Categories: Synthesis of N-Heterocycles >
Synthesis of pyridines and related compounds
Addition of Grignard reagents to pyridine N-oxides in THF at room temperature and subsequent treatment with acetic anhydride at 120°C afforded 2-substituted pyridines in good yields. By exchanging acetic anhydride for DMF in the second step, 2-substituted pyridine N-oxides were obtained, enabling the synthesis of 2,6-disubstituted pyridines.
H. Andersson, F. Almqvist, R. Olsson, Org. Lett., 2007, 9, 1335-1337.
The success of a one-step transformation of heterocyclic N-oxides to 2-alkyl-, aryl-, and alkenyl-substituted N-heterocycles hinges on the combination of copper catalysis and activation by lithium fluoride or magnesium chloride. The utility for the scaffold decoration of a broad range of complex N-heterocycles is exemplified by syntheses of new structural analogues of several antimalarial, antimicrobial, and fungicidal agents.
O. V. Larionov, D. Stephens, A. Mfuh, G. Chavez, Org. Lett., 2014, 16, 864-867.
Cross-coupling of aryl bromides with 2-thienyl, 3-thienyl, 2-pyridyl, and 3-pyridyl aluminum reagents in the presence of Pd(OAc)2 and (o-tolyl)3P provides useful biaryl building blocks. Additionally, the catalytic system was also suited well for the coupling reaction of benzyl halides with pyridyl aluminum reagents to afford a series of pyridylarylmethanes.
X. Chen, L. Zhou, Y. Li, T. Xie, S. Zhou, J. Org. Chem., 2014, 79, 230-239.
Two new varieties of solid, moderately air-stable 2-pyridylzinc reagents are alternatives to unstable or unreliable 2-pyridylboron reagents. Both reagents can be manipulated in air and are competent nucleophiles in Negishi cross-coupling reactions.
J. R. Colombe, S. Bernhardt, C. Stathakis, S. L. Buchwald, P. Knochel, Org. Lett., 2013, 15, 5754-5757.
Suzuki reactions of electron-deficient 2-heterocyclic boronates generally give low conversions and remain challenging. A successful copper(I) facilitated Suzuki coupling of 2-heterocyclic boronates is broad in scope and affords greatly enhanced yields of these notoriously difficult couplings. Furthermore, mechanistic investigations suggest a possible role of copper in the catalytic cycle.
J. Z. Deng, D. V. Paone, A. T. Ginnetti, H. Kurihara, S. D. Dreher, S. A. Weissman, S. R. Stauffer, C. S. Burgey, Org. Lett., 2009, 11, 345-347.
A Suzuki-Miyaura cross-coupling of tetrabutylammonium 2-pyridyltriolborate salts with various aryl and heteroaryl chlorides produces the corresponding desired coupling products with good to excellent yields in the presence of catalytic amounts of PdCl2dcpp and CuI/MeNHCH2CH2OH in anhydrous DMF without bases. Tetrabutylammonium 2-pyridyltriolborate salts are more reactive than the corresponding lithium salts.
S. Sakashita, M. Takizawa, J. Sugai, H. Ito, Y. Yamamoto, Org. Lett., 2013, 15, 4308-4311.
Heteroaromatic tosylates and phosphates are suitable electrophiles in iron-catalyzed cross-coupling reactions with alkyl Grignard reagents. These reactions are performed at low temperature allowing good functional group tolerance with full conversion within minutes.
T. M. Gøgsig, A. T. Lindhardt, T. Skrydstrup, Org. Lett., 2009, 11, 4886-4888.
A redox-neutral, [3+3]-type condensation of O-acetyl ketoximes and α,β-unsaturated aldehydes, that is synergistically catalyzed by a copper(I) salt and a secondary ammonium salt (or amine), allows modular synthesis of a variety of substituted pyridines under mild conditions with tolerance of a broad range of functional groups. The reaction is driven by a merger of iminium catalysis and redox activity of the copper catalyst.
