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.
A copper-catalyzed reaction of acetophenones and 1,3-diaminopropane provides direct access to 2-arylpyridines. A range of electronically diverse acetophenones undergo this transformation, affording 2-arylpyridines in good yields.
L.-Y. Xi, R.-Y. Zhang, S. Liang, S.-Y. Chen, X.-Q. Yu, Org. Lett., 2014, 16, 5269-5271.
Primary amines can be transformed into their corresponding pyridinium salts in the presence of glutaconaldehyde in acidic medium, including those substrates that remain unreactive toward the typically used Zincke salt.
G. Asskar, M. Rivard, T. Martens, J. Org. Chem., 2020, 85, 1232-1239.
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 reaction sequence involving a Wittig reaction, a Staudinger reaction, an aza-Wittig reaction, a 6π-3-azatriene electrocyclization, and a 1,3-H shift enables a quick one-pot synthesis of polysubstituted pyridines in very good yields from aldehydes, phosphorus ylides, and propargyl azide.
H. Wei, Y. Li, K. Xiao, B. Cheng, H. Wang, L. Hu, H. Zhai, Org. Lett., 2015, 17, 5974-5977.
An efficent cyclization of readily available α,β,γ,δ-unsaturated ketones with ammonium formate under air atmosphere provides asymmetrical 2,6-diarylpyridines. The reaction is metal-free and operationally convenient.
Y. Gao, R. Chen, Y. Ma, Synthesis, 2019, 51, 3875-3882.
The combination of iodine and triethylamine triggers an oxime-based synthesis of 2-aryl-substituted pyridines with high chemo-selectivity and wide functional group tolerance. A broad range of functional pyridines were prepared in good yields using this metal-free protocol. While neither iodine nor triethylamine could trigger this transformation, mechanistic experiments indicated a radical pathway for the reaction.
H. Huang, J. Cai, L. Tang, Z. Wang, F. Li, G.-J. Deng, J. Org. Chem., 2016, 81, 1499-1505.
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 provide 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.
Regioselective hydroamination of alkynes with N-silylamine using a bis(amidate)bis(amido)titanium(IV) precatalyst, addition of α,β-unsaturated carbonyls to the crude mixture followed by oxidation affords 47 examples of pyridines in good yields containing variable substitution patterns, including pharmaceutically relevant 2,4,5-trisubstituted pyridines.
E. K. J. Lui, D. Hergesell, L. L. Schafer, Org. Lett., 2018, 20, 6663-6667.
A photoredox coupling of α,α-difluoro-β-iodoketones with silyl enol ethers catalyzed by fac-Ir(ppy)3 under blue LED irradiation with subsequent one-pot condensation with ammonium acetate provides diversely substituted 3-fluoropyridines.
S. I. Scherbinina, O. V. Fedorov, V. V. Levin, V. A. Kokorekin, M. I. Struchkova, A. D. Dilman, J. Org. Chem., 2017, 82, 12967-12974.
A convenient base-promoted reaction of 1-arylethylamines with ynones gives polysubstituted pyridines via direct β-C(sp3)-H functionalization of enaminones under metal-free conditions. This procedure features high regioselectivity, high efficiency, and environmental friendliness. Various polysubstituted pyridines were provided in high yields.
J. Shen, D. Cai, C. Kuai, Y. Liu, M. Wei, G. Cheng, X. Cui, J. Org. Chem., 2015, 80, 6584-6589.
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 ruthenium-catalyzed formal dehydrative [4 + 2] cycloaddition of enamides and alkynes enables a mild and economic construction of a broad range of highly substituted pyridines. The reaction tolerates many functional groups and offers excellent regioselectivities.
J. Wu, W. Xu, Z.-X. Yu, J. Wang, J. Am. Chem. Soc., 2015, 137, 9489-9495.
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.
Oxidative one-pot sequential reactions of inactivated saturated ketones with electron-deficient enamines enable an efficient synthesis of 3-acylpyridines and pyridine-3-carboxylates. The reaction involve oxidative dehydrogenation of the saturated ketone substrate, followed by [3+3] annulation with β-enaminone or β-enaminoester via a cascade process, including Michael addition, aldol type condensation, and oxidative aromatization.
