Oxazolidinones 1,3-dipolar cycloaddition reactions

In most TiCl2-TADDOLate-catalyzed Diels-Alder and 1,3-dipolar cycloaddition reactions oxazolidinone derivatives are applied as auxiliaries for the alkenoyl moiety in order to obtain the favorable bidentate coordination of the substrate to the catalyst... 

In a more recent study on 1,3-dipolar cycloaddition reactions the use of succi-nimide instead of the oxazolidinone auxiliary was introduced (Scheme 6.19) [58]. The succinimide derivatives 24a,b are more reactive towards the 1,3-dipolar cycloaddition reaction with nitrone la and the reaction proceeds in the absence of a catalyst. In the presence of TiCl2-TADDOLate catalyst 23a (5 mol%) the reaction of la with 24a proceeds at -20 to -10 °C, and after conversion of the unstable succinimide adduct into the amide derivative, the corresponding product 25 was obtained in an endojexo ratio of <5 >95. Additionally, the enantioselectivity of the reaction of 72% ee is also an improvement compared to the analogous reaction of the oxazolidinone derivative 19. Similar improvements were obtained in reactions of other related nitrones with 24a and b. 

High levels of asymmetric induction (97-74% ee) along with high diastereoselectivity (>99 1-64 36) were reported for asymmetric 1,3-dipolar cycloaddition reactions of fused azomethine imines 315 and 3-acryloyl-2-oxazolidinone 709 leading to 711 using a chiral BINIM-Ni(n) complex 710 as a chiral Lewis acid catalyst (Equation 100) <20070L97>. 

Thermolysis of oxazolidinone 82 gives the reactive azomethine ylide 83 (Equation 7) which readily takes part in 1,3-dipolar cycloaddition reactions (see Section 2.04.6.3). 

The 1,3-dipolar cycloaddition reaction [57] between alkene and nitrone [58] is an effective procedure for generating new chiral centers attached to heteroatoms. J0r-gensen et al. [59a] found that remarkably high endo selectivity was induced in the 1,3-dipolar reaction by use of a phenanthroline-coordinated Mg(II) catalyst prepared in the presence of I2 as a co-catalyst (Sch. 32). By reaction of 74, an alkene bearing a chiral oxazolidinone, with benzylidenephenylamine A -oxide 73 in the presence of the Mg(II)-phenanthroline catalyst (10 mol %), one of the four possible diastereomers of the isoxazolines 75 was formed exclusively in an almost quantitative yield. 

Suga and coworkers reported utility of a Yb(OTf)3-PyBOX complex in 1,3-dipolar cycloaddition reactions of carbonyl ylide generated using Rh2(OAc)4 [71, 72]. As shown in Scheme 13.26, the Yb(OTf)3/Ph-PyBOX complex promoted the reaction of 2-benzopyryrium-4-olate with 3-acryloyl-2-oxazolidinone in endojexo = 12 88,... 

Several successful chiral catalysts have been reported so far for catalytic asymmetric 1,3-dipolar cycloaddition reactions of nitrones with oxazolidinone derivatives (Figure 16.3) [27a,b,c] Recently, Kiindig et al. [27] had reported that the single coordination site Fe and Ru transition-metal Lewis acids can efficiently promote enantioselective 1,3-dipolar cycloadditions of nitrones with a,p-unsaturated aldehydes and represent a rapid access to substrates of high synthetic potential. The Fe catalyst (81) was found to be an excellent catalyst for 1,3-dipolar cycloaddition reactions between methacrolein and nitrone (83) (Scheme 16.24, Table 16.5). Isox-azolidine (84a) was formed as a single region- and diastereoisomer in excellent... 

A series of 2,6-bis(oxazolinyl)pyridine (pybox) ligands (95) and 4,5-bis(2-oxazolinyl)-(2,7-di-t-butyl-9,9-dimethyl)-9H-xanthenes (xabox) (96) and their transition-metal complexes were synthesized and applied to 1,3-dipolar cycloaddition of nitrone with oxazolidinones. Xabox-Bn-Mn(II) and xabox-Bn-Mg(II) complexes were found to be efficient catalysts in nitrone 1,3-dipolar cycloaddition reaction resulting in good to excellent enatioselectivities ranging from 96 4 to >99 1 of endo exo ratio and 91% to 96% ee for the endo adduct [6, 29, 30]. 

Iwasa, S., Ishima, Y., Widagdo, H. S., Aoki, K., Nishiyama, H. (2004). Synthesis of novel chiral bis(2-oxazolinyl)xanthene (xabox) ligands and their evaluation in catalytic asymmetric 1,3-dipolar cycloaddition reactions of nitrones with 3-crotonoyl-2-oxazolidinone. Tetrahedron Letters, 45, 2121-2124. 

Suga, H., Funyu, A., Kakehi, A. (2007). Highly enantioselective and diastereoselective 1,3-dipolar cycloaddition reactions between azomethine imines and 3-acryloyl-2-oxazolidinone catalyzed by binaphthyldiimine-Ni(II) Complexes. Organic Letters, 9, 97-100. 

