Enantioselective synthesis of indolizidines bearing quaternary substituted stereocenters via rhodium-catalyzed [2+2+2] cycloaddition of alkenyl isocyanates and terminal alkynes

An enantioselective synthesis of indolizidines bearing quaternary substituted stereocenters by way of a rhodium-catalyzed [2+2+2] cycloaddition of substituted alkenyl isocyanates and terminal alkynes is described. The reaction provides lactam products using aliphatic alkynes, whereas aryl alkynes give rise to vinylogous amide products. Through modification of the phosphoramidite ligand, high levels of enantioselectivity, regioselectivity, and product selectivity are obtained for both products.     

Rhodium-catalyzed [2 + 2 + 2] cycloaddition of alkenyl isocyanates and alkynes

A rhodium(I)-catalyzed [2 + 2 + 2] cycloaddition between alkenyl isocyanates and alkynes has been developed. Heating a mixture of an alkenyl isocyanate and a symmetrical internal alkyne in the presence of [Rh(ethylene)2Cl]2/P(4-OMe-C6H4)3 in toluene delivers substituted indolizinones and quinolizinones. Depending on the substrates, a rare fragmentation of the isocyanate unit can be involved within the cycloaddition process to furnish a vinylogous amide embedded in the indolizinone.     

Regioselective rhodium-catalyzed intermolecular [2+2+2] cycloaddition of alkynes and isocyanates to form pyridones

A highly regioselective rhodium-catalyzed intermolecular [2+2+2] cycloaddition of terminal alkynes with a variety of isocyanates to provide 2- and 4-pyridones has been developed. This reaction proceeds in good to excellent yields and overcomes the problem of dimerization and trimerization through the use of phosphoramidite ligands. A CO migration in the metallacycle is proposed to account for the formation of 4-pyridone.     

Rhodium-catalyzed chemo-, regio-, and enantioselective [2 + 2 + 2] cycloaddition of alkynes with isocyanates

[reaction: see text] We have developed a cationic rhodium(I)/modified-BINAP complex-catalyzed chemoselective [2 + 2 + 2] cycloaddition of alkynes with isocyanates leading to a wide range of 2-pyridones. This method was successfully applied to the chemo-, regio-, and enantioselective synthesis of axially chiral 2-pyridones from unsymmetrical alpha,omega-diynes, bearing an ortho-substituted phenyl at one terminal position, and alkyl isocyanates.     

Total Synthesis of Indolizidine Alkaloid (−)‐209D: Overriding Substrate Bias in the Asymmetric Rhodium‐Catalyzed [2+2+2] Cycloaddition

CO! You had me at hello : The use of chiral biphenyl‐based phosphoramidite ligands on rhodium provides an efficient [2+2+2] cycloaddition between terminal alkyl alkynes and alkenyl isocyanates (see scheme). The cycloaddition proceeds through a CO migration pathway, and facilitates a rapid four‐step asymmetric synthesis of indolizidine (?)‐209D.

     

Ruthenium-catalyzed [2 + 2 + 1] cocyclization of isocyanates, alkynes, and CO enables the rapid synthesis of polysubstituted maleimides

Intermolecular [2 + 2 + 1] cocyclization of isocyanates, alkynes, and CO (1 atm) proceeded smoothly in the presence of a catalytic amount of Ru3(CO)12 (3.3 mol %) in mesitylene at 130 degrees C for 3 approximately 42 h to give a variety of polysubstituted maleimides in excellent yields with high selectivity. The reaction may involve an azaruthenacyclopentenone intermediate derived from oxidative cyclization of an isocyanate and an alkyne on an active ruthenium species.     

A general and regioselective synthesis of cyclopentenone derivatives through nickel(0)-mediated [3 + 2] cyclization of alkenyl Fischer carbene complexes and internal alkynes

A broad range of substituted 2-cyclopentenone derivatives 3-6 are synthesized by the nickel(0)-mediated [3 + 2] cyclization reaction of chromium alkenyl(methoxy)carbene complexes 1 and internal alkynes 2. The reaction takes place with complete regioselectivity with both unactivated alkynes and activated alkynes (electron-withdrawing and electron-donating substituted alkynes). Representative cycloadducts containing boron and tin substituents are further demonstrated to be active partners in classical Pd-catalyzed C-C coupling processes to allow the production of 2-aryl- and 2-alkynyl-substituted cyclopentenones 9-13.     

