Imine Substrates Research Articles

Advances in the Catalytic Asymmetric Arylation of Imines using Organoboron Reagents: An Approach to Chiral Arylamines

AbstractThe production of chiral amines by means of catalytic asymmetric synthesis is a current challenge in the field of drug discovery and is discussed in this review. The use of cheap, easily handled, and low toxic organoboron reagents, such as boronic acids and derivatives, and easily prepared imine substrates, such as diphenylphosphinoyl, N‐Boc, N‐tosylaryl, N‐nosylaryl, or dimethylsulfamoyl imines, together with rhodium and palladium catalysts give the corresponding chiral amine products in excellent yields and enantioselectivities. A diverse range of chiral ligands, such as phosphines, phosphites, phosphoramidites, P,O‐ligands, olefins, NHCs, and N,N‐ligands can be used with this method, showing, therefore, its versatility. The application of aliphatic imine substrates and with the use of different palladium complexes show, on the other hand, the versatility of the method described.

Asymmetric Synthesis of Amines by the Knochel-Type MgCl2-Enhanced Addition of Benzyl Zinc Reagents to N-tert-Butanesulfinyl Aldimines

The MgCl(2)-enhanced addition of benzyl zinc reagents to N-tert-butanesulfinyl imines proceeds readily at room temperature to afford the N-tert-butanesulfinyl-protected amine products in good yields and diastereomeric ratios. This method is functional group tolerant in both the imine substrate and benzyl zinc coupling partner. Moreover, benzyl zinc reagent addition to the N-tert-butanesulfinyl imine 3o prepared from isopropylidene-protected glyceraldehyde proceeds in high yield and with exceptional selectivity to provide rapid entry to hydroxyethylamine-based aspartyl protease inhibitors.

Mesoporous silicabis(ethylsulfanyl)propane palladium catalysts for hydrogenation and one-pot two-step Suzuki cross-coupling followed by hydrogenation

The solid phase catalytic activity of mesoporous silicabis(ethylsulfanyl)propane palladium catalysts for hydrogenation and novel one-pot two-step Suzuki cross-coupling followed by hydrogenation is described. The efficiency of catalytic hydrogenation was measured for substrate nitrobenzene with 5, 7 and 14 nm average pore diameter materials. The 5 nm pore material performed best and was also very effective in the catalytic hydrogenation of alkene, nitrile and imine substrates. Novel one-pot two-step Suzuki cross-coupling and hydrogenation was demonstrated using bromonitro- and bromodinitrobenzene and phenylboronic acid as substrates with conversion to the corresponding coupled amino compounds. As a consequence of the high affinity of the sulfur ligands for palladium, none was detected in leaching tests and the catalyst is easily separated and recycled.

Reaction Monitoring of Heterogeneously Catalyzed Hydrogenation of Imines by Coupled ATR‐FTIR, UV/Vis, and Raman Spectroscopy

AbstractCoupled ATR‐FTIR, UV/Vis, and Raman spectroscopy has been introduced for the monitoring of liquid phase hydrogenation reactions under elevated H2 pressure by implementation of spectroscopic immersion probes into a modified autoclave reactor. The setup was successfully tested for the heterogeneously catalyzed hydrogenation of several imine substrates under H2 pressures up to 20 bar. The conversion of the imines could be analyzed by Raman spectroscopy and the product formation was observable by attenuated total reflectance FTIR spectroscopy (ATR‐FTIR), which illustrates the benefits of coupling complementary spectroscopic methods. Separate spectroscopic investigations show that imines intensively interact with the phosphoric acid ester that is used as catalyst modifier, indicated by a shift of the original ν(CN) band of the imine to higher wavenumbers. UV/Vis spectroscopic investigations reveal a distinct shift of the absorption edge to a higher wavelength. Furthermore, the formation of adsorbates on the surface of used Pt/Al2O3 catalysts, resulting mainly from adsorbed imine, was detected by FTIR spectroscopic analysis. The potential of UV/Vis spectroscopy in transmission mode for analyzing the organic components was tested. Due to its high sensitivity at low concentrations this method offers an additional possibility for a quantitative in situ analysis of the reaction progress in real time.

Copper‐Catalyzed One‐Pot Synthesis of 2‐Alkylidene‐1,2,3,4‐ tetrahydropyrimidines

AbstractA one‐pot synthesis of N‐sulfonyl‐2‐alkylidene‐1,2,3,4‐tetrahydropyrimidines via a highly selective and copper‐catalyzed multicomponent reaction of sulfonyl azides, terminal alkynes and α,β‐unsaturated imines has been developed. The α,β‐unsaturated imine substrates could be generated from amines and α,β‐unsaturated aldehydes in a one‐pot process. The procedure is concise, general and efficient.

