Chiral C3-symmetric trisoxazolines are highly efficient stereodirecting ligands in enantioselective Cu(II) Lewis acid catalysis which is based on the concept of a stereoelectronic hemilability of the divalent copper; in direct comparison with the analogous bisoxazoline systems they are more efficient in the enantioselective alpha-amination as well as the enantioselective Mannich reaction of prochiral beta-ketoesters.
Nucleophilic substitution of p-3-trialkylsilyl-1,1-dimethyleneallyl palladium complexes 2a,b occurred on the carbon bearing the silyl group whatever the hard (hydride) or soft (malonate anion) nature of the nucleophiles. Conversely, when located on the cyclopropane ring, i.e., in b of the p-allyl palladium complex 12, the silyl group appeared able to overcome the ring strain effect and to direct the substitution on the three-membered ring. This effect was however reversed by the simultaneous presence of these two trialkylsilyl substituents on the p-allyl palladium complex 27. Electrophilic substitution of 1,1-dimethyleneallylsilanes 4a,b by benzaldehyde occurred regioselectively on the cyclopropane ring.Functionally substituted alkylidenecyclopropanes undergo readily in high yields inter-2 and intramolecular Pauson-Khand reactions, 3 as well as inter-4 and intramolecular 1,3-dipolar cycloaddition. 5 This reactive entity (SE = 40.9 kcal.mol -1 ) is however stable enough to be present in natural products which display powerful bioactivities. [6][7][8][9] As the presence of a silyl group was demonstrated to favour electrophilic substitution over simple addition to alkenes, 10,11 it appeared worthwhile to investigate the effect of s-donor and p-acceptor silyl groups 12 on the preparation and behaviour of silylated alkylidenecyclopropanes.It has been recently reported that the palladium(0) catalyzed hydrogenolysis of 1-(1-alkenyl)cyclopropyl esters, which are readily available from cyclopropanone hemiacetals, 13 constituted one of the most efficient preparation of alkylidenecyclopropanes 14 and offered an alternative to the Wittig reaction. 15 The regio-and diastereoselectivity of this new procedure, which allowed the first asymmetric synthesis of alkylidenecyclopropanes 15b appeared highly dependent on ring strain, substituents and phosphorus ligands steric effects. 16 Thus, hydrogenolysis of (E) 1-tosyloxy-1-(2-trimethylsilylethenyl)cyclopropane 1a (R=Me) 16 with sodium formate as hydride source in THF containing 10% of [15]-crown-5-ether, in the presence of 5% of palladium(0) [from Pd(dba) 2 -2 PPh 3 ] gave after stirring for 10 h at room temperature the (2-trimethylsilylethylidene)cyclopropane 4a, exclusively. Unsymmetric p-allyl palladium complex 2a with the palladium positioned closer to the cyclopropane moiety, i.e. on the allylic carbon bearing the least pronounced positive charge, as confirmed by high level calculations 5,17 and s-complex 3a arising from nucleophilic substitution by the formate anion were considered as intermediates to explain this unexpected high regioselectivity. Then, S Ni transfer of hydride with reductive Ln Pd(0) elimination and CO 2 extrusion led to 4a in 90% yield. 18 On the other hand, nucleophilic substitution of 2a by n-butylzinc chloride (from n-BuLi and ZnCl 2 ) provided in 85% yield, likely via the s-complexes 5a and 6a arising from b-elimination, the E-(2-trimethylsilylethenyl)cyclopropane 7a, exclusively. 18To overcome the problem resulting from the volatility of the 1,1-dime...
