Structurally Divergent Lithium Catalyzed Friedel–Crafts Reactions on Oxetan‐3‐ols: Synthesis of 3,3‐Diaryloxetanes and 2,3‐Dihydrobenzofurans

The first examples of 3,3‐diaryloxetanes are prepared in a lithium‐catalyzed and substrate dependent divergent Friedel–Crafts reaction. para‐Selective Friedel–Crafts reactions of phenols using oxetan‐3‐ols afford 3,3‐diaryloxetanes by displacement of the hydroxy group. These constitute new isosteres for benzophenones and diarylmethanes. Conversely, ortho‐selective Friedel–Crafts reactions of phenols afford 3‐aryl‐3‐hydroxymethyl‐dihydrobenzofurans by tandem alkylation–ring‐opening reactions; the outcome of the reaction diverging to structurally distinct products dependent on the substrate regioselectivity. Further reactivity of the oxetane products is demonstrated, suitable for incorporation into drug discovery efforts.     

Fe(OTf)3‐Catalyzed α‐Benzylation of Aryl Methyl Ketones with Electrophilic Secondary and Aryl Alcohols

Acid‐catalyzed Friedel–Crafts alkylation of 1,3‐dicarbonyl compounds with electrophilic alcohols, is known to be an effective C? C bond forming reaction. However, until now, this reaction has not been amenable for α‐alkylation of aryl methyl ketones because of the notoriously low nucleophilicities of these compounds. Therefore, α‐alkylation of aryl methyl ketone relies on precious metal catalysts and also, the use of primary alcohols is mandatory. In this study, we found that a system composed of a Fe(OTf)₃ catalyst and chlorobenzene solvent is sufficient to promote the title Friedel–Crafts reaction by using benzhydrols as electrophiles. 3,4‐Dihydro‐9‐(2‐hydroxy‐4,4‐dimethyl‐6‐oxo‐1‐cyclohexen‐1‐yl)‐3,3‐dimethyl‐xanthen‐1(2 H)‐one was also applicable as an electrophile in this type of benzylation reaction. On the basis of this result, a three‐component reaction of salicylaldehyde, dimedone, and aryl methyl ketone was also developed, and this provided an efficient way for the synthesis of densely substituted 4H‐chromene derivatives.     

BF3⋅OEt2‐Catalyzed Intermolecular Reactions of Vinylidenecyclopropanes with Bis(p‐alkoxyphenyl)methanols: A Novel Cationic 1,4‐Aryl‐Migration Process

BF₃?OEt₂‐catalyzed reactions of vinylidenecyclopropanes (VDCPs) 1 with bis(aryl)methanols 2 were thoroughly investigated. When VDCPs 1 reacted with electron‐rich bis(aryl)methanols 2 , diastereomeric rotamers of indene derivatives formed in excellent yields by a novel cationic 1,4‐aryl migration between two carbon atoms and the subsequent intramolecular Friedel–Crafts reaction pathways in the presence of BF₃?OEt₂ under mild conditions. As for electron‐deficient or less‐electron‐rich bis(aryl)methanols 2 , either trialkene products formed in good yields by direct deprotonation, or another type of indene derivative was produced by direct intramolecular Friedel–Crafts reaction, depending on the substituents on the cyclopropane of VDCPs. In addition, DFT calculations were carried out to explain the experimental results. Plausible mechanisms for all these transformations are proposed on the basis of the experimental and computational results.     

Highly Enantioselective Synthesis of β‐Heteroaryl‐Substituted Dihydrochalcones Through Friedel–Crafts Alkylation of Indoles and Pyrrole

A highly enantioselective Friedel–Crafts (F–C) alkylation of indoles and pyrrole with chalcone derivatives catalyzed by a chiral N,N′‐dioxide–Sc(OTf)₃ complex has been developed that tolerates a wide range of substrates. The reaction proceeds in moderate to excellent yields and high enantioselectivities (85–92 % enantiomeric excess) using 2 mol % (for indole) or 0.5 mol % (for pyrrole) catalyst loading, which showed the potential value of the catalyst system. Meanwhile, a strong positive nonlinear effect was observed. On the basis of the experimental results and previous reports, a possible working model is proposed to explain the origin of the activation and asymmetric induction.     

