Oxazoline, formation

In addition to a-additions to isocyanides, copper oxide-cyclohexyl isocyanide mixtures are catalysts for other reactions including olefin dimerization and oligomerization 121, 125, 126). They also catalyze pyrroline and oxazoline formation from isocyanides with a protonic a-hydrogen (e.g., PhCH2NC or EtOCOCHjNC) and olefins or ketones 130), and the formation of cyclopropanes from olefins and substituted chloromethanes 131). The same catalyst systems also catalyze Michael addition reactions 119a). 

The 1-t-butylphospholane sulfide intermediate to TangPhos was also used to prepare the P,N ligands 48 by reacting the lithium complex with C02 and then oxazoline formation with a range of chiral amino alcohols [69b, 74]. The Ir complexes of these ligands have been successfully used in the reduction of / -methylcinnamic esters (80-99% ee) and methylstilbene derivatives (75-95% ee), a particularly challenging class of unfunctionalized olefins [4 c]. 

The synthesis is similar to that of the PHOX catalysts (Scheme 29.6), starting with oxazoline formation from the pyrrole nitrile and an amino alcohol, followed by introduction of the phosphine group. 

Ham et al. [60] used an unselective attack of a vinyl Grignard reagent on the iST-benzoyl-protected phenylalaninal 92 to generate alcohols 93 (Scheme 25). A tmns-selective, Pd(0)-catalyzed oxazoline formation starting from the homoallylic amide 93 was subsequently employed to build up the (S)-configuration at carbon atom C-3 of oxazoline 94. 

Unexpected oxazoline formation was observed during a study to prepare nonsedating anxiolytic 1-styrylisoquinolines 27a-h from 2-(trifluoromethyl)aryl-ethylamines 25a-h under Pictet-Gams conditions (POCI3 in refluxing toluene). This deviation from the normal reaction pathway was hypothesized to result from the electron-withdrawing effect of trifluoromethyl group that inhibited the formation of a benzylic cation required for isoquinoline formation (Scheme 8.12). 

Conversion of the hydroxyl group of a p-hydroxy amide to a mesylate, triilate, ° ° or an acetate ° ° followed by intramolecular displacement of the leaving group is a commonly employed strategy for oxazoline formation. Some examples from the recent literature are hsted in Table Oxazolines... 

A common strategy to invert the stereochemistry at the hydroxyl bearing carbon of an amino alcohol involves oxazoline formation with inversion followed by hydrolysis. This strategy has been applied to Taxol resulting in a practical semisynthesis of 2 -epi-Taxol 44 from Taxol 42 (Scheme 8.17). ... 

An unusual example of oxazoline formation is illustrated in the following example in which the hydroxyl moiety is masked as a tetrahydrofuran ring. Depending on reaction conditions, regioselective ring closure to one of the two oxazolines can be realized. Thus, addition of methanesulfonyl chloride to a mixture of substrate and EtsN resulted in the expected oxazoline 46. On the other hand, addition of < 1 equiv of triethylamine to a mixture of substrate and methanesulfonyl chloride, followed by acid catalysis produced oxazoline 47. Intermediate 47, obtained in 72% overall yield from 45, was susequently converted to the human immunodeficiency virus (HlV)-protease inhibitor Nelfinavir 48 (Scheme 8.18). 

Activation of the hydroxyl group as an acetate leaving group to promote oxazoline formation has been applied extensively in carbohydrates to afford p-glycosylation with high selectivity. A Lewis acid such as ferric chloride (FeCL), tin chloride (SnCLt), or TMSOTf is usually added to facilitate cyclization. Several recent examples are shown in Scheme 8.20. Compound 54 has been further elaborated to 1,2-dideoxynojmmycin 54a, a potent p-Al-acetylglycosamine inhibitor. 

TABLE 8.8. OXAZOLINE FORMATION USING BURGESS REAGENT... 

Oxazoline formation under Mitsunobu conditions is very facile. As shown in the last example in Table 8.10, as much as 30% of the oxazoline is formed in addition to the desired vinylaziridine that is obtained in 64% yield. Only amide groups participate in this cyclization since the oxazoline is not formed when the nitrogen is protected as a benzyloxycarbonyl (Cbz) or ferf-butyloxycarbonyl (Boc) derivative. 

Oxazoline formation under Mitsunobu conditions requires that the amide substituent be in an antipepriplanar orientation to the activated hydroxyl substituent. With flWo-threonines 77, these groups are predisposed in such an orientation in the most stable conformation (transition state 78b). As a result, frani-oxazolines 79 are easily formed. With threonines, the formation of c/i-oxazoline 76 is disfavored because of destabilizing gauche interactions between the ot-carboxyl... 

