Nitriles pyridine synthesis

In the context of pyridin synthesis from alkynes and nitriles homogeneously catalyzed by (cyclopentadienyl)cobalt complexes (Eq. 13), it was found that electron-withdrawing groups on the cyclopentadienyl ring significantly increase the activity [63]. During the screening of various cobalt half-sandwich complexes... 

The cobalt-catalyzed pyridine synthesis is the only known one-step process for the selective preparation of the industrially significant 2-substituted-pyridine derivatives. Moreover, the method is applicable to a broad variety of substituted alkynes and nitriles, thereby giving access to a whole range of pyridine derivatives having 1,2,3 or 5 substituents in the ring. Selected examples follow and are compared to the prior state of the art. 

Co arene chemistry has been expanded by the preparation of a number of (arene)Co(j7" -diene)+ and (arene)Co( , -enyl) complexes starting from (10). Hydrogenation of (10) in the presence of an arene and a base (piperidine or quinuclidine for obvious stabilization of coordinatively unsaturated cobalt intermediates) gives cyclooctenyl complexes (37) (equation 53). This reaction occurs with a large niunber of arenes even CeFg gives an j -arene complex. The resulting complexes (37) are moderately active catalysts in the pyridine synthesis from alkynes and nitriles (Section 5.1.4). 

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]. 

Azines and their Hydro- and Benzo-derivatives Pyridines. - Synthesis. A key step in a synthesis of optically active nicotine derivatives is the hydrogen-bromide-induced cyclization of the nitrile (1) to the bromopyridine (2). ... 

Pyridine synthesis. This organometaUic reagent catalyzes the reaction of acetylene and monosubstituted acetylenes with nitriles to form pyridines (equations I and II). Disubstituted acetylenes do not undergo this reaction. 

The [4+2] cycloaddition is of increasing utility for pyridine synthesis [69]. The pyridine nitrogen is introduced either via the diene component [1- or 2-azadienes, oxazoles (cf. p 131)] or via the dienophile (activated imine or nitrile). 

Treatment of 6-ethoxy-2-phenyl-3-carboxy-5,6-dihydro-4/7-pyran with hydroxylamine transforms the heterocycle to 2-phenylnicotinate <97JHC93>. However, an isoxazole is obtained if the pyran is substituted with an acyl group rather than the ester functionality. Nitriles continue to be key components in pyridine synthesis. The bicyclic ketal 8 is converted cleanly to the pyridine 9 in the presence of an alkyl nitrile using 5 equiv of TMSOMs and 1 equiv of BFrEt20. This combination, generating the active ingredient boron difluoromethanesulfonate, avoids the byproduct cyclohexanones <97JHC325>. 

Efficiency of pyridine synthesis from alkynes and nitriles is improved with light (Scheme 3) <93AOC(7)641>. 

Additionally, several nickel-catalyzed systems for pyridines synthesis have also been developed by Louie and coworkers. In 2005, they reported that with Ni(COD)2 as the catalyst and carbene as the ligand, the cyclization can be carried out at room temperature (Scheme 3.23a) [51]. Both intramolecular and intermolecular reactions were proceeded well and the cycloaddition of an asymmetrical diyne afforded a single pyridine regioisomer. This catalytic system was extended to cyanamides as well [52], In their systematic studies, they found the in situ formed dimeric [Ni(IPr)RCN]2 from the reaction of Ni(COD)2, IPr, and nitrile are catalytically competent in the formation of pyridines from the cycloaddition of diynes and nitriles. X-ray analysis revealed that these species display simultaneous f- and 17 -nitrile binding modes. Kinetic... 

Additionally, Pd-catalyzed cross-coupling reactions were explored in pyridines synthesis also. In 2007, a multicomponent sequential process for the synthesis of trisubstituted pyridines was reported [59]. The reaction involves the formation of an enamine by Pd-catalyzed amination of an alkenyl bromide, formation of a 2-aza-1,3-butadiene by Pd-catalyzed cross-coupling of a trimethylsilylimine with an alkenyl bromide, and Lewis acid (Yb(OTf)3 (20mol%)) catalyzed cycloaddition between the enamine and the azadiene. Moderate yields can be achieved (Scheme 3.26). A zinc-mediated tandem reaction of nitriles... 

Polysubstituted pyrimidines 39 can be obtained from a,P-unsaturated imines 38 and amidines or guanidines in a one-pot procedure [270]. The imines 38 are generated in situ in a sequential three-component process from methyl phosphonate, nitriles, and aldehydes (both preferentially aromatic for the utihty of 38 in pyridine synthesis, cf p. 373) ... 

