Arylimines, enantioselective

Recently, enantioselective organo-catalytic procedures for the aza-Henry reaction have been disclosed. The presence of either an acidic or a basic function appears to be a requisite of the catalyst. In fact, the condensation of ni-tromethane with M-phosphinoyl arylimines 72 is catalyzed by the chiral urea 85 derived from (R,R)-l,2-diaminocyclohexane and gives the product (R)-74 with good yield and moderate enantioselectivity (Scheme 15) [50]. The N-phosphinoyl substituent is determinant, as the addition of nitromethane to the N-phenyl benzaldimine failed and the reaction of the N-tosyl ben-zaldimine gave the expected adduct with quantitative yield but almost no... 

As already discussed for aldol and Robinson annulation reactions, proline is also a catalyst for enantioselective Mannich reactions. Proline effectively catalyzes the reactions of aldehydes such as 3-methylbutanal and hexanal with /V-arylimines of ethyl glyoxalate.196 These reactions show 2,3-syn selectivity, although the products with small alkyl groups tend to isomerize to the anti isomer. 

Other 2, 2 -disubstitued biferrocene derivatives (ligands 2, Fig. 3) also tested using the dinuclear [Ir( r-Cl)(COD)]2 as the iridium source provided total conversion in arylimine hydrogenation, although with poor-to-moderate enantioselectivity (20-33% ee) [17]. The low enantioselectivies are assumed to be related to the conformational flexibility of this type of bifep ligands. 

An iridium(I) complex with the l,2-bis(tcrt-butylmethylphosphino)ethane (4) and tetrakis(3,5-bis(trifluoromethyl)phenyl)borate as the counter anion catalyzes the hydrogenation of several acyclic aromatic Ai-arylimines under atmospheric hydrogen pressure at room temperature, giving the desired chiral amines with high-to-excellent enantioselectivities (up to 99%, Fig. 6) [19]. The authors also tested (S )-BINAP (Fig. 1) and (/ )-Ph-PHOX (PHOX = 2-[2-(diphenylphosphino) phenyl]-4,5-dihydrooxazole) hgands with lower enantioselectivities [19]. Both steric and electronic properties of the ligand and the combination with the BArF anion are in the base of the efficacy of this catalytic system. On the other hand, attempted hydrogenations of Ai-(2,2,2-trifluoro-l-phenylethylidene)aniline and M-(l,2,2-trimethyl-propylidene)aniline under the same conditions resulted in... 

Later, furanoside diphosphinite ligands 12, but with C2-symmetry, provided enantioselectivities up to 70% in the asymmetric hydrogenation of several N-arylimines (Fig. 12) [26]. The electronic effect of the ligand on enantioselectivity is considerable. Results were best when electron-donating groups are present on the phenyl rings (ligand 12b). On the other hand, the use of additives was detrimental to both conversion and enantioselectivity. 

The furanoside phosphite-phosphinite ligand 13, related to the previously diphosphinite ligands 12, was also applied to the asymmetric hydrogenation of N-arylimines, increasing the enantioselectivities up to 76% (Fig. 13) [26]. Precursors based on cationic [Ir(cod)2]BF4 provided better yields and enantioselectivities than... 

L-Pipecolinic acid-derived formamides have been developed as highly efficient and enantioselective Lewis basic organo-catalysts for the reduction of IV-arylimines with trichlorosilane. High isolated yields and enantioselectivities up to 96% are obtained under mild conditions with a large substrate spectrum.365... 

In the absence of organic solvents, Sc(OTf)3 catalysed the cycloaddition of aziridines to nitriles to produce substituted imidazolines in good to excellent yields at room temperature and in an air atmosphere. The reaction is believed to progress through a highly reactive cationic intermediate in which the aziridine nitrogen is coordinated to Sc(OTf)3.65 The phosphine-catalysed enantioselective 3 + 2-cycloaddition of buta-2,3-dienoates with arylimines yielded 2-aryl-3-pyrrolidines with 64% ee.66... 

Sigman and Jacobsen reported the first example of a metal-catalyzed enantioselective Strecker-type reaction using a chiral Alnl-salen complex (salen = N,N -bis(salicyhdene)-ethylenediamine dianion) [4]. A variety of N-allylimines 4 were evaluated in the reaction catalyzed by complex 5 to give products 6, which were isolated as trifluoroacetamides in good yields and moderate-to-excellent enantioselectivities (Scheme 3). Substituted arylimines 4 were the best substrates, while alkyl-substituted imines afforded products with considerably lower ee values. Jacobsen and co-workers also reported that non-metal Schiff base catalysts 8 and 9 proved to be effective in the Strecker reaction of imines 7 with hydrogen cyanide to afford trifluoroacetamides 10 after reaction with trifluoroacetic anhydride, since the free amines were not stable to chromatography (Scheme 4) [5]. 

Enantioselective silver-catalyzed aza-Diels-Alder reactions have also been described. Whereas the use of BINAP as the chiral ligand gave only unsatisfactory enantioselectivities,367,367a Hoveyda etal 6 used the peptidic phosphine 373 which has already been used for silver-catalyzed asymmetric Mannich reactions (see Scheme 108) in the efficient Ag(i)-catalyzed cycloaddition of arylimines 449 with Danishefsky s diene (Scheme 135). After acidic work-up, the chiral pyridones 450 were obtained with excellent yields and enantioselectivities. The presence of isopropanol as a proton source is essential for obtaining high conversions and stereoselectivities. Similar to the Mannich reactions, the cycloaddition is not affected by the presence of air or the use of undistilled THF. 

Enantioselective Hydrogenation of A -Arylimines in the Synthesis of the Chiral Herbicide, ( S)-Metolachlor... 

