Synthesis of isoquinolines and pyridines by the palladium-catalyzed iminoannulation of internal alkynes.

A wide variety of substituted isoquinoline, tetrahydroisoquinoline, 5,6-dihydrobenz[f]isoquinoline, pyrindine, and pyridine heterocycles have been prepared in good to excellent yields via annulation of internal acetylenes with the tert-butylimines of o-iodobenzaldehydes and 3-halo-2-alkenals in the presence of a palladium catalyst. The best results are obtained by employing 5 mol % of Pd(OAc)(2), an excess of the alkyne, 1 equiv of Na(2)CO(3) as a base, and 10 mol % of PPh(3) in DMF as the solvent. This annulation methodology is particularly effective for aryl- or alkenyl-substituted alkynes. When electron-rich imines are employed, this chemistry can be extended to alkyl-substituted alkynes. Trimethylsilyl-substituted alkynes also undergo this annulation process to afford monosubstituted heterocyclic products absent the silyl group.     

Palladium-catalyzed carbonylative cyclization of unsaturated aryl iodides and dienyl triflates,iodides, and bromides to indanones and 2-cyclopentenones

Indanones and 2-cyclopentenones have been successfully prepared in good to excellent yields by the palladium-catalyzed carbonylative cyclization of unsaturated aryl iodides and dienyl triflates, iodides, and bromides, respectively. The best results are obtained by employing 10 mol % of Pd(OAc)(2), 2 equiv of pyridine, 1 equiv of n-Bu(4)NCl, 1 atm of CO, a reaction temperature of 100 degrees C, and DMF as the solvent. This carbonylative cyclization is particularly effective on substrates that contain a terminal olefin. The proposed mechanism for this annulation includes (1) Pd(OAc)(2) reduction to the active palladium(0) catalyst, (2) oxidative addition of the organic halide or triflate to Pd(0), (3) coordination and insertion of carbon monoxide to produce an acylpalladium intermediate, (4) acylpalladation of the neighboring carbon-carbon double bond, (5) reversible palladium beta-hydride elimination and re-addition to form a palladium enolate, and (6) protonation by H(2)O to produce the indanone or 2-cyclopentenone.     

Synthesis of isoindolo[2,1-alpha]indoles by the palladium-catalyzed annulation of internal acetylenes.

A wide variety of substituted isoindolo[2,1-alpha]indoles have been prepared via annulation of internal alkynes by imines derived from o-iodoanilines in the presence of a palladium catalyst. This methodology provides an extremely efficient route for the synthesis of these tetracyclic heterocycles from readily available starting materials. The mechanism of this interesting annulation process appears to involve (1) oxidative addition of the aryl iodide to Pd(0), (2) alkyne insertion, (3) addition of the resulting vinylic palladium intermediate to the C-N double bond of the imine, (4) either electrophilic palladation of the resulting sigma-palladium intermediate onto the adjacent aromatic ring derived from the internal alkyne or oxidative addition of the neighboring aryl carbon-hydrogen bond, and (5) reduction of the tetracyclic product and Pd(0). A variety of internal acetylenes have been employed in this annulation process in which the aromatic ring of the alkyne contains either a phenyl or a heterocyclic ring.     

Palladium-catalyzed carbonylative annulation of terminal alkynes: synthesis of coumarins and 2-quinolones

o-Iodophenols and o-iodoaniline derivatives react with terminal alkynes under 1 atm of CO in the presence of pyridine and catalytic amounts of Pd(OAc)₂ to generate coumarins and 2-quinolones, respectively, as the only products. Terminal alkynes bearing alkyl, aryl, silyl, hydroxyl, ester and cyano substituents are effective in these processes affording the desired products in moderate yields. The formation of coumarins and 2-quinolones in this process is in stark contrast with all previously described palladium-catalyzed reactions of o-iodophenols or o-iodoanilines with terminal alkynes and CO, which have afforded chromones and 4-quinolones. Moreover, under our reaction conditions terminal alkynes insert into the carbonpalladium bond instead of undergoing a Sonogashira-type coupling as confirmed by an isotope labeling experiment.     

Synthesis of coumarins via palladium-catalyzed carbonylative annulation of internal alkynes by o-iodophenols

A variety of substituted coumarins have been prepared in good yields by the palladium-catalyzed coupling of o-iodophenols with internal alkynes and 1 atm of carbon monoxide. Unlike most of the previous work on the palladium-catalyzed carbonylation of alkynes, the insertion of the internal alkyne occurs in preference to the insertion of CO.     

