Alkynes cyclotrimerization with nitriles

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... 

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>. 

In contrast to carbocyclic alkyne cyclotrimerizations, the catalytic pyridine synthesis from alkynes and nitriles relies exclusively on cobalt catalysts with a few exceptions where rhodium [16] and iron complexes [17] could be applied. The cobalt-catalyzed pyridine synthesis can even be carried out in a one-potreac-tion generating the catalyst from C0CI2 6 H20/NaBH4 -1- nitrile/alkyne in situ [18]. 

Yamazaki s complex (Structure 5) contains two alkyne molecules linked together to form a five-membered metallacycle. Arene-solvated cobalt atoms, obtained by reacting cobalt vapor and arenes, have been used by Italian workers to promote the conversion of a,w-dialkynes and nitriles giving alkynyl-substituted pyridines [20]. -Tolueneiron(0) complexes have also been utilized for the co-cyclotrimerization of acetylene and alkyl cyanides or benzonitrile giving a-substituted pyridine derivatives. However, the catalytic transformation to the industrially important 2-vinylpyridine fails in this case acrylonitrile cannot be co-cyclotrimerized with acetylene at the iron catalyst [17]. 

The Co(I)-catalysed co-oligomerization of nitriles with alkynes (Bonnemann 1978 [67]) is important in preparative chemistry. Reaction of 2 mol acetylene with nitriles results in a virtually quantitative yield of 2-substituted pyridines. The competing cyclotrimerization of acetylene to benzene can be suppressed by using an excess of nitrile ... 

Accordingly, stable azazirconiacyclopentadienes 180 (formed from nitriles, alkynes and Cp2ZrEt2) react with alkynes in a Ni-catalyzed process to give pyridines 181 which formally result from cyclotrimerization of nitriles with two different alkynes [68]. 

Likewise when two alkyne molecules coordinate to a transition metal such as Co(I) with subsequent coupling of the C-C bond, oxidative cyclization takes place to give a metallacyclopentadiene. Further reaction of another alkyne molecule with the metallacyclopentadiene followed by reductive elimination liberates benzene derivatives. Thus cyclotrimerization of three alkyne molecules catalyzed by a cobalt complex [40,41] can be performed. If a nitrile is used as the second component, pyridine derivatives are obtained catalytically as shown in Scheme 1.13 [42]. The catalytic cyclotrimerization and cyclodimerization of alkynes and conjugated enynes have found extensive applications in synthesis of complex cyclic compounds such as steroid derivatives [43]. 

In the 1990s, Zenneck and Mathey [33] described the use of a Fe(0) piano-stool-type complex. This approach was hampered by difficult catalyst preparation and poor chemoselectivity, leading to the pyridine products. In 2002, Ferr6 et al. [34] described the [2-I-2-I-2] cyclotrimerization with alkynes and a nitrile using stoichiometric quantities of CpFe(MeCN)3 to form pyridines. 

This approach was then extended to the immobilization of diynes, for example, 64, and their reaction with a soluble nitrile. This immobilization strategy effectively suppressed undesired reactions, including the formation of benzenes via trimeiization of the alkynes, and does not require the typically high-dilution and syringe pump conditions required in solution phase. " The reaction of 64 with a variety of nitriles afforded fused pyridines 65 in excellent yields after cleavage from the resin to 66 (Scheme 6.16). In contrast, a solution-phase reaction of trityl-protected dipropargylamine under otherwise identical conditions resulted in only a 46% yield due to both pyridine formation between two diynes and the nitrile, and benzene formation from the reaction of two or three diynes. Similar results were observed in the formation of pyridones 67 (via cyclotrimerization with isocyanates, R NCO) and iminopyridines 68 (via cyclotrimerization with carbodiimides, R NCNR ). 

In addition to 6, different ruthenium complexes have been investigated as catalysts for alkyne cyclotrimerizations and cyclocotrimerization of alkynes with nitriles. Among them, Grubbs-type carbene complexes are of particular importance since they catalyze inter- and intramolecular metathesis-cascade cyclotrimerizations under mild conditions. In addition, they have good tolerance toward a variety of functional groups. 

Although in principle the thermal [2-I-2-I-2] cycloaddition process is allowed by orbital symmetry rules, there are problems with the entropy component, which may be overcome by using transition metal catalysis. This approach (Scheme 2.35) is one of the most convenient for the synthesis of pyridines 2.100. Metal-induced cycloaddition of two alkyne and one nitrile molecules has been described in general reviews of cycloaddition reactions [3,4]. However in some reviews on heterocycles the nitriles are considered as equivalent to alkyne in the [2+2+2] cyclotrimerization reaction [76], in particular, for the synthesis of pyridines and pyridinones in the reactions catalyzed by cobalt, ruthenium, titanium, and zirconium. 

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. 

Among transition-metal complex catalyzed reactions of alkynes with carbon-heteroatom unsaturated compounds the most studied is co-cyclotrimer-ization of alkynes with nitriles to pyridines. For this process the same complexes can be used as for the cyclotrimerization of alkynes. The first report of a cyclopentadienylcobalt complex catalyzed co-cyclotrimerization of alkynes with nitriles appeared in 1973 [92] and was soon followed by other papers [93]. Co-cyclotrimerization of alkynes and nitriles with all its aspects has been recently reviewed [94] and because of that we will focus only on recent developments in this area. In this regard, advances have been made in simple co-cy-clotrimerization of ethyne with various nitriles [95], combinatorial synthesis of substituted pyridines [96], and co-cyclotrimerization of hydroxyalkynes with nitriles in aqueous media catalyzed by cobalt complex with hydrophobic chain attached to the cyclopentadienyl ring [97]. 

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. 

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... 

The first application of phosphinines in catalysis was reported by Zenneck et al. in 1996 in the case of t 6-Fe complexes [46, 98], It was shown that complex 73 could catalyse the cyclotrimerization of dimethyl acetylenedicarboxylate as well as the formation of pyridines from alkynes and nitriles. Importantly, the catalytic activity of this complex was found to be superior to that of the corresponding benzene [Fe(n6-C6FI6)(COD)] complex. Reactions of methylpropargyl ether with butyronitrile in the presence of complex 73 as catalyst in a ratio 620 2,720 1 afforded a mixture of functional benzenes and pyridines. Turn over numbers (TON) for the conversion into pyridines reached 160 and those for the formation of functional benzenes reached 326, thus corresponding to a chemoselectivity of 0.49 (Scheme 26). 

Axially chiral biaryls are an important class of molecules primarily because of their biological activity, as well as their use as chiral ligands. Although enantioselective cyclotrimerization of 1,6-diynes with alkynes or nitriles catalyzed by transition metals has been developed, it was difficult to realize the intermolecular cross-cyclotrimerization process with three alkynes. However, a cationic Rh-complex with (5)-H8-BINAP was found to catalyze effectively the regioselective and enantioselective intermolecular cross-cyclotrimerization of two alkynes 392 and 394 to give chiral biaryls 395 with 89-96% ee in good yields (Scheme 2-35). ... 

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... 

The cyclotrimerization can be extended to the synthesis of heterocycles by the use of either cumulenes or nitriles in place of an alkyne (Scheme 11.24). Nitriles yield pyridines on reaction with diynes," the alkyl... 

---