Chiral Thiourea‐Phosphine Organocatalysts in the Asymmetric Aza‐Morita–Baylis–Hillman Reaction

A new kind of bifunctional (thio)urea‐phosphine catalyst was synthesized and applied to the aza‐Morita–Baylis–Hillman reaction of N‐sulfonated imines with methyl vinyl ketone, phenyl vinyl ketone, ethyl vinyl ketone or acrolein. Moderate to excellent ee and yields of the products were obtained under mild reaction conditions.     

Asymmetric Aza‐Morita–Baylis–Hillman‐Type Reactions: The Highly Enantioselective Reaction between Unmodified α,β‐ Unsaturated Aldehydes and N‐Acylimines by Organo‐co‐catalysis

The highly enantioselective organo‐co‐catalytic aza‐Morita–Baylis–Hillman (MBH)‐type reaction between N‐carbamate‐protected imines and α,β‐unsaturated aldehydes has been developed. The organic co‐catalytic system of proline and 1,4‐diazabicyclo[2.2.2]octane (DABCO) enables the asymmetric synthesis of the corresponding N‐Boc‐ and N‐Cbz‐protected β‐amino‐α‐alkylidene‐aldehydes in good to high yields and up to 99% ee. In the case of aza‐MBH‐type addition of enals to phenylprop‐2‐ene‐1‐imines, the co‐catalytic reaction exhibits excellent 1,2‐selectivity. The organo‐co‐catalytic aza‐MBH‐type reaction can also be performed by the direct highly enantioselective addition of α,β‐unsaturated aldehydes to bench‐stable N‐carbamate‐protected α‐amidosulfones to give the corresponding β‐amino‐α‐alkylidene‐aldehydes with up to 99% ee. The organo‐co‐catalytic aza‐MBH‐type reaction is also an expeditious entry to nearly enantiomerically pure β‐amino‐α‐alkylidene‐amino acids and β‐amino‐α‐alkylidene‐lactams (99% ee). The mechanism and stereochemistry of the chiral amine and DABCO co‐catalyzed aza‐MBH‐type reaction are also discussed.     

Dendritic Chiral Phosphine Lewis Bases‐Catalyzed Asymmetric Aza‐Morita–Baylis–Hillman Reaction of N‐Sulfonated Imines with Activated Olefins

A series of polyether dendritic chiral phosphine Lewis bases was synthesized, and successfully applied to the asymmetric aza‐Morita–Baylis–Hillman reaction of N‐sulfonated imines (N‐arylmethylidene‐4‐methylbenzenesulfonamides) with methyl vinyl ketone (MVK), ethyl vinyl ketone (EVK), and acrolein to give the adducts in good to excellent yields along with up to 97 % ee, which are more effective than our previously reported original chiral phosphine Lewis bases. In addition, the dendrimer‐supported chiral phosphine Lewis bases can be easily recovered and reused.     

Magnetic Nanoparticle‐Supported Morita–Baylis–Hillman Catalysts

A magnetic nanoparticle‐supported quinuclidine was prepared and evaluated as a recoverable Morita–Baylis–Hillman catalyst. The supported catalyst 2 demonstrated comparable activity with that of DABCO and could be simply recycled with the assistance of an external magnet. The thus recycled catalyst could be reused for 7 times without significant loss of activity.     

Tunable Bifunctional Phosphine–Squaramide Promoted Morita–Baylis–Hillman Reaction of N‐Alkyl Isatins with Acrylates

A series of highly tunable bifunctional phosphine‐squaramide H‐bond donor organocatalysts 6 has been synthesized from inexpensive and commercially available β‐amino alcohols in moderate yields. Catalyst 6 f can efficiently promote the asymmetric Morita–Baylis–Hillman (MBH) reaction of N‐alkyl isatins with acrylate esters providing the chiral 3‐substituted 3‐hydroxy‐2‐oxindoles in good yields and enantioselectivities (up to 93 % yield and 95 % ee), in which the challenging substrate tert‐butyl acrylate 9 d , provided the best ee value to date. Moreover, this methodology was applied successfully in the synthesis of chiral cyclic spiropyrrolizidineoxindole and γ‐butyrolactone derivatives without enantioselectivity deterioration. The possible mechanism of this MBH reaction was also investigated by ³¹P NMR, ESI‐MS and KIE studies. The KIE experiments show that the electrophilic addition of N‐methyl isatin to the complex of acrylate ester and phophine‐squaramide is the rate‐determing step of the asymmetric MBH reaction.

     

Chiral Phosphine‐Catalyzed Enantioselective [3+2] Annulation of Morita–Baylis–Hillman Carbonates with Cyclic 1‐Azadienes: Synthesis of Functionalized Cyclopentenes

With the use of a bifunctional chiral phosphine as the catalyst, the asymmetric [3+2] annulation of Morita–Baylis–Hillman carbonates with cyclic 1‐azadienes proceeded smoothly under mild conditions to give various enantiomerically enriched cyclopentene derivatives bearing three consecutive tertiary stereocenters and a sulfamate moiety in moderate to excellent yields with moderate to excellent enantioselectivities and excellent diastereoselectivities.

