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.     

Morita–Baylis–Hillman (MBH) Reaction Derived Nitroallylic Alcohols,Acetates and Amines as Synthons in Organocatalysis and Heterocycle Synthesis

The Morita–Baylis–Hillman (MBH) reaction is one of the most useful and efficient protocols for constructing new carbon–carbon bonds between an activated olefin and electrophiles in the presence of a tertiary amine/phosphine. Herein, we present the use of MBH alcohols, which are obtained from the reaction of nitrostyrenes with aldehydes, as well as acetates and amines derived thereof in several organocatalytic transformations. Densely functionalised MBH adducts can also be used to synthesise substituted heteroaromatic compounds, such as furan, pyrrole, pyrazole and imidazole derivatives.     

Regioselective,Unconventional Pictet–Spengler Cyclization Strategy Toward the Synthesis of Benzimidazole‐Linked Imidazoquinoxalines on a Soluble Polymer Support

A novel strategy for an unconventional Pictet–Spengler reaction has been developed for the regioselective cyclization of the imidazole ring system at the C2 position. The developed strategy was utilized to develop a diversity‐oriented parallel synthesis for bis(heterocyclic) skeletal novel analogs of benzimidazole‐linked imidazoquinoxalines on a soluble polymer support under microwave conditions. Condensation of polymer‐immobilized o‐phenylenediamines with 4‐fluoro‐3‐nitrobenzoic acid followed by nucleophilic aromatic substitution with an imidazole motif affords bis(heterocyclic) skeletal precursors for the Pictet–Spengler reaction. The unconventional Pictet–Spengler cyclization with various aldehydes was achieved regioselectively at the C2 position of the imidazole ring to furnish rare imidazole‐fused quinoxaline skeletons. During the Pictet–Spengler cyclization, aldehydes bearing electron‐donating groups afford 4,5‐dihydro‐imidazoquinoxalines, which then auto‐aromatize into benzimidazole‐linked imidazo[1,2‐a]quinoxalines. However, interestingly, aldehydes bearing electron‐withdrawing groups directly provide aromatized imidazo[1,2‐a]quinoxalines, which unexpectedly afford novel benzimidazole‐linked 4‐methoxy‐4,5‐dihydro‐imidazo[1,2‐a]quinoxalines after polymer cleavage.     

Asymmetric Hydrogenation of Furans and Benzofurans with Iridium–Pyridine–Phosphinite Catalysts

Enantioselective hydrogenation of furans and benzofurans remains a challenging task. We report the hydrogenation of 2‐ and 3‐substituted furans by using iridium catalysts that bear bicyclic pyridine–phosphinite ligands. Excellent enantioselectivities and high conversions were obtained for monosubstituted furans with a 3‐alkyl or 3‐aryl group. Furans substituted at the 2‐position and 2,4‐disubstituted furans proved to be more difficult substrates. The best results (80–97 % conversion, 65–82 % enantiomeric excess) were obtained with monosubstituted 2‐alkylfurans and 2‐[4‐(trifluoromethyl)phenyl]furan. Benzofurans with an alkyl substituent at the 2‐ or 3‐position also gave high conversions and enantioselectivity, whereas 2‐aryl derivatives showed essentially no reactivity. The asymmetric hydrogenation of a 3‐methylbenzofuran derivative was used as a key step in the formal total synthesis of the cytotoxic naphthoquinone natural product (?)‐thespesone.     

Visible‐Light‐Promoted Nickel‐ and Organic‐Dye‐Cocatalyzed Formylation Reaction of Aryl Halides and Triflates and Vinyl Bromides with Diethoxyacetic Acid as a Formyl Equivalent

A simple formylation reaction of aryl halides, aryl triflates, and vinyl bromides under synergistic nickel‐ and organic‐dye‐mediated photoredox catalysis is reported. Distinct from widely used palladium‐catalyzed formylation processes, this reaction proceeds by a two‐step mechanistic sequence involving initial in situ generation of the diethoxymethyl radical from diethoxyacetic acid by a 4CzIPN‐mediated photoredox reaction. The formyl‐radical equivalent then undergoes nickel‐catalyzed substitution reactions with aryl halides and triflates and vinyl bromides to form the corresponding aldehyde products. Significantly, besides aryl bromides, less reactive aryl chlorides and triflates and vinyl halides serve as effective substrates for this process. Since the mild conditions involved in this reaction tolerate a plethora of functional groups, the process can be applied to the efficient preparation of diverse aromatic aldehydes.     

