Selective syntheses of metalated pyridines from two different unsymmetrical acetylenes, a nitrile, and a titanium(II) alkoxide

Cyclotrimerization of two different, unsymmetrical acetylenes and p-toluenesulfonylnitrile with a divalent titanium alkoxide reagent, Ti(O-i-Pr)4/2 i-PrMgCl, yielded single pyridyltitanium compounds in a highly selective manner. These metalated pyridines were confirmed by deuteriolysis to give the corresponding deuterated pyridines and underwent iodinolysis and copper-catalyzed alkylation to demonstrate their synthetic utility. Alternatively, a different type of cyclotrimerization of an alkynamide, terminal acetylenes, and alpha-alkoxynitriles mediated by the same titanium(II) alkoxide again proceeded in a highly selective manner to give single pyridines having a titanated side chain.     

Facile preparation of various heteroaromatic compounds via azatitanacyclopentadiene intermediates

Coupling of acetylene, nitrile, and a titanium reagent, Ti(O-i-Pr)(4)/2 i-PrMgCl, generated new azatitanacyclopentadienes in a highly regioselective manner. Their subsequent reaction with sulfonylacetylene afforded pyridyltitanium compounds, which, upon reaction with electrophiles, gave substituted pyridines virtually as a single isomer. When optically active nitriles were used in this reaction, chiral pyridines were obtained without loss of the enantiopurity. Alternatively, the azatitanacyclopentadiene prepared from an unsymmetrical acetylene reacted with an aldehyde or another nitrile to give furans or pyrroles having four different substituents again in a regioselective manner.     

Synthesis of isoquinolines and pyridines by the palladium/copper-catalyzed coupling and cyclization of terminal acetylenes and unsaturated imines: the total synthesis of decumbenine B.

Monosubstituted isoquinolines and pyridines have been prepared in good to excellent yields via coupling of terminal acetylenes with the tert-butylimines of o-iodobenzaldehydes and 3-halo-2-alkenals in the presence of a palladium catalyst and subsequent copper-catalyzed cyclization of the intermediate iminoalkynes. In addition, isoquinoline heterocycles have been prepared in excellent yields via copper-catalyzed cyclization of iminoalkynes. The choice of cyclization conditions is dependent upon the nature of the terminal acetylene that is employed, as only aryl and alkenyl acetylenes cyclize under the palladium-catalyzed reaction conditions that have been developed. However, aryl-, vinylic-, and alkyl-substituted acetylenes undergo palladium-catalyzed coupling and subsequent copper-catalyzed cyclization in excellent yields. The total synthesis of the isoquinoline natural product decumbenine B has been accomplished in seven steps and 20% overall yield by employing this palladium-catalyzed coupling and cyclization methodology.     

钯催化偶联-消去法合成芳基末端炔的研究进展

钯催化偶联-消去法合成芳基末端炔的研究进展;芳炔;偶联反应;钯催化剂;合成;综述     

Selective preparation of benzyltitanium compounds by the metalative Reppe reaction. Its application to the first synthesis of alcyopterosin A

Dialkoxytitanacyclopentadienes, prepared from two different acetylenes and a divalent titanium alkoxide reagent, Ti(O-i-Pr)4/2 i-PrMgCl, reacted with propargyl bromide to give directly benzyltitanium compounds. The resultant benzyltitanium compounds underwent deuteriolysis, iodinolysis (with I2), or oxygenation (with O2 gas) to give the corresponding deuterium-labeled compounds, iodides, or alcohols, illustrating their synthetic versatility. The first synthesis of alcyopterosin A, a bicyclic aromatic sesquiterpenoid recently isolated and characterized, has been achieved by this method, starting with an appropriate combination of an acetylene and a diyne.     

Cross‐Metathesis of Terminal Alkynes

Terminal acetylenes are amongst the most problematic substrates for alkyne metathesis because they tend to undergo rapid polymerization on contact with a metal alkylidyne. The molybdenum complex 3 endowed with triphenylsilanolate ligands, however, is capable of inducing surprisingly effective cross‐metathesis reactions of terminal alkyl acetylenes with propynyl(trimethyl)silane to give products of type R¹?C?CSiMe . This unconventional way of introducing a silyl substituent onto an alkyne terminus complements the conventional tactics of deprotonation/silylation and excels as an orthogonal way of alkyne protecting group chemistry for substrates bearing base‐sensitive functionalities. Moreover, it is shown that even terminal aryl acetylenes can be cross‐metathesized with internal alkyne partners. These unprecedented transformations are compatible with various functional groups. The need to suppress acetylene formation, which seems to be a particularly effective catalyst poison, is also discussed.     