     

Synthesis of an Enantiocomplementary Catalyst of β‐Isocupreidine (β‐ICD) from Quinine

Compound 20 , a pseudoenantiomer of β‐isocupreidine (β‐ICD), was synthesized from quinine employing a Barton reaction of nitrosyl ester 13 and acid‐catalyzed cyclization of carbinol 18 as key steps. The Baylis–Hillman reaction of benzaldehyde, p‐nitrobenzaldehyde, and hydrocinnamaldehyde with 1,1,1,3,3,3‐hexafluoroisopropyl acrylate (HFIPA) using 20 as a chiral amine catalyst was found to give the corresponding S‐enriched adducts in high optical purity (>91% ee) in contrast to the β‐ICD‐catalyzed reaction which affords R‐enriched adducts. This result suggests that compound 20 can serve as an enantiocomplementary catalyst of β‐ICD in the asymmetric Baylis–Hillman reaction of aldehydes with HFIPA.     

Enantioselective Synthesis of Highly Functionalized Trifluoromethyl‐Bearing Cyclopentenes: Asymmetric [3+2] Annulation of Morita–Baylis–Hillman Carbonates with Trifluoroethylidenemalonates Catalyzed by Multifunctional Thiourea‐Phosphines

On the basis of the design and synthesis of multifunctional thiourea‐phosphines, a catalytic method for the asymmetric [3+2] annulation of Morita–Baylis–Hillman carbonates with trifluoroethylidenemalonates has been developed, affording highly functionalized trifluoromethyl‐bearing cyclopentenes in excellent yields, high diastereoselectivities and enantioselectivities under mild conditions.     

Organocatalytic Enantioselective Aza‐Michael Addition of Purine Bases to α,β‐Unsaturated Ketones

The first organocatalytic enantioselective aza‐Michael addition of purine bases to α,β‐unsaturated ketones has been developed, affording Michael adducts in moderate to high yields (up to 96% yield) and high to excellent enantioselectivities (up to >99% ee). A wide range of α,β‐unsaturated ketones including aliphatic and aromatic enones are tolerated in this process, generally demonstrating good reactivity, regioselectivity and enantioselectivity. The aromatic α,β‐unsaturated ketones showing quite low reactivity in the reported catalytic systems, were first successfully employed as Michael acceptors in this transformation, yielding high enantioselectivities (up to 94% ee). The utility of this method was also applied for the synthesis of enantioenriched non‐natural nucleoside analogues with potential biological activities.     

Synthesis of chitosan‐graft‐poly[2‐cyano‐1‐(pyridin‐3‐yl)allyl acrylate] copolymer from a novel monomer,prepared using a Morita–Baylis–Hillman reaction,and characterization of its antimicrobial activity

A novel method has been developed to modify the natural polymer chitosan. The process utilizes a monomer prepared by employing a Morita–Baylis–Hillman (MBH) reaction. Specifically, the vinyl monomer 2‐[hydroxy(pyridin‐3‐yl)methyl]acrylonitrile (HPA) was synthesized using a high‐yielding MBH reaction of acrylonitrile with pyridine‐3‐carboxaldehyde in the presence of 1,4‐diazabicyclo[2.2.2]octane. Conversion of HPA to 2‐cyano‐1‐(pyridin‐3‐yl)allyl acrylate (CPA) was then carried out by reaction of acryloyl chloride. The highly functionalized monomer CPA was grafted onto chitosan through a reaction in 2% acetic acid containing a persulfate and a sulfite (K₂S₂O₈/Na₂SO₃) as redox promoter. An optimal grafting percentage of 123% is obtained when the grafting process is conducted at 60 °C for 4 h employing a 1:0.5 ratio of K₂S₂O₈ and Na₂SO₃ at a concentration of 2.5 × 10^?3 mol L^?1. Chitosan‐graft‐poly[2‐cyano‐1‐(pyridin‐3‐yl)allyl acrylate] graft copolymers, having various grafting percentages, were characterized using Fourier transform infrared, ¹H NMR and ¹³C NMR spectroscopies, X‐ray diffraction, thermogravimetric analysis and scanning electron microscopy. Finally, the results of studies probing the antimicrobial activities of the polymers against selected microorganisms show that the graft copolymers display higher growth inhibition activities against bacteria and fungi than does chitosan. © 2014 Society of Chemical Industry     

Chiral Phosphoric Acid‐Catalyzed Enantioselective Aza‐Friedel–Crafts Alkylation of Indoles with γ‐Hydroxy‐γ‐lactams

An enantioselective aza‐Friedel–Crafts reaction of indoles with γ‐hydroxy‐γ‐lactams using a chiral phosphoric acid catalyst is reported. The approach described herein provides an efficient access to 5‐indolylpyrrolidinones in good to quantitative yields and excellent enantioselectivities (up to >99% ee). The results suggest that the reaction may proceed via N‐acyliminium intermediates associated with the chiral phosphoric acid anion.     

