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Synthesis of isoquinolines

Recent Literature

A palladium-catalyzed coupling of tert-butylimine of o-iodobenzaldehyde with aryl- and alkenyl-substituted terminal acetylenes followed by a copper-catalyzed cyclization provide isoquinolines in excellent yields and short reaction times, whereas 3-halo-2-alkenals can similarly be converted into pyridines.
K. R. Roesch, R. C. Larock, Org. Lett., 1999, 1, 553-556.

Sequential coupling-imination-annulation reactions of ortho-bromoarylaldehydes and terminal alkynes with ammonium acetate in the presence of a palladium catalyst under microwave irradiation gives various substituted isoquinolines, furopyridines, and thienopyridines in good yields.
D. Yang, S. Burugupalli, D. Daniel, Y. Chen, J. Org. Chem., 2012, 77, 4466-4472.

A copper(I)-catalyzed tandem reaction of 2-bromoaryl ketones, terminal alkynes, and CH₃CN efficiently produces densely functionalized isoquinolines via N atom transfer and a three-component [3 + 2 + 1] cyclization in a facile, highly selective, and general manner.
L. Su, S. Xie, J. Dong, F. Liu, S.-F. Yin, Y. Zhou, Org. Lett., 2022, 24, 5994-5999.

A Ru(II)-catalyzed C-H functionalization/annulation of primary benzylamines with sulfoxonium ylides provides isoquinolines without external oxidant. The reaction utilizes the free amine as a directing group for the Ru-catalyzed C-H functionalization.
Y. N. Aher, A. B. Pawar, J. Org. Chem., 2022, 87, 12608-12621.

An efficient one-pot synthesis of isoquinolines and heterocycle-fused pyridines by a three-component reaction involves condensation of aryl ketones and hydroxylamine, rhodium(III)-catalyzed C-H bond activation of the in situ generated oxime, and cyclization with an internal alkyne. This protocol enables rapid assembly of multisubstituted isoquinolines as well as fused heterocycles.
L. Zheng, J. Ju, Y. Bin, R. Hua, J. Org. Chem., 2012, 77, 5794-5800.

Aromatic and heteroaromatic ketoximes underwent a regioselective cyclization with alkynes in the presence of a catalytic amount of [{RuCl₂(p-cymene)}₂] and NaOAc to give isoquinoline derivatives in good to excellent yields.
R. K. Chinnagolla, S. Pimparkar, M. Jeganmohan, Org. Lett., 2012, 14, 3032-3035.

Oximes serve as a directing group and an internal oxidant in an efficient strategy for synthesis of isoquinolines via Pd(II)-catalyzed homocoupling or cyclization with vinyl azides. This reaction features good functional group tolerance and provides various isoquinolines under mild conditions.
Z. Zhu, X. Tang, X. Li, W. Wu, G. Deng, H. Jiang, J. Org. Chem., 2016, 81, 1401-1409.

A sequential copper-catalyzed azidation/aza-Wittig condensation enables an efficient and straightforward synthesis of isoquinolines from internal alkenyl boronic esters, easily prepared from the corresponding 1,2-bis(boronates). This synthetic method has been used to synthesize quinisocaine, a topical anesthetic, and further extended to thieno[2,3-c]pyridines.
V. Jaryaram, T. Sridhar, G. V. M. Sharma, F. Berrée, B. Carboni, J. Org. Chem., 2018, 83, 843-853.

A reaction of iminoalkynes with a variety of electrophiles under mild reaction conditions provides substituted isoquinolines and naphthyridines in good yields.
Q. Huang, J. A. Hunter, R. C. Larock, Org. Lett., 2001, 3, 2973-2976.

A bidentate 2-hydrazinylpyridine directing system enables a high catalytic reactivity without the need for a high-cost privileged ligand in a cobalt-catalyzed synthesis of isoquinolines via C-H coupling/cyclization with alkynes.
S. Zhou, M. Wang, L. Wang, K. Chen, J. Wang, C. Song, J. Zhu, Org. Lett., 2016, 18, 5632-5635.