The Behaviors of Metal Acetylides with Dinitrogen Tetroxide

Lithium phenylacetylide ( 1a ) and N₂O₄ ( 2 ) at −78° yield diphenylbutadiyne ( 6a ) by oxidative coupling, phenylacetylene ( 7a ) by oxidation and then solvent H‐abstraction, and benzoyl cyanide ( 8 ) by dimerizative‐rearrangement of nitroso(phenyl)acetylene ( 23 ). Nitro(phenyl)acetylene ( 3 , R=Ph) is not obtained. Benzonitrile ( 9 ), a further product, possibly results from hydrolytic decomposition of nitroso(phenyl)ketene ( 27 ) generated from phenylacetylenyl nitrite ( 26 ). Phenylacetylene ( 7a ) and 2 give, along with (E)‐ and (Z)‐1,2‐dinitrostyrenes ( 34 and 35 , resp.), 3‐benzoyl‐5‐phenylisoxazole ( 10 ), presumably as formed by cycloaddition of benzoyl nitrile oxide ( 40 ) to 7a . Further, 2 reacts with other lithium acetylides ( 1b – 1e ), and with sodium, magnesium, zinc, copper, and copper lithium phenylacetylides, 1f – 1l , to yield diacetylenes 6a – 6c and monoacetylenes 7a – 7c . Conversions of metallo acetylide aggregates to diacetylenes are proposed to involve generation and addition reactions of metallo acetylide radical cationic intermediates in cage, further oxidation, and total loss of metal ion. Loss of metal ions from metallo acetylide radical cations and H‐abstraction by non‐caged acetylenyl radicals will give terminal acetylenes. The principal reactions (75–100%) of heavy metal acetylides phenyl(trimethylstannyl)acetylene ( 44 ) and bis(phenylacetylenyl)mercury ( 47 ) with 2 are directed nitrosative additions (NO⁺) and loss of metal ions to give nitroso(phenyl)ketene ( 27 ), which converts to benzoyl cyanide ( 8 ).     

Formation of pyridine from acetylenes and nitriles catalyzed by RuCpCl, CoCp, and RhCp derivatives - A computational mechanistic study

The mechanism of the catalytic formation of pyridines from the coupling of two alkynes and the nitriles NCR (R = H, Me, Cl, COOMe) with the fragments CpRuCl, CpCo, and CpRh has been investigated by means of DFT/B3LYP calculations. According to the proposed mechanism, the key reaction step is the oxidative coupling of two alkyne ligands to give metallacyclopentatriene (Ru, Rh) and metallacyclopentadiene (Co) intermediates. In the case of ruthenium, this process is thermodynamically clearly favored over the oxidative coupling between one alkyne and one nitrile ligand to afford an azametallacycle. This alternative pathway however cannot be dismissed in the case of Co and Rh. The rate determining step of the overall catalytic cycle is the addition of a nitrile molecule to the metallacyclopentatriene and metallacyclopentadiene intermediates, respectively, which has to take place in a side-on fashion. Competitive alkyne addition leads to benzene formation. Thus, also the chemoselectivity of this reaction is determined at this stage of the catalytic cycle. In the case of the RuCpCl fragment, the addition of nitriles R-CN and acetylenes RCCH has been studied in more detail. For R = H, Cl, and COOMe the side-on addition of nitriles is kinetically more favored than alkyne addition and, in accordance with experimental results, pyridine formation takes place. In the case of R = Me nitrile addition could not be achieved and the addition of alkynes to give benzene derivatives seems to be kinetically more favored. Once the nitrile is coordinated facile C-C bond coupling takes place to afford an unusual five- and four-membered bicyclic ring system. This intermediate eventually rearranges to a very unsymmetrical azametallaheptatriene complex which in turn provides CpRuCl(κ¹-pyridine) via a reductive elimination step. Completion of the catalytic cycle is achieved by an exergonic displacement of the respective pyridine product by two acetylene molecules regenerating the bisacetylene complex.     

Practical preparation of N-(1-alkynyl)sulfonamides and their synthetic utility in titanium alkoxide-mediated coupling reactions

Aliphatic and aromatic sulfonamides were alkynylated with 1-bromo-1-alkynes in the catalytic presence of CuI to give N-(1-alkynyl)sulfonamides in good to excellent yields. Racemization of optically active sulfonamides was not observed during this alkynylation. The acetylene-titanium complexes generated from the resultant N-(1-alkynyl)sulfonamides and Ti(O-i-Pr)₄/2 i-PrMgCl underwent regio-, olefinic stereo-, and diastereoselective addition to aldehydes to give virtually single allyl alcohols. Alternatively, inter- or intramolecular coupling reaction between N-(1-alkynyl)sulfonamides and another acetylene or olefin with the above titanium alkoxide reagent generated the corresponding titanacycles, hydrolysis of which furnished stereo-defined (sulfonylamino)dienes or cyclic compounds.     