Iwasa and Nishiyama reported catalytic enantioselective 1,3-dipolar cycloaddition reactions of nitrones using chiral Mg(II) complexes (Scheme 4.7) [5]. They synthesized chiral tridentate bis(2-oxazolinyl)xanthene ligands (Xabox, 19) and the chiral environments were evaluated in the 10mol% Xabox-Mg(Cl04)-(H20)6-catalyzed enantioselective 1,3-dipolar cycloaddition of nitrones (1 equiv) with 3-crotonyl-2-oxazolidinone (1 equiv). The reactions of (16) and (17) in dichloromethane at 10 °C proceeded smoothly to give the corresponding adduct (18) with 92% ee and an endo exo ratio of > 99 1. 

Recently, Suga et al. demonstrated that BINIM-Ni(II) catalysts are also effective in affording high levels of asymmetric induction (up to 97% ee) for 1,3-dipolar cycloaddition reactions between ethyl diazoacetate and 3-acryloyl-2-oxa-zolidinone or 2- (2-alkenoyl)-3-pyrazolidinone derivatives in the selective formation of 2-pyrazolines having a methine carbon substituted to the coordination auxiliary groups [27]. The cycloadditions of 3-acryloyl-2-oxazolidinone and its... 

The exo selectivity of the TiCl2-TADDOLate-catalyzed 1,3-dipolar cycloaddition is improved by the use of succinimide instead of oxazolidinone as auxiliary for the a,(3-unsaturated carbonyl moiety (Eq. 8.55).86 A strong bidentate coordination of the alkenyl moiety to the metal catalyst is important in these reactions. 

The three-component reaction between isatin 432a, a-aminoacids 433 (proline and thioproline) and dipolarophiles in methanol/water medium was carried out by heating at 90 °C to afford the pyrrolidine-2-spiro-3 -(2-oxindoles) 51. The first step of the reaction is the formation of oxazlidinones 448. Loss of carbon dioxide from oxazolidinone proceeds via a stereospecific 1,3-cycloreversion to produce the formation of oxazolidinones almost exclusively with /razw-stereoselectivity. This /f-azomethine ylide undergo 1,3-dipolar cycloaddition with dipolarophiles to yield the pyrrohdinc-2-r/ V -3-(2-oxindolcs) 51. (Scheme 101) <2004EJ0413>. 

Reaction of isatin or thioisatin 263 with (R)-(—)-thiaproline afforded thiazolo-oxazolidinones 264 as precursor of azomethine ylides, obtained by decarboxylation, for 1,3-dipolar cycloadditions (Equation 116) <2002SC435, 2004PS2549>. Condensation of 5-(alkylamino)methyl-2-pyrazolines 265 with ketones or aldehydes led to tetrahy-dro-imidazo[l,5-7]pyrazoles 266 (Equation 117) <1998JCCS375>. 

Due to the presence of an electron-withdrawing group on the dipolarophile, these processes are classified as type 1 reactions. The process involves the transference of charge from the dipole to the dipolarophile. When catalyzed by metallic compounds, coordination of the dipolarophile is highly desired. Usually, coordination of a nitrone to the Lewis acid is more feasible than coordination of a carbonyl compound. For this reason, alkenes that enable a bidentate coordination to the Lewis acid, such as 3-alkenoyl-oxazolidinones (Scheme 5), have been frequently employed as a model system to smdy the metal-catalyzed 1,3-dipolar cycloaddition... 

The amino acid derived chiral oxazolidinone 188 is a very commonly used auxiliary in Diels-Alder and aldol reactions. However, its use in diastereoselective 1,3-dipolar cycloadditions is less widespread. It has, however, been used with nitrile oxides, nitrones, and azomethine ylides. In reactions of 188 (R = Bn, R =Me, R = Me) with nitrile oxides, up to 92% de have been obtained when the reaction was performed in the presence of 1 equiv of MgBr2 (303). In the absence of a metal salt, much lower selectivities were obtained. The same observation was made for reactions of 188 (R = Bn, R = H, R = Me) with cyclic nitrones in an early study by Murahashi et al. (277). In the presence of Znl2, endo/exo selectivity of 89 11 and up to 92% de was observed, whereas in the absence of additives, low selectivities resulted. In more recent studies, it has been shown for 188 (R =/-Pr, R = H, R =Me) that, in the presence of catalytic amounts of Mgl2-phenanthroline (10%) (16) or Yb(OTf)3(20%) (304), the reaction with acyclic nitrones proceeded with high yields and stereoselectivity. Once again, the presence of the metal salt was crucial for the reaction no reaction was observed in their absence. Various derivatives of 188 were used in reactions with an unsubstituted azomethine ylide (305). This reaction proceeded in the absence of metal salts with up to 60% de. The presence of metal salts led to decomposition of the azomethine ylide. 

Several chiral Ti(IV) complexes are efficient catalysts and have been applied to numerous reactions, especially in combination with the TADDOL 244 ligands (350). Chiral TiCl2-TADDOLates were the first asymmetric catalysts to be applied in the normal electron-demand 1,3-dipolar cycloaddition of nitrones 225 with alkenoyl-oxazolidinones 241 (Scheme 12.73) (351). These substrates have turned... 