Synthesis of Pyrrolidines and Pyrrolizidines with α‐Pseudoquaternary Centers by Copper‐Catalyzed Condensation of α‐Diazodicarbonyl Compounds and Aryl γ‐Lactams

N‐aryl γ‐lactams react intermolecularly with acceptor–acceptor diazo reagents, usually dicarbonyl compounds, in a copper‐catalyzed process to yield functionalized pyrrolidines with α‐pseudoquaternary centers. As 1,2‐acyl or ‐phosphoryl migration is preferred, single regioisomers are obtained. Furthermore, in the presence of a Lewis acid, subsequent Friedel–Crafts reactions yield tricyclic pyrrolizidines in excellent yields (90–96 %) and diastereoselectivities (up to >20:1).     

Chiral Brønsted Acid Directed Iron‐Catalyzed Enantioselective Friedel–Crafts Alkylation of Indoles with β‐Aryl α′‐Hydroxy Enones

A cooperative catalytic system established by the combination of an iron salt and a chiral Brønsted acid has proven to be effective in the asymmetric Friedel–Crafts alkylation of indoles with β‐aryl α′‐hydroxy enones. Good to excellent yields and enatioselectivities were observed for a variety of α′‐hydroxy enones and indoles, particularly for the β‐aryl α′‐hydroxy enones bearing an electron‐withdrawing group at the para position of the phenyl ring (up to 90 % yield and 91 % ee). The proton of the chiral Brønsted acid, the Lewis acid activation site, as well as the inherent basic site for the hydrogen‐bonding interaction of the Brønsted acid are responsible for the high catalytic activities and enantioselectivities of the title reaction. A possible reaction mechanism was proposed. The key catalytic species in the catalytic system, the phosphate salt of Fe^III, which was thought to be responsible for the high activity and good enantioselectivity, was then confirmed by ESIMS studies.     

Organocatalytic Friedel–Crafts Alkylation/Lactonization Reaction of Naphthols with 3‐Trifluoroethylidene Oxindoles: The Asymmetric Synthesis of Dihydrocoumarins

Naphthols and 3‐trifluoroethylidene oxindoles were found to undergo an asymmetric Friedel–Crafts alkylation/lactonization reaction, catalyzed by only 2.5 mol % of a quinine‐derived squaramide catalyst, to afford the corresponding α‐aryl‐β‐trifluoromethyl dihydrocoumarin derivatives in high yields (up to 99 %) with excellent enantio‐ and diastereoselectivities (up to 98 % ee , >20:1 d.r.). Importantly, the lactonization proceeded by nucleophilic attack of the naphthol hydroxy group at the amide motif of the oxindoles under mild reaction conditions. This protocol represents a new strategy for the formation of dihydrocoumarins by an efficient intramolecular amide C−N bond‐cleavage and esterification process.     

Linking Conformational Flexibility and Kinetics: Catalytic 1,4‐Type Friedel–Crafts Reactions of Phenols Utilizing 1,3‐Diamine‐Tethered Guanidine/Bisthiourea Organocatalysts

Herein, we present details of our conformationally flexible, 1,3‐diamine‐tethered guanidine/bisthiourea organocatalysts for chemo‐, regio‐, and enantioselective 1,4‐type Friedel–Crafts reactions of phenols. These organocatalysts show a unique stereo‐discrimination governed by the differential activation entropy (ΔΔS^≠), rather than by the differential activation enthalpy (ΔΔH^≠). Extensive kinetic analyses using Eyring plots for a series of guanidine/bisthiourea organocatalysts revealed the key structural motif in the catalysts associated with a large magnitude of differential activation entropy (ΔΔS^≠). A plausible guanidine–thiourea cooperative mechanism for the enantioselective Friedel–Crafts reaction is proposed.     

Chemoselective Borane‐Catalyzed Hydroarylation of 1,3‐Dienes with Phenols

A B(C₆F₅)₃‐catalyzed hydroarylation of a series of 1,3‐dienes with various phenols has been established through a combination of theoretical and experimental investigations, affording structurally diverse ortho‐allyl phenols. DFT calculations show that the reaction proceeds through a borane‐promoted protonation/Friedel–Crafts pathway involving a π‐complex of a carbocation–anion contact ion pair. This protocol features simple and mild reaction conditions, broad functional‐group tolerance, and low catalyst loading. The obtained ortho‐allyl phenols could be further converted into flavan derivatives using B(C₆F₅)₃ with good cis diastereoselectivity. Furthermore, this transformation was applied in the late‐stage modification of pharmaceutical compounds.     

