Nitriles metal-catalyzed substitution

The first, and so far only, metal-catalyzed asymmetric 1,3-dipolar cycloaddition reaction of nitrile oxides with alkenes was reported by Ukaji et al. [76, 77]. Upon treatment of allyl alcohol 45 with diethylzinc and (l ,J )-diisopropyltartrate, followed by the addition of diethylzinc and substituted hydroximoyl chlorides 46, the isoxazolidines 47 are formed with impressive enantioselectivities of up to 96% ee (Scheme 6.33) [76]. 

Novel transition metal-mediated strategies were also well represented this past year. Takahashi and co-workers reported a s nickel-catalyzed reaction between azaziconacyclopentadienes (9) and alkynes to form pyridines (10) of varying substitution patterns <00JA4994>. This methodology, a formal cyclotrimerization, is also noteworthy since two different alkynes can be used. In similar fashion, Eaton reported an aqueous, cobalt(II) catalyzed cyclotrimerization between two identical acetylenes and one nitrile to afford substituted pyridines . 

Starting from optically active nitriles, Botteghi and co-workers [32] have applied the cobalt-catalyzed reaction for the prepartion of optically active 2-substituted pyridines (eq. (8)). The chiral center is maintained during the alkyne-nitrile co-cyclization reaction. This reaction has recently been extended to the synthesis of bipyridyl compounds having optically active substituents [33] and provides an access to chiral ligands of potential interest in transition metal-catalyzed asymmetric synthesis. 

Transition metal-catalyzed [2 + 2 + 2]-cycloaddition reaction of two alkynes with a nitrile is an atom-economical and powerful method to synthesize versatile and highly substituted pyridines. ... 

Recent advances on the synthesis of piperidines through ruthenium-catalyzed ring-closing metathesis reactions 12H(84)75. Rhodium-catalyzed [2+2+2] cycloaddition for the synthesis of substituted pyridines, pyridones, and thiopyranimines 12H(85)1017. Synthesis of 2,2 -bipyridines by transition metal-catalyzed alkyne/nitrile [2+2+2] cycloaddition reactions 12H(85)1579. 

Wakatsuki and Yamazaki pioneered the Co-catalyzed reaction of alkynes with nitriles to give substituted pyridines [21], Recently, there have been extensive studies on the development of transition-metal catalysts other than Co. Ru [22], Rh [23], and Ni [24] catalysts have been reported. Details are provided in other sections. 

Originally, the pyridine construction reaction was based on cobalt catalysis and restricted to the use of acetonitrile or alkyl nitriles as one of the cycloaddition partners. However, recent advancements in this area have led to the development of certain ruthenium or rhodium catalysts, allowing the use of methylcyanoformate as an electron-deficient nitrile component in crossed [2 - - 2 - - 2]-cycloaddition reactions [39]. From the point of view of applications, the use of methylcyanoformate in transition-metal-catalyzed pyridine formation reaction is quite beneficial because the ester moiety might serve as a functional group for further manipulations. It might also serve as a protective group of the cyanide moiety, because cyanide itself cannot be used in this reaction. These considerations led to the design of a quite flexible approach to substituted 3-(130)- and y-carbolines (131) based on transition-metal-catalyzed [2 -f 2 -I- 2] cycloaddition reactions between functionalized yne-ynamides (129) and methylcyanoformate (Scheme 7.28) [40]. 

Synthesis of Substituted Heterocycles Transition-metal-mediated or transition-metal-catalyzed co-cycloaddition of two alkynes and one nitrile is one of the simplest synthetic pathways to construct pyridine framework. However, there is a critical problem in selectivity in the intermolecular coupling of two different alkynes and a nitrile resulting from the reaction mechanism via metalacyclopentadi-ene [17]. For example, in Co-mediated pyridine formation, cobaltacyclopentadiene 37 was first prepared from two different alkynes by sequential addition because aza-cobaltacyclopentadiene could not be formed via selective coupling of one alkyne and a nitrile. A mixture of two pyridine regioisomers was obtained in the final step due to the existence of two possible orientations of the nitrile toward cobaltacyclopentadiene intermediate 37 [Scheme 11.15, Eq. (1)] [17b,c]. To control the... 