The underlying conceptual differences in exploiting two- and threefold rotational symmetry in the design of chiral ligands for asymmetric catalysis have been addressed in a comparative study of the catalytic performance of bisoxazoline (BOX) and tris(oxazolinyl)ethanes (trisox) containing copper(II) Lewis acid catalysts. The differences become apparent in constructing new catalysts by systematically "deforming" the stereodirecting ligand by inverting chiral centres or replacing chiral by achiral oxazolines. The catalytic alpha-amination of ethyl 2-methylacetoacetate with dibenzyl azodicaboxylate, which occurs with high enantioselectivity for both Ph(2)-BOX and Ph(3)-trisox copper catalysts, has been employed as the test reaction. In the trisox-copper complex [Cu(II)(iPr(3)-trisox)(kappa(2)-O,O'-MeCOCHCOOEt)](+)[BF(4)](-) (1), which was characterised by X-ray diffraction, two of the oxazoline groups are coordinated to the central copper atom, whilst the third oxazoline unit is dangling with the N-donor pointing away from the metal centre. A similar arrangement is found for the stereochemically "mixed" C(1)-trisox complex [Cu(II){(Ph(3)-trisox(R,S,S)}(kappa(2)-O,O'-MeCOCHCOOEt)(H(2)O)](+)[ClO(4)](-) (2), in which the phenyl substituents adopt a first coordination sphere meso arrangement. The almost identical selectivity of the Ph(3)-trisox(R,R,R)- and Ph(2)-BOX(R,R)-derived catalysts is as expected from the proposed model of the active catalyst based on a partially decoordinated podand. The behaviour of the "desymmetrised" trisox-Cu catalysts may be rationalised in terms of a general steady-state kinetic model for the three possible active bisoxazoline-copper species, which are expected to be in rapid exchange with each other in solution. This applies to both the trisox derivatives with stereochemically inverted and achiral oxazoline rings. The study underscores previous observations of superior performance of the catalysts bearing C(3)-chiral stereodirecting ligands as compared to systems of lower symmetry.
Thirty-three different N,N-dialkyl- and N-alkyl-N-phosphorylalkyl-substituted carboxamides 9-17 were treated with unsubstituted as well as with 2-alkyl-, 2,2-dialkyl-, and 3-alkenyl-substituted ethylmagnesium bromides 6 in the presence of stoichiometric amounts of titanium tetraisopropoxide or methyltitanium triisopropoxide to furnish substituted cyclopropylamines 20-25 in 20-98% yield, depending on the substituents with no (1:1) to excellent (>25:1) diastereoselectivities. Generally higher yields (up to 98%) of the cyclopropylamines 20-28 without loss of the diastereoselectivity were obtained with methyltitanium triisopropoxide as the titanium mediator. Under these conditions, even dioxolane-protected ketones and halogen-substituted and chiral as well as achiral alkyloxyalkyl-substituted carboxamides could be converted to the correspondingly substituted cyclopropylamines with unsubstituted as well as phenyl- and a variety of alkyl-substituted ethylmagnesium bromides in addition to numerous heteroatom-containing (e.g., halogen-, trityloxy-, tetrahydropyranyloxy-substituted) Grignard reagents (62 examples altogether). The transformation of N,N-diformylalkylamines 54 with ethylmagnesium bromide in the presence of methyltitanium triisopropoxide to N,N-dicyclopropyl-N-alkylamines 55 can be brought about in up to 82% yield (6 examples). An asymmetric variant of the titanium-mediated cyclopropanation of N,N-dialkylcarboxamides has been developed by applying chiral titanium mediators generated from stoichiometric amounts of titanium tetraisopropoxide and chiral diamino or diol ligands, respectively. The most efficient chiral mediators turned out to be titanium bistaddolates that provided the corresponding cyclopropylamines with enantiomeric excesses (ee) of up to 84%. Evaluation of several silyl-based additives revealed that the reaction can also efficiently be carried out with substoichiometric amounts (down to 25 mol%) of the titanium reagent, as long as 2-aryl- or 2-ethenyl-substituted ethylmagnesium halides are used and a concomitant slight decrease in yields is accepted. The newly developed methodology was successfully applied for the preparation of analogues with cyclopropylamine moieties of known drugs and natural products such as the nicotine metabolite (S)-Cotinine as well as the insecticides Dinotefuran and Imidacloprid.
3-Phenylallyl ether 17, 2,5-dihydrofuran (1) and N-acceptor-substituted 2,5-dihydropyrrols 4, 6, 8, 10, 12 upon treatment with cyclohexylmagnesium bromide in the presence of Ti(Oi-Pr) 4 were found to undergo a diastereoselective dihydrodimerization affording 1,5-dienes, d,l-2,3-diethenylbutane-1,4-diol (51% yield) and d,l-2,3-diethenyl-1,4-bis(sulfonylamino)butanes (43-52%), respectively. In the presence of titanium bis(4R,5R)-taddolate, the dihydrodimerization of 1 proceeded with 35-38% chemical yield and up to 94% ee.
N,N‐ Dibenzyl‐ N‐ (2‐ethylenylcyclopropyl)amine N,N‐ Dimethylformamide Methyl tris(isopropoxy)titanium Titanium tetraisopropoxide Titanium tetrachloride Methyllithium
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