Enantioselective addition of terminal alkynes to N-(diphenylphosphinoyl)imines catalyzed by Zn–BINOL complexes

Chiral nonracemic N-(diphenylphosphinoyl)-protected propargylic amines have been prepared by addition of terminal alkynes to N-(diphenylphosphinoyl)aldimines in the presence of dimethylzinc and 3,3′-dibromo-BINOL as catalyst. The reaction works with a variety of aromatic and heteroaromatic aldimines and with different alkynes, providing the expected products in generally good yields and enantiomeric excesses (up to 96%).     

Design and synthesis of new chiral phosphorus-olefin bidentate ligands and their use in the rhodium-catalyzed asymmetric addition of organoboroxines to N-sulfonyl imines

Novel chiral phosphorus-olefin bidentate ligands have been synthesized in a few steps from a readily available enantiopure compound. These ligands have been applied to a rhodium-catalyzed asymmetric addition of organoboroxines to N-sulfonyl aldimines, achieving high yield and enantioselectivity.     

Asymmetric radical addition of ethers to enantiopure N-p-toluenesulfinyl aldimines, mediated by dimethylzinc-air

Asymmetric radical addition of ethers to enantiopure aromatic N-p-toluenesulfinyl aldimines has been achieved. The requisite radicals were generated by dimethylzinc-air. Lewis acid activation of the N-p-toluenesulfinyl aldimines followed by radical addition gives a mixture of sulfinamide and sulfonamide products. Subsequent treatment of the mixture with dry m-CPBA affords the sulfonamide product in enantiomerically enriched form. [reaction: see text]     

A novel reductive dimerization/oxidative dehydrogenation of aldimines mediated by lanthanoid metals.

A lanthanoid metal-mediated novel reductive dimerization/oxidative dehydrogenation of a variety of aldimines has been achieved. Aromatic aldimines (1) were dimerized in the presence of 0.5 mol of ytterbium metal (Yb) and 1-naphthaldehyde (1-NpCHO) to give the corresponding vicinal diimines (2) in good to high yields. Samarium metal (Sm) or samarium(II) diiodide (SmI2) gives unsatisfied yields under the same reaction conditions. As an oxidant, 1-NpCHO gives the best result. In addition, HMPA plays an important role as a cosolvent in this reaction. Reaction of various aldimines with Yb metal is discussed in detail. Moreover, it has been found that the electron-donating substitutents on the benzene ring promote the reaction and that the electron-withdrawing substitutents retard the reaction. The reaction of deuterated N-benzylideneaniline with Yb metal confirmed that transformation of the hydride occurred from aldimines to the oxidant aldehyde. The mechanism of the reaction was discussed.     

Ni(II)/mono-RuPHOX-catalyzed asymmetric addition of alkenylboronic acids to cyclic aldimines

A Ni(II)-catalyzed asymmetric addition of alkenylboronic acids to aldimines has been developed employing a mono-RuPHOX ligand. A series of cyclic aldimines and alkenylboronic acids are tolerated under our catalytic system, giving various chiral allylamines in good yields and ees.     

Magnesium Aldimines Prepared by Addition of Organomagnesium Halides to 2,4,6-Trichlorophenyl Isocyanide: Synthesis of 1,2-Dicarbonyl Derivatives

The selective addition of organomagnesium reagents to 2,4,6-trichlorophenyl isocyanide leading to magnesiated aldimines is reported. These aldimines react with Weinreb amides, ketones, or carbonates to provide the corresponding carbonyl derivatives after acidic cleavage. This allows for an efficient synthesis of 1,2-dicarbonyl compounds and α-hydroxy ketones.     

Enantioselective Addition of Silicon Nucleophiles to Aldimines Using a Preformed NHC–Copper(I) Complex as the Catalyst

A remaining major challenge in the asymmetric addition of silicon nucleophiles to typical prochiral acceptors, the enantioselective 1,2‐addition to aldimines, is addressed. Activation of the Si? B bond in the silicon pronucleophile by a copper(I) alkoxide with McQuade’s chiral six‐membered N‐heterocyclic carbene as a supporting ligand releases the silicon nucleophile, which adds to various aldimines with high levels of enantioselectivity. The new method provides a catalytic asymmetric access to α‐silylated amines.     

Stereoselective vinylation of aryl N-(2-pyridylsulfonyl) aldimines with 1-alkenyl-1,1-heterobimetallic reagents

Vinylation of aryl N-(2-pyridylsulfonyl) aldimines with versatile 1-alkenyl-1,1-borozinc heterobimetallic reagents is disclosed. In situ hydroboration of air-stable B(pin)-alkynes followed by chemoselective transmetalation with dimethylzinc and addition to aldimines provides B(pin)-substituted allylic amines in 53-93% yield in a one-pot procedure. The addition step can be followed by either B-C bond oxidation to provide α-amino ketones (71-98% yield) or Suzuki cross-coupling to furnish trisubstituted 2-arylated (E)-allylic amines (51-73% yield).     