Synthesis of 2,3-disubstituted benzo[b]thiophenes via palladium-catalyzed coupling and electrophilic cyclization of terminal acetylenes

2,3-Disubstituted benzo[b]thiophenes have been prepared in excellent yields via coupling of terminal acetylenes with commercially available o-iodothioanisole in the presence of a palladium catalyst and subsequent electrophilic cyclization of the resulting o-(1-alkynyl)thioanisole derivatives. I(2), Br(2), NBS, p-O(2)NC(6)H(4)SCl, and PhSeCl have been utilized as electrophiles. Aryl-, vinyl-, and alkyl-substituted terminal acetylenes undergo this coupling and cyclization to produce excellent yields of benzo[b]thiophenes. (Trimethylsilyl)acetylene also undergoes this coupling/cyclization process with I(2), NBS, and the sulfur and selenium electrophiles to afford the corresponding 2-(trimethylsilyl)benzo[b]thiophenes. However, cyclization of the silyl-containing thioanisole using Br(2) affords 2,3-dibromobenzo[b]thiophene.     

"Click" on tubes: a versatile approach towards multimodal functionalization of SWCNTs

Organic functionalization of carbon nanotube sidewalls is a tool of primary importance in material science and nanotechnology, equally from a fundamental and an applicative point of view. Here, an efficient and versatile approach for the organic/organometallic functionalization of single-walled carbon nanotubes (SWCNTs) capable of imparting multimodality to these fundamental nanostructures, is described. Our strategy takes advantage of well-established Cu-mediated acetylene-azide coupling (CuAAC) reactions applied to phenylazido-functionalized SWCNTs for their convenient homo-/heterodecoration with a number of organic/organometallic frameworks, or mixtures thereof, bearing terminal acetylene pendant arms. Phenylazido-decorated SWCNTs were prepared by chemoselective arylation of the CNT sidewalls with diazonium salts under mild conditions, and subsequently used for the copper-mediated cycloaddition protocol in the presence of terminal acetylenes. The latter reaction was performed in one step by using either single acetylene derivatives or equimolar mixtures of terminal alkynes bearing either similar functional groups (masked with orthogonally cleavable protecting groups) or easily distinguishable functionalities (on the basis of complementary analytical/spectroscopic techniques). All materials and intermediates were characterized with respect to their most relevant aspects/properties by TEM microscopy, thermogravimetric analysis coupled with MS analysis of volatiles (TG-MS), elemental analysis, cyclic voltammetry (CV), Raman and UV/Vis spectroscopy. The functional loading and related chemical grafting of both primary amino- and ferrocene-decorated SWCNTs were spectroscopically (UV/Vis, Kaiser test) and electrochemically (CV) determined, respectively.     

Electrophilic alkynylation: the dark side of acetylene chemistry

In addition to the well-established nucleophilic alkynylation, the use of electrophilic alkynes can expand tremendously the scope of acetylene transfer reactions. The use of metal catalysis has recently led to a rebirth of this research area. Halogenoalkynes, hypervalent alkynyliodoniums, acetylene sulfones and in situ oxidized terminal acetylenes are the most often used reagents for electrophilic alkynylation. Heteroatoms such as N, O, S and P can be now efficiently alkynylated. For C-C bond formation, electrophilic acetylenes can be coupled with different organometallic reagents. Recently, the first breakthrough in direct C-H and C[double bond, length as m-dash]C bond alkynylation has also been reported. Finally, sulfonyl acetylenes are efficient for alkyne transfer on carbon-centered radicals.     

Synthetic Reactions Using Low‐valent Titanium Reagents Derived from Ti(OR)4 or CpTiX3 (X = O‐i‐Pr or Cl) in the Presence of Me3SiCl and Mg

In the presence of Me₃SiCl, Ti(OR)₄ or CpTiX₃ (X = O‐i‐Pr or Cl) is reduced by Mg powder in THF to gradually generate a specific low‐valent titanium (LVT) species that mediates several synthetic reactions. The LVT‐catalyzed C–O bond‐cleaving reactions of allyl and propargyl ethers and esters generate parent alcohols and carboxylic acids, respectively. O‐allyl and propargyl carbamates are also readily deprotected by the LVT to afford parent amines. In addition, the respective reductive N–S or O–S bond cleavage of sulfonamides or sulfonyl esters mediated by the LVT was developed as a novel facile deprotection method. The reagent catalyzes intra‐ and intermolecular alkyne or alkyne/nitrile cycloaddition to produce substituted benzenes and pyridines, while epoxides and oxetanes are reduced to alcohols via an LVT‐mediated homolytic ring opening. The McMurry coupling of aryl aldehydes and ketones proceeds with the LVT under homogeneous and mild reaction conditions and is effective for the polymerization of aromatic dialdehydes, generating conjugated polymers. Finally, imino‐pinacol coupling of imines is mediated by the LVT to provide 1,2‐diamines.     