As noted in Section 11.2.2, nucleophilic substitution of aromatic halides lacking activating substituents is generally difficult. It has been known for a long time that the nucleophilic substitution of aromatic halides can be catalyzed by the presence of copper metal or copper salts.137 Synthetic procedures based on this observation are used to prepare aryl nitriles by reaction of aryl bromides with Cu(I)CN. The reactions are usually carried out at elevated temperature in DMF or a similar solvent. 

Another type of Cinchona alkaloid catalyzed reactions that employs azodicarbo-xylates includes enantioselective allylic amination. Jprgensen [51-53] investigated the enantioselective electrophilic addition to aUyhc C-H bonds activated by a chiral Brpnsted base. Using Cinchona alkaloids, the first enantioselective, metal-free aUyhc amination was reported using alkylidene cyanoacetates with dialkyl azodi-carboxylates (Scheme 12). The product was further functionalized and used in subsequent tandem reactions to generate useful chiral building blocks (52, 53). Subsequent work was applied to other types of allylic nitriles in the addition to a,P-unsaturated aldehydes and P-substituted nitro-olefins (Scheme 13). 

Hydrosilylation of aryl nitriles.5 This metal carbonyl catalyzes hydrosilyla-tion of aryl nitriles to provide N,N-disilylamines. The rate is slower in reactions of substrates substituted by electron-withdrawing groups. The actual reagent may be (CH3)3SiCo(CO)4. 

Cyclopropane formation occurs from reactions between diazo compounds and alkenes, catalyzed by a wide variety of transition-metal compounds [7-9], that involve the addition of a carbene entity to a C-C double bond. This transformation is stereospecific and generally occurs with electron-rich alkenes, including substituted olefins, dienes, and vinyl ethers, but not a,(J-unsaturated carbonyl compounds or nitriles [23,24], Relative reactivities portray a highly electrophilic intermediate and an early transition state for cyclopropanation reactions [15,25], accounting in part for the relative difficulty in controlling selectivity. For intermolecular reactions, the formation of geometrical isomers, regioisomers from reactions with dienes, and enantiomers must all be taken into account. 

Metal-mediated approaches to the synthesis of imidazoles have been reported. PaUadium(ll)-catalyzed intermolecular 1,2-diamination of conjugated dienes with ureas led to 4-alk enyl-2-imidazolones in good yields rmder mild conditions <05JA7308>. Palladium-catalyzed cyclization of O-pentafluorobenzoylamidoximes 74 furnished l-benzyl-2-substituted-4-methylimidazoles 75 <050L609>. Direct copper(I)-chloride mediated reaction of nitriles 76 with a-amino acetals 77 followed by acidic reaction led to a variety of 2-substituted imidazoles 78 <05TL8369>. 

Hydrolysis of primary amides catalyzed by acids or bases is very slow. Even more difficult is the hydrolysis of substituted amides. The dehydration of amides which produces nitriles is of great commercial value (8). Amides can also be reduced to primary and secondary amines using copper chromite catalyst (9) or metallic hydrides (10). The generally unreactive nature of amides makes them attractive for many appHcations where harsh conditions exist, such as high temperature, pressure, and physical shear. 

Most of the described procedures of forming tetrazoles (catalyzed and uncatalyzed) suffer from some disadvantages hke the use of both toxic metals and expensive reagents, drastic reaction conditions, water sensitivity, and the presence of dangerous hydrazoic acids. The zinc(II)-catalyzed reactions to form tetrazoles by Sharpless and coworkers [212,224,225] are safe, but in the case of stericaUy hindered aromatic or alkyl inactivated nitriles, high temperatures (140-170 °C) are required. Amantini et aL reported TBAF to be an efficient catalyst in the synthesis of 5-substituted IH-tetrazoles by using TMSN3 without solvents (Scheme 65) [226]. 

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