Organocatalytic One‐Pot Synthesis of Highly Substituted Pyridazines from Morita–Baylis–Hillman Carbonates and Diazo Compounds

A biologically inspired organocatalytic one‐pot synthesis of highly functionalized pyridazines, which are ubiquitous structural units in a number of biologically active compounds, has been developed by starting from readily available diazo compounds and Morita–Baylis–Hillman (MBH) carbonates. Under mild reaction conditions, this synthetic route tolerated significant substrate variation to deliver a broad range of substituted products, including CF₃‐substituted pyridazines derivatives. Moreover, the introduction of trifluoromethyl groups into the ring of pyridazine could be completed conveniently from 2,2,2‐trifluorodiazoethane.     

Direct Umpolung Morita–Baylis–Hillman like α‐Functionalization of Enones via Enolonium Species

Herein we report on the umpolung of Morita–Baylis–Hillman type intermediates and application to the α‐functionalization of enone C?H bonds. This reaction gives direct access to α‐chloro‐enones, 1,2‐diketones and α‐tosyloxy‐enones. The latter are important intermediates for cross‐coupling reaction and, to the best of our knowledge, cannot be made in a single step from enones in any other way. The proposed mechanism is supported by spectroscopic studies. The key initial step involves conjugate attack of an amine (DABCO or pyridine), likely assisted by hypervalent iodine acting as a Lewis acid leading to formation of an electrophilic β‐ammonium‐enolonium species. Nucleophilic attack by acetate, tosylate, or chloride anion is followed by base induced elimination of the ammonium species to give the noted products. Hydrolysis of α‐acetoxy‐enones lead to formation of 1,2‐diketones. The α‐tosyl‐enones participate in Negishi coupling reactions under standard conditions.     

Brønsted Acid Catalyzed Morita–Baylis–Hillman Reaction: A New Mechanistic View for Thioureas Revealed by ESI‐MS(/MS) Monitoring and DFT Calculations

A Morita–Baylis–Hillman (MBH) reaction catalyzed by thiourea was monitored by ESI‐MS(/MS) and key intermediates were intercepted and characterized. These intermediates suggest that thiourea acts as an organocatalyst in all steps of the MBH reaction cycle, including the rate‐limiting proton‐transfer step. DFT calculations, performed for a model MBH reaction between formaldehyde and acrolein with trimethylamine as base and in the presence or the absence of thiourea, suggest that thiourea accelerates MBH reactions by decreasing the transition‐state (TS) energies through bidentate hydrogen bonding throughout the whole catalytic cycle. In the rate‐limiting proton‐transfer step, the thiourea acts not as a proton shuttle, but as a Brønsted acid stabilizing the basic oxygen center that is formed in the TS.     

Asymmetric Morita–Baylis–Hillman Reaction: Catalyst Development and Mechanistic Insights Based on Mass Spectrometric Back‐Reaction Screening

An efficient protocol for the evaluation of catalysts for the asymmetric Morita–Baylis–Hillman (MBH) reaction was developed. By mass spectrometric back‐reaction screening of quasi‐enantiomeric MBH products, an efficient bifunctional phosphine catalyst was identified that outperforms literature‐known catalysts in the MBH reaction of methyl acrylate with aldehydes. The close match between the selectivities measured for the forward and back reaction and kinetic measurements provided strong evidence that the aldol step and not the subsequent proton transfer is rate‐ and enantioselectivity‐determining.     

Dual Organocatalysis: Asymmetric Allylic–Allylic Alkylation of α,α‐Dicyanoalkenes and Morita–Baylis–Hillman Carbonates

The first highly enantioselective allylic–allylic alkylation of α,α‐dicyanoalkenes and Morita–Baylis–Hillman carbonates by dual catalysis of (DHQD)₂AQN and (S)‐BINOL has been investigated. Excellent stereoselectivities have been achieved for a broad spectrum of substrates (d.r. > 99:1, up to 99 % ee). The multifunctional allylic products could be efficiently converted to a range of complex chiral cyclic frameworks. EWG=electron‐withdrawing group, (DHQD)₂AQN=hydroquinidine (anthraquinone‐1,4‐diyl) diether, (S)‐BINOL =(S)‐(?)‐1,1′‐bi‐2‐naphthol.