Y. Wei, N. Yoshikai, J. Am. Chem. Soc., 2013, 135, 3756-3759.
Cationic half-sandwich rare-earth catalysts provides an efficient, general and atom-economical method for the synthesis of 2-alkylated pyridine derivatives via C-H addition to olefins. A wide range of pyridine and olefin substrates including α-olefins, styrenes, and conjugated dienes are compatible with the catalysts.
B.-T. Guan, Z. Hou, J. Am. Chem. Soc., 2011, 133, 18066-18089.
The use of Pd2(dba)3 and X-Phos as a ligand enables a mild Negishi cross-coupling of 2-heterocyclic organozinc reagents and aryl chlorides providing 2-aryl-substituted pyridines and thiophenes in high yields. An efficient method to generate the organozinc reagents at room temperature is also demonstrated.
M. R. Luzung, J. S. Patel, J. Yin, J. Org. Chem., 2010, 75, 8330-8332.
An efficient lithiation/isomerization/intramolecular carbolithiation sequence provides a divergent and straightforward entry to a wide range of polysubstituted dihydropyridines and pyridines starting from readily available N-allyl-ynamides.
W. Gati, M. M. Rammah, M. B. Rammah, F. Couty, G. Evano, J. Am. Chem. Soc., 2012, 134, 9078-9081.
The olefin cross-metathesis reaction provides a rapid and efficient method for the synthesis of α,β-unsaturated 1,5-dicarbonyl derivatives which then serve as effective precursors to pyridines with a wide range of substitution patterns. High levels of regiocontrol, short reaction sequences, and facile substituent variation are all notable aspects of this methodology.
T. J. Donohoe, J. A. Basutto, J. F. Bower, A. Rathi, Org. Lett., 2011, 13, 1036-1039.
Ring-closing olefin metathesis (RCM)/elimination and RCM/oxidation/deprotection of nitrogen-containing dienes are the key processes of new synthetic routes to substituted 3-hydroxypyridines. An application of RCM/oxidation/deprotection allows the synthesis of 3-aminopyridine derivatives.
K. Yoshida, F. Kawagoe, K. Hayashi, S. Horiuchi, T. Imamoto, A. Yanagisawa, Org. Lett., 2009, 11, 515-518.
A simple and highly efficient protodecarboxylation of various heteroaromatic carboxylic acids is catalyzed by Ag2CO3 and AcOH in DMSO. This methodology enables also a selective monoprotodecarboxylation of several aromatic dicarboxylic acids.
P. Lu, C. Sanchez, J. Cornella, I. Larrosa, Org. Lett., 2009, 11, 5710-5713.
Reactions of vinyl azides with monocyclic cyclopropanols provided pyridines in the presence of Mn(acac)3, whereas those with bicyclic cyclopropanols led to the formation of 2-azabicyclo[3.3.1]non-2-en-1-ol derivatives using a catalytic amount of Mn(acac)3.
Y.-F. Wang, S. Chiba, J. Am. Chem. Soc., 2009, 131, 12570-12572.
A DBU-promoted metal-free reaction of 2-allyl-2H-azirines affords 1-azatrienes that in situ electrocyclize to pyridines in very good yields. The reaction displays a broad substrate scope and tolerates various substituents. In addition, one-pot synthesis of pyridines from oximes via in situ formation of 2H-azirines was achieved.
Y. Jiang, C.-M. Park, T.-P. Loh, Org. Lett., 2014, 16, 3432-3435.
A one-pot synthesis of substituted pyridines via a domino cyclization-oxidative aromatization approach is based on the use of a new bifunctional noble metal-solid acid catalyst, Pd/C/K-10 montmorillonite and microwave irradiation. The cyclization readily takes place on the strong solid acid while palladium dehydrogenates the dihydropyridine intermediate.