G. Chen, Z. Wang, X. Zhang, X. Fan, J. Org. Chem., 2017, 82, 11230-11237.
A 2-fluoro-1,3-dicarbonyl-initiated one-pot Michael addition/[5 + 1] annulation/dehydrofluorinative aromatization reaction sequence enables a transition-metal catalyst-free, regioselective synthesis of di-, tri-, tetra-, and pentasubstituted pyridines as well as fused pyridines from readily available starting materials.
Z. Song, X. Huang, W. Yi, W. Zhang, Org. Lett., 2016, 18, 5640-5643.
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.
DABCO promotes an efficient, solvent-free, and eco-friendly domino reaction of various β,γ-unsaturated α-ketocarbonyls with 5/6-membered cyclic sulfamidate imines in neat conditions under MW irradiation to provide densely functionalized picolinates in short reaction times.
S. Biswas, D. Majee, S. Guin, S. Samanta, J. Org. Chem., 2017, 82, 10928-10938.
A domino reaction of 5-membered cyclic sulfamidate imines with various Morita-Baylis-Hillman acetates of nitroolefins/nitrodienes provides a series of 4,6-diarylpicolinates in excellent yields in the presence of DABCO as an organic base at 55 °C.
D. Majee, S. Biswas, S. M. Mobin, S. Samanta, J. Org. Chem., 2016, 81, 4378-4385.
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 copper-catalyzed N-O bond cleavage/C-C/C-N bond formation procedure enables the synthesis of multisubstituted pyridines from various oxime acetates, activated methylene compounds, and a wide range of aldehydes. This method features inexpensive catalysts, no need for extra oxidant, and high step-economy.
H. Jiang, J. Yang, X. Tang, J. Li, W. Wu, J. Org. Chem., 2015, 80, 8763-8771.
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.
Trapping of in situ generated active intermediate 1,4-oxazepines, formed from base-promoted 7-exo-dig cyclization reaction of N-propargyl enaminones, with alcohols/thiols and aldehydes provides 2-alkoxy/2-sulfenylpyridines and dihydrofuro[2,3-b]pyridines in good yields within 30 min at room temperature. This cascade reaction generates 1 equiv of H2O as the sole byproduct.
G. Cheng, L. Xue, Y. Weng, X. Cui, J. Org. Chem., 2017, 82, 9515-9524.
A K2CO3-mediated cyclization and rearrangement of γ,δ-alkynyl oximes for the synthesis of pyridols employs readily accessible starting materials, tolerates a wide range of functional groups, and gives various synthetically challenging pyridols in good yields. The reaction proceeds via an efficient [1,3] rearrangement of an O-vinyl oxime intermediate which is in situ generated by intramolecular nucleophilic addition of γ,δ-alkynyl oximes.
S. Wang, Y.-Q. Guo, Z.-H. Ren, Y.-Y. Wang, Z.-H. Guan, Org. Lett., 2017, 19, 1574-1577.
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.
In a ligand-free chromium(II)-catalyzed amination reaction of various N-heterocyclic chlorides, CrCl2 regioselectively catalyzes the reaction of chloropyridines, chloroquinolines, chloroisoquinolines, and chloroquinoxalines with a broad range of magnesium amides in the presence of lithium chloride as additive. The reactionse provide the desired aminated products in good yield.
A. K. Steib, S. Fernandez, O. M. Kuzmina, M. Corpet, C. Gosmini, P. Knochel, Synlett, 2015, 26, 1049-1054.
Base-mediated cascade reactions of α,β-unsaturated ketones and 1,1-enediamines, which include Michael addition, intramolecular cyclization, aromatization, and a base-dependent optional loss of HNO2, provide 2-amino-4,6-diarylpyridine derivatives. The methods are suitable for efficient parallel synthesis of pyridines.
Q. Luo, R. Huang, Q. Xiao, Y. Yao, J. Lin, S.-J. Yan, J. Org. Chem., 2019, 84, 1999-2011.
The use of the commercially available N-fluorobenzenesulfonimide (NFSI) as an amination reagent enables a copper-catalyzed aminative aza-annulation of enynyl azide to provide amino-substituted nicotinate derivatives in a single step in good yield.
C. R. Reddy, S. K. Prajapti, R. Ranjan, Org. Lett., 2018, 20, 3128-3131.
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.
[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.