Mechanism of the Transition‐Metal‐Catalyzed Hydroarylation of Bromo‐Alkynes Revisited: Hydrogen versus Bromine Migration

A comprehensive mechanistic study of the InCl₃‐, AuCl‐, and PtCl₂‐catalyzed cycloisomerization of the 2‐(haloethynyl)biphenyl derivatives of Fürstner et al. was carried out by DFT/M06 calculations to uncover the catalyst‐dependent selectivity of the reactions. The results revealed that the 6‐endo‐dig cyclization is the most favorable pathway in both InCl₃‐ and AuCl‐catalyzed reactions. When AuCl is used, the 9‐bromophenanthrene product could be formed by consecutive 1,2‐H/1,2‐Br migrations from the Wheland‐type intermediate of the 6‐endo‐dig cyclization. However, in the InCl₃‐catalyzed reactions, the chloride‐assisted intermolecular H‐migrations between two Wheland‐type intermediates are more favorable. These Cl‐assisted H‐migrations would eventually lead to 10‐bromophenanthrene through proto‐demetalation of the aryl indium intermediate with HCl. The cause of the poor selectivity of the PtCl₂ catalyst in the experiments by the Fürstner group was predicted. It was found that both the PtCl₂‐catalyzed alkyne–vinylidene rearrangement and the 5‐exo‐dig cyclization pathways have very close activation energies. Further calculations found the former pathway would lead eventually to both 9‐ and 10‐bromophenanthrene products, as a result of the Cl‐assisted H‐migrations after the cyclization of the Pt–vinylidene intermediate. Alternatively, the intermediate from the 5‐exo‐dig cyclization would be transformed into a relatively stable Pt–carbene intermediate irreversibly, which could give rise to the 9‐alkylidene fluorene product through a 1,2‐H shift with a 28.1 kcal mol^?1 activation barrier. These findings shed new light on the complex product mixtures of the PtCl₂‐catalyzed reaction.     

Functionalized Benzofurans via Microwave‐Promoted Tandem Claisen‐Rearrangement/5‐endo‐dig Cyclization

Ortho‐allyloxy alkinyl benzenes undergo, upon microwave irradiation in dimethylformamide, a tandem sequence of Claisen‐rearrangement and 5‐endo‐dig cyclization to furnish 7‐allyl‐substituted benzofurans. With terminal alkynes, chroman‐4‐ones and enaminoketones become the main products. A mechanistic proposal for this observation relies on a reaction of the starting material with the solvent dimethylformamide under the microwave conditions.     

Frustrated Lewis Pair‐Catalyzed Cycloisomerization of 1,5‐Enynes via a 5‐endo‐dig Cyclization/Protodeborylation Sequence

The first frustrated Lewis pair‐catalyzed cycloisomerization of a series of 1,5‐enynes was developed. The reaction proceeds via the π‐activation of the alkyne and subsequent 5‐endo‐dig cyclization with the adjacent alkene. The presence of PPh₃ was of utmost importance on the one hand to prevent side reactions (for example, 1,1‐carboboration) and on the other hand for the efficient protodeborylation to achieve the catalytic turnover. The mechanism is explained on the basis of quantum‐chemical calculations, which are in full agreement with the experimental observations.     

Gold‐Catalyzed Cyclization of Diynes: Controlling the Mode of 5‐endo versus 6‐endo Cyclization—An Experimental and Theoretical Study by Utilizing Diethynylthiophenes