Tf<Subscript>2</Subscript>O-TMDS combination for the direct reductive transformation of secondary amides to aldimines,aldehydes, and/or amines

The direct partial reduction of highly stable secondary amides to more reactive aldimines and aldehydes is a challenging yet highly demanding transformation. In this context, only three methods have been reported. We report herein an improved version of the Charette’s method. Our protocol consists of activation of secondary amides with triflic anhydride/2-fluoropyridine, and partial reduction of the resulting intermediates with 1,1,3,3-tetramethyldisiloxane (TMDS), which delivered aldimines or aldehydes upon acidic hydrolysis. Aromatic amides were reduced to the corresponding aldimines in 85%–100% NMR yields, and yields (NMR) from aliphatic amides were 72%–86%. Acidic hydrolysis of the aldimine intermediates afforded, in one-pot, the corresponding aldehydes in 80%–96% yields. A simple protocol was established to isolate labile aldimines in pure form in 92%–96% yields. The improved method gave generally higher yields as compared to the known ones, and features the use of cheaper and more atom-economical TMDS as a chemoselective reducing agent. In addition, a convenient extraction protocol has been established to allow the isolation of amines, which constitutes a mild method for the N-deacylation of amides, another highly desirable transformation. The extended method retains the advantages of the original method of Charette in terms of mild conditions, good functional group tolerance, and excellent chemoselectivity.     

Quantification of the electrophilic reactivities of aldehydes, imines, and enones

The rates of the epoxidation reactions of aldehydes, of the aziridination reactions of aldimines, and of the cyclopropanation reactions of α,β-unsaturated ketones with aryl-stabilized dimethylsulfonium ylides have been determined photometrically in dimethyl sulfoxide (DMSO). All of these sulfur ylide-mediated cyclization reactions as well as the addition reactions of stabilized carbanions to N-tosyl-activated aldimines have been shown to follow a second-order rate law, where the rate constants reflect the (initial) CC bond formation between nucleophile and electrophile. The derived second-order rate constants (log k(2)) have been combined with the known nucleophilicity parameters (N, s(N)) of the aryl-stabilized sulfur ylides 4a,b and of the acceptor-substituted carbanions 4c-h to calculate the electrophilicity parameters E of aromatic and aliphatic aldehydes (1a-i), N-acceptor-substituted aromatic aldimines (2a-e), and α,β-unsaturated ketones (3a-f) according to the linear free-energy relationship log k(2) = s(N)(N + E) as defined in J. Am. Chem. Soc.2001, 123, 9500-9512. The data reported in this work provide the first quantitative comparison of the electrophilic reactivities of aldehydes, imines, and simple Michael acceptors in DMSO with carbocations and cationic metal-π complexes within our comprehensive electrophilicity scale.     

Highly enantioselective aza-Henry reaction of N-tosyl imines catalyzed by N,N'-dioxide-Cu(I) complexes

The N,N'-dioxide-Cu(I) complexes have been developed to catalyze the addition of nitromethane to N-tosyl aldimines. The aza-Henry reaction proceeds smoothly affording the corresponding nitro amines in good yields with high enantioselectivities. A catalytic cycle is proposed to explain the origin of reactivity.     

Enantio- and diastereoselectivities in chiral sulfur ylide promoted asymmetric aziridination reactions

Density functional theory investigation on the factors controlling enantio- and diastereoselection in asymmetric aziridination reaction by the addition of chiral bicyclic sulfur ylides to substituted aldimines is presented. High levels of enantioselection are predicted toward the formation of (2S,3S)-cis and (2R,3S)-trans aziridines by the addition of stabilized ylide (R = COMe) respectively to SO2Me and CO2Me protected aldimines. Similarly, high %ee is predicted for the formation of (2S,3R)-cis aziridines from semistabilized (R = Ph) ylide. Moderate to high levels of diastereoselectivity is noticed as well. The present study highlights that a correct prediction on extent of enantioselection requires the knowledge of the activation barriers for elementary steps beyond the initial addition step. In the case of stabilized ylides the ring-closure (or elimination of sulfur compound) is found to be crucial in controlling enantio- and diastereoselection. A cumulative effect of electronic as well as other weak interactions is identified as factors contributing to the relative energies of transition states leading to enantio- and diastereomeric products for the stabilized ylide addition to aldimines. On the contrary, steric control appears quite dominant with semistabilized ylide addition. With the smallest substituent on ylide (R = Me), high enantioselectivity is predicted for the formation of (2R,3R)-trans aziridines although the %de in this case is found to be very low.     