O. De Paolis, J. Baffoe, S. M. Landge, B. Török, Synthesis, 2008, 3423-3428.
A simple, modular method to prepare highly substituted pyridines in good isolated yields employs a cascade reaction comprising a novel Cu-catalyzed cross-coupling of alkenylboronic acids with α,β-unsaturated ketoxime O-pentafluorobenzoates, electrocyclization of the resulting 3-azatriene, and air oxidation.
S. Liu, L. S. Liebeskind, J. Am. Chem. Soc., 2008, 130, 6918-6919.
A single-step conversion of various N-vinyl and N-aryl amides to the corresponding pyridine and quinoline derivatives involves amide activation with trifluoromethanesulfonic anhydride in the presence of 2-chloropyridine followed by π-nucleophile addition to the activated intermediate and annulation. Compatibility of this chemistry with various functional groups is noteworthy.
M. Movassaghi, M. D. Hill, O. K. Ahmad, J. Am. Chem. Soc., 2007, 129, 10096-10097.
A range of highly functionalised pyridines is prepared from enamino and alkynones in a single synthetic step by the use of acetic acid or amberlyst 15 ion exchange resin at 50°C.
M. C. Bagley, J. W. Dale, J. Bower, Synlett, 2001, 1149-1151.
N-Propargylic β-enaminones are common intermediates for the synthesis of polysubstituted pyrroles and pyridines. In the presence of Cs2CO3 N-propargylic β-enaminones are cyclized to pyrroles in good to high yields, whereas CuBr leads to pyridines.
S. Cacchi, G. Fabrizi, E. Filisti, Org. Lett., 2008, 10, 2629-2632.
Polysubstituted pyridines are prepared in good yield and with total regiocontrol by the one-pot reaction of an alkynone, 1,3-dicarbonyl compound and ammonium acetate in alcoholic solvents. This new three-component heteroannulation reaction proceeds under mild conditions in the absence of an additional acid catalyst.
X. Xiong, M. C. Bagley, K. Chapaneri, Tetrahedron Lett., 2004, 45, 6121-6124.
Tri- or tetrasubstituted pyridines are prepared by microwave irradiation of ethyl β-aminocrotonate and various alkynones in a single synthetic step and with total control of regiochemistry. This new one-pot Bohlmann-Rahtz procedure conducted at 170°C gives superior yields to similar experiments conducted using conductive-heating techniques in a sealed tube.
M. C. Bagley, R. Lunn, X. Xiong, Tetrahedron Lett., 2002, 43, 8331-8334.
The direct conversion of amides, including sensitive N-vinyl amides, to the corresponding trimethylsilyl alkynyl imines followed by a ruthenium-catalyzed protodesilylation and cycloisomerization gives various substituted pyridines and quinolines.
M. Movassaghi, M. D. Hill, J. Am. Chem. Soc., 2006, 128, 4592-4593.
A rhodium-catalyzed chelation-assisted C-H activation of α,β-unsaturated ketoximes and the reaction with alkynes affords highly substituted pyridine derivatives.
K. Parthasararathy, M. Jeganmohan, C.-H. Cheng, Org. Lett., 2008, 10, 325-328.
A convenient one-pot C-H alkenylation/electrocyclization/aromatization sequence allows the synthesis of highly substituted pyridine derivatives from alkynes and α,β-unsaturated N-benzyl aldimines and ketimines. The reaction proceeds through dihydropyridine intermediates.
D. A. Colby, R. G. Berman, J. A. Ellman, J. Am. Chem. Soc., 2008, 130, 3645-3651.
A concise one-pot synthesis of highly functionalized pyridines involves a formal insertion of rhodium vinylcarbenoids derived from diazo compounds across the N-O bond of isoxazoles. Upon heating, the insertion products undergo a rearrangement to give 1,4-dihydropyridines. DDQ oxidation then affords the corresponding pyridines in good yield.