Asymmetric Synthesis of Densely Functionalized Medium‐Ring Carbocycles and Lactones through Modular Assembly and Ring‐Closing Metathesis of Sulfoximine‐Substituted Trienes and Dienynes

An asymmetric synthesis of densely functionalized 7–11‐membered carbocycles and 9–11‐membered lactones has been developed. Its key steps are a modular assembly of sulfoximine‐substituted C‐ and O‐tethered trienes and C‐tethered dienynes and their Ru‐catalyzed ring‐closing diene and enyne metathesis (RCDEM and RCEYM). The synthesis of the C‐tethered trienes and dienynes includes the following steps: 1) hydroxyalkylation of enantiomerically pure titanated allylic sulfoximines with unsaturated aldehydes, 2) α‐lithiation of alkenylsulfoximines, 3) alkylation, hydroxy‐alkylation, formylation, and acylation of α‐lithioalkenylsulfoximines, and 4) addition of Grignard reagents to α‐formyl(acyl)alkenylsulfoximines. The sulfoximine group provided for high asymmetric induction in steps 1) and 4). RCDEM of the sulfoximine‐substituted trienes with the second‐generation Ru catalyst stereoselectively afforded the corresponding functionalized 7–11‐membered carbocyles. RCDEM of diastereomeric silyloxy‐substituted 1,6,12‐trienes revealed an interesting difference in reactivity. While the (R)‐diastereomer gave the 11‐membered carbocyle, the (S)‐diastereomer delivered in a cascade of cross metathesis and RCDEM 22‐membered macrocycles. RCDEM of cyclic trienes furnished bicyclic carbocycles with a bicyclo[7.4.0]tridecane and bicyclo[9.4.0]pentadecane skeleton. Selective transformations of the sulfoximine‐ and bissilyloxy‐substituted carbocycles were performed including deprotection, cross‐coupling reaction and reduction of the sulfoximine moiety. Esterification of a sulfoximine‐substituted homoallylic alcohol with unsaturated carboxylic acids gave the O‐tethered trienes, RCDEM of which yielded the sulfoximine‐substituted 9–11‐membered lactones. RCEYM of a sulfoximine‐substituted 1,7‐dien‐10‐yne showed an unprecedented dichotomy in ring formation depending on the Ru catalyst. While the second‐generation Ru catalyst gave the 9‐membered exo 1,3‐dienyl carbocycle, the first‐generation Ru catalyst furnished a truncated 9‐membered 1,3‐dieny carbocycle having one CH₂ unit less than the dienyne.     

exo‐Selective Asymmetric Diels–Alder Reaction Catalyzed by Diamine Salts as Organocatalysts

An organocatalyst formed from a binaphthyl‐substituted diamine and trifluoromethanesulfonic acid exhibited unprecedented levels of exo selectivity in the Diels–Alder reaction of α,β‐unsaturated aldehydes with cyclopentadiene. A novel axially chiral diamine was also designed as an organocatalyst for an asymmetric variant of this reaction, in which the desired cycloadducts were formed with high diastereo‐ and enantioselectivities. The highest diastereoselectivity observed was greater than 20:1 in favor of the exo cycloadduct in the asymmetric Diels–Alder reaction of crotonaldehyde with cyclopentadiene.     

Iodine-Mediated One-Pot Synthesis of 1,4,5-Substituted Pyrazoles from MBH Acetates via Allyl Hydrazone Intermediate

Herein, we report the regioselective one-pot synthesis of 1,4,5-trisubstituted pyrazoles by reacting Morita-Baylis-Hillman (MBH) acetates derived from aryl aldehydes with alkyl or aryl hydrazines in the presence of iodine under aerobic conditions. The reaction proceeds through sequential S_N2′ nucleophilic substitution of substituted hydrazine onto the MBH acetate, I₂-catalyzed oxidation of the allylic hydrazine to allylic hydrazone, heating-induced intramolecular aza-Michael reaction and cyclization, and oxidative aromatization. The key intermediate, the s-trans allyl hydrazones were isolated in good yields by performing the reactions at room temperature. However, the allyl hydrazones prepared from the MBH acetates of aliphatic aldehydes did not furnish the pyrazole owing to the absence of an activated methylene group in the substrate. The synthetic applications of the pyrazoles in Ugi reactions, decarboxylative halogenation, Pd-catalyzed benzoylation of the N-aryl ring, and metal-free tetrazole synthesis has been demonstrated.     