Stereoselective allylation and reduction of N-tert-butanesulfinyl-α-keto aldimines

A simple methodology for the synthesis of N-tert-butanesulfinyl-α-keto aldimines from both α-keto aldehydes and carboxylic esters has been developed. The addition of an in situ formed allyl indium reagent to these chiral imines was also studied. The addition took place in a sequential manner, first to the imine group with excellent diastereoselectivity and then to the carbonyl group with lower diastereoselectivity. Ruthenium-catalyzed ring closing metathesis of the resulting 5-aminoocta-1,7-dien-4-ol derivatives provided access to 6-aminocyclohex-3-enols. Reduction of the α-keto aldimines led to N-tert-butanesulfinyl-1,2-aminoalcohols as a 1:1 diastereomeric mixture.     

Self-condensation of N-tert-butanesulfinyl aldimines: application to the rapid asymmetric synthesis of biologically important amine-containing compounds

[reaction: see text] Highly diastereoselective intra- and intermolecular self-condensation reactions of N-tert-butanesulfinyl aldimines have been developed and applied to the rapid, asymmetric synthesis of trans-2-aminocyclopentanecarboxylic acid and the drug candidate SC-53116. Key to both syntheses is a novel microwave-assisted reaction in which N-sulfinyl aldimines are cleanly converted into nitriles in high-yielding concerted elimination processes.     

Divergent selectivity in MgI(2)-mediated ring expansions of methylenecyclopropyl amides and imides

We report a novel approach to prepare five- and six-membered heterocyclic compounds via a ring expansion of monoactivated methylenecyclopropanes (MCPs) with aldimines and aldehydes in the presence of MgI(2). Monoactivated MCPs behave as homo-Michael acceptors to afford bifunctional vinylogous enolates in the presence of MgI(2). The carbonyl moiety of the monoactivated MCP dramatically influences the reaction site in the dienolate with aryl aldimines and aldehydes as well as the size of the ring. Excellent divergent selectivity to five- vs. six-membered heterocycles is observed: alpha-alkylation/5-exo-tet cyclization (Z = NPh(2)) vs. gamma-alkylation/6-exo-trig cyclization (Z = 2-oxazolidone). Analogously, the reaction of the MCP imide with alkyl aldimines demonstrates the same selectivity by varying the size of electrophile or the reaction temperature. In addition, we observe the first example of the formation of the gamma-alkylation adduct in the reaction of a vinylogous imide enolate with a carbonyl compound.     

Asymmetric synthesis of protected 1,2-amino alcohols using tert-butanesulfinyl aldimines and ketimines.

tert-Butanesulfinyl aldimines and ketimines bearing an alpha-benzyloxy or alpha-silyloxy substituent serve as precursors in the synthesis of protected 1,2-amino alcohols in high yields and diastereoselectivities. General protocols are described for the addition of unbranched alkyl, branched alkyl, and aryl organometallic reagents to N-sulfinyl aldimines 1 and 2 and ketimines 5 and 6. Furthermore, the selective N- or O-deprotection of sulfinamide products 3, 4, 7, and 8 is described, enabling further synthetic transformations of the reaction products.     

Synthesis of thiazole aminophosphine oxides, aminophosphonic and aminophosphinic acids and Cu(II) binding abilities of thiazole aminophosphonic acids

A series of new aminophosphine oxides, aminophosphonic and aminophosphinic acids derived from thiazole was synthesized by addition of phosphine oxides or silylated phosphorus esters to the corresponding thiazole aldimines. The thiazole aldimines were obtained from 2-thiazole aldehyde and primary amines by a standard procedure. The corresponding phosphine oxides were obtained by alkylation of diethyl phosphite or ethyl phenylphosphinate with the appropriate Grignard reagents. The silylated phosphorus esters were prepared from trimethyl phosphite and from methyl- or phenylphosphinic ethyl ester by treatment with bromotrimethylsilane. The coordination ability towards Cu(II) ions are described for two obtained aminophosphonate ligands.     

Rhodium-catalyzed arylation and alkenylation of imines with organostannanes

A rhodium complex catalyzed the addition of aryl- and alkenyl-stannanes to activated aldimines under mild and neutral conditions, affording the corresponding amines in good yields.     

Chiral trans-carboxylic trifluoromethyl 2-imidazolines by a Ag2O-catalyzed Mannich-type reaction

Trifluoromethyl aldimines derived from α-amino esters have proven to be very good starting materials to obtain the title compounds. A Ag₂O-catalyzed Mannich-type/cyclization cascade reaction starting from suitable α-isocyano acetates leads to enantiopure valuable trans-carboxylic trifluoromethyl substituted 2-imidazolines by a highly stereoselective addition without the need to add organocatalysts.     

Solid-Liquid Phase Transfer Catalytic Synthesis (V) Michael Addition,Carbonyl Addition Reactions of the Aldimines

Nucleophilic addition of aldimines to the active methylene compounds and aldehyde compounds can be performed in solidliquid PTC conditions. The reactions are synthetically useful in preparing α-amino acids.