Miscellaneous.—A new pyridine synthesis has been reported that involves the addition of 2 moles of a nitrile (RCN) to a dianion, and then ring closure (Scheme 7)/ a-Metallated isocyanides also provide routes to nitrogen heterocycles, as shown in Scheme 8/ ... 

Another particularly significant breakthrough results from the direct synthesis of pyridine and of its derivatives by Co oligomerization of two molecules of acetylenes with a nitrile (Bonnemann synthesis [4]). The potentialities of the Bonnemann reaction are well illustrated by its application to the synthesis of heterocyclic systems, a particularly illustrative example being the synthesis of vitamine B6 [5g]. 

A typical example of such an application is the one step synthesis of pyridines directly from acetylenes and nitriles (Bonnemann synthesis [4]). 

In the pyridine synthesis, the cationic rhodium(I)/biaryl bisphosphine complexes are widely applicable catalysts for both intermolecular and intramolecular [2 + 2 + 2 cycloaddition of alkynes with nitriles under mild conditions. Wilkinson s complex [RhCl(PPh3)3] is effective for intramolecular [2-f 2-1-2] cycloaddition of diyneni-triles under microwave heating. 

H. Bonnemann, Cobalt-Catalysed Pyridine Synthesis from Alkynes and Nitriles , Angew. Chem. Internat. Edn., 1978,17, 505. 

Ring Synthesis From Nonheterocyclic Compounds. These methods may be further classified based on the number of bonds formed during the pyridine ring formation. Synthesis of a-picoline (2) from 5-oxohexanenitrile is a one-bond formation reaction (eq. 16) (49). The nitrile is obtained by reaction between acetone and acrylonitrile (50). If both reaction steps are considered together, the synthesis must be considered a two-bond forming one, ie, formation of (2) from acetone and acrylonitrile in a single step comes under the category of two-bond formation reaction. 

By-Products. Almost all commercial manufacture of pyridine compounds involves the concomitant manufacture of various side products. Liquid- and vapor-phase synthesis of pyridines from ammonia and aldehydes or ketones produces pyridine or an alkylated pyridine as a primary product, as well as isomeric aLkylpyridines and higher substituted aLkylpyridines, along with their isomers. Furthermore, self-condensation of aldehydes and ketones can produce substituted ben2enes. Condensation of ammonia with the aldehydes can produce certain alkyl or unsaturated nitrile side products. Lasdy, self-condensation of the aldehydes and ketones, perhaps with reduction, can lead to alkanes and alkenes. 

A useful synthesis of polysubstituted pyridines (i.e., 11) is based on the legioselective addition of Uthiated -enaminophosphonates to unsaturated carbonyl compounds. These pyridines can also be obtained via a one-pot reaction from metalated phosphonates and sequential addition of nitriles and unsaturated caibonyl compounds <96TL(37)4577>. 

The cycloadducts formed from the Diels-Alder reaction of 3-amino-5-chloro-2(17/)-pyrazinones with methyl acrylate in toluene are subject to two alternative modes of ring transformation yielding either methyl 6-cyano-l,2-dihydro-2-oxo-4-pyridinecarboxylates or the corresponding 3-amino-6-cyano-l,2,5,6-tetrahydro-2-oxo-4-pyridinecarboxylates. From the latter compounds, 3-amino-2-pyridones can be generated through subsequent loss of HCN <96 JOC(61)304>. Synthesis of 3-spirocyclopropane-4-pyridone and furo[2,3-c]pyridine derivatives can be achieved by the thermal rearrangement of nitrone and nitrile oxide cycloadducts of bicyclopropylidene <96JCX (61)1665>. 

The addition of Grignard reagents to aldehydes, ketones, and esters is the basis for the synthesis of a wide variety of alcohols, and several examples are given in Scheme 7.3. Primary alcohols can be made from formaldehyde (Entry 1) or, with addition of two carbons, from ethylene oxide (Entry 2). Secondary alcohols are obtained from aldehydes (Entries 3 to 6) or formate esters (Entry 7). Tertiary alcohols can be made from esters (Entries 8 and 9) or ketones (Entry 10). Lactones give diols (Entry 11). Aldehydes can be prepared from trialkyl orthoformate esters (Entries 12 and 13). Ketones can be made from nitriles (Entries 14 and 15), pyridine-2-thiol esters (Entry 16), N-methoxy-A-methyl carboxamides (Entries 17 and 18), or anhydrides (Entry 19). Carboxylic acids are available by reaction with C02 (Entries 20 to 22). Amines can be prepared from imines (Entry 23). Two-step procedures that involve formation and dehydration of alcohols provide routes to certain alkenes (Entries 24 and 25). 

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. 

---