Herein, a dual‐gold catalyzed cyclization of 3,4‐diethynylthiophenes generating pentaleno[c]thiophenes through gold–vinylidenes and C?H bond activation is disclosed. Various new heteroaromatic compounds—substrate classes unexplored to date—exhibiting three five‐membered annulated ring systems could be synthesized in moderate to high yields. By comparison of the solid‐state structures of the corresponding gold–acetylides, it could be demonstrated that the cyclization mode (5‐endo versus 6‐endo) is controlled by the electronic and not steric nature of the diyne backbone. Depending on different backbones, we calculated thermodynamic stabilities and full potential‐energy surfaces giving insight into the crucial dual‐activation cyclization step. In the case of the 3,4‐thiophene backbone, in which the initial cyclization is rate and selectivity determining, two energetically distinct transition states could be localized explaining the observed 5‐endo cyclization mode by classical transition‐state theory. In the case of vinyl and 2,3‐thiophene backbones, the theoretical analysis of the cyclization mode in the bifurcated cyclization area demonstrated that classical transition‐state theory is no longer valid to explain the high experimentally observed selectivity. Herein, for the first time, the influence of the backbone and the aromatic stabilization effect of the 6‐endo product in the crucial cyclization step could be visualized and quantified by calculating and comparing the full potential‐energy surfaces.     

Metal‐Free Radical 5‐exo‐dig Cyclizations of Phenol‐Linked 1,6‐Enynes for the Synthesis of Carbonylated Benzofurans

A new metal‐free radical 5‐exo‐dig cyclization of phenol‐linked 1,6‐enynes with O₂, 2,2,6,6‐tetramethyl‐1‐piperidinyloxy (TEMPO), and tBuONO is described. With this general method, carbonylated benzofurans can be accessed through incorporation of two oxygen atoms into the product from O₂ and TEMPO through dioxygen activation and oxidative cleavage of the N? O bond, respectively.     

Ligand‐Controlled Regiodivergent Nickel‐Catalyzed Annulation of Pyridones

The 1,6‐annulated 2‐pyridone motif is found in many biologically active compounds and its close relation to the indolizidine and quinolizidine alkaloid core makes it an attractive building block. A nickel‐catalyzed C? H functionalization of 2‐pyridones and subsequent cyclization affords 1,6‐annulated 2‐pyridones by selective intramolecular olefin hydroarylation. The switch between the exo‐ and endo‐cyclization modes is controlled by two complementary sets of ligands. Irrespective of the ring size, the regioselectivity during the cyclization is under full catalyst control. Simple cyclooctadiene promotes an exo‐selective cyclization, whereas a bulky N‐heterocyclic carbene ligand results in an endo‐selective mode. The method was further applied in the synthesis of the lupin alkaloid cytisine.     

Mechanistic Understanding of the Divergent Cyclizations of o‐Alkynylbenzaldehyde Acetals and Thioacetals Catalyzed by Metal Halides

The mechanisms of regiodivergent cyclizations of o‐alkynylbenzaldehyde acetals and thioacetals catalyzed by Pd and Pt halides are studied. DFT calculations found that both reactions are initiated by electrophilic activation of the acetylenic moiety instead of the previously proposed metal‐triggered C?X (X=O, S) cleavage. Both the regioselective cyclization of the π‐alkyne complex and the chemoselective [1,2]‐migration in the carbenoid intermediate were determined as key steps to achieving the observed divergence. For acetal derivatives containing an internal alkyne, the 6‐endo‐dig cyclization is more favorable and leads to the carbenoid intermediate easily through further steps of C?X fragmentation and carbocation cyclization. Then, from the carbenoid intermediate, the [1,2]‐migration of sulfur is easier than that of H, Me, and Ph; whereas, a reversed aptitude was predicted for the oxygen analogue, which is consistent with the greater ability of sulfur atoms to stabilize β‐carbocations. However, for precursors containing a terminal alkyne, the 5‐exo‐dig pathway is preferred and only the 1,2‐disubstituted indene product is seen, irrespective of the nature of the acetal; thus, a different product from that reported in the literature is predicted for benzaldehyde acetal with a terminal alkyne at the ortho position. This prediction led us to reconsider some of the reported results and hidden realities were uncovered with solid new experimental evidence.     