     

Novel Organocatalytic Activation of Unmodified Morita–Baylis–Hillman Alcohols for the Synthesis of Bicyclic α‐Alkylidene‐Ketones

The organocatalytic activation of Morita–Baylis–Hillman alcohols via H‐bonding‐iminium‐ion formation is demonstrated for the first time. This activation strategy enables the Morita‐Baylis–Hillman alcohols to undergo a formal S_N2′ reaction. In combination with the well‐established enamine reactivity, this creates a new reactivity pattern. The application of this new activation mode for the synthesis of bicyclic α‐alkylidene‐ketones is demonstrated. The developed reaction sequence proceeds efficiently affording nature‐inspired target products with four contiguous stereogenic centers in a highly stereoselective manner.     

Use of MEKC for the analysis of reactant and product of Baylis–Hillman reaction

A facile, fast and high efficiency micellar EKC has been explored for the analysis and UV detection of p‐nitrobenzaldehyde and 2‐[hydroxy(4‐nitrophenyl)methyl]‐2‐cyclopenten‐1‐one with a buffer electrolyte of 30.0 mM tetraborate and 50.0 mM sodium taurodeoxycholate at pH 9.3. Under the optimal conditions, a linear range from 7.8×10^–2 to 5.0×10² mM for those analytes (r² > 0.99) was achieved. The LOD was 3.9 μM for 2‐[hydroxy(4‐nitrophenyl)methyl]‐2‐cyclopenten‐1‐one and 7.8 μM for p‐nitrobenzaldehyde, respectively (S/N = 3). The applicability of this new method for the analysis of reactants (p‐nitrobenzaldehyde and cyclopent‐2‐enone), catalysts (imidazole or N‐methyl imidazole or 1‐benzyl‐imidazole) and product (2‐[hydroxy(4‐nitrophenyl)methyl]‐2‐cyclopenten‐1‐one) on offline Baylis–Hillman reaction was examined. The relationship between the reaction time and the amount of product has been studied. Meanwhile, three different kinds of catalysts were investigated for getting the desired moderate to good amount products. It was found that comparing with N‐methyl imidazole or 1‐benzyl‐imidazole catalyst, imidazole‐catalyzed reaction could produce more products within the same reaction time. Furthermore, the results indicated that the rate law for the investigated Baylis–Hillman reaction was second‐order reaction. The rate constant for the reaction is 1.34 (±0.01)×10^–3 mol^–1 m³/s.     

Enantioselective Synthesis of β‐Iodo Morita–Baylis–Hillman Esters by a Catalytic Asymmetric Three‐Component Coupling Reaction

A catalytic route toward chiral Morita–Baylis–Hillman esters by asymmetric coupling between α,β‐acetylenic esters, aldehydes, and trimethylsilyl iodide has been developed (see scheme). The reaction proceeds with high to excellent enantioselectivities, and the products can be transformed into β‐branched derivatives in a single step and with excellent retention of configuration. TMS=trimethylsilyl

     

Asymmetric Baylis–Hillman Reactions Promoted by Chiral Imidazolines

The coupling of electrophiles with activated alkenes by using tertiary amines or phosphines is generally known as the Baylis–Hillman reaction. It is a useful and atom‐economical carbon–carbon bond‐forming reaction that generates multifunctionalized products. This reaction is notoriously slow; yields are often low and substrate‐dependent. The asymmetric reaction is still limited especially for unactivated olefins such as acrylates. Imidazolines have been developed as ligands in metal‐catalyzed reactions and have also been used as privileged structures in diversity‐oriented synthesis. A series of novel chiral imidazolines were prepared and used to develop asymmetric Baylis–Hillman reactions. These imidazolines promote the reactions of various aromatic aldehydes with unactivated acrylates. Enantiomeric excesses of up to 60 % and high yields were obtained by using stoichiometric amounts of the promoter. Furthermore, the imidazolines are also suitable promoters for the reactions between aromatic aldehydes and alkyl vinyl ketones. Enantiomeric excesses of up to 78 % and high yields were obtained with 50 mol % of an imidazoline with a chiral methylnaphthyl group. These chiral imidazolines are easily prepared from commercially available amino alcohols and can be easily recovered for reuse without loss of product enantioselectivity.     