Squaramide‐Catalyzed Asymmetric aza‐Friedel–Crafts/N,O‐Acetalization Domino Reactions Between 2‐Naphthols and Pyrazolinone Ketimines

N‐Boc ketimines derived from pyrazolin‐5‐ones were explored to develop an unprecedented domino aza‐Friedel–Crafts/N,O‐acetalization reaction with 2‐naphthols. The novel method requires a catalyst loading of only 0.5 mol % of a bifunctional squaramide catalyst, is scalable to gram amounts, and provides a new series of furanonaphthopyrazolidinone derivatives bearing two vicinal tetra‐substituted stereogenic centers in excellent yields (95–98 %) and stereoselectivity (>99:1 d.r. and 97–98 % ee ). A different reactivity was observed in the case of 1‐naphthols and other electron‐rich phenols, which led to the aza‐Friedel–Crafts adducts in 70–98 % yield and 47–98 % ee .     

One‐Pot Synthesis of Pyrrolo[1,2‐a]quinolin‐1‐ones by the Cyclocondensation of 5‐Hydroxy‐1‐arylpyrrolidin‐2‐ones with Dicarbonyls

A one‐pot synthesis of pyrrolo[1,2‐a]quinolin‐1‐ones has been developed from the reactions of 5‐hydroxy‐1‐arylpyrrolidin‐2‐ones with 1,3‐dicarbonyl compounds under the promotion of H₃PO₄/P₂O₅ or HOAc/H₂SO₄. The pyrrolo[1,2‐a]quinolin‐1‐ones are formed by two‐step reactions, that is, the coupling of N‐acyliminium ion intermediates produced from 5‐hydroxy‐1‐arylpyrrolidin‐2‐ones with 1,3‐dicarbonyls and subsequent Friedel–Crafts reactions of the resulting ketone with the aryl ring.     

Biaryl Synthesis by Ring‐Opening Friedel–Crafts Arylation of 1,4‐Epoxy‐1,4‐dihydronaphthalenes Catalyzed by Iron Trichloride

Biaryl and heterobiaryl compounds are important frameworks across a range of fields including pharmaceutical and functional material chemistries. We have accomplished the efficient synthesis of various naphthalene‐linked arenes and heteroarenes as biaryls and heterobiaryls by the FeCl₃‐catalyzed Friedel‐Crafts reactions accompanied by the ring‐opening of the 1,4‐epoxy moiety of 1,4‐epoxy‐1,4‐dihydronaphthalenes. Especially, it is noteworthy that 1‐silylated substrates were regioselectively transformed to the 3‐aryl‐1‐silylnaphthalenes and the double Friedel–Crafts reactions using thiophene derivatives could directly produce the corresponding bis‐naphthlated thiophene derivatives.     

New Synthesis of 7‐(3‐chloropropoxy)‐4‐hydroxy‐6‐methoxyquinoline‐3‐carbonitrile,a Key Intermediate to Bosutinib

A new and convenient synthesis of 7‐(3‐chloropropoxy)‐4‐hydroxy‐6‐methoxyquinoline‐3‐carbonitrile, the key intermediate to bosutinib, is described on a hectogram scale. 5‐Bromo‐2‐methoxyphenol is adopted as the starting material via the simple chemical process including Friedel‐Crafts reaction, alkylation, bromination, cyano substitution, and so on to give the 3‐amino‐2‐(2‐bromobenzoyl)acrylonitrile compound 25 , which underwent key intramolecular cyclization at K₂CO₃/DMF condition; the title product was obtained in 36.9% yield over 7 steps and 98.71% purity (HPLC).     

Catalytic Asymmetric Synthesis of 3‐(α‐Hydroxy‐β‐carbonyl) Oxindoles by a ScIII‐Catalyzed Direct Aldol‐Type Reaction

A direct catalytic asymmetric aldol‐type reaction of 3‐substituted‐2‐oxindoles with glyoxal derivatives and ethyl trifluoropyruvate, catalyzed by a chiral N,N′‐dioxide–Sc(OTf)₃ (Tf=trifluoromethanesulfonyl) complex, has been developed that tolerates a wide range of substrates. The reaction proceeds in good yields and excellent enantioselectivities (up to 93 % yield, 99:1 diastereomeric ratio (dr), and >99 % enantiomeric excess (ee)) under mild conditions, to deliver 3‐(α‐hydroxy‐β‐carbonyl) oxindoles with vicinal quaternary–tertiary or quaternary–quaternary stereocenters. Even with 1 mol % catalyst loading or on scaleup (10 mmol of starting material), maintenance of ee was observed, which showed the potential value of the catalyst system. In studies probing the reaction mechanism, a positive nonlinear effect was observed and Sc^III‐based enolate intermediates were detected by using ESIMS. On the basis of the experimental results and previous reports, a possible catalytic cycle was assumed.     

