Nitrile cyclotrimerization

Alkyne-nitrile cyclotrimerization is a powerful synthetic methodology for the synthesis of complex heterocyclic aromatic molecules.118 Recently, Fatland et al. developed an aqueous alkyne-nitrile cyclotrimerization of one nitrile with two alkynes for the synthesis of highly functionalized pyridines by a water-soluble cobalt catalyst (Eq. 4.62). The reaction was chemospecific and several different functional groups such as unprotected alcohols, ketones, and amines were compatible with the reaction.119 In addition, photocatalyzed [2+2+2] alkyne or alkyne-nitrile cyclotrimerization in water120 and cyclotrimerization in supercritical H2O110121 have been reported in recent years. 

Among the most exciting frontiers in boratabenzene chemistry is the development of transition metal-boratabenzene complexes as catalysts. As early as 1984, it had been demonstrated that these adducts can accelerate useful reactions— specifically, Bonnemann established that (C5H5B-Ph)Co(cod) serves as a catalyst for pyridine-forming cyclotrimerization reactions of alkynes and nitriles.39... 

By analogy with the cyclotrimerization of acetylenes into arenes, and with the cocyclooligomerization of nitriles and acetylenes into pyridines (see Scheme 131 in Section V,A,1), the cyclization of benzonitrile into 2,4,6-triphenyl-s-triazine can be achieved by means of Fe(CO)5 or Fe2(CO)9.241... 

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 . 

An intermolecular cyclotrimerization of an acetylenic nitrile was reported to proceed via the same alkyne-tantalum complex. The resultant pyridine derivative was obtained in 73% yield (Scheme 56).210... 

Based on this work, Itoh and co-workers developed ruthenium(n)-catalyzed [2 + 2 + 2]-cyclotrimerizations of 1,6-diynes 174 and electron-deficient nitriles (Equation (34)),368>368a These partially intramolecular cycloadditions proceed through ruthenacycle intermediates as well. The importance of using electronically activated nitriles is underlined by the fact that acetonitrile and benzonitrile gave only very low yields. 

The cobalt catalyzed cocyclization of alkynes with heterofunctional substrates is not limited to nitriles. cpCo-core complexes are capable of co-oligomerizing alkynes with a number of C,C, C,N or C,0 double bonds in a Diels-Alder-type reaction. Chen, in our laboratories, has observed that these cycloadditions are best performed with the help of stabilizers such as ketones or acetic esters that are weakly coordinated to the cobalt and prevent the alkynes from being cyclotrimerized at the metal center... 

These results can be summarized as follows (1) the cobalt-mediated pyridine formation and alkyne cyclotrimerization depend on the square of the alkyne concentration and are independent of the nitrile concentration (2) a common cobaltacydopentadiene intermediate is responsible for both the pyridine and the benzene formation and may be regarded as a key intermediate for both hetero- and carbocyclic pathways. 

Reactions involving the [4 + 1 + 1] principle, an example of which is shown in equation (136), are rather uncommon and of strictly limited utility [3 + 2 + 1] and [2 + 2 + 2] processes, on th,e other hand, are well known. Representative [3 + 2+1] three-bond formation processes are given in equations (137)—(141), from which it can be seen that the common situation is where ammonia, a substituted amine or formamide constitutes the one-atom fragment. Many [2 + 2 + 2] atom fragment syntheses are known and some are familiar reactions. Thus, the cobalt(I)-catalyzed condensation of nitriles and isocyanates with alkynes gives pyridines and 2-pyridones, often in excellent yield (e.g. equation 142), while the cyclotrimerizations of nitriles, imidates, isocyanates, etc., are well established procedures for the synthesis of 1,3,5-triazine derivatives (e.g. equation 143). Further representative examples are given in equations (144)-(147), and the reader is referred to the monograph chapters for full discussion of these and other [2 + 2 + 2] processes. Examination of the... 

Cyclotrimerization of nitriles is the best-known route to 1,3,5-triazines (for a detailed discussion see CHEC 2.18). The reaction is of value for preparing the symmetrical derivatives only. Nevertheless, many important triazines, such as cyanuric chloride, are made in this way. Other cyclotrimerization reactions are useful thus, an easy route to 1,3,5-triazine involves heating ammonium acetate with ethyl orthoformate. 

Trimerization of imidates is a valuable route to 1,3,5-triazines. Imidates can be considered as activated nitriles and cyclotrimerize more readily. Most symmetrical 2,4,6-trialkyl-1,3,5-triazines are easily formed, although large alkyl substituents may give rise to steric hindrance (61JOC2778). Symmetrical isocyanurates (525) are readily available from isocyanates, RNCO catalysts include tertiary amines, phosphines and sodium methoxide. Aldehydes RCHO and ammonia give hexahydro-1,3,5-triazines (526), known as aldehyde ammonias (73JOC3288). 

Cyclotrimerization of nitriles with heteroatomic substituents are also facile and important reactions. Melamine is formed on heating cyanamide above its melting point (equation 74) (59HC(l3)l, p. 309). Substituted cyanamides react to give either the expected 1,3,5-triazine or the isomer (142). The 1,3,5-triazine is the preferred product at high temperatures, under acid catalysis, and for cyanamides with bulky substituents, whilst the isomer is favoured by basic conditions and low temperatures (Scheme 80). The mechanism of formation of (142) has been proposed (Scheme 81) (78RCR975). 

Selective cyclotrimerization of alkynes with nitriles produced pentasubstituted pyridines (1) with little formation of benzenoid products (Scheme 1) <94CB(127)2535>. 

Numerous transition metal-mediated [2 + 2+2] cycloadditions have been utilized in the synthesis of pyridines . Selective cyclotrimerization of alkynes with nitriles leads to pentasubstituted pyridines 310 with minimal formation of benzenoid byproducts (Scheme 157) <20000L3131>. Different alkynes can be utilized in the same strategy if a sequential approach is used (Scheme 158) <2000JA4994>. 

Dibromopyrrole 1084 (R = Br) and benzyne generated from anthranilic acid and isoamyl nitrile gave dibromo-derivative 1086, the metallation of which led to product 1087 (Scheme 211) <20050L1003>, which was later successfully used in a cyclotrimerization reaction. 

Become integrated by cyclotrimerization into ben-zenoid hydrocarbons or pyridines by reacting with each other or nitriles (including HCN), respectively. 

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