AgNO3 Catalyzed Regio‐Selective Synthesis of 3‐Alkyl/Aryl‐idene‐3,4‐dihydro‐4‐tosyl‐2H‐1,4‐Benzoxazine: Novel Anti‐Tubercular Scaffolds

A facile and efficient method for the construction of 3‐alkyl/aryl substituted 1,4‐benzoxazine and benzoxazepine via AgNO₃ catalyzed cyclization of propargyloxy sulfonamides and their anti‐tubercular activity against Mycobacterium tuberculosis H₃₇R_V is described. This cyclization proceeds through 6‐exo‐dig manner to generate the products in moderate to good yields.     

Umpolung Reactivity of Ynamides: An Unconventional [1,3]‐Sulfonyl and [1,5]‐Sulfinyl Migration Cascade

A regioselective sulfonyl/sulfinyl migration cycloisomerization cascade of alkyne‐tethered ynamides is developed in the presence of XPhosgold catalyst. This reaction is the first example of a general [1,3]‐sulfonyl migration from the nitrogen center to the β‐carbon atom of ynamides, followed by umpolung 5‐endo‐dig cyclization of the ynamide α‐carbon atom to the gold‐activated alkyne, and final deaurative [1,5]‐sulfinylation. This process allows the synthesis of peripherally decorated unconventional 4‐sulfinylated pyrroles with broad scope from N‐propargyl‐tethered ynamides. In contrast, N‐homopropargyl‐tethered ynamides undergo intramolecular tetradehydro Diels–Alder reaction to provide 2,3‐dihydro‐benzo[f]indole derivatives. Control experiments and density‐functional theory studies were used to study the reaction pathways.     

1‐Bromo‐2‐(cyclopropylidenemethyl)benzene: A Useful Building Block in the Palladium‐Catalyzed Reaction of 2‐Alkynylbenzenamine

A novel palladium‐catalyzed domino reaction of 1‐bromo‐2‐(cyclopropylidenemethyl)benzene and 2‐alkynylbenzenamine is reported, which generates 2‐(naphthalen‐2‐yl)benzenamines and 5H‐indeno[1,2‐c]quinolines via 6‐endo and 5‐exo cyclization, respectively. The regioselectivity for the final outcome can be affected by phosphine and N‐heterocyclic carbene ligands.     

Synthesis of Anionic Phosphorus‐Containing Heterocycles by Intramolecular Cyclizations Involving N‐Functionalized Phosphinecarboxamides

We report that the 2‐phosphaethynolate anion (PCO^?) reacts with propargylamines in the presence of a proton source to afford novel N‐derivatized phosphinecarboxamides bearing alkyne functionalities. Deprotonation of these species gives rise to novel five‐ and six‐membered anionic heterocycles resulting from intramolecular nucleophilic attack of the resulting phosphide at the alkyne functionality (via 5‐exo‐dig or 6‐endo‐dig cyclizations, respectively). The nature of the substituents on the phosphinecarboxamide can be used to influence the outcome of these reactions. This strategy represents a unique approach to phosphorus‐containing heterocylic systems that are closely related to known organic molecules with interesting bio‐active properties.     

3,4‐Di­hydro‐6‐methyl‐3‐β‐d‐ribo­furan­osyl‐4,5′‐cyclo‐9H‐imidazo[1,2‐a]­purin‐9‐one hydrate

In the title compound, C₁₃H₁₃N₅O₄·H₂O (4,5′‐cyclo­wyosine·H₂O), the cyclization forces a syn arrangement of the aglycon with respect to the sugar moiety. The ribo­furan­ose part of the mol­ecule displays a β‐d configuration with an envelope C1′‐endo pucker. The mol­ecules are arranged in columns along the short a axis and are linked to water mol­ecules through O—H?O and O—H?N hydrogen bonds.     