J. R. Manning, H. M. L. Davies, J. Am. Chem. Soc., 2008, 130, 8602-8603.
Cationic rhodium(I)/modified-BINAP complexes catalyze a chemo- and regioselective [2+2+2] cycloaddition of a wide variety of alkynes and nitriles leading to highly functionalized pyridines under mild reaction conditions.
K. Tanaka, N. Suzuki, G. Nishida, Eur. J. Org. Chem., 2006, 3917-3922.
Conversion of unsaturated ketones and aldehydes derived from the cycloisomerization of primary and secondary propargyl diynols in the presence of [CpRu(CH3CN)3]PF6 to 1-azatrienes and a subsequent electrocyclization-dehydration provides pyridines with excellent regiocontrol.
B. M. Trost, A. C. Gutierrez, Org. Lett., 2007, 9, 1473-1476.
Coupling of acetylene, nitrile, and a titanium reagent generated new azatitanacyclopentadienes in a highly regioselective manner. The subsequent reaction with sulfonylacetylene and electrophiles gave substituted pyridines virtually as a single isomer. Alternatively, the reaction of azatitanacyclopentadienes with an aldehyde or another nitrile gave furans or pyrroles having four different substituents again in a regioselective manner.
D. Suzuki, Y. Nobe, R. Tanaka, Y. Takayama, F. Sato, H. Urabe, J. Am. Chem. Soc., 2005, 127, 7474-7479.
A mild, efficient, and general aromatization of Hantzsch 1,4-dihydropyridines with oxygen was realized at room temperature with 5 mol % of 9-phenyl-10-methylacridinium perchlorate as photocatalyst, which could be easily recovered and reused.
X. Fang, Y.-C. Liu, C. Li, J. Org. Chem., 2007, 72, 8608-8610.
In the presence of activated carbon, Hantzsch 1,4-dihydropyridines and 1,3,5-trisubstituted pyrazolines were aromatized with molecular oxygen to the corresponding pyridines and pyrazoles in excellent yields.
N. Nakamichi, Y. Kawashita, M. Hayashi, Synthesis, 2004, 1015-1020.
4-Substituted-1,4-dihydropyridines are readily and efficiently aromatized in only one minute using commercial manganese dioxide in the absence of an inorganic support at 100 °C under microwave irradiation. This rapid procedure gives the dehydrogenated or 4-dealkylated product in excellent yield.
M. C. Bagley, M. C. Lubinu, Synthesis, 2006, 1283-1288.
Hantzsch 1,4-dihydropyridines undergo smooth aromatization catalyzed by iodoxybenzoic acid (IBX) to afford the corresponding pyridine derivatives in high yields. All the reactions were carried out in DMSO solvent at 80-85 °C for a period of two to four hours to complete conversion of the substrates.
J. S. Yadav, B. V. S. Reddy, A. K. Basak, G. Baishya, A. V. Narsaiah, Synthesis, 2006, 451-454.
An intermolecular, Rh(III)-catalyzed cyclization of oximes and diazo compounds involving tandem C-H activation, cyclization, and condensation steps gives multisubstituted isoquinoline and pyridine N-oxides under mild conditions. The reaction obviates the need for oxidants, releases N2 and H2O as the byproducts, and displays a broad substituent scope.
Z. Shi, D. C. Koester, M. Boultadakis-Arapinis, F. Glorius, J. Am. Chem. Soc., 2013, 135, 12204-12205.
[bmim]OH, a basic ionic liquid, efficiently promotes a one-pot condensation of aldehydes, malononitrile, and thiophenols to produce highly substituted pyridines in high yields. The ionic liquid can be recovered and recycled.
B. C. Ranu, R. Jana, S. Sowmiah, J. Org. Chem., 2007, 72, 3152-3154.
Pyridine N-oxides were converted to 2-aminopyridines in a one-pot fashion using Ts2O-tBuNH2 followed by in situ deprotection with TFA. The amination proceeded in high yields, excellent 2-/4-selectivity, and with good functional group compatibility.