DFT conformational studies of alpha-maltotriose

Recent DFT optimization studies on alpha-maltose improved our understanding of the preferred conformations of alpha-maltose. The present study extends these studies to alpha-maltotriose with three alpha-D-glucopyranose residues linked by two alpha-[1-->4] bridges, denoted herein as DP-3's. Combinations of gg, gt, and tg hydroxymethyl groups are included for both "c" and "r" hydroxyl rotamers. When the hydroxymethyl groups are for example, gg-gg-gg, and the hydroxyl groups are rotated from all clockwise, "c", to all counterclockwise, "r", the minimum energy positions of the bridging dihedral angles (phi(H) and psi(H)) move from the region of conformational space of (-, -), relative to (0 degrees , 0 degrees), to a new position defined by (+, +). Further, it was found previously that the relative energies of alpha-maltose gg-gg-c and "r" conformations were very close to one another; however, the DP-3's relative energies between hydroxyl "c" or "r" rotamers differ by more than one kcal/mol, in favor of the "c" form, even though the lowest energy DP-3 conformations have glycosidic dihedral angles similar to those found in the alpha-maltose study. Preliminary solvation studies using COSMO, a dielectric solvation method, point to important solvent contributions that reverse the energy profiles, showing an energy preference for the "r" forms. Only structures in which the rings are in the chair conformation are presented here.     

Density Functional Study of Proline‐Catalyzed Intramolecular Baylis–Hillman Reactions

A rationalization of stereoselectivity : The mechanisms of proline‐catalyzed and imidazole‐co‐catalyzed intramolecular Baylis–Hillman reactions have been studied by using density functional theory methods. The computational data has allowed us to rationalize the experimental outcome, validating some of the mechanistic steps proposed in the literature, as well as to propose new ones that considerably change and improve our understanding of the full reaction path (see scheme).

     

A DFT and AIM analysis of the spin–spin couplings across the hydrogen bond in the 2‐fluorobenzamide and related compounds

In 1975 a large number of coupling constants were measured in 2‐fluorobenzamide labeled with ¹⁵N. Some of them were assigned to couplings through intramolecular N? H···F hydrogen bonds (HBs). These couplings change dramatically when CDCl₃ is replaced by DMSO‐d₆. In this theoretical paper we provide density functional theory (DFT) calculations that justify the existence of a weak HB in the absence of solvent, while solvents that act as HB acceptors break down the intramolecular hydrogen bond (IMHB) of 2‐fluorobenzamide. Atoms in molecules (AIM) analyses and Steiner‐Limbach plots were used to analyze the structure of the compounds. Copyright © 2009 John Wiley & Sons, Ltd.     

DFT investigation of sites of protonation of antitumor of 2‐(4‐aminophenyl)benzazoles in the gas phase and in solution

The proton affinity on each of the possible sites in the antitumor 2‐(4‐aminophenyl)benzazoles has been calculated at the B3LYP/6‐311G** level of theory in the gas phase and in solution. The N₃‐site of protonation is found to be strongly favored over the NH₂‐site for the studied compounds both in gas phase and in solution. The stability of N₃‐protonated species is explained by the resonance interaction of the NH₂‐group with the heterocyclic ring. The potential energy surface (PES) for the protonation process was studied at the density functional theory (DFT)/B3LYP/6‐311++G** level of theory. Solvent effects on the PES were also examined using two models: Onsager self‐consistent field and polarizable continuum model (PCM). © 2005 Wiley Periodicals, Inc. Int J Quantum Chem, 2005     

Synthetic Applications of the Baylis–Hillman Reaction: Simple and Convenient Synthesis of Five Important Insect Pheromones

A simple and convenient synthesis of five important insect pheromones by means of Baylis–Hillman adducts is described, i.e., of (2E,4S)‐2,4‐dimethylhex‐2‐enoic acid ( 1 ), a mandibular‐gland secretion of the male carpenter ant in the genus Camponotus, of (+)‐(S)‐manicone ( 2 ) and (+)‐(S)‐normanicone ( 3 ), two mandibular‐gland constituents of Manica ants, and of (+)‐dominicalure‐I ( 6 ) and (+)‐dominicalure‐II ( 7 ), two aggregation pheromones of the lesser grain borer Rhyzopertha dominica (F). For the first time, the potential of the Baylis–Hillman chemistry for the stereoselective synthesis of trisubstituted olefins was successfully applied to the synthesis of these pheromone compounds.