Palladium‐Catalyzed Carbonylative Annulation of 1‐Hydroxy‐o‐Carborane and Internal Alkynes via Regioselective B‐H Activation

A Pd‐catalyzed three‐component carbonylative‐annulation of 1‐hydroxy‐o‐carborane, internal alkyne and carbon monoxide has been achieved via direct and regioselective cage B?H activation. A class of C,B‐substituted carborano‐coumarin derivatives with potential applications in pharmaceuticals were facilely prepared in moderate to high yields with excellent chemoselectivity and regioselectivity. A plausible reaction mechanism including CO insertion, electrophilic B?H metalation, alkyne insertion and reductive elimination was proposed.     

Rapid access to pyrazolo[3,4-c]pyridines via alkyne annulation: limitations of steric control in nickel-catalyzed alkyne insertions

Polyfunctionalized pyrazolo[3,4-c]pyridines were readily prepared by the annulation of alkynes with tert-butyl 4-iodopyrazolocarboximines. The reaction was found to be catalyzed by both NiBr2(PPh3)2/Zn or PdCl2(PhCN)2 to yield complex heterocycles in good to moderate yields. Annulation using nickel catalysis was found to be regio-random, implying that steric control in nickel-catalyzed alkyne insertion has limitations based on the character of the Ni-C bond in the pre-insertion complex.     

Ruthenium-catalyzed cascade C–H activation/annulation of N-alkoxybenzamides: reaction development and mechanistic insight

A highly selective ruthenium-catalyzed C–H activation/annulation of alkyne-tethered N-alkoxybenzamides has been developed. In this reaction, diverse products from inverse annulation can be obtained in moderate to good yields with high functional group compatibility. Insightful experimental and theoretical studies indicate that the reaction to the inverse annulation follows the Ru(ii)–Ru(iv)–Ru(ii) pathway involving N–O bond cleavage prior to alkyne insertion. This is highly different compared to the conventional mechanism of transition metal-catalyzed C–H activation/annulation with alkynes, involving alkyne insertion prior to N–O bond cleavage. Via this pathway, the in situ generated acetic acid from the N–H/C–H activation step facilitates the N–O bond cleavage to give the Ru-nitrene species. Besides the conventional mechanism forming the products via standard annulation, an alternative and novel Ru(ii)–Ru(iv)–Ru(ii) mechanism featuring N–O cleavage preceding alkyne insertion has been proposed, affording a new understanding of transition metal-catalyzed C–H activation/annulation.

A highly selective ruthenium-catalyzed C–H activation/annulation through a pathway involving N–O bond cleavage prior to alkyne insertion is developed.     

Palladium/Norbornene‐Catalyzed C−H Alkylation/Alkyne Insertion/Indole Dearomatization Domino Reaction: Assembly of Spiroindolenine‐Containing Pentacyclic Frameworks

Reported is a highly chemoselective intermolecular annulation of indole‐based biaryls with bromoalkyl alkynes by using palladium/norbornene (Pd/NBE) cooperative catalysis. This reaction is realized through a sequence of Catellani‐type C?H alkylation, alkyne insertion, and indole dearomatization, by forming two C(sp²)?C(sp³) and one C(sp²)?C(sp²) bonds in a single chemical operation, thus providing a diverse range of pentacyclic molecules, containing a spiroindolenine fragment, in good yields with excellent functional‐group tolerance. Preliminary mechanistic studies reveal that C?H bond cleavage is likely involved in the rate‐determining step, and the indole dearomatization might take place through an olefin coordination/insertion and β‐hydride elimination Heck‐type pathway.     

Selective preparation of pyridines, pyridones, and iminopyridines from two different alkynes via azazirconacycles

Selective preparation of pyridine derivatives from two different alkynes and a nitrile was achieved by a novel procedure in which an alkyne and a nitrile couple first to give an azazirconacyclopentadiene followed by reaction with the second alkyne in the presence of 1 equiv of NiCl(2)(PPh(3))(2). This procedure gives only single products of pyridine derivatives from two different symmetrical alkynes and a nitrile. Our novel procedure can be used even with two similar alkyl-substituted alkynes such as 3-hexyne and 4-octyne. Two possible pyridine isomers from 3-hexyne, 4-octyne, and acetonitrile could be completely and independently prepared as single products by this method. The origin of the selectivity comes from the addition order of two different alkynes. This method was applied for the formation of pyridones and iminopyridines using isocyanate and carbodiimide derivatives instead of nitriles, respectively. Reaction of an alkyne with Cp(2)ZrEt(2) and an isocyanate or a carbodiimide gives an azazirconacycle. Treatment of the azazirconacycle with the second alkyne in the presence of 1 equiv of NiCl(2)(PPh(3))(2) gave a pyridone or an iminopyridine derivative. The use of two different unsymmetrical alkynes afforded the pyridine with five different substituents when the first alkyne has a trialkylsilyl group and the second alkyne has a phenyl group as functional groups. On the other hand, azazirconacyclopentadienes reacted with propargyl bromide in the presence of CuCl with excellent regioselectivity to give tetrasubstituted pyridine derivatives as single products. With the assistance of the trialkylsilyl groups, pyridines with all different substituents including H were also prepared.     