Gold(I)‐Catalyzed Cycloisomerizations and Alkoxycyclizations of ortho‐(Alkynyl)styrenes

Indenes and related polycyclic structures have been efficiently synthesized by gold(I)‐catalyzed cycloisomerizations of appropriate ortho‐(alkynyl)styrenes. Disubstitution at the terminal position of the olefin was demonstrated to be essential to obtain products originating from a formal 5‐endo‐dig cyclization. Interestingly, a complete switch in the selectivity of the cyclization of o‐(alkynyl)‐α‐methylstyrenes from 6‐endo to 5‐endo was observed by adding an alcohol to the reaction media. This allowed the synthesis of interesting indenes bearing an all‐carbon quaternary center at C1. Moreover, dihydrobenzo[a]fluorenes can be obtained from substrates bearing a secondary alkyl group at the β‐position of the styrene moiety by a tandem cycloisomerization/1,2‐hydride migration process. In addition, diverse polycyclic compounds were obtained by an intramolecular gold‐catalyzed alkoxycyclization of o‐(alkynyl)styrenes bearing a nucleophile in their structure. Finally, the use of a chiral gold complex allowed access to elusive chiral 1H‐indenes in good enantioselectivities.     

A Versatile Synthesis of β‐Lactam‐Fused Oxacycles through the Palladium‐Catalyzed Chemo‐, Regio‐, and Diastereoselective Cyclization of Allenic Diols

Chemo‐, regio‐ and stereocontrolled palladium‐catalyzed preparations of enantiopure morpholines, oxocines, and dioxonines have been developed starting from 2‐azetidinone‐tethered γ,δ‐, δ,ε‐, and ε,ζ‐allendiols. The palladium‐catalyzed cyclizative coupling reaction of γ,δ‐allendiols 2 with allyl bromide or lithium bromide was effective as 8‐endo cyclization by attack of the primary hydroxy group to the terminal allene carbon to afford enantiopure functionalized oxocines; whereas the palladium‐catalyzed cyclizative coupling reaction of 2‐azetidinone‐tethered ε,ζ‐allendiols 4 furnished dioxonines 16 through a totally chemo‐ and regioselective 9‐endo oxycyclization. By contrast, the palladium‐catalyzed cyclizative coupling reaction of 2‐azetidinone‐tethered δ,ε‐allendiols 3 with aryl and alkenyl halides exclusively generated six‐membered‐ring compounds 14 a and 15 a . These results could be explained through a 6‐exo cyclization by chemo‐ and regiospecific attack of the secondary hydroxy group to the internal allene carbon. Chemo‐ and regiocontrol issues are mainly influenced by the length of the tether rather than by the nature of the metal catalysts and substituents. This reactivity can be rationalized by means of density functional theory calculations.     

Switchable [3+2] and [4+2] Heteroannulation of Primary Propargylamines with Isonitriles to Imidazoles and 1,6‐Dihydropyrimidines: Catalyst Loading Enabled Reaction Divergence

Isonitrile 1 due to its carbene‐like reactivity serves generally as a one‐carbon synthon in a diverse set of organic transformations. We report in this article that the isocyano group can also act as a polarized triple bond to undergo, as a two‐atom synthon, heteroannulation with primary propargylamines 15 . In addition, we serendipitously discovered that the reaction pathways can be modulated by simply changing the catalyst loading. In the presence of 0.1 equiv of Yb(OTf)₃ or TfOH, the reaction between 1 and 15 afforded exclusively imidazoles 16 by a formal [3+2] cycloaddition. At a higher catalyst loading (Yb(OTf)₃ (0.4 equiv) or TfOH (0.5 equiv)) under otherwise identical conditions, the same reaction furnished 1,6‐dihydropyrimidines 17 in good to excellent yields by way of a formal [4+2] cycloaddition process. Mechanistic investigations indicated that both annulations went through an amidine intermediate resulting from the insertion of the isocyano group to the NH bond of the primary amine. Subsequent catalyst‐loading‐dependent 5‐exo‐dig or 6‐endo‐dig cyclization provided selectively the two heterocycles, respectively.     