Iron(III)‐Catalyzed Arylation of Spiro‐Epoxyoxindoles with Phenols/Naphthols towards the Synthesis of Spirocyclic Oxindoles

An efficient and highly regioselective iron(III)‐catalyzed Friedel–Crafts‐type arylation of spiro‐epoxyoxindoles with phenols was developed for rapid access to 3‐(3‐indolyl)‐oxindole‐3‐methanols, which could be further elaborated into benzofuranyl‐spirooxindoles under Mitsunobu conditions. When spiro‐epoxyoxindoles were reacted with naphthols in the presence of a catalytic amount of FeCl₃?6 H₂O in dichloromethane, they underwent a tandem Friedel–Crafts‐type arylation and O‐cyclization to yield novel naphthofuranyl‐spirooxindoles in excellent yields. This method is applied to enable the efficient and highly regioselective synthesis of a small‐molecule inhibitor of the sodium channel Na_v1.7 (±)‐XEN402, which is currently in a phase IIb clinical trial for the treatment of pain.     

Reactions of 2,2,6‐Trimethyl‐1,3‐dioxin‐4‐one with the Aryl Aldimines Prepared from Thiophene‐2‐carbaldehyde

The reactions of aryl aldimines derived from thiophene‐2‐carbaldehyde ( 5–9 ) with 2,2,6‐trimethyl‐1,3‐dioxin‐4‐one (1) were investigated. The new 1,3‐oxazin‐4‐ones and thienylidene acetoacetamides were obtained in good yields. The synthetic utility of the latter via an intramolecular tandem Friedel–Crafts alkylation–acylation to give tetracyclic heterocyclic rings was also explored.     

Friedel–Crafts Alkylation of N‐(2‐Chloropropionyl)aniline and the Generation Mechanism of Byproducts

The cyclization of N‐(2‐chloropropionyl)aniline to 3‐methylindolin‐2‐one through Friedel–Crafts alkylation was studied. It was found that N‐phenylacrylamide (12.6%) and 3,4‐dihydro‐2(1H)‐quinolinone (1.5%) as main byproducts were obtained. On the basis of the mechanism of Friedel–Crafts alkylation, the generation mechanisms of these two compounds were proposed.     

Synthesis of 5‐aryl and 5‐amidocamptothecins

A variety of 5‐aryl‐(20S)‐camptothecin derivatives were synthesized by the reaction of 5‐hydroxy‐(20S)‐camptothecin with aromatic hydrocarbons under Friedel‐Craft reaction conditions in moderate to good yield as diastereomeric pairs. The methodology was then extended for the synthesis of 5‐amido‐(20S)‐camptothecin derivatives by reacting 5‐hydroxy‐(20S)‐camptothecin with alkyl and aryl nitriles under Ritter type reaction conditions. The reaction is presumed to proceed through an iminium ion intermediate under Friedel Craft and Ritter type reaction condition, which is further trapped by nucleophile present in the reaction medium. J. Heterocyclic Chem., 00 , 00 (2011).     

Facile synthesis of chiral 2-amino-4-(indol-3-yl)-4H-chromene derivatives using thiourea as the catalyst

The enantioselective Friedel–Crafts alkylation of indoles with iminochromenes catalyzed by a bifunctional thiourea organocatalyst was investigated. This reaction afforded chiral functionalized 2-amino-4-(indol-3-yl)-4H-chromenes in good yields (up to 87% yield) and with moderate to good enantioselectivities (up to 86% ee).     

Enantioselective Continuous‐Flow Production of 3‐Indolylmethanamines Mediated by an Immobilized Phosphoric Acid Catalyst

A polystyrene‐supported 1,1’‐bi‐2‐naphthol derived phosphoric acid has been synthesized and applied in the enantioselective Friedel–Crafts reaction of indoles and sulfonylimines. The immobilized catalyst was highly active and selective, and gave rise to a broad range of 3‐indolylmethanamines (19 examples) in high yields and excellent enantioselectivities (up to 98 % enantiomeric excess) after short reaction times under very convenient reaction conditions (RT in dichloromethane). Moreover, repeated recycling (14 cycles) was possible with no substantial loss in catalytic performance and the system could be adapted to a continuous‐flow operation (6 h). Finally, the applicability of the system was further confirmed by rapid access to a library of compounds with three points of diversity in a single continuous‐flow experiment that involved sequential pumping of different substrate combinations.