Pyridines copper catalyzed synthesis

The use of A/ -heterocychc carbenes (NHC) as catalysts in the preparation of3,4-dihydro-2H-pyran-2-ones (14EJ05631),the copper-catalyzed synthesis of 3-substimted isocoumarins from o-halobenzoic acids and 1,3-diketones (14JOC8507) and the synthesis and reactivity of pyridine-flised 3-substituted 2-amino-4-arylchromenes (14H(89)1557) have been reviewed. 

In 2014, Wan and coworkers developed a copper-catalyzed synthesis of pyridines from enaminones and ammonium chloride [93]. Under the assistant of copper catalyst and aerobic conditions, C—N and C=C bonds of enaminones were cleavage. 4-Unsubstituted pyridines were produced in good yields (Scheme 3.44). 

Liebeskind and Liu developed a copper-catalyzed synthesis of pyri-dines from a,(3-unsaturated ketoxime O-pentafluorobenzoates and alkenylboronic acids in 2008 [118], This cascade reaction consisted of a novel A/ -iminative, Cu-catalyzed cross-coupling of alkenylboronic acids at the NsO bond of a,(3-unsaturated ketoxime O-pentafluorobenzoates, electrocyclization of the resulting 3-azatriene, and air oxidation at the last stage. Highly substituted pyridines were formed in moderate to excellent isolated yields (Scheme 3.59). 

The copper-catalyzed synthesis of imidazo[l,2-a]pyridines via C—H activation using oxygen as the sole oxidant has been reported by Adimurthy et al. ° The reaction proceeds in the presence of the radical-scavenger TEMPO, thns confirming that it does not occur via a radical reaction pathway. 

Halothiophenes, which are not activated through the presence of —I—M-substituents, undergo substitution smoothly under more forcing conditions with copper salts in pyridine or quinoline. Hence 3-cyanothiophene and 5-methyl-2-cyanothiophene have been obtained from the corresponding bromo compounds. 2-Bromothiophene reacts readily with aliphatic cuprous mercaptides in quinoline at 200°C to give thioethers in high yields. The use of the copper-catalyzed Williamson synthesis of alkoxythiophenes from iodo- or bromo-thiophenes and alcoholate has been mentioned before. The reaction of 2-bromothiophene with acetanilide in nitrobenzene in... 

The most useful approaches to the synthesis of di- and poly-ynes from terminal alkynes are undoubtedly the copper-catalyzed couplings discovered by Glaser (CuCl, NH4OH, EtOH, 02)," Eglinton [Cu(OAc)2, hot pyridine or quinoline, 02], and Hay [Cu(I), tmed, 02]. Some of the many applications of these reactions are discussed in the following. 

The displacement of halogen with a copper(I) acetylide and subsequent or synchronous copper catalyzed addition of a neighboring nucleophilic substituent to the triple bond (equation 2) constitutes a versatile synthesis of heterocycles. This reaction has been utilized both for the synthesis of furo[3,2-c]pyridines (equation 3) and furo[3,2-6]pyridines (equation 4) (68JHC227, 72MI31700>. 

Synthesis of thiazolo[3,2-a]pyridin-3(2//)-one can also be accomplished by an alternate route in which a thiazole ring is built onto a pyridine ring. Thus, copper-catalyzed reaction of piperidine-2-thione (95) with methyl diazoacetate affords 5,6-dihydro-7//-thiazolo[3,2-a]pyridin-3(2//)-one 97) (80LAI68) (Scheme 22). During the reaction uncyclized intermediate (96) could not be isolated, it evidently cyclized immediately to the bicyclic product (97), whereas with the pyrrolidine-2-thione the corresponding uncyclized product was isolated (80LAI68) (Scheme 22). 

A synthesis of 4-alkyl-3-pyridinols (55) from 3-benzyloxypyridine (52) utilizes a copper-catalyzed Grignard reaction. The dihydropyridine intermediates 53 are aromatized to 4-alkyl-3-benzyloxypyridines (54), which on hydrogenolysis provide the pyridinols 55 (85JHC1419). Substitution at the 4-position of 3-pyridinecarboxaldehydes can be achieved via 1-acylpyri-dinium salt 56. The intermediate acetal 57 is hydrolyzed to give pyridine-carboxaldehyde 58 (84H339). 

One can indirectly substitute the pyridine ring with electrophiles by using an electron-rich dihydropyridine intermediate. Dihydropyridines 150 can be prepared by a one-pot synthesis utilizing a copper-catalyzed Grignard addition to l-(phenoxycarbonyl)pyridinium chloride (149). Dihydropyridines 150 undergo regiospecific Friedel-Crafts acylation in good yield with many... 

The copper-catalyzed amination of bromopyridine 29 was reported by workers at Merck on route to the synthesis of muscarinic (M3) antagonist 31 <01TL3251>. Interestingly, an uncatalyzed amination of 3-nitropyridines has also been reported <01JCS(P1)376>. Other metal mediated processes have been used to access pyridines with important biological activity as well <0lJOC605x01TL6811>. 

Application of carbon-carbon cross-coupling/67C-electrocyclization cascade reactions in pyridine synthesis is well known. Larock and coworkers developed a palladium-catalyzed coupling of vinylic imines 279 with terminal alkynes 280 followed by subsequent copper-catalyzed cyclization of 281 to give aryl, vinyl, and alkyl-substituted pyridines 282 in moderate yields. ... 