Enantioselective Trifunctional Organocatalysts for Rate‐ Enhanced Aza‐Morita–Baylis–Hillman Reactions at Room Temperature

Abstractmagnified imageA Brønsted acid‐activated trifunctional organocatalyst, based on the BINAP scaffold, was used for the first time to catalyze aza‐Morita‐Baylis–Hillman reactions between N‐tosylimines and methyl vinyl ketone with fast reaction rates and good enantioselectivity at room temperature. This trifunctional catalyst, containing a Lewis base, a Brønsted base, and a Brønsted acid, required acid activation to confer its enantioselectivity and rate improvement for both electron‐rich and electron‐deficient imine substrates. The role of the amino Lewis base of 1a was investigated and found to be the activity switch in response to an acid additive. The counterion of the acid additive was found to influence not only the excess ratio but also the sense of asymmetric induction.

Remarkable Positive Effect of Silver Salts on Asymmetric Hydrogenation of Acyclic Imines with Cp*Ir Complexes Bearing Chiral N-Sulfonylated Diamine Ligands

A family of bifunctional Ir, Rh, and Ru complexes bearing chiral monosulfonylated diamine ligands has been evaluated for asymmetric hydrogenation of acyclic imines (1) to the corresponding amines (2). A chiral Ir complex, [Cp*IrCl{(S,S)-Tscydn}] (3a), combined with silver salts caused a marked improvement in the catalyst performance in terms of the activity and selectivity. The use of an excess amount of the silver salt, AgSbF6, increased enantioselectivity up to 72% ee in the asymmetric hydrogenation of N-(1-phenylethylidene)benzylamine (1a). A stoichiometric reaction of 3a with AgSbF6 in acetonitrile afforded an isolable cationic complex, [Cp*Ir(Tscydn)(CH3CN)]+SbF6− (4) which was fully characterized by NMR spectroscopy and X-ray crystallography. The resulting cationic complex 4 readily reacted with H2 under ambient conditions in the presence of triethylamine to give a hydridoiridium complex, [Cp*IrH{(S,S)-Tscydn}] (5) and showed comparable catalytic behavior to that for the catalyst system generated in situ from 3a and AgSbF6. On the basis of the additive effect on the outcome of the hydrogenation as well as the 13C{1H} NMR spectrum of a reaction mixture of imine 1a and AgSbF6, the mechanism of the imine hydrogenation including heterolytic bond cleavage of H2 on a cationic complex to generate a hydrido intermediate and the following H− transfer to the imine substrates activated by the silver cation was proposed.

Synthesis of highly enantiomerically enriched amines by the diastereoselective addition of triorganozincates to N-( tert-butanesulfinyl)imines

The reaction of triorganozincates with ( R)- N-( tert-butanesulfinyl) imines gives the expected α-branched sulfinamides in good to excellent yields with diastereomeric ratios of up to 98:2. The N-sulfinyl group of the products can be easily removed by acidic treatment, affording the corresponding chiral primary amines in enantiomeric excesses of up to 96%. The reactivity and the selectivity shown by the triorganozincates are different from the ones observed with the corresponding Grignard reagents, which allows, in several cases, the preparation of both enantiomers of an amine from the same imine substrate. When mixed triorganozincates are used, one can take advantage of the slow transfer rate of the methyl group to use it as a non-transferable one. Both aromatic and aliphatic aldimines, as well as activated ketimines, are good substrates for these addition reactions.

Vanadium(I) Chloride and Lithium Vanadium(I) Dihydride as Selective Epimetallating Reagents for π‐ and σ‐Bonded Organic Substrates

AbstractSubvalent vanadium(I) salts, of empirical formulas, VCl, vanadium(I) chloride and LiVH2, lithium vanadium(I) dihydride, whose efficient preparation, structural constitution and mode of reaction toward certain organic substrates have been described in a preceding article, are here evaluated in their reactions toward a wide variety of π‐ and σ‐bonded organic substrates, namely carbonyl, imine, azo, alkene, 1,3‐diene, nitrile π‐bonds and C–X, C–O, C–N and N–N σ‐bonds. Compared with the high reactivity of CrCl and LiCrH2 reagents in attacking both types of bonds, the VCl and LiVH2 reagents were much milder and selective in epimetallating π‐bonds, often forming the 1:1 adduct of LiVH2 and π‐bonded substrate as the major product. Finally, the vanadium reagents showed little tendency to cleave C–O, C–S and C–N bonds and a smaller scope in cleaving C–X bonds than their chromium counterparts. Because of their selectivity these vanadium reagents offer the following preparative promise: 1) smooth McMurry carbonyl coupling to their reductive dimers; 2) deoxygenation of epoxides; 3) selective aromatic C–X reduction; 4) high yields of epimetallated carbonyls or imines as intermediates to ‐hydroxy and ‐amino acids; 5) 1,4‐reductions of 1,3‐alkadienes; 6) reductive dimerization of nitriles to ketones; 7) 1,4 or 1,n‐epimetallations leading to acyloins or indoles; and 8) reductive dimerizations of azines to produce unusual imidazole derivatives. In explaining the greater kinetic stability of the 1:1 LiVH2 adduct with carbonyl or imine substrates it is pointed out that such epimetallated adducts from LiVH2 would likely be diamagnetic, whereas such adducts from LiCrH2 have an unpaired electron on the Cr center and hence would rupture, so that the electron would be on the C center.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)