A first regioselective synthesis of 3-fluoroalkylated benzofurans via palladium-catalyzed annulation of fluorine-containing internal alkynes with variously substituted 2-iodophenol

The palladium-catalyzed annulation reaction of a variety of fluorine-containing internal alkynes with 2-iodophenol derivatives was investigated. The use of P(t-Bu)₃ as a ligand on palladium was found to be crucial in this annulation reaction, resulting in the exclusive formation of 3-fluoroalkylated benzofurans in high yields. ¹⁹F NMR analysis of the reaction mixture revealed that the addition of phenol to the fluoroalkylated alkynes was followed by intramolecular Heck reaction, giving to the corresponding 3-fluoroalkylated benzofurans.     

Regio- and stereospecific synthesis of novel 3-enynyl-substituted thioflavones/flavones using a copper-free palladium-catalyzed reaction

[reaction: see text] A variety of 3-enynyl substituted flavones/thioflavones were synthesized via a sequential one-pot procedure using copper-free palladium-catalyzed cross coupling in a simple synthetic operation. The cross coupling between 3-iodo(thio)flavone and a broad range of terminal alkynes was carried out in the presence of Pd(PPh3)2Cl2 and triethylamine to afford the corresponding 3-enynyl derivatives in a regio- and stereoselective fashion. The best results are obtained by employing 3 equiv of the terminal alkynes. The process worked well irrespective of the substituents present on the (thio)flavone ring as well as in the terminal alkynes except arylalkynes. The reaction is quite regioselective, placing the substituent of the terminal alkyne at the far end of the double bond attached with the (thio)flavone ring. The orientation of the (thio)flavonyl and acetylenic moieties across the double bond was found to be syn in the products isolated. A tandem C-C bond-forming reaction in the presence of palladium catalyst rationalized the formation of coupled product. The catalytic process apparently involves heteroarylpalladium formation, regioselective addition to the C-C triple bond of the terminal alkyne, and subsequent displacement of palladium by another mole of alkyne. The present methodology is useful for the introduction of an enynyl moiety at the C-3 position of flavones and thioflavone rings to afford novel compounds of potential biological interest. In the presence of CuI the process afforded 3-alkynyl (thio)flavones in good yields.     

Tertiary Carbinamine Synthesis by Rhodium‐Catalyzed [3+2] Annulation of N‐Unsubstituted Aromatic Ketimines and Alkynes

A convenient and waste‐free synthesis of indene‐based tertiary carbinamines by rhodium‐catalyzed imine/alkyne [3+2] annulation is described. Under the optimized conditions of 0.5–2.5 mol % [{(cod)Rh(OH)}₂] (cod=1,5‐cyclooctadiene) catalyst, 1,3‐bis(diphenylphosphanyl)propane (DPPP) ligand, in toluene at 120 °C, N‐unsubstituted aromatic ketimines and internal alkynes were coupled in a 1:1 ratio to form tertiary 1H‐inden‐1‐amines in good yields and with high selectivities over isoquinoline products. A plausible catalytic cycle involves sequential imine‐directed aromatic C? H bond activation, alkyne insertion, and a rare example of intramolecular ketimine insertion into a Rh^I–alkenyl linkage.     

Synthesis of beta- and gamma-carbolines by the palladium-catalyzed iminoannulation of alkynes

A variety of substituted beta- and gamma-carbolines have been prepared in moderate to excellent yields by the palladium-catalyzed annulation of internal and terminal acetylenes by the tert-butylimines of N-substituted 3-iodoindole-2-carboxaldehydes and 2-haloindole-3-carboxaldehydes, respectively. This annulation chemistry is effective for a wide range of alkynes, including aryl-, alkyl-, hydroxymethyl-, ethoxycarbonyl-, and trimethylsilyl-substituted alkynes. When an unsymmetrical internal alkyne is employed, this method generally gives two regioisomers. When a terminal alkyne is employed, only one regioisomer has been isolated. This palladium-catalyzed annulation chemistry has also been successfully applied to the synthesis of two biologically interesting beta-carboline alkaloids, ZK93423 and abecarnil (ZK112119).     