J. Yin, B. Xiang, M. H. Huffman, C. E. Raab, I. W. Davies, J. Org. Chem., 2007, 72, 4554-4557.
An efficient protecting-group-free two-step route to a broad range of aza- and diazaindoles was established, starting from chloroamino-N-heterocycles. The method involves an optimized Suzuki-Miyaura coupling with (2-ethoxyvinyl)borolane followed by acetic acid-catalyzed cyclization.
D. K. Whelligan, D. W. Thomson, D. Taylor, S. Hoelder, J. Org. Chem., 2010, 75, 11-15.
The biologically important 1,2,4-triazolo[1,5-a]pyridines were readily synthesized from N-(pyridin-2-yl)benzimidamides via PIFA-mediated intramolecular annulation via a direct metal-free oxidative N-N bond formation in short reaction times and high yields.
. Zheng, S. Ma, L. Tang, D. Zhang-Negrerie, Y. Du, K. Zhao, J. Org. Chem., 2014, 79, 4687-4693.
A simple and efficient protocol enables the synthesis of 3-arylimidazo[1,2-a]pyridines by a catalyst-free cascade process from 2-aminopyridine and 1-bromo-2-phenylacetylene or 1,1-dibromo-2-phenylethene in yields up to 86%.
Z. Wu, Y. Pan, X. Zhou, Synthesis, 2011, 2255-2260.
A CuI-catalyzed aerobic oxidative synthesis of imidazo[1,2-a]pyridines from 2-aminopyridines and acetophenones is compatible with a broad range of functional groups. The reaction also enables the formation of alkenyl-substituted imidazoheterocycles by using unsaturated ketones as substrates. Preliminary mechanistic studies indicate that this reaction proceeds through a catalytic Ortoleva-King reaction.
Y. Zhang, Z. Chen, W. Wu, Y. Zhang, W. Su, J. Org. Chem., 2013, 78, 12494-12504.
A rapid, copper-catalyzed aerobic dehydrogenative cyclization of pyridines with ketone oxime esters enables an environmentally friendly synthesis of imidazo[1,2-a]pyridines.
H. Huang, X. Ji, X. Tang, M. Zhang, X. Li, H. Jiang, Org. Lett., 2013, 15, 6218-6221.
Microwave irradiation enables an expeditious one-pot, ligand-free, Pd(OAc)2-catalyzed, three-component reaction for the synthesis of 2,3-diarylimidazo[1,2-a]pyridines. This methodology offers high availability of commercial reagents and great efficiency in expanding molecule diversity.
Y. Wang, B. Frett, H.-y. Li, Org. Lett., 2014, 16, 3016-3019.
An iron-catalyzed denitration reaction enables the synthesis of 3-methyl-2-arylimidazo[1,2-a]pyridine derivatives in good yields from aminopyridines and 2-methyl-nitroolefins. The procedure is simple and inexpensive and tolerates various functional groups.
H. Yan, S. Yang, X. Gao, K. Zhou, C. Ma, R. Yan, G. Huang, Synlett, 2012, 23, 2961-2962.
An aqueous syntheses gives methylimidazo[1,2-a]pyridines, imidazo[1,2-a]pyrazines, and imidazo[2,1-a]isoquinolines without any deliberate addition of catalyst. Using acetonitrile as solvent, Ag-catalyzed intramolecular aminooxygenation produced imidazo[1,2-a]pyridine-3-carbaldehydes in good yields.
D. C. Mohan, S. N. Rao, S. Adimurthy, J. Org. Chem., 2013, 78, 1266-1272.
With a mixed Cu(I)-Cu(II) system in situ generated by partial reduction of CuSO4 with glucose, an efficient and eco-friendly multicomponent cascade reaction of A3-coupling of heterocyclic amidine with aldehyde and alkyne, 5-exo-dig cycloisomerization, and prototropic shift has afforded therapeutically important versatile N-fused imidazoles.
