Pyridyl reactions with aromatics

Ring-fused pyridines of type 300 and 301 have been prepared by condensation of enamines with immonium salts170, and by reaction of morpholino enamines derived from a-pyridyl ketones with aromatic aldehydes and further treatment with ammonium acetate171,172, respectively. 

Kotschy et al. also reported a palladium/charcoal-catalyzed Sono-gashira reaction in aqueous media. In the presence of Pd/C, Cul, PPI13, and z -Pr2NH base, terminal alkynes smoothly reacted with aryl bromides or chlorides, such as 2-pyridyl chloride, 4-methylphenyl bromide, and so on, to give the expected alkyne products in dimethyl-acetamide (DMA)-H20 solvent. Wang et al. reported an efficient cross-coupling of terminal alkynes with aromatic iodides or bromides in the presence of palladium/charcoal, potassium fluoride, cuprous iodide, and triph-enylphosphine in aqueous media (THF/H20, v/v, 3/1) at 60°C.35 The palladium powder is easily recovered and is effective for six consecutive runs with no significant loss of catalytic activity. 

Since the nitrogen in pyridine is electron attracting it seemed reasonable to predict that the trihalopyridynes would also show the increased electrophilic character necessary to form adducts with aromatic hydrocarbons under similar conditions to those employed with the tetra-halogeno-benzynes. The availability of pentachloropyridine suggested to us and others that the reaction with w-butyl-lithium should lead to the formation of tetrachloro-4-pyridyl-lithium 82 84>. This has been achieved and adducts obtained, although this system is complicated by the ease with which pentachloropyridine undergoes nucleophilic substitution by tetrachloro-4-pyridyl lithium. Adducts of the type (45) have been isolated in modest yield both in the trichloro- and tribromo- 58) series. 

Several 3-aryl-2-methylimidazo[4,5-b]pyridines (36 X = H, R = H, 4-F, 4-Et X = Cl, R = H, 4-F, 3-CF3, 2,4-Me2, 2,4-Ch, 2-Me-6-Et, 3-CF3-4-C1) with pesticidal activity have been prepared in moderate yields by the reaction of /V-(2-chloro-3-pyridyl)acetamides (37) with aromatic amines in the presence of P2O5 and Et3N-HCl at 150 C.140 With X = H the cyclized products were isolated directly, whereas with X = Cl treatment of the intermediate amidines (38) with K2CO3 in DMF was required to arrive at the final cyclized product. 

This chelation-assisted C-H/olefin and C-H/acetylene coupling can be applied to a variety of aromatic compounds with a directing group such as ester, aldehyde, imine, azo, oxazolyl, pyridyl, and nitrile [7]. In this section, we describe the coupling reactions of aromatic carbonyl compounds with olefins using a transition metal catalyst. 

According to Larock and Kuo the Heck reaction of 2-iodoaniline (20) with allylic alcohols initiates cydocondensation to an imine which finally gives quinolines, in good to moderate yields, by subsequent oxidative aromatization [7]. The analogous reaction with homoallylic alcohols stops at the stage of the imine, thus resulting in benzazepines 23 (Scheme 4) [8]. The result with pyridyl-substituted homoallylic... 

Representative results for the reaction of benzothiazolyl and pyridyl sulfones with unbranched aliphatic and benzyhc aldehydes are shown in Table 12. Anions were generated in situ with LDA (BT sulfones) or separately using n-butyllithium (Pyr sulfones). The yields vary between low and 95%. High stereoselectivities with -isomers favored were recorded for aromatic aldehydes. 

The previous cycloaddition reaction discussed is believed to proceed through an aldimine anion (19). Such delocalized anions can also be generated by treatment of suitable aldimines with a strong base. Subsequent cyclocondensation with a nitrile produces imidazoles [25-28]. The 2-azaallyl lithium compounds (19) are made by treatment of an azomethine with lithium diiso-propylamide in THF-hexane ( 5 1) (Scheme 4.2.9) [29. To stirred solutions of (19) one adds an equimolar amount of a nitrile in THF at —60°C. Products are obtained after hydrolysis with water (see also Section 2.3). If the original Schiff base is disubstituted on carbon, the product can only be a 3-imidazoline, but anions (19) eliminate lithium hydride to give aromatic products (20) in 37-52% yields (Scheme 4.2.9). It is, however, not possible to make delocalized anions (19) with R = alkyl, and aliphatic nitriles react only veiy reluctantly. Examples of (20) (Ar, R, R, yield listed) include Ph, Ph, Ph, 52% Ph, Ph, m-MeCeUi, 50% Ph, Ph, p-MeCeUi, 52% Ph, Ph, 3-pyridyl, 47% Ph, Ph, nPr, 1% [25]. Closely related is the synthesis of tetrasubstituted imidazoles (22) by regioselective deprotonation of (21) and subsequent reaction with an aryl nitrile. Even belter yields and reactivity are observed when one equivalent of potassium t-butoxide is added to the preformed monolithio anion of (21) (Scheme 4.2.9) [30]. 

Best yields for these mixed cyclotrimerizations are obtained with imidates of lower aliphatic nitriles higher aliphatic derivatives give progressively lower yields and with aromatic and electron-withdrawing substituents the reaction is sluggish. Methyl isonicotinimidate (33) reacts with 2 equivalents of formimidamide hydrochloride under base catalysis to give 2-(4-pyridyl)-1,3,5-triazine (34).317... 

The asymmetric aldol reactions of cyclohexanone with aromatic aldehydes in water using the (3-cyclodextrin/proline derivative inclusion complex 21 was reported hy Woggon et al. in 2007 (Scheme 11.18). The reactions proceeded smoothly with excellent diastereo- and enantioselectivities, with the exception of pyridyl aldehydes. Complex 21 was recycled four times without significant changes in reactivity and enantioselectivity. 

S-(2-Pyridyl) aromatic thiolates have been used as substrates for the symmetrical ketone synthesis by the reaction with bis(l,5-cyclooctadiene) nickel in DMF Goto, T. Onaka, M. Mukaiyama, T. Chem. Lett. 1980, 51. 

Reaction of [bis(2-pyridyldimethylsilyl)methyl]lithium with Carbonyl Compounds. The Peterson-t)fpe reaction of [bis(2-pyridyldimethylsilyl)methyl]lithium with primary, secondary, and tertiary aliphatic and aromatic aldehydes produces the corresponding 2-pyridyl-suhstituted vinylsilanes in essentially quantitative yields (entries 1-7, Table 1, eq 3). The reaction is also applicable to sterically hindered aldehydes (entries 3 and 6) and di-aldehyde (entry 7). The reactions with ketones give disubstituted vinylsilanes with somewhat lower yields (entries 8-10). The reaction can be applied to the stereoselective synthesis of dienylsilanes as well (entries 11-13). In all cases, the reaction occurs in a complete stereoselective fashion (>99% E). 

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