Nitriles intermolecular coupling

Shono and coworkers achieved electroreductive intra- and intermolecular couplings of ketones and nitriles in 2-propanol solutions containing Et4NTos using Sn cathodes at controlled potential (-2.8 V SCE). Intramolecular coupling of cyclic y- and (5-cyano ketones, besides good to excellent yields, proved to be cis stereoselective when a-hydroxy ketones with bicyclo[3.3.0] or [4.3.0] skeletons were formed. When the reactions were carried out at 65 °C instead of 25 °C, dehydration of hydroxy ketones occurred and the corresponding a,jS-unsaturated ketones were obtained. The presence of alkyl or 2-ethoxycarbonyl substituents did not hinder the cyclization. In Table 13 some representative examples are shown. 

Attempted intermolecular coupling of ketones and nitriles under conditions similar to those used for intramolecular coupling led to mixtures of two types of ketone-nitrile coupling products and alcohols resulting from ketone electroreduction. Product selectivity could be changed altering nitrile/solvent (2-propanol or ethanol) composition. Some results for cyclohexanone/acetonitrile reductions are shown in Scheme 27. 

Subsequent to this intramolecular reaction, optimized conditions were found for the parent intermolecular coupling of alkenes with heteroarenes (Scheme 19.87) [128]. A variety of functional groups were tolerated on the alkene, including esters, nitriles, acetals, and phthalimide. Furthermore, both electron-rich and electron-deficient groups could be introduced on the heteroarenes. This work was extended to nonaromatic heterocycles [129] and dihydroquinazoHnes [130] using [HPCy3][Cl] as a Bronsted acid additive. 

Takahashi T, Xi C, Xi Z et al (1998) Selective intermolecular coupling of alkynes with nitriles and ketones via p,p carbon-carbon bond cleavage of ztrconacyclopentenes. J Org Chem 63 6802-6806... 

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... 

Six-membered heterocycles were obtained from two different alkynes and other unsaturated organic substrates involving C=0 and C=N moieties. The Reppe-type cyclotrimerization can be also applied for preparation of pyridine derivatives when one of the alkynes is replaced by a nitrile. The pyridine formation from two alkynes and a nitrile with Co complexes was originated by Wakatsuki and Yamazaki [77]. Although this method is effective, there is a critical problem for the selective intermolecular coupling of two different alkynes with a nitrile. As shown in Eq. 67, two isomers of pyridine derivatives are formed when a metallacyclopentadiene reacts with a nitrile, due to the two possible orientations of the nitrile in its coupling with the unsymmetrically substituted metallacyclopentadienes. 

Catalytic intermolecular coupling of alkene and alkyne is quite a challenging task. Nevertheless, cyclopentadienyl rutheniumcomplexes are able to catalyze alkyne-alkene coupling (an Alder-ene type reaction) to a mixture of the re-gioisomeric products 120 and 121 (Scheme 52). The most efficient catalysts are the complexes 78 or 53. The latter is more reactive. The scope of the reaction with respect to substituents attached to the both reactants is enormous ester, hydroxy, nitrile, ether, amino, and arylhalide groups are tolerated. Both terminal and internal alkynes and alkenes can be used. Some typical examples are summarized in Table 24 [67,69]. 

Likewise, intermolecular reactions are possible and lead to coupling products which correspond retrosynthetically to the addition of an acyl anion synthon to a ketone. The presence of a proton-donor cosolvent is crucial, otherwise j8-hydroxy nitriles are formed preferentially. The nitrile addition reaction proceeds with good stereoselectivity, e.g. preferentially one diastereoisomer is formed from the electro-reductive addition of acetonitrile (which can advantageously be used as solvent) to dihydrocarvone. 

Matsuda et al. have studied the hydroxyl group directed intermolecular ketone-olefin coupling reactions, induced by Sml2, between a-hydroxy ketones and a,P-unsaturated esters or nitriles (Scheme 30). It was noted that reactions... 

The first asymmetric intermolecular synthesis of 0-methylancistrocladine (2) involved the use of a Meyers biaryl coupling, successfully utilised in the earlier synthesis of dehydroancistrocladine (66), to construct the biaryl linkage atropisomer-selectively (ref. 60,61). It was envisaged that 2 could arise from the acetamide 102 which in turn could be derived from biaryl 103 (Scheme 14). A coupling between the Grignard reagent 104 and chiral oxazoline 105 could then provide 103 stereospecifically. This approach required the synthesis of chiral oxazoline 105 which is outlined in Scheme 15 and begins with the nitrile 71 available in three steps from 1,5-diacetoxynaphthalene (see Scheme 8). 

Axially chiral biaryls are an important class of molecules for both biologically active compounds and chiral ligands (78-80). The most common approach to obtain biaryls is by aryl coupling followed by resolution of the racemic product to afford enantiopure biaryls. Even though enantioselective partial intramolecular cyclotrimerization of diyne with alkynes (81,82) or nitriles (83) were developed with various transitional metals, it was difficult to carry out complete intermolecular reaction. Using a cationic chiral rhodium complex as catalyst, a regioselective intermolecular cross-cyclotrimerization of alkynes 72 and 73 for... 

Under conditions of high dilution to prevent intermolecular reactions, two allylic halide groups in the same molecule can be coupled to give a cyclic product. Macrocyclic lactones have been made in this way. Coupling occurs only at the primary centres. Note that the nickel reagents do not attack ester groups. Neither do they react with acid chlorides, ethers, nitriles, olefins or alkyl, aryl or vinyl chlorides (in contrast to bromides or iodides). Aldehydes and cyclic ketones are attacked, however, above 40°C affording homoallylic alcohols. 

Initial work in the early 1970s by Stetter and co-workers established the scope of the intermolecular reaction. Aromatic and heteroaromatic aldehydes are smoothly coupled to a,(3-unsaturated ketones, esters and nitriles under sodium cyanide or thiazolylidine catalysis (entries 1-5, 3a-d). In contrast, the coupling of aliphatic aldehydes and activated olefins (entry 6, 3e) is successful only under thiazolylidine catalysis. ... 

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