Liebeskind reported a copper-catalyzed Chan-Lam C-N crosscoupling methodology for JV-imination of boronic acids by using oxime O-carboxylates 291 as iminating agents and either Cu(I)-thiophene-2-carboxylate (CuTC) or Cu(OAc)2 as the catalyst under nonbasic and nonoxidizing conditions.Subsequently, the A-alkenylated a,3-unsaturated ketoxime 0-pentafluorobenzoates 293, were preeursors in a cascade reaction for the one-pot synthesis of tri-, tetra-, and penta-substituted pyridines 295 in moderate to excellent isolated yields. 

P-carbohnes [29] (Schane 3, equation 1). A variety of secondary amines were employed, and the method was adapted to the preparation of pyrrolo[3,2-/lindoles and dipyrrolo[3,2-h 2, 3 -c]pyridines [30]. Cacchi and colleagues synthesized 3-aroylindoles from the copper-catalyzed cyclization of lV-(2-iodoaryl)enaminones (equation 2) [31]. The latter were prepared from 2-haloanilines and a,p-ynones, which can react directly with 2-iodoaniline under the copper protocol to give 3-benzoyl-2-phenylindole (76%), thus bypassing the enaminone. Patel described a copper-catalyzed 3-aroylindole synthesis from 2-alkynylated... 

An efficient and simple tandem protocol for the synthesis of 1,2,3-triazole-fused imidazo-[l,2-a]pyridines was reported in 2013. The reactions followed a copper-catalyzed tandem azide-allq ne cycloaddition (CuAAC), Ullmann-type C-N coupling, and intramolecular direct arylation sequence and showed high generality and functional group tolerance. Good yields (59-77%) of 1,2,3-triazole-fused imidazo[l,2-a]pyridines were produced in a single step (Scheme 3.7). 

In 2013, Yoshikai and Wei developed a copper-catalyzed pyridines synthesis from oximes and enals [65]. Under redox-neutral reaction conditions, with 0-acetyl ketoximes and 0 ,/3-unsaturated aldehydes as the substrates and using copper(I) salt and a secondary ammonium salt (or amine) as the catalyst system, a variety of substituted pyridines were prepared with a broad range of functional groups tolerance (Scheme 3.29). By merging iminium catalysis and copper catalyst, imder the redox activity of the copper catalyst, the reaction started to reduce the oxime N—O bond to generate a nucleophilic copper(II) enamide and later oxidize a dihydropyridine intermediates to the final products. 

A sequential one-pot synthesis of unsymmetrical aryl urea derivatives was developed by arylation of N-substituted cyanamides under metal-free conditions, followed by a second N-arylation under copper-catalyzed conditions [96]. Chen and Chen devised the arylation of pyridine N-oxides with At21X via initial O-arylation followed by a 1,3-radical rearrangement to o-pyridinium phenolates, and arylation of pyridine N-amidates delivered o-pyridinium anilines (Scheme 5d) [97]. 

Roesch, K. R., Larock, R. C. (2002). Synthesis of isoquinolines and pyridines by the paUadium/copper-catalyzed coupling and cyclization of terminal acetylenes and unsaturated imines. The total synthesis of decumbenine. J. Org Chem 67,86-94. 

SCHEME 3.59 Synthesis of imidazo[l,2-a]pyridines through copper-catalyzed cyclization/ oxidation process [65]. 

An efficient Cu(OTf)2-catalyzed 2,4,6-trisubstituted pyridine derivatives synthesis via C-N bond cleavage of aromatic methylamines and C(sp )-H bond activated of ketones was developed by Jiang s group (Scheme 8.80). A wide range of 2,4,6-trisubstituted pyridines could be obtained up to 95% yield at 100 °C under CU/O2 under this catalytic system with neat conditions. This process should be initiated by copper-catalyzed aerobic oxidative cleavage of C-N bond of aromatic methylamines [150]. 

Jiao et al. developed copper-catalyzed diverse constructions of 3,5-diarylpyridines and 2-(lTf)-pyridones through tandem Chichibabin-type cyclization, C(sp )-C(sp ) bond cleavage, and aerobic oxidation with high selectivity. Azide, ceric ammonium nitrate (CAN), and 2-aminopyridine are efficient nitrogen donors in this Cu catalytic system for the selective synthesis of pyridines and pyridones [151] (Scheme 8.81). 

A Cul-catalyzed synthesis of acridones via intramolecular cyclization including C(sp )-H bond activation and C(0)-CHj bond cleavage process using air as the oxidant was reported in 2013 (Scheme 8.100). Many substituents on the aromatic rings are tolerable in the reaction, and the acridin-9(10//)-ones could be obtained in moderate to excellent yields. C-labeling experiments show that only about 86% of carbon atom of carbonyl originates from the substrate. They proposed that a copper-catalyzed intramolecular Friedel-Crafts-type reaction pathway is disfavored [172]. Shortly after the previous report, Fu and coworkers developed a relevant aerobic synthesis of acridone derivatives from l-[2-(arylamino)aryl]ethanones under Cu(02CCF3)2/pyridine/02 catalytic system [173]. 

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