Palladium(II)-catalyzed annulation of alkynes with ortho-ester-containing phenylboronic acids

Palladium(II) catalyzes annulation of internal alkynes with methyl 2-boronobenzoate and (2-boronophenyl)acetate to provide 2,3-disubstituted indenones and 3,4-disubstituted 2-naphthols, respectively. The annulation reaction would proceed through transmetalation of Pd(II) with the boron reagents and insertion of the alkynes, followed by unprecedented 1,2-addition of the generated alkenylpalladium(II) species to the intramolecular ester group.     

Synthesis of 3,4-disubstituted cinnolines by the Pd-catalyzed annulation of 2-iodophenyltriazenes with an internal alkyne

A simple and efficient synthesis of cinnolines was achieved by a palladium-catalyzed annulation methodology. 3,4-Disubstituted cinnolines are prepared via palladium-catalyzed annulation of 2-iodophenyltriazenes with an internal alkyne in moderate to good yields. Several internal alkynes are applicable to this reaction and it is compatible with a number of functional groups.     

Palladium-catalyzed C-CN activation for intramolecular cyanoesterification of alkynes

Conditions for the C-CN activation and intramolecular cyanoesterification of alkynes to provide butenolides in good to excellent yields are presented. Pd catalysts, high temperatures/short reaction times (microwave irradiation), and Lewis basic solvents minimized competitive decarbonylation. Less sterically encumbered, electron-rich alkynes underwent cyanoesterification with greater ease compared to sterically encumbered, electron-deficient alkynes. The results led to the hypothesis that migratory insertion of the alkyne, rather than C-CN activation, might be the product-determining step.     

Regio- and Chemoselective Formal (4+1) Carbocyclization of Chalcones with Internal Alkynes via Rhodium(III) Catalysis

A rhodium(III)-catalyzed oxidative cyclization of chalcones with internal alkynes is reported, generating biologically important 3,3-disubstituted 1-indanones along with reusable aromatic aldehydes. This transformation features unique (4+1) reaction mode, excellent regioselectivity in alkyne insertion, broad substrate scope, allows for the construction of quaternary carbon centers, and is scalable. Steric hindrance from substrate and ligand probably controls the chemoselectivity of this carbocyclization. Importantly, this discovery enables a practical two-step protocol switching the overall reaction of acetophenones with internal alkynes from a (3+2) to a (4+1) annulation.     

Ruthenium(II)‐Catalyzed Synthesis of Spirobenzofuranones by a Decarbonylative Annulation Reaction

The first decarbonylative insertion of an alkyne through C?H/C?C activation of six‐membered compounds is reported. The Ru‐catalyzed reaction of 3‐hydroxy‐2‐phenyl‐chromones with alkynes works most efficiently in the presence of the ligand PPh₃ to provide spiro‐indenebenzofuranones. Unlike previously reported metal‐catalyzed decarbonylative annulation reactions, in the present decarbonylative annulation reaction, the annulation occurs before extrusion of carbon monoxide.     

Palladium/nickel-cocatalyzed cycloaddition of 1,3-dehydro-o-carborane with alkynes. Facile synthesis of C,B-substituted carboranes

o-Carboryne (1,2-dehydro-o-carborane) has been reported as a very reactive intermediate and regarded as a three-dimensional relative of benzyne, whereas the 1,3-dehydro-o-carborane has remained elusive. In this article, we present the preparation of 1,3-dehydro-o-carborane from 3-iodo-1-lithio-o-carborane mediated by palladium(0). This reactive intermediate can be trapped by alkynes via Pd/Ni-cocatalyzed [2 + 2 + 2] cycloaddition reaction, leading to the formation of C,B-substituted-o-carborane derivatives. The possible reaction mechanism involving the formation of metal-1,3-dehydro-o-carborane followed by stepwise insertions of 2 equiv of alkyne and reductive elimination is proposed, and the relative reactivity of M-C versus M-B bond in metal-1,3-dehydro-o-carborane complexes is also discussed. This work offers a new methodology for B-functionalization of carboranes and demonstrates that metal-1,3-dehydro-o-carborane can be viewed as a new kind of boron nucleophile.