Reaction of N-carbamoyl-functionalized enamine derivatives with benzyne affords substituted indolines. An orthogonal reactivity is uncovered when related enamine derivatives are modified as amides, such that isoquinolines are formed as the product of condensation with benzyne.
C. D. Gilmore, K. M. Allan, B. M. Stoltz, J. Am. Chem. Soc., 2008, 130, 1558-1559.

The direct conversion of various amides to isoquinoline and β-carboline derivatives via mild electrophilic amide activation, with trifluoromethanesulfonic anhydride in the presence of 2-chloropyridine followed by cyclodehydration upon warming provides the desired products with short overall reaction times.
M. Movassaghi, M. D. Hill, Org. Lett., 2008, 10, 3485-3488.

A rhodium(I) catalyst enables practical and efficient carbothiolation reactions of alkynes with ortho-ketone-bearing aryl methyl sulfides. The resulting carbothiolation adducts are convenient precursors to highly substituted isoquinolines.
M. Arambasic, J. F. Hooper, M. C. Willis, Org. Lett., 2013, 15, 5162-5165.

Ag-catalyzed cyclization of 2-alkynyl benzyl azides offers an efficient method for the synthesis of substituted isoquinolines. The reaction proceeds smoothly in good yields and tolerates various functional groups.
Y.-N. Niu, Z.-Y. Yan, G.-L. Gao, H.-L. Wang, X.-Z. Shu, K-G. Ji, Y.-M. Liang, J. Org. Chem., 2009, 74, 2893-2896.

An efficient palladium-catalyzed reaction of N-propargyl oxazolidines provides 4-substituted isoquinolines under microwave irradiation through a sequential palladium-catalyzed reductive cyclization/ring-opening/aromatization cascade via C-O and C-N bond cleavages of the oxazolidine ring.
X. Xu, H. Feng, E. V. Van der Eycken, Org. Lett., 2021, 23, 6578-6582.

The use of vinyl ethers as robust, inexpensive acetyl sources enables a mild, operationally simple Minisci C-H acetylation of N-heteroarenes. The reaction does not require a catalyst or high temperature and is therefore significantly more sustainable than previously reported methods in terms of cost, reagent toxicity, and waste generation.
J. Dong, J. Liu, H. Song, Y. Liu, Q. Wang, Org. Lett., 2021, 23, 4374-4378.

An efficient and transition-metal-free reaction of easily accessible 2-(formylphenyl)acrylates and phenacyl azides provides 3-keto-isoquinolines in very good yields.
B. Prasad, M. Phanindrudu, D. K. Tiwari, A. Kamal, J. Org. Chem., 2019, 84, 12334-12343.

An oxidative cross-dehydrogenative coupling (CDC) strategy enables an efficient acylation of quinolines and isoquinolines with arylmethanols as the acylating agents. This C-aroylation reaction was carried out in the presence of K₂S₂O₈ as oxidant and methyltrioctylammonium chloride (Aliquat 336) as transfer agent in MeCN at 80°C under transition-metal-free conditions.
M. Adib, R. Pashazadeh, S. Rajai-Daryasarei, R. Kabiri, S. J. A. Gohari, , Synlett, 2016, 27, 2241-2245.

A copper/acid-catalyzed oxidative carbamoylation of various electron-deficient nitrogen heteroarenes (isoquinolines, quinolines, pyridines, phenanthridines, quinoxalines, and phthalazines) with hydrazinecarboxamide hydrochlorides provides structurally diverse nitrogen-heteroaryl carboxamides as single regioisomers in moderate to excellent yields.
Z.-Y. He, C.-F. Huang, S.-K. Tian, Org. Lett., 2017, 19, 4850-4853.

A regioselective rhodium-catalyzed annulation of commercially available primary benzylamines with α-diazo compounds provides isoquinolines in good yields.
H. Chu, P. Xue, J.-T. Yu, J. Cheng, J. Org. Chem., 2016, 81, 8009-8013.

Visible light mediates facile syntheses of isoquinolines, benzothiazoles, and quinazolines from isocyanides and inexpensive acyl peroxides. Singlet-excited isocyanides decompose acyl peroxides into aryl/alkyl radicals. The latter attack the isocyanides, yielding imidoyl radicals that subsequently cyclize to afford heteroarene products.
N. Yadav, S. R. Bhatta, J. N. Moorthy, J. Org. Chem., 2023, 88, 5431-5439.