Hexafluoroantimonic Acid Catalysis: Formal [3+2+2] Cycloaddition of Aziridines with Two Alkynes

A practical method for the synthesis of azepine derivatives, a typical seven‐membered heterocyclic ring system, was developed and involves the use of hexafluoroantimonic acid to catalyze a formal [3+2+2] cycloaddition of aziridines with two alkynes. This method was applicable to two of the same or different terminal alkynes for the [3+2+2] cycloaddition with unactivated aziridines, and furnished the corresponding azepine derivatives in good yields with good levels of chemo‐ and regioselectivity. The mechanism was also discussed according to the results of the in situ HRMS and ¹H NMR analysis.     

One pot synthesis of maleimide and hydantoin by Fe(CO)5 catalyzed [2 + 2 + 1] co-cyclization of acetylene, isocyanate and CO

In the presence of a catalytic amount of Fe(CO)(5), terminal acetylenes, isocyanates and CO undergo [2 + 2 + 1] cyclization to form substituted maleimides and hydantoins; when internal alkynes are used, exclusive maleimide formation is observed. While the maleimides can be obtained as the major products, in up to 90% yield, when the reaction is carried out in CO atmosphere, in absence of CO, the hydantoins are formed in up to 87% yield. Formation of maleimides has been shown to occur via the formation of a ferrole intermediate, whereas the hydantoins are proposed to form through successive insertion of isocyanate into the iron-acetylide bond. All compounds were characterized by spectroscopic methods and molecular structures of some compounds were established by single crystal X-ray diffraction method.     

Cobalt-mediated macrocyclizations. Facile synthesis of 2-oxo pyridinophanes via [2 + 2 + 2] cycloaddition of alpha, omega-diynes and isocyanates

[reaction: see text] Cobalt-mediated [2 + 2 + 2] cycloaddition of alpha,omega-diynes and isocyanates provides a direct approach to macrocyclic 2-oxopyridinophanes. This macrocyclization process, which proceeded most efficiently with aliphatic isocyanates, was conveniently performed at a moderate temperature (85 degrees C) without irradiation or syringe-pump addition.     

Synthesis of macrocycles via cobalt-mediated [2 + 2 + 2] cycloadditions

We investigated the formation of macrocycles from alpha,omega-diynes in cobalt-mediated co-cyclotrimerization reactions. Long-chain alpha,omega-diynes underwent metal-mediated [2 + 2 + 2] cycloadditions with nitriles, cyanamides, or isocyanates in the presence of CpCo(CO)2 (Cp = cyclopentadienide) to yield pyridine-containing macrocycles, i.e., meta- and para-pyridinophanes, such as 5m/5p, 35m/35p, and 41m/41p. The regioselectivity of these reactions was affected by the length and type of linker unit between the alkyne groups, as well as by certain stereoelectronic factors. An analogous alpha,omega-cyano-alkyne, 28, combined with an alkyne to yield two isomeric meta-pyridinophanes, such as 5m and 29m, and an ortho cycloadduct (benzannulation product), such as 29o. We developed a reaction protocol for these cobalt-based [2 + 2 + 2] cycloadditions that involves markedly improved conditions such that this process offers a convenient, flexible synthetic approach to macrocyclic pyridine-containing compounds. For example, diyne 6 reacted with p-tolunitrile in 1,4-dioxane to give 7p and 7m (7:1 ratio) in 87% yield at a moderate temperature of ca. 100 degrees C in 24 h without photoirradiation or syringe-pump addition. Isocyanates were also effective reactants, as exemplified by the formation of 44p almost exclusively (44p:44m > 50:1) in 64% yield from diyne 8 and 2-phenylethylisocyanate. By using this improved protocol we were able to co-cyclotrimerize long-chain alpha,omega-diynes with alkynes in certain cases to demonstrate a successful macrocyclic variant of the Vollhardt reaction. For instance, diyne 6 reacted with dipropylacetylene to give paracyclophane 57p and benzannulene 57o (2:1 ratio) in 29% yield.     

RhCl3/amine-catalyzed [2+2+2] cyclization of alkynes

The RhCl₃·3H₂O/i-Pr₂NEt-catalyzed [2+2+2] cyclotrimerization of alkynes has been achieved. The reaction can be widely used for various alkynes and provides tri- or hexa-substituted benzenes regioselectively in high yields. The [2+2+2] cycloaddition of diynes and alkynes is also developed, and it affords benzene derivatives in moderate to high yields.     

Rhodium-catalyzed [2 + 2 + 2] cyclotrimerization in an aqueous-organic biphasic system

Macrocyclization via rhodium-catalyzed intramolecular [2 + 2 + 2] annulation of triynes has been explored in an aqueous-organic biphasic system. The biphasic system controls the concentration of hydrophobic substrates in the aqueous reaction phase and offers diluted reaction conditions without the use of a slow addition technique. The system also achieves selective cross-annulation between hydrophobic diynes and hydrophilic alkynes.     