Similarly, Jacquot and co-workers observed oxazoline formation from sodium ethyl glycolate (excess) and a 4,4-dichloro-azadiene derivative 109. However, the generality of this reaction has not been established. The product can be rationalized according to the series of reactions shown in Scheme 8.34. 

Kang and co-workers prepared the (3-halo amide arrangement required for oxazoline formation from allylic alcohols via a two-step process. For example, treatment of the allylic alcohol 122 with trichloroacetonitrile and base followed by activation of the double bond with iodine monochloride, provides 123. Hydrolysis of 123 gave 124 from which cyclization provided the oxazoline 18a used for paclitaxel synthesis (Scheme 8.36). 

Oxazoline formation from 5-vinyloxazolidinones promoted by palladium (0) is also known. Oxidative insertion of palladium with loss of CO2 results in a pair of equihbrating 71-allyl palladium complexes. The stereochemistry of the vinyl group is therefore not important. Ring closure from the thermodynamically more stable transition state accounts for the trans-isomer as the major product. Depending on the exact substitution, diastereoselectivities ranging from 2.5 1 to 16 1 can be obtained (Scheme 8.68). 

In their synthesis of lankacidin antibiotics, an insertion reaction of an azidoformate-derived acyinitrene on the electron-rich dihydrofuran 290 to introduce the sterically hindered C-3 amino appendage in the macrocyclic framework. The oxazoline formation is totally stereospecific with the... 

TABLE 8.9 OXAZOLINE FORMATION USING PEG-SUPPORTED BURGESS REAGENT, 366... 

MAPO ( see Table IV) has also been used effectively as a curing agent for prepolymers containing carboxylic acid, and like BITA it undergoes homopolymerization and oxazoline formation, particularly in the presence of ammonium perchlorate. The polymer network formed, however, is unstable and softens rapidly when exposed to higher temperatures. This phenomenon is caused by the presence of three phosphorus—nitro-... 

Mitsunobu conditions with DIAD 58 and PPh3 have also been employed for oxazoline formation.23... 

The Boyer reaction - a relative of the Schmidt process - involves 2-oxazoline formation from a 2-azidoethanol and an aldehyde (RCHO).282 Using a 2-aryl-2-azidoethanol, a 2-oxazoline product and its 3-isomer are obtained using BF3 catalysis. However, on using copper(II) triflate, an acetal, RCH[OCH2CH(Ph)N3]2, resulted. 

In the case of GlcNAc, it is desirable to replace the iV-acetyl with an electron-withdrawing group like A-allyloxycarbonyl (Aloe), A-trichloroethoxycarbonyl (Troc), or A-dithiasuccinoyl (Dts) in order to decrease side product (oxazoline) formation. 

Bidentate phosphaferrocene-oxazoline 7, generated by acylation with the corresponding phos-phaferrocene trifluoroacetate followed by oxazoline formation, has proved to be a highly efficient ligand for asymmetric induction in the copper-catalyzed conjugate addition of diethylzinc to a, (3-... 

The cycloaddition of aroyl nitrenes to electron rich double bonds such as in dihydropyran (compound 85) [Sch. 23] also results in oxazoline formation without any reference to an intermediate aziridine [22,39]. The same holds true for polar 7r-bonds of ketones and aldehydes that are added to aroyl nitrenes forming dioxazolines such as compound 89 (Sch. 24) [40]. 

Treatment of trehazolamine analogue 38 with isothiocyanate 7 in the presence of Et3N afforded 421 in 84% yield. Oxazoline formation from 421 with 2-chloro-3-ethylbenzoxazolium tetrafluoroborate gave 422 (84%), hydrogenolysis of which gave diepimer 416 in 43% yield (Scheme 58).106,107... 

Martin s sulfurane (PhlCFsljCO-SPha, CH2CI2, rt, 79-94% yield. Oxazoline formation depends on the stereochemistry of the substrate. Threo derivatives give elimination to dehydroamino acids. ... 

A planar, four-center, transition state is favored in the 1,2 ionic eliminations that lead, for example, to epoxides and aziridines in a cyclohexane system, this condition is fulfilled when the substituents on C-1 and C-2 can be fixed in a imns-diaxial relationship. The conformational requirements for formation of a five-membered ring by C-1, C-2 neighboring-group interaction have been studied in much less detail. Sicher and coworkers measured the rates of oxazoline formation from trans-2-(benzamido)cyclohexyl raethanesulfonate (A), lmns-2-(benzamido)-a s-4-ter<-butylcyclohexylmethanesulfonate (R), and (mns-2-(benzamido)-(m7is-... 

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