Remarkable Salt Effect on In-Mediated Allylation of N-tert-Butanesulfinyl Imines in Aqueous Media: Highly Practical Asymmetric Synthesis of Chiral Homoallylic Amines and Isoindolinones

A highly practical and efficient asymmetric synthesis of chiral homoallylic amines by In-mediated allylation of chiral N-tert-butanesulfinyl imines in aqueous media at room temperature was developed. With 2-formylbenzoate imine substrates, the method allows the highly enantioselective achievement of a variety of pharmacologically important 3-allyl isoindolinone compounds.

Enantioselective Aza-Henry Reaction with an N-Sulfinyl Urea Organocatalyst

A new class of organocatalyst has been developed that incorporates a sulfinyl group as a urea or thiourea substituent. The sulfinyl group serves to simultaneously acidify the urea and provide asymmetric induction in hydrogen-bond-catalyzed reactions. The utility of this new catalyst structure is demonstrated by the high selectivity provided in the aza-Henry reaction not only for aromatic N-Boc imine substrates but also for aliphatic imines for which enantioselective H-bonding catalysis has not previously been demonstrated.

Asymmetric Intramolecular Alkylation of Chiral Aromatic Imines via Catalytic C-H Bond Activation

The asymmetric intramolecular alkylation of chiral aromatic aldimines, in which differentially substituted alkenes are tethered meta to the imine, was investigated. High enantioselectivities were obtained for imines prepared from aminoindane derivatives, which function as directing groups for the rhodium-catalyzed C-H bond activation. Initial demonstration of catalytic asymmetric intramolecular alkylation also was achieved by employing a sterically hindered achiral imine substrate and catalytic amounts of a chiral amine.

Direct Access to N-H-Aziridines from Asymmetric Catalytic Aziridination with Borate Catalysts Derived from Vaulted Binaphthol and Vaulted Biphenanthrol Ligands

The asymmetric catalytic aziridination reaction (AZ reaction) of N-dianisylmethylimines (N-DAM-imines) with ethyl diazoacetate is developed with chiral catalysts prepared from triphenylborate and both the vaulted binaphthol (VANOL) and vaulted biphenanthrol (VAPOL) ligands. Catalysts derived from both ligands were equally effective in terms of asymmetric induction, but the VANOL catalyst was slightly faster. Up to 400 turnovers could be achieved with the VANOL catalyst while still maintaining>or=90% ee in the aziridine product. The ligand could be recovered in 95% yield with no loss in optical purity. Excellent asymmetric inductions were observed with arylimines, and although slightly lower inductions were observed for alkyl-substituted imines, the optical purity of the aziridines from all of the imine substrates could be enhanced to>or=99% ee with a single crystallization. Methods were developed for deprotection of the N-DAM-aziridines under acidic conditions without causing an acid-promoted opening of the ring. Excellent yields of the N-H-aziridines could be obtained with both alkyl- and aryl-substituted aziridines. Finally, activation of the N-H-aziridines was achieved with Boc, tosyl, and Fmoc groups. The activated aziridines can be converted to beta3-amino esters, and unexpectedly, the N-Boc-protected aziridine-2-carboxylate 16b with a phenyl substituent in the 3-position cis to the ester group was found to undergo ring expansion to a mixture of cis- and trans-oxazolidinones.

Solvent Effects in the Enantioselective Catalytic‐Phase‐Transfer Alkylation of Polymer‐Supported Glycine–Imine tert‐Butyl Ester: Asymmetric Solid‐Phase Synthesis of (R)‐α‐Amino Acid Derivatives

AbstractPolymer‐supported glycine–imine tert‐butyl esters (3, 8) were prepared from Merrifield‐ or Wang‐resin and used in the enantioselective synthesis of (R)‐α‐amino acid derivatives by using (S,S)‐3,4,5‐trifluorophenyl‐NAS bromide (5) as the chiral phase‐transfer catalyst. The chemical yields and enantioselectivities were found to be dramatically dependent upon the ratio of water to organic solvent. The optimal solvent was a mixture of toluene/chloroform/water (9:1:0.5). The catalytic enantioselective solid‐phase phase‐transfer alkylation of polymer‐supported glycine–imine substrate 3 with various alkyl halides with the use of 50 % aqueous CsOH in the optimal solvent system at 0 °C followed by hydrolysis and benzoylation afforded the corresponding (R)‐N‐benzoyl‐α‐amino acid tert‐butyl esters 11 in 60–80 % yield and with enantiomeric ratios (er) of 96.5:3.5 to 99.5:0.5.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)

Enantioselective Ring Expansion of Methylenecyclopropane Carboxamides

A nice approach for enantioselective ring expansion of monoactivated methylene­cyclopropanes has been developed. The use of MgI2 as Lewis acid starting material and CP-IndaBOX as chiral ligand afforded the best results, giving adducts in the range of 49-86% ee. Of the tested imine substrates, electron-withdrawing groups on the aryl ring succeeded in yielding higher selectivities than substrates with strongly electron-donating groups.