Phosphine-catalyzed regioselective heteroaromatization between activated alkynes and isocyanides leading to pyrroles

The organophosphine catalyzed reaction of activated alkynes with isocyanides produces the corresponding heteroaromatization products, pyrroles, regioselectively in good yields. The reaction proceeds most probably through the 1,4-addition of the nucleophilic phosphine catalyst to the alkynes, followed by a [3+2] cycloaddition between the resulting alkenyl phosphine intermediates and a carbanion derived from the isocyanides.     

Tethered 2 + 2 + 2 cycloaddition reactions of cobalt-cycloheptyne complexes

Cycloheptyne-dicobalt hexacarbonyl complexes, substituted by propargylic ether functions, undergo 2 + 2 + 2 cycloaddition reactions with alkynes to give tricyclic benzocycloheptanes; an all-intramolecular version of this transformation is also possible.     

Copper‐Catalyzed [2+2+2] Modular Synthesis of Multisubstituted Pyridines: Alkenylation of Nitriles with Vinyliodonium Salts

A [2+2+2] modular synthesis of multisubstituted pyridines, with excellent regioselectivity, has been realized by copper catalysisand involves three distinct components: vinyliodonium salts, nitriles, and alkynes. The reactions proceeded with the facile formation of an aza‐butadienylium intermediate by alkenylation of the nitrile with a vinyliodonium salt. Moreover, the alkynes in the reaction were extended to alkenes, which are an advantage of expense and relative scarceness of alkynes.     

Diastereoselective synthesis of five- and seven-membered rings by [2+2+1], [3+2], [3+2+2], and [4+3] carbocyclization reactions of beta-substituted (alkenyl)(methoxy)carbene complexes with methyl ketone lithium enolates

beta-Substituted alkenylcarbene complexes react with methyl ketone lithium enolates to give different carbocyclization products depending on the structure of the lithium enolate, on the metal of the carbene complex, and on the reaction media. Thus, the reactions of aryl and alkyl methyl ketone lithium enolates with beta-substituted alkenyl chromium and tungsten carbene complexes in diethyl ether afford 1,3-cyclopentanediol derivatives derived from a formal [2+2+1] carbocyclization reaction. However, the lithium enolates of acetone and tungsten complexes furnish formal [3+2+2] carbocyclization products. In the case of alkynyl methyl ketone lithium enolates, competitive formal [2+2+1] and [3+2] carbocyclization reactions occur and 1,3-cyclopentanediol and 3-cyclopentenol derivatives are formed. Conversely, alkenyl methyl ketone lithium enolates react with alkenylcarbene complexes under the same reaction conditions to form 2-cycloheptenone derivatives by a formal [4+3] carbocyclization reaction. Finally, when the reaction was performed in the presence of a coordinating medium, the [3+2] carbocyclization pattern was observed independently of the nature of the methyl ketone lithium enolate used.     

Enantioselective construction of quaternary carbon centers by catalytic [2 + 2 + 2] cycloaddition of 1,6-enynes and alkynes

[reaction: see text] The enantioselective [2 + 2 + 2] cycloaddition of 1,6-enynes and alkynes using chiral rhodium catalysts gave cycloadducts containing quaternary carbon stereocenters. Both symmetrical and unsymmetrical alkynes and acetylene could be used as coupling partners, and the corresponding bicyclic cyclohexa-1,3-dienes were obtained in good to excellent ee.     

Nickel-mediated regioselective [2 + 2 + 2] cycloaddition of carboryne with alkynes

Transition metal-benzyne complexes have found many applications in organic synthesis, mechanistic studies, and the synthesis of functional materials. In sharp contrast, the chemistry of transition metal-carboryne complexes, especially late transition metal complexes, is virtually unknown. This communication reports a novel nickel-mediated regioselective [2 + 2 + 2] cycloaddition reaction of carboryne with alkynes via the Ni-carboryne intermediate (eta2-C2B10H10)Ni(PPh3)2. Because of the bulkiness of the carborane moiety, a high regioselectivity was achieved in the reactions involving unsymmetrical alkynes. This work furnishes a novel method for the preparation of highly substituted benzocarboranes which are difficult to obtain by other methods.     

Intermolecular rhodium-catalyzed [2+2+2] carbocyclization reactions of 1,6-enynes with symmetrical and unsymmetrical alkynes

The crossed intermolecular rhodium-catalyzed [2+2+2] carbocyclization of carbon and heteroatom tethered 1,6-enynes can be accomplished with symmetrical and unsymmetrical alkynes, to afford the corresponding bicyclohexadienes in an efficient and highly selective manner.