Synthesis of 3-iodoindoles by the Pd/Cu-catalyzed coupling of N,N-dialkyl-2-iodoanilines and terminal acetylenes, followed by electrophilic cyclization

[reaction: see text] 3-Iodoindoles have been prepared in excellent yields by coupling terminal acetylenes with N,N-dialkyl-o-iodoanilines in the presence of a Pd/Cu catalyst, followed by an electrophilic cyclization of the resulting N,N-dialkyl-o-(1-alkynyl)anilines using I2 in CH2Cl2. Aryl-, vinylic-, alkyl-, and silyl-substituted terminal acetylenes undergo this process to produce excellent yields of 3-iodoindoles. The reactivity of the carbon-nitrogen bond cleavage during cyclization follows the following order: Me > n-Bu, Me > Ph, and cyclohexyl > Me. Subsequent palladium-catalyzed Sonogashira, Suzuki, and Heck reactions of the resulting 3-iodoindoles proceed smoothly in good yields.     

Reductive Decarboxylative Alkynylation of N‐Hydroxyphthalimide Esters with Bromoalkynes

A new method for the synthesis of terminal and internal alkynes from the nickel‐catalyzed decarboxylative coupling of N‐hydroxyphthalimide esters and bromoalkynes is presented. This reductive cross‐electrophile coupling is the first to use a C(sp)−X electrophile, and appears to proceed via an alkynylnickel intermediate. The internal alkyne products are obtained in yields of 41–95 % without the need for a photocatalyst, light, or a strong oxidant. The reaction displays a broad scope of carboxylic acid and alkyne coupling partners, and can tolerate an array of functional groups, including carbamate NH, halogen, nitrile, olefin, ketone, and ester moieties. Mechanistic studies suggest that this process does not involve an alkynylmanganese reagent and instead proceeds through nickel‐mediated bond formation.     

Preparation of titanated alkoxyallenes from 3-alkoxy-2-propyn-1-yl carbonates and (eta(2)-Propene)Ti(O-i-Pr)(2) as an efficient ester homoaldol equivalent

3-Alkoxy-2-propyn-1-yl carbonates (2) react with a divalent titanium reagent (eta(2)-propene)Ti(O-i-Pr)(2) to afford titanated alkoxyallenes 1 which, in turn, react with aldehydes regiospecifically to provide the corresponding gamma-addition products in good to excellent yields, thus affording a convenient method for synthesizing gamma-hydroxy esters 3 and/or gamma-butyrolactones 4.     

Regioselective Sonogashira couplings of 2,4-dibromoquinolines. A correction

Heteronuclear multiple bond correlation (HMBC) was used to determine the regiochemical outcome of palladium-catalyzed carbon-carbon bond formation between 2,4-dibromoquinolines and terminal acetylenes. The observed regioselectivity of these coupling reactions is opposite to that reported in the literature for analogous reactions.     

Efficient synthesis of substituted thieno[3,2-e]indoles

Efficient cyclization reactions of 5-aminobenzothiophene derivatives with internal and terminal acetylenes, giving 7- and 8-substituted thieno[3,2-e]indoles, are described. The reaction of 4-iodo-5-(methylsulfonamido)benzothiophene with terminal alkynes gave 7-substituted thienoindoles using general Sonogashira reaction conditions. Reaction of 5-amino-4-iodobenzothiophene with internal acetylenes, using Larock's heterocyclization reaction conditions, gave 7,8-disubstituted thieno[3,2-e]indoles.     

A Convenient Procedure for the Alkylation of Acetylenes

Internal acetylenes are traditionally prepared by the alkylation of terminal acetylenes in liquid ammonia using sodium amide as the base.¹ Although the yields of internal acetylenes prepared in this manner are sometimes good, they are usually in the range of 30–60%. Normant has previously pointed out the efficacy of hexamethylphosphoramide (HMPA) as a solvent for alkylations of sodium acetylide.² In connection with other synthetic work, we have worked out a facile procedure which allows the synthesis of certain internal acetylenes in high yield. A typical experimental procedure follows     

New approach to phosphinoalkynes based on Pd- and Ni-catalyzed cross-coupling of terminal alkynes with chlorophosphanes

[reaction: see text] The first example of direct phosphination of terminal alkynes with chlorophosphanes catalyzed by Ni or Pd complexes is described. Both aromatic and aliphatic terminal acetylenes undergo the coupling reaction to give corresponding coupling product in high yield.