A broad range of isoquinoline derivatives was synthesized with high chemo- and regioselectivities, via a copper-catalyzed cascade reaction of 2-haloaryloxime acetates with β-diketones, β-keto esters, and β-keto nitriles. Furthermore, this strategy provides functionalized indolo[1,2-a]quinazolines by using indoles instead of an active methylene compound.
H. Jiang, J. Yang, X. Tang, W. Wu, J. Org. Chem., 2016, 81, 2053-2061.

silver triflate catalyzed reaction of 2-alkynylbenzaldehyde with 2-isocyanoacetate efficiently provides isoquinolines. The reaction proceeds smoothly in air under mild conditions with high efficiency.
D. Zheng, S. Li, J. Wu, Org. Lett., 2012, 14, 2655-2657.

CuI-catalyzed coupling of 2-halobenzylamines with β-keto esters or 1,3-diketones in i-PrOH in the presence of of K₂CO₃ produced 1,2-dihydroisoquinolines as the cyclization products, which underwent smooth dehydrogenation under air atmosphere to afford substituted isoquinolines.
B. Wang, B. Lu, Y. Jiang, Y. Zhang, D. Ma, Org. Lett., 2008, 10, 2761-2763.

α-Azido carbonyl compounds bearing a 2-alkenylaryl moiety at the α-position are promising precursors for synthesis of isoindole and isoquinoline derivatives via 1,3-dipolar cycloaddition of azides onto alkenes and 6π-electrocyclization of N-H imine intermediates, respectively.
B. W.-Q. Hui, S. Chiba, Org. Lett., 2009, 11, 729-732.

The reaction of 2-alkynyl-1-methylene azide aromatics with iodium donors gave 1,3-disubstituted 4-iodoisoquinolines in good yields. Electron-donating and withdrawing substituents on the aromatic ring were equally tolerated. At the alkyne terminus, electron-neutral or donating substituents are clearly favored. A short synthesis of norchelerythrine is described.
D. Fischer, H. Tomeba, N. K. Pahadi, N. T. Patil, Z. Huo, Y. Yamamoto, J. Am. Chem. Soc., 2008, 130, 15720-15725.

Readily available 2-azido-3-arylacrylates react with α-diazocarbonyl compounds and triphenylphosphine to furnish isoquinolines in good yields. The efficient and general procedure involves a Wolff rearrangement, an aza-Wittig reaction, and an electrocyclic ring closure.
Y.-Y. Yang, W.-G. Shou, Z.-B. Chen, D. Hong, Y.-G. Wang, J. Org. Chem., 2008, 73, 3928-3930.

A zinc salt promotes cyclization as well as provides a counteranion in a redox-neutral synthesis of isoquinolinium salts via C-H activation of presynthesized or in situ formed imines and coupling with α-diazo ketoesters. Under three-component conditions, both ketone and aldehydes are viable substrates. The coupling of imines with diazo malonates under similar conditions afforded isoquinolin-3-ones as the coupling product.
M. Tian, G. Zheng, X. Fan, X. Li, J. Org. Chem., 2018, 83, 6477-6488.

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.

Vinyl selenone is an effective acetylene surrogate for a Rh-catalyzed annulative coupling to provide 3,4-nonsubstituted isoquinolines under mild conditions. The Se fragment can be recovered as diselenide and recycled. The product can readily be converted to 1-aminoisoquinolines.
A. Inami, Y. Nishii, K. Hirano, M. Miura, Org. Lett., 2023, 25, 3206-3209.

A facile synthesis of pharmaceutically interesting 1-aminoisoquinoline derivatives by gold(III)-mediated domino reactions starts from readily available 2-alkynylbenzamides and ammonium acetate and takes place under mild reaction conditions compatible with a variety of functional groups. A plausible mechanism for the domino process is proposed.
Y. Long, Z. She, X. Liu, Y. Chen, J. Org. Chem., 2013, 78, 2579-2588.

A Cu-catalyzed denitrogenative transannulation of 3-aminoindazoles provides diverse functionalized 3-aminobenzothiophenes and 1-aminoisoquinolines. This transformation proceeds via an "