Ionic liquids have been proved to be efficient pre-catalysts (in solution of THF, containing 10% Cs COj) in the Staudinger reaction of arylalkylketenes with a variety of N-t-butoxycarbonyl arylimines to give the corresponding P-lactams in good yields with good diastereoselectivity and enantioselectivity (Scheme 16.8) [96]. 

Table 2. Synthetically useful catalysts for the enantioselective reduction of N-arylimines 1 (see...

Table 3. Effect of imine structure on catalyst performance for the enantioselective reduction of JV-arylimines 1 with Ir-diop iodide at 20 bar H2 and r.t. [17]...

The first report of enantioselective addition of organometallic reagents to an azomethine function appeared in 1990. Tomioka and co-workers reported the addition of organohthium compounds to J -arylimines in the presence of a stoichiometric amount of a chiral P-amino ether as the asymmetric controller [19a]. This significant contribution resulted from an observation made earlier in the context of a related synthetic project [20aj. Tomioka et al. studied the addition of methylhthium (MeLi) and -butyllithium ( -BuLi) to unsaturated N-(4-methoxyphenyljimines derived from benzaldehyde (2a), cinnamaldehyde (2b),... 

The synthetic utility of this enantioselective alkylation of an arylimine rehes on a practical method for the dearylation of the resulting chiral amine. A two-step procedure was illustrated for amine 3a (R =Me), which begins with a protection step (n-BuLi/ClC02CH2Ph) followed by oxidative cleavage of the aryl moiety (ceric ammonium nitrate CAN). The N-protected amine 4a was isolated in only 58% overall yield without significant loss of enantiomeric purity (Scheme 3). 

Various chiral catalysts have been explored in the search for enantioselective ami-noalkylation. Zhou and coworkers used hA-oxazolines with W-tosyl-C-arylimines. The best results were obtained with a dibenzyl h T-oxazoline in the presence... 

Spindler, F., Pugin, B., Jalett, H.-P., Buser, H.P., Pittelkow, U. and Blaser, H.U. (1996) A technically useful catalyst for the homogeneous enantioselective hydrogenation of N-arylimines a case study. Chemistry Industry Catalysis of Organic Reactions), (Dekker) 68, 153-166. 

Some recent work has been directed towards the use of organocatalysts, in particular Lewis basic pipecolinic formamides, in the asymmetric hydrosilylation of N-arylimines. These catalysts function by activating the silane and exhibit broad substrate scope. For example formamide (3.186) effects enantioselective hydrosilylation of aryl-derived ketimines along with isopropyl-substituted imine (3.187) and a,P-unsaturated imine (3.188). 

Besides being the first study published accounting on this catalytic reaction, the chiral amine products were obtained with excellent enantioselectivities (a maximum of 98% ee was achieved). The downside was the moderate yields (a maximum of 77% yield was achieved), due most probably to rapid Ru-catalyzed hydrolysis of the rJdimine substrates to the corresponding aldehydes that were themselves competitors with the arylimines for arylation (see Chapter 7) and rJso the possible formation of unreactive ruthenacycle species which deplete the active catalyst [44]. 

In addition, various chiral amine-thioureas have been successfully applied to promote asymmetric Mannich reactions. As an example, Takemoto and Miyabe have employed a chiral bifunctional organocatalyst possessing a thiourea moiety and a tertiary amino group as catalyst of the Mannich reaction between ethyl malonate and A-Boc arylimines, which provided the corresponding products in excellent yields and enantioselectivities (93-98% ee), as shown in Scheme S.lb. The degree of enantioselectivity was shown to be dependent on the reaction temperature, with the best results obtained at low temperature. 

Enamines of cyclohexylamine have been enantioselectively cyclized to bicyclo[3.3.1] nonanedione systems, using acryloyl chloride and chiral pyrrolidine catalysis. Enantio-pure A-sulflnylimines have been used in asymmetric synthesis of isoquinolone alkaloids, and a stereocontrolled synthesis of 3,4,5,6-tetrahydropyrimidine-based amino acids from imino ethers has been reported. Diastereoselective additions of chiral acetals of (2-lithiophenyl)acetaldehyde to arylimines have been used in an asymmetric synthesis of 1-aryltetrahydroisoquinolines. " Organolithiums react with chiral imines, in the presence of Lewis acids or bases, to give amines in up to 100% de. Diastereoselective additions of copper reagents to imines derived from (5)-l-phenylethylamine have been reported. 

Addition of lithiated alkoxy ethynyl anion with chiral Al-sulfinyl imines proceeds with dr >95 5, which can be reversed in the presence of BF3. Excellent diastereoselec-tivity has been reported for zinc-mediated addition of methyl and terminal alkynes to chiral IV-f-butanesulfinyl ketimines (to form 3-amino oxindoles). Zinc-BINOL complexes have been used to achieve enantioselective addition of terminal alkynes to N-(diphenylphosphinoyl)imines (up to 96% cc) and terminal 1,3-diynes to IV-arylimines to trifluoropyruvates (up to 97% yield and 97% ee). ... 

More recent developments of this reaction include the use of chiral metal diene complexes [186]. In this context, Hayashi developed the Cj-symmetric diene ligand 293 and demonstrated its application in asymmetric arylations of N-tosyl arylimines, such as 291, to give optically active diaryl carbamines as exemplified by 294 (99%, 99% ee. Equation 31) [187], Hayashi has proffered an explanation of the observed enantioselectivity based on steric considerations. The C2-symmetric ligand 293 enforces preferential coordination of the si-face of the imine to the rhodium center, which subsequently delivers the arene to give 294 as depicted in the suggested transition state assembly 295. 

---