S. K. Guchhait, A. L. Chandgude, G. Priyadarshani, J. Org. Chem., 2012, 77, 4438-4444.
A one-pot reaction of aldehydes, 2-aminopyridines, and terminal alkynes, in the presence of the copper(I) iodide-CuI-NaHSO4•SiO2 combination catalyst in refluxing toluene, generates the corresponding imidazo[1,2-a]pyridines in high to excellent yields.
S. Mishra, R. Ghosh, Synthesis, 2011, 3463-3470.
N-Phenacylpyridinium bromides, which were prepared in situ from the addition of pyridines to α-bromoketones, undergo nucleophilic addition of ammonium acetate under microwave irradiation and solvent-free conditions to afford the corresponding imidazo[1,2-a]pyridines in excellent yields.
M. Adib, A. Mohamadi, E. Sheikhi, S. Ansari, H. R. Bijanzadeh, Synlett, 2010, 1606-1608.
A metal-free sequential dual oxidative amination of C(sp3)-H bonds under ambient conditions affords imidazo[1,5-a]pyridines in very good yields. The reaction involves two oxidative C-N couplings and one oxidative dehydrogenation process with six hydrogen atoms removed.
Y. Yan, Y. Zhang, Z. Zha, Z. Wang, Org. Lett., 2013, 15, 2274-2277.
A facile formation of C-N, C-O, and C-S bonds from ynals, pyridin-2-amines, and alcohols or thiols enables a transition-metal-free three-component reaction for the construction of imidazo[1,2-a]pyridines.
H. Cao, X. Liu, L. Zhao, J. Cen, J. Lin, Q. Zhu, M. Fu, Org. Lett., 2014, 16, 146-149.
A copper-catalyzed one-pot procedure enables the synthesis of imidazo[1,2-a]pyridines with aminopyridines and nitroolefins using air as oxidant. This general reaction appears to be very suitable for the construction of various imidazo[1,2-a]pyridines.
R.-L. Yan, H. Yan, C. Ma, Z.-Y. Ren, X.-A. Gao, G.-S. Huang, Y.-M. Liang, J. Org. Chem., 2012, 77, 2024-2028.
An efficient microwave-assisted metal-free amino benzannulation of aryl(4-aryl-1-(prop-2-ynyl)-1H-imidazol-2-yl)methanone with dialkylamines affords various 2,8-diaryl-6-aminoimidazo[1,2-a]pyridines in good yield.
M. Nagaraj, M. Boominathan, S. Muthusubramanian, N. Bhuvanesh, Synlett, 2012, 23, 1353-1357.
A Pd-catalyzed amide coupling reaction enables a facile synthesis of imidazo[4,5-b]pyridines and -pyrazines. This reaction provides quick access to various substituted products. A model system relevant to the natural product pentosidine has been demonstrated, as well as the total synthesis of the mutagen 1-Me-5-PhIP.
A. J. Rosenberg, J. Zhao, D. A. Clark, Org. Lett., 2012, 14, 1761-1767.
The reaction of 2-halopyridines with trimethylsilyl azide in the presence of tetrabutylammonium fluoride hydrate gives tetrazolo[1,5-a]pyridines. 8-bromotetrazolo[1,5-a]pyridine is further transformed into a variety of novel tetrazolo[1,5-a]pyridine derivatives.
J. K. Laha, G. D. Cuny, Synthesis, 2008, 4002-4006.
Treatment of pyridine N-oxides with 4-toluene sulfonyl chloride and sodium azide in toluene at elevated temperature enables an efficient and convenient synthesis of tetrazolopyridines.
S. Liu, D. Lentz, C. C. Tzschucke, J. Org. Chem., 2014, 79, 3249-3254.
Pyridine N-oxides were converted to tetrazolo[1,5-a]pyridines in good yield in the presence of sulfonyl or phosphoryl azides and pyridine by heating in the absence of solvent. Diphenyl phosphorazidate (DPPA) was the most convenient reagent.
J. M. Keith, J. Org. Chem., 2006, 71, 9540-9543.