Thermal Intramolecular [2+2] Cycloaddition: Synthesis of 3‐Azabicyclo[3.1.1]heptanes from Morita–Baylis–Hillman Adduct‐Derived 4,4‐Diaryl‐1,3‐dienes

Various 3‐azabicyclo[3.1.1]heptane derivatives were synthesized from Morita–Baylis–Hillman adduct‐derived 1,3‐dienes bearing a 4,4‐diaryl moiety through a thermal intramolecular [2+2] cycloaddition approach. By using the same approach, bicyclo[3.1.1]heptane, 3‐azabicyclo[3.2.0]heptane, and 3‐oxabicyclo[3.1.1]heptane derivatives could also be synthesized. A structurally similar dimethylallyl derivative underwent an intramolecular ene reaction to afford the pyrrolidine derivative.

     

Palladium‐Catalyzed Domino Cyclization (5‐exo/3‐exo), Ring‐ Expansion by Palladium Rearrangement,and Aromatization: An Expedient Synthesis of 4‐Arylnicotinates from Morita–Baylis–Hillman Adducts

Various 4‐arylnicotinate derivatives were synthesized via a palladium‐catalyzed cascade reaction of N‐(2‐bromoallyl)‐N‐cinnamyltosylamides in a one‐pot procedure in good yields. The reaction involves a domino 5‐exo/3‐exo carbopalladation, ring‐expansion by palladium rearrangement, and an aromatization process.     

Organocatalytic Enantioselective Michael Reaction of Malononitrile with β,β‐Disubstituted Nitroalkenes

We have developed and optimized an enantioselective Michael reaction of malononitrile with β,β‐disubstituted nitroalkenes. This reaction was catalyzed by a cinchona alkaloid derived thiourea catalyst, producing products of high yields (up to 98 %) and stereoselectivities (up to 93 % ee). One of the adducts was used as an intermediate for the synthesis of dihydropyrrole derivative bearing a synthetically valuable quaternary chiral center.

     

The First Catalytic,Enantioselective Aza‐Henry Reaction of an Unactivated Cyclic Imine

The aza‐Henry reaction is an efficient route to important chiral, vicinal diamines. Reports of the asymmetric version typically use electron‐deficient acyclic imines. We report the first example of a catalytic, asymmetric aza‐Henry reaction on an unfunctionalized cyclic imine that gives access to enantiopure diamine derivatives under experimentally straightforward conditions. The stereocentre is established through the initial nitromethane addition to the imine. The scalemic intermediate may be trapped through acylation, then crystallized.     

Construction of Adjacent Quaternary and Tertiary Stereocenters via an Organocatalytic Allylic Alkylation of Morita–Baylis–Hillman Carbonates

Racemic Baylis–Hillman carbonates can be converted in densely functionalized products by reaction with cyano esters in the presence of a catalytic amount of a modified Cinchona alkaloid in high enantioselectivities and fair diastereoselectivities. A rational for the observed stereoselectivity is presented.     

Rhodium‐Catalyzed [2+2+2] Cycloadditions of Diynes with Morita–Baylis–Hillman Adducts: A Stereoselective Entry to Densely Functionalized Cyclohexadiene Scaffolds

A rhodium‐catalyzed asymmetric synthesis of 5,5‐disubstituted cyclohexa‐1,3‐dienes has been achieved by [2+2+2] cycloaddition reactions between diynes and Morita–Baylis–Hillman (M‐B‐H) adducts as unsaturated substrates. Products containing two adjacent chiral centres (quaternary and tertiary, respectively) were obtained with complete diastereoselectivity and high enantioselectivity (84–97%) through a kinetic resolution of the M‐B‐H adduct. Furthermore, these highly substituted cyclohexadienes reacted with dienophiles to afford the corresponding Diels–Alder cycloadducts in good yields.

     

Organocatalytic Enantioselective Aziridination of α‐Substituted α,β‐Unsaturated Aldehydes: Asymmetric Synthesis of Terminal Aziridines

The first example of a highly enantioselective organocatalytic aziridination of α‐substituted α,β‐unsaturated aldehydes is presented. The reaction is catalyzed by simple chiral amines and gives access to highly functional terminal azirdines containing an α‐tertiary amine stereocenter in high yields and enantiomeric ratios (95.5:4.5–98:2).     

A Highly Enantioselective Catalytic Domino Aza‐Michael/Aldol Reaction: One‐Pot Organocatalytic Asymmetric Synthesis of 1,2‐Dihydroquinolidines

The highly enantioselective organocatalytic domino aza‐Michael/aldol reaction is presented. The unprecedented, chiral amine‐catalyzed asymmetric domino reactions between 2‐aminobenzaldehydes and α,β‐unsaturated aldehydes proceed with excellent chemo‐ and enantioselectivity to give the corresponding pharmaceutically valuable 1,2‐dihydroquinolines derivatives in high yields with 90 to >99 % ee.