(1; R = Ph)

[148461-15-8]  · C27H22NOP  · (S)-2-[2-(Diphenylphosphino)phenyl]-4-phenyloxazoline  · (MW 407.47) (2; R = i-Pr)

[148461-14-7]  · C24H24NOP  · (S)-2-[2-(Diphenylphosphino)phenyl]-4-isopropyloxazoline  · (MW 373.46) (3; R = t-Bu)

[148461-16-9]  · C25H26NOP  · (S)-2-[2-(Diphenylphosphino)phenyl]-4-t-butyloxazoline  · (MW 387.49)

(readily available chiral ligands for enantiocontrol of palladium-catalyzed allylic substitution reactions1,2)

Physical Data: (1) amorphous solid; [a]D +30.8° (c = 1.0, CHCl3). (2) amorphous solid; [a]D -44.9° (c = 1.4, CHCl3). (3) mp 105 °C; [a]D 58.2° (c = 1.2, CHCl3).

Solubility: insol H2O; sol most organic solvents.

Preparative Methods: chiral phosphinoaryloxazolines, a class of ligands developed independently in three different laboratories,1,3,4 are readily prepared in enantiomerically pure form starting from chiral amino alcohols and aromatic carboxylic acids or nitriles. Several short, convenient syntheses from 2-bromobenzonitrile (eq 1),1,5 2-bromobenzoic acid (eq 2),3 or 2-fluorobenzonitrile (eq 3)4 have been described. Alternatively, derivatives such as (2), which do not contain any reactive groups in the oxazoline ring that are attacked by BuLi, can be prepared from aryloxazolines by orthometalation and subsequent reaction with Ph2PCl (eq 4).1 Phosphino-oxazolines with an additional stereogenic center at the phosphorus atom, such as (4), and phosphinomethyl oxazolines of type (5) have also been reported.3 The different synthetic routes allow for a wide range of structural modifications at the oxazoline ring, the phosphine group, and the ligand backbone.

Purification: impurities such as phosphine oxides, formed by air oxidation, can be removed by column chromatography on silica gel or, for crystalline derivatives, by recrystallization.

Handling, Storage, and Precautions: Phosphino oxazolines of this type are sufficiently stable to be handled in air. For longer periods of time, they should be stored at -20 °C under argon.

Palladium-Catalyzed Allylic Substitution.

Palladium complexes of chiral phosphino oxazolines are highly effective catalysts for enantioselective allylic substitution reactions.1-4 The catalysts are usually prepared in situ from Bis(allyl)di-m-chlorodipalladium and the corresponding ligands. In the presence of 1-2 mol % of catalyst and a mixture of N,O-Bis(trimethylsilyl)acetamide (BSA) and catalytic amounts of KOAc as a base, racemic 1,3-diphenyl-2-propenyl acetate reacts smoothly at rt with dimethyl malonate to afford the substitution product in essentially quantitative yield and with excellent enantioselectivity (eq 5). For this substrate, the phenyloxazoline (1) is the optimal ligand.1 The observed ee of 99% exceeds the selectivities previously obtained with other ligands such as ferrocenyl phosphines,6 chiraphos,7 BINAP,7 5-azasemicorrins,8 or bis(oxazolines).8,9 The corresponding isopropyl- and t-butyl-oxazolines (2) and (3) afford slightly lower en antiomeric excesses (98 and 95% ee, respectively).1,3 Acetylacetonate1 and diethyl acetaminomalonate,1 as well as N-nucleophiles such as benzylamine, p-toluenesulfonamide, benzoylhydrazine, and (Boc)2NNa,10 also react with excellent enantioselectivity (eq 6).

Moderate to high selectivities have been observed in allylic alkylations of 1,3-dialkyl-2-propenyl acetates.1 Here, the t-butyloxazoline derivative (3) is the ligand of choice. Under standard conditions, n-alkyl-substituted allylic acetates smoothly react at rt with selectivities of 70-80% ee (eq 7). Similar results have been obtained with various N-nucleophiles.10 The corresponding diisopropylallyl acetate is much less reactive, but under more vigorous conditions with NaCH(CO2Me)2 in DMF at 65 °C the reaction proceeds in good yield with high enantioselectivity (eq 8).1 Analogous reactions of this substrate with N-nucleophiles are impracticably slow. In this case, the corresponding diethyl phosphate gives much better results (eq 9).10

Related Reagents.

2,2-Bis(diphenylphosphino)-1,1-binaphthyl; 2,3-Bis(diphenylphosphino)butane; (R)-N-[2-(N,N-Dimethylamino)ethyl]-N-methyl-1-[(S)-1,2-bis(diphenylphosphino)ferrocenyl]ethylamine; (1S,9S)-1,9-Bis{[(t-butyl)dimethylsilyloxy]methyl}-5-cyanosemicorrin; (R)-N,N-Dimethyl-1-[(S)-2-(diphenylphosphino)ferrocenyl]ethylamine.

1. von Matt, P.; Pfaltz, A. AG 1993, 105, 614; AG(E) 1993, 32, 566.
2. Reiser, O. AG 1993, 105, 576; AG(E) 1993, 32, 547.
3. Sprinz, J.; Helmchen, G. TL 1993, 34, 1769.
4. Dawson, G. J.; Frost, C. G.; Williams, J. M. J.; Coote, S. J. TL 1993, 34, 3149.
5. von Matt, P. Dissertation, University of Basel, 1993.
6. Hayashi, T. PAC 1988, 60, 7.
7. Yamaguchi, M.; Shima, T.; Yamagishi, T.; Hida, M. TL 1990, 31, 5049; TA 1991, 2, 663.
8. Leutenegger, U.; Umbricht, G.; Fahrni, Ch.; von Matt, P.; Pfaltz, A. T 1992, 48, 2143.
9. Pfaltz, A. ACR 1993, 26, 339.
10. von Matt, P.; Loiseleur, O.; Koch, G.; Pfaltz, A. Lefeber, C.; Feucht, T.; Helmchen, G. TA 1994, 5, 573.

Andreas Pfaltz

University of Basel, Switzerland

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