Direct Catalytic Asymmetric Mannich Reaction via a Dinuclear Zinc Catalyst

The authors have found that different imine protecting groups provide different dia­stereoselectivity in the direct Mannich reaction. The use of their dinuclear zinc catalyst results in good yields and high selectivities for the condensation of α-hydroxy ketones and imines. The use of enolizable imines was tolerated with various alkyl-substituted imine substrates giving good results.

Chiral Diphosphine ddppm‐Iridium Complexes: Effective Asymmetric Imine Hydrogenations at Ambient Pressures.

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Mechanistic Investigations of Imine Hydrogenation Catalyzed by Cationic Iridium Complexes

Complexes [IrH2(eta6-C6H6)(PiPr3)]BF4 (1) and [IrH2(NCMe)3(PiPr3)]BF4 (2) are catalyst precursors for homogeneous hydrogenation of N-benzylideneaniline under mild conditions. Precursor 1 generates the resting state [IrH2{eta5-(C6H5)NHCH2Ph}(PiPr3)]BF4 (3), while 2 gives rise to a mixture of [IrH{PhN=CH(C6H4)-kappaN,C}(NCMe)2(PiPr3)]BF4 (4) and [IrH{PhN=CH(C6H4)-kappaN,C}(NCMe)(NH2Ph)(PiPr3)]BF4 (5), in which the aniline ligand is derived from hydrolysis of the imine. The less hindered benzophenone imine forms the catalytically inactive, doubly cyclometalated compound [Ir{HN=CPh(C6H4)-kappaN,C}2(NH2CHPh2)(PiPr3)]BF4 (6). Hydrogenations with precursor 1 are fast and their reaction profiles are strongly dependent on solvent, concentrations, and temperature. Significant induction periods, minimized by addition of the amine hydrogenation product, are commonly observed. The catalytic rate law (THF) is rate = k[1][PhN=CHPh]p(H2). The results of selected stoichiometric reactions of potential catalytic intermediates exclude participation of the cyclometalated compounds [IrH{PhN=CH(C6H4)-kappaN,C}(S)2(PiPr3)]BF4 [S = acetonitrile (4), [D6]acetone (7), [D4]methanol (8)] in catalysis. Reactions between resting state 3 and D2 reveal a selective sequence of deuterium incorporation into the complex which is accelerated by the amine product. Hydrogen bonding among the components of the catalytic reaction was examined by MP2 calculations on model compounds. The calculations allow formulation of an ionic, outer-sphere, bifunctional hydrogenation mechanism comprising 1) amine-assisted oxidative addition of H2 to 3, the result of which is equivalent to heterolytic splitting of dihydrogen, 2) replacement of a hydrogen-bonded amine by imine, and 3) simultaneous H delta+/H delta- transfer to the imine substrate from the NH moiety of an arene-coordinated amine ligand and the metal, respectively.

Chiral Diphosphine ddppm‐Iridium Complexes: Effective Asymmetric Imine Hydrogenations at Ambient Pressures

AbstractComplexes of the type [Ir(ddppm)(COD)]X were prepared and tested in the asymmetric hydrogenation of a range of imine substrates. Contrary to known iridium catalysts, the ddppm complexes formed efficient catalysts under an atmospheric hydrogen pressure, whereas at higher pressures the catalytic activity of the system was drastically reduced. Depending upon the reaction conditions, N‐arylimines, Ar′NCMeAr, were hydrogenated to the corresponding secondary amines in high yields and enantioselectivities (80–94% ee). In contrast to the [BF4]− and [PF6]− complexes, coordinating anions such as chloride did not form active Ir‐ddppm hydrogenation catalysts. The cationic Ir‐ddppm hydrogenation system performed well in chlorinated solvents, whereas coordinating solvents deactivated the system. Dimeric and trimeric Ir(III) polyhydride complexes were formed from the reaction of [Ir(ddppm)(COD)]PF6 with molecular hydrogen at atmospheric pressure and were found to inhibit catalytic activity.

Allylation of Aldehyde and Imine Substrates with in situ Generated Allylboronates — A Simple Route to Enantioenriched Homoallyl Alcohols.

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