1.3- Enynes pyridines

In 2009, Chirik reported a hydrogen-mediated reductive enyne cyclization catalyzed by the bis(imino)pyridine iron complex 5 (Scheme 37) [119]. In the... 

A single report appears in the literature regarding the use of chirally modified palladium catalysts in reductive enyne cyclization.60 Upon exposure of 1,6-enyne 36a to the indicated palladium pyridine-oxazoline complex in the presence of EtjSiH, cyclization product 36b is formed in good yield, but with only modest levels of asymmetric induction (Scheme 26). 

Yet the first examples of cyclization of 1,5-enynes with gold were disclosed by the group of Arcadi in the context of a new synthesis of pyridines (equation 48). The cyclization of propargyl enamines catalyzed by sodium tetrachloroaurate gives substituted pyridines in a general way. The enamines were formed in situ from propargylamine and the corresponding ketone. 

The dehydration of alcohols under mild conditions is affected by copper(II) Lewis acids. Copper sulfate has long been utilized as a dehydrating agent. An example of its effectiveness for alcohol dehydration is demonstrated in the conversion of the sensitive propargylic alcohol 1 to enyne 2 (Sch. 1) [4]. A carbocation mechanism is suggested by the formation of bis ethers in these reactions [5]. The addition of pyridine... 

Diazafulvene 424 reacts with alkenylcarbenes 425 through a formal [64-3] heterocyclization in a regio- and stereoselective manner to afford dihydroimidazo[l,2- ]pyridines 426. When enyne carbenes are treated with diazafulvene 424, consecutive and diastereoselective [64-2]/cyclopentannulation cyclization reactions take place affording new polycyclic complex systems 429 that can be appropriately demetallated to the corresponding imidazole-based fused systems. Finally, enyne carbenes undergo consecutive [64-2]/[54-l] cyclization reactions with diazafulvene 424 and rt-butyl-NC to yield tetracyclic adducts 432 (Scheme 102) <2006CEJ3201>. 

As described above (Section 5.2), the Stephens-Castro reaction of alkynylcopper with aryl and vinyl halides in boiling pyridine is a useful route to aryl and vinyl acetylenes. Direct cross-coupling of organic halides, such as sp halides, with terminal alkynes is a more convenient procedure. Such a reaction is not so easy, but it can be done using a Pd-complex catalyst [41]. Especially facile Pd-catalyzed cross-coupling of aryl and alkenyl halides with terminal alkynes proceeds smoothly under mild conditions in the presence of a cocatalyst of cuprous iodide in amine solvents [Eq. (28)] [42]. This methodology is now used widely for the constiuction of conjugated arylalkyne or enyne systems [43], as described below. It is attractive from a synthetic point of view because mild reaction conditions and simplicity of the procedure are associated with recent developments in modem acetylene chemistry [44]. 

To synthesize enynes (17 examples, 70-87%) one of the 1-alkynes is hydroborated and then treated with another alkyne and Cul and pyridine. The reaction of iodoalkynes with organostannanes is also catalyzed by Cul, i.e., no Pd catalyst is necessary. ... 

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]. 

Fused pyridines. 1-Ethynylcyclopentanol added dropwise with stirring to a mixture of acetyl chloride and a little ZnCl2 and POCI3 at 0° (exothermic to 35-40°), cooled to 20°, stirred for 1 h, and the mixture poured into 23% aq. NH4OH at 0° - 2-methyl-3,4-cyclopentenopyridine. Y 55% (85-93% with acetyl bromide or iodide). F.e.s. F.A. Selimov et al., Izv. Akad. Nauk SSSR Ser. Khim. 1988, 2604-7 2,4-dialkyl-, 2,3,4-trialkyl-, and 2,4-diaryl-pyridines (without POCI3), also 2,3,4,6-tetra-subst. pyridines from 1,3-enynes, s. ibid. 2600-4. 

Basic treatment of pyridines bearing an enyne substituent has been shown to generate an indolizidine carbene in a singlet ground state. This carbene can be... 

Irradiation of the pyridone (182) with a tethered enyne afforded the intramolecular [2 + 2] cycloadducts (183), whereas the compound (184) led to intramolecular [4 + 4] cycloadduct (185). The resulting (185) was unstable and underwent subsequent photochemical [2 + 2] dimerization. An intermolecular [4 + 4] photocycloaddition of a pyridine with an enyne was also reported. " ... 

Once the NHC was introduced onto the ruthenium center, the addition of pyridine (10 equiv.) led to the 16-electron, monopyridine indenylidene complexes 54a-f (Scheme 14.24) [55, 56, 65, 66]. Interestingly, from a synthetic point of view, this preparation can also be achieved starting from (triphenylphos-phine)(indenylidene)ruthenium complexes, thereby avoiding the use of the costly and sensitive tricyclohexylphosphine [50,66]. The monopyridine complexes bearing mesityl substituents on the nitrogens were not very active at room temperature for the RCM of dienes and enynes, nor in the CM of methyl acrylate [66]. However, the controlled ROMP of norbornene-type monomers was allowed [65]. In contrast, the indenylidene complexes 54b and 54f, which bear 2,6-diisopropylphenyl substituents on the NHC and either a pyridine or 3-bromopyridine ligand, were... 

Reactions with conjugated enynes as dienes in Diels-Alder reactions yield cyclohexadiene or benzene products on reaction with alkene or alkyne dienophiles, respectively. These reactions proceed via a stepwise mechanism to avoid formation of a cyclic allene and are referred to as dehydro-Diels-Alder reactions. In 2008, Barluenga and Aguilar demonstrated that gold catalysts promote intermolecular hetero-dehydro-Diels-Alder reactions between dienynes and nitriles. Dienyne 99 combines with phenyinitrile (100) to afford substituted pyridine 101. ... 

An efficient gold-catalyzed oxidative domino reaction of enyne aldehydes and ketones, as well as related substrates, afforded tetracyclic keto-ethers and heteroaromatic analogues by using pyridine N-oxides as external oxidants (13CEJ14787). 

Scheme 15 A cyclization of enynes to form polysubstituted pyridines.

Substituted pyridines are prepared via cyclization 3-aza-l,5-enynes in a facile, one-pot approach (Scheme 15) (13T10245).This reaction works with various substituents present on the arene electron-donating, electron-withdrawing, and halides. Steric hindrance slows the reaction rate. If the aryl ring at C-2 is replaced with alkyl groups, the reaction fails to provide any cyclized product. 

A tandem one-pot method for the construction of highly substituted pyridine derivatives from nitriles, Reformatsky reagents, and 1,3-enynes was developed by Lee and coworkers in 2011 [64], The reaction sequential consisted of the reaction of nitrile with a Reformatsky reagent and then selective addition of the Blaise reaction intermediate to 1,3-enyne, followed by isomerization, cyclization, and an aromatiza-tion cascade to give the final pyridines in moderate to excellent yields. 

In 2013, Rose et al. [18] reported the Co(I)-catalyzed benzannulation of 2-pyridine-substituted enynes to give 2,3-bis(2-pyridyl)styrenes in moderate yields. 

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