthesis of 2,2-disubstituted 5(2/f)-oxazolones is the condensation of a- (hydroxylamino) acids with ketones (equation 157) (80S55). The dehydrogenation of 2,2-bis(trifluoromethyl)-5-oxazolidinones affords bis(trifluoromethyl) derivatives (equation 158) (79LA1547). 

Disubstituted thiochroman-4-ols are formed with excellent enantio- and diastereo-selectivity when thiosalicylaldehydes react with an a,P-unsaturated oxazolidinone in the presence of a chiral bifunctional amine-thiourea catalyst. A tandem Michael - aldol process is involved (Scheme 43) <07JA1036>. 

The raws-3,4-disubstituted cyclohexene 84 affords the corresponding 2-oxazolidinone 9 by treatment with bromonium dicollidine perchlorate. 

Other examples of the synthesis of (4S,5S)-disubstituted 2-oxazolidinones. with inversion of configuration, are known, e.g., the conversion of 24 into 25. 

Analogously, after enolization with Ihmds, hypervalent iodine compounds such as PhI(OAc)2 have been used for the stereoselective synthesis of 2,3-disubstituted succinates by using the chiral oxazolidinone auxiliary (45 )-4-(phenylmethyl)-2-oxazolidinone (equation 19) . 

Solid-phase synthesis of substituted pyrazolones 550 from polymer-bound /3-keto esters 549 has been described (Scheme 68) <2001EJ01631>. Trisubstituted pyrazole carboxylic acids were prepared by reaction of polymer-bound arylidene- or alkylidene-/3-oxo esters with phenylhydrazines <1999S1961>. 2-(Pyrazol-l-yl)pyrimi-dine derivatives were prepared by cyclocondensation of ethyl acetoacetate and (6-methyl-4-oxo-3,4-dihydropyrimi-din-2-yl)hydrazine with aromatic aldehydes <2004RJC423>. Reactions of acylated diethyl malonates with hydrazine monohydrochloride in ethanol afforded 3,4-disubstituted-pyrazolin-5-ones <2002T3639>. Reactions of hydrazines with A -acetoacetyl derivatives of (45 )-4-benzyloxazolidin-2-one (Evans oxazolidinone) and (2R)-bornane-10,2-sultam (Oppolzer sultam) in very acidic media gave pyrazoles retaining the 3(5)-chiral moiety <1999S157>. 

Amino alcohols. By decomposition of allylic azidoformates to produce bicyclic oxazolidinone substrates for ring opening reactions, a stereoselective entry into jyn-1,2-amino alcohols is delineated. Thus, after treatment of the aziridines with organocopper species, trani-4,5-disubstituted oxazolidin-2-ones (14 examples, 55-91%) are obtained. 

Another standard method for the synthesis of 2-oxazolidinones is by reaction of epoxides with isocyanates. Although 4,5-disubstituted derivatives are not readily accessible by this route, it has been shown that iminodioxolanes (192) add to epoxides in the presence of AICI3 to afford these oxazolidinones in high yield <9lJOC2684>. The reaction proceeds through a spirocyclic intermediate (193) (Scheme 96). The reaction of vinyl epoxides with aryl isocyanates is facilitated by palladium catalysis (Equation (28)) <89TL3893>. The products are obtained by a double inversion process, but... 

Oxidation of the 1,1-disubstituted hydrazine, 3-amino-2-oxazolidinone (1), with bromine water, with potassium iodate-HN03, or with potassium bromate in 6 N HC1 affords a compound melting at 299° and now recognized as the trans-3,3 -azobis(2-oxazolidinone) of formula (2). Forgione et al. 5 explored oxidation with yellow mercuric oxide in dioxane or THF at 25° and obtained an isomeric product, m.p. 171°, in 50% yield along with a little of the trans isomer (2). Infrared, UV,... 

Evans s oxazolidinones 1.116 and 1.117 are a class of chiral auxiliaries that has been widely applied [160, 167, 261, 411]. Deprotonation of 7/-acyl-l,3-oxa-zolidin-2-ones 5 30 and 5.31 smoothly gives chelated Z-enolates, which then suffer alkylation between -78 and -30°C on their least hindered face [167, 1036]. After hydrolysis, the corresponding enantiomeric acids are obtained according to the auxiliary that was used (Figure 5.21). Due to the low reactivity of lithium enolates, sodium analogs are preferred in some cases [411, 862, 1036], This methodology has been applied to the synthesis of chiral a-arylpropionic acid anti-inflammatory drugs [1037, 1038], natural products [1039, 1040], and a-substituted optically active 3-lactams en route to nonracemic a,a-disubstituted aminoacids [136,1041]. 

As one application of cobalt-mediated radical carbon-to-carbon bond forming reactions, the reaction between 2-oxazolidinone (255) and cobaloxime(I) gave an inseparable mixture of (Z) and ( ) 3-oxo-6,7-disubstituted perhydropyrrolo[l,2-c]oxazole (256) in high yield, and variable amounts of the a,)8-unsaturated esters (257) (Equation (28)) <92T9373>. 

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