An important catalyst-substrate intermediate that applies to both the TiCl2-TADDOLate catalyzed 1,3-dipolar cycloadditions and Diels-Alder reactions has been isolated and characterized (353). The crystalline compound 248 has been characterized by X-ray analysis, showing that the oxazolidinone is coordinated to the titanium center in a bidentate fashion (Scheme 12.75). The four oxygen atoms. 

Furukawa and co-workers (368,369) succeeded in applying the softer dicationic Pd-BINAP 260 as a catalyst for the 1,3-dipolar cycloaddition between 225 and 241a (Scheme 12.82). In most cases, mixtures of endo-243 and exo-243 were obtained, however, enantioselectives of up to 93% ee were observed for reactions of some derivatives of 225. A transition state structure has been proposed to account for the high selectivities obtained for some of the substrates (368). In the structure shown in Scheme 12.82, the two phosphorous atoms of the Tol-BINAP ligand and the two carbonyl oxygens of the crotonoyl oxazolidinone are arranged in a square-planar fashion around the palladium center. This leaves the ii-face of the alkene available for the cycloaddition reaction, while the re-face is shielded by one of the Tol-BINAP tolyl groups. 

The application of two different chiral ytterbium catalysts 263 and 264 for the 1,3-dipolar cycloaddition was reported almost simultaneously by two independent research groups in 1997 (372,373). In both reports, it was observed that the achiral Yb(OTf)3 and Sc(OTf)3 salts catalyze the 1,3-dipolar cycloaddition between nitrones 225 and aUcenoyl oxazolidinones 241 with endo-selectivity (Scheme 12.84). In the first study, 20 mol% of the Yb(OTf)2-pyridine-bis(oxazo-line) complex 263 was used as the catalyst for reactions of several derivatives of... 

The first effective enantioselective 1,3-dipolar cycloaddition of diazoalkanes catalyzed by chiral Lewis acids was reported in the year 2000 (139). Under catalysis using zinc or magnesium complexes and the chiral ligand (/ ,/ )-DBFOX/Ph, the reaction of diazo(trimethylsilyl)methane with 3-alkenoyl-2-oxazolidin-2-one 75 (R2 = H) gave the desilylated A2-pyrazolines (4S,5R)-76 (R =Me 87% yield, 99% ee at —40°C) (Scheme 8.18). Simple replacement of the oxazolidinone with the 4,4-dimethyloxazolidinone ring resulted in the formation of (4/ ,5S)-77 (R1 = Me 75% yield, 97% ee at -78 °C). 

Copper Lewis acids have also been used with effect in dipolar cycloadditions. Activation of both the dipolarophile and the dipole by copper Lewis acids has been reported. A copper(fl) phenanthroline complex coordinates to an oxazolidinone crotonate (dipolarophile) and facilitates addition of the nitrone even when catalytic amounts of the Lewis acid are employed (Sch. 54). The endolexo selectivity and chemical yield were modest [101]. The yields and selectivity of the reactions were higher when Mg(Il) Lewis acids were used in place of copper. 

High diastereomeric ratios were observed in the 1,3-dipolar cycloaddition of various nitrile oxides to the optically active alcohol 491 <1999TL4349> and the chiral acryloylhydrazides 492 and 493. For example, benzonitrile oxide afforded the isoxazoline 494 in dr = 99 1 <2000TL1453>. The level of facial selectivity obtained in the same 1,3-dipolar cycloaddition with the chiral 3-acryloyl-2-oxazolidinone 493 was very low (d.r. = 43 57), but in the presence of MgBr2 (1 equiv) the reaction proceeded with high diastereoselectivity to give preferentially the isoxazolidine 495 in d.r. =96 4 <2000TL3131>. 

Reports on the advances of asymmetric 1,3-dipolar cycloadditions include the reaction of diazoalkanes to 7V-(2-alkenoyl)oxazolidin-2-ones catalyzed by Mg or Zn complexes of 73, showing cooperative chiral control by the achiral oxazolidinone auxiliary and the chiral ligand.An intramolecular cycloaddition of the same kind from substrates containing a chiral cyclic AiA -dimethylaminal unit adjacent to the dipolarophilic double bond (i.e., 74) proves very successful in the asymmetric sense, although the reaction of an analogous nitrone lacks stereoselectivity. 

Dipolar cycloaddition between the carbonyl yHde obtained in situ by treatment of the diazoimide 965 with rhodium(Il) acetate and the N-acryloyl oxazolidinone 966 was the opening gambit in the synthesis of (+)-tashiromine (929) by Suga et al. (Scheme 119). ° This reaction. 

To circumvent this problem, asymmetric 1,3-dipolar cycloaddition catalyzed by a metallic Lewis acid catalyst was designed to use electron-deficient alkene as a dipolarophile that has a chelating ligand structure, such as A-acyl oxazolidinone (Figure 11.2). The incorporation of a Lewis acid was expected to be equilibrating between 1,3-dipole and dipolarophile in the reaction and the reaction rate acceleration of cycloaddition occurs only in the Lewis acid/dipolarophile complex [4]. 

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