Reaction of OH radical with mono‐, di‐, and trichloroacetaldehyde: an ab initio study

The hydrogen abstraction reactions between chlorine‐substituted acetaldehydes and OH radicals have been investigated by using ab initio molecular orbital theory. Equilibrium geometries and transition‐state structures have been optimized at the (U)MP2/6‐311G(d,p) level. Activation barriers and heats of reaction for different reaction channels have been estimated from the single‐point calculations at the (U)MP2/6‐311G(2df,2p) level. Three, two, and one hydrogen abstraction channel have been found for the mono‐, di‐, and trichloroacetaldehyde, respectively. At a higher temperature region, hydrogen abstraction from the formyl group is found to be the major reaction channel for all the three chloroacetaldehydes. The effect of halogen substitution on reactivity toward hydrogen abstraction has been discussed. © 2001 John Wiley & Sons, Inc. J Comput Chem 22: 1509–1521, 2001     

Breslow Intermediates from Aromatic N‐Heterocyclic Carbenes (Benzimidazolin‐2‐ylidenes,Thiazolin‐2‐ylidenes)

We report the first generation and characterization of elusive Breslow intermediates derived from aromatic N‐heterocyclic carbenes (NHCs), namely benzimidazolin‐2‐ylidenes (NMR, X‐ray analysis) and thiazolin‐2‐ylidenes (NMR). In the former case, the diamino enols were generated by reaction of the free N,N‐bis(2,6‐diisopropylphenyl)‐ and N,N‐bis(mesityl)‐substituted benzimidazolin‐2‐ylidenes with aldehydes while the dimer of 3,4,5‐trimethylthiazolin‐2‐ylidene served as the starting material in the latter case. The unambiguous NMR identification of the first thiazolin‐2‐ylidene‐based Breslow intermediate rests on double ¹³C labeling of both the NHC and the aldehyde component. The acyl anion reactivity was confirmed by benzoin formation with excess aldehyde.     

Iridium‐Catalyzed Asymmetric Allylic Aromatization Reaction

Described herein is an asymmetric allylic aromatization (AAAr) strategy that employs readily accessible equivalents of benzylic nucleophiles in iridium‐catalyzed allylic substitution reactions with the concomitant formation of aromatic rings by aromatization. The optimized reaction conditions involving a catalyst derived from a commercially available iridium precursor and the Carreira ligand are compatible with equivalents of benzylic nucleophiles derived from 4‐ or 5‐methyloxazoles, 5‐methylthiazoles, 4‐ or 5‐methylfurans, 2‐ or 3‐methylbenzofurans, 3‐methylbenzothiophene, 3‐methylindole, 1‐methylnaphthalene, and methylbenzene. This strategy provides straightforward accesses to valuable heterocyclic aromatic compounds, bearing a homobenzylic stereogenic center, in an enantiopure form and would be difficult to access otherwise. The versatility of the reaction was showcased by the further elaboration of the products into useful building blocks and a drug analogue.     

Organocatalytic Domino Michael–Knoevenagel Condensation Reaction for the Synthesis of Optically Active 3‐Diethoxyphosphoryl‐2‐oxocyclohex‐3‐enecarboxylates

Versatile dominoes : A novel, organocatalytic, Michael–Knoevenagel condensation domino reaction of ethyl 4‐diethoxyphosphoryl‐3‐oxobutanoate with various aryl‐ and aliphatic‐substituted α,β‐unsaturated aldehydes catalyzed by a chiral diarylprolinol ether has been successfully performed. The reaction proceeds in a highly enantio‐ and diastereoselective manner giving access to optically active 6‐substituted‐3‐diethoxyphosphoryl‐2‐oxocyclohex‐3‐enecarboxylates (see scheme).

     

(5,6‐Dihydro‐1,4‐dithiin‐2‐yl)methanol as a Versatile Allyl‐Cation Equivalent in (3+2) Cycloaddition Reactions

The title heterocyclic alcohol readily generates a sulfur‐substituted allylic cation upon simple treatment with a protic acid, thus facilitating a synthetically useful stepwise (3+2) cycloaddition reaction pathway with a range of conjugated‐olefin‐type substrates. The introduction of an allyl fragment in this way provided rapid access to a variety of cyclopentanoid scaffolds. The cyclic nature of the cation precursor alcohol was shown to be instrumental for efficient cycloaddition reactions to take place, thus indicating an attractive strategy for controlling the reactivity of heteroatom‐substituted allyl cations. The formal cycloaddition reaction is highly regio‐ and stereoselective and was also used for a short total synthesis of the natural product cuparene in racemic form through a cycloaddition–hydrodesulfurization sequence.     