A General Synthesis of Alkenyl‐Substituted Benzofurans,Indoles, and Isoquinolones by Cascade Palladium‐Catalyzed Heterocyclization/Oxidative Heck Coupling

Structurally diverse C3‐alkenylbenzofurans, C3‐alkenylindoles, and C4‐alkenylisoquinolones are efficiently prepared by using consecutive Sonogashira and cascade Pd‐catalyzed heterocyclization/oxidative Heck couplings from readily available ortho‐iodosubstituted phenol, aniline, and benzamide substrates, alkynes, and functionalized olefins. The cyclization of O‐ and N‐heteronucleophiles follows regioselective 5‐endo‐dig‐ or 6‐endo‐dig‐cyclization modes, whereas the subsequent Heck‐type coupling with both mono‐ and disubstituted olefins takes place stereoselectively with exclusive formation of the E isomers in most cases.     

Stereoselective Synthesis of Chiral Polycyclic Indolic Architectures through Pd0‐Catalyzed Tandem Deprotection/Cyclization of Tetrahydro‐β‐carbolines on Allenes

Enantioenriched N‐allyl tetrahydro‐β‐carbolines were prepared by chiral phosphoric acid‐catalyzed Pictet–Spengler reactions. The compounds undergo Pd⁰‐catalyzed cyclizations through a tandem deprotection/cyclization process. The regioselectivity of the attack is controlled by the chain length and by the substitution pattern of the allene function. Products resulting from 5‐exo‐ or 6‐exo‐attack were obtained with diastereoisomeric ratio up to 95:5. Azepinopyrrido[3,4‐b]indoles were obtained by 7‐endo‐cyclizations.     

Reaction Mechanism for the Dual Gold‐Catalyzed Synthesis of Dibenzopentalene: A DFT Study

A wide range of gold‐catalyzed reactions based on a dual activation mechanism has recently been reported in the literature. Herein, we present a computational investigation of the mechanism for the formation of dibenzopentalenes from 1‐ethynyl‐2‐(phenylethynyl)benzene. Transition states have been found, which substantiate the dual activation mechanism previously published and furthermore point towards a continuous presence of two gold moieties throughout the mechanistic cycle, an observation of high importance for all reactions in the field of dual activation. The initial activation of the diyne has been shown to proceed via an intermolecular transfer of a cationic gold catalyst from the thermodynamically preferred geminal‐σ,π‐acetylide complex to the active non‐geminal analogue. Furthermore, the regioselectivity of a 5‐endo versus a 6‐endo cyclization has been addressed, and the 5‐endo cyclization was found to be most favorable both thermodynamically and with regard to the activation barrier.     

Chiral 2‐endo‐Substituted 9‐Oxabispidines: Novel Ligands for Enantioselective Copper(II)‐Catalyzed Henry Reactions

A flexible approach, applicable on a gram scale, to chiral 2‐endo‐substituted 9‐oxabispidines was developed. The key intermediate, a cis‐configured 6‐aminomethylmorpholine‐2‐carbonitrile, was prepared from (R)‐3‐aminopropane‐1,2‐diol and 2‐chloroacrylonitrile. The 2‐endo substituent was introduced by Grignard addition, cyclization, and exo‐selective reduction, thus furnishing the enantiomerically pure bi‐ and tricyclic 9‐oxabispidines in 19–59 % yield. The CuCl₂ complex of the tricyclic 9‐oxabispidine, which carries an 2‐endo,N‐anellated piperidine ring, is an excellent catalyst for enantioselective Henry reactions giving the S‐configured β‐nitro alcohols in 91–98 % ee (13 examples). Surprisingly, the analogous copper complexes of the bicyclic 9‐oxabispidines delivered the enantiocomplementary R‐configured products in 33–57 % ee. The respective transition states were discussed.