Copper‐Catalyzed Borylative Allyl–Allyl Coupling Reaction

Borylative allyl–allyl coupling using allenes, bis(pinacolato)diboron, and allyl phosphates has been developed in the presence of a copper catalyst bearing an N‐heterocyclic carbene ligand. The reaction affords boryl‐substituted 1,5‐diene derivatives in good to high yields with high regioselectivity and Z selectivity.     

Synthesis of 2‐Hydroxy‐1,4‐oxazin‐3‐ones through Ring Transformation of 3‐Hydroxy‐4‐(1,2‐dihydroxyethyl)‐β‐lactams and a Study of Their Reactivity

The reactivity of 3‐hydroxy‐4‐(1,2‐dihydroxyethyl)‐β‐lactams with regard to the oxidant sodium periodate was evaluated, unexpectedly resulting in the exclusive formation of new 2‐hydroxy‐1,4‐oxazin‐3‐ones through a C3? C4 bond cleavage of the intermediate 4‐formyl‐3‐hydroxy‐β‐lactams followed by a ring expansion. This peculiar transformation stands in sharp contrast with the known NaIO₄‐mediated oxidation of 3‐alkoxy‐ and 3‐phenoxy‐4‐(1,2‐dihydroxyethyl)‐β‐lactams, which exclusively leads to the corresponding 4‐formyl‐β‐lactams without a subsequent ring enlargement. In addition, this new class of functionalized oxazin‐3‐ones was further evaluated for its potential use as building blocks in the synthesis of a variety of differently substituted oxazin‐3‐ones, morpholin‐3‐ones and pyrazinones. Furthermore, additional insights into the mechanism and the factors governing this new ring‐expansion reaction were provided by means of density functional theory calculations.     

One-pot synthesis of heterocyclic compounds initiated by chemoselective addition to β-acyl substituted unsaturated aldehydes with nucleophilic tin complexes

β-Acyl substituted unsaturated aldehydes 1 were revealed to be good precursors for the synthesis of various heterocyclic compounds by the combination with tin nucleophiles. Various 2-monosubstituted pyrroles were prepared in an one-pot procedure via the reductive amination of formyl groups of 1 by using Bu₂SnIH–HMPA complex. One-pot synthesis of heterocycles was carried out initiated by chemoselective reduction of 1 with Bu₃SnH–HMPA complex and the subsequent reaction with heterocumulenes. Furthermore, the one-pot synthesis of nitrogen heterocyclic compounds accompanying chemo-, regio- and diastereoselective carbon–carbon bond formation in side chain moieties was effectively accomplished initiated by the regio- and diastereoselective allylation of the formyl group of 1 with allylic tin species.     

Synthesis of 3,4,5‐Trisubstituted Isoxazoles from Morita–Baylis–Hillman Acetates by an NaNO2/I2‐Mediated Domino Reaction

An efficient NaNO₂/I₂‐mediated one‐pot transformation of Morita–Baylis–Hillman (MBH) acetates into alkyl 3‐nitro‐5‐(aryl/alkyl)isoxazole‐4‐carboxylates is described. In a cascade event, initial Michael addition of NaNO₂ to the MBH acetate furnishes the allylnitro intermediate which undergoes I₂‐catalyzed oxidative α‐C H nitration of the nitromethyl subunit followed by [3+2] cycloaddition to afford the title compounds. Structural elaborations of these highly substituted isoxazoles by S_NAr reactions and hydrogenolysis allows access to useful products.     

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.     

Synthesis of polysubstituted isoquinolines through cross-coupling reactions with α-alkoxytosylhydrazones

A Pd-catalyzed cross-coupling reaction of α-alkoxytosylhydrazones with sulfonates derived from salicyl aldehydes gives rise to protected 1,5-dicarbonyl compounds. Treatment with ammonium hydroxide readily transforms these alkenes into isoquinolines with diverse substitution patterns at positions 3 and 4. In a similar way, the employment of o-cyanononaflates in the coupling reaction, followed by treatment with an organometallic, provides isoquinolines that incorporate substitution also at position 1. The combination of both approaches represents a versatile method for the preparation of isoquinolines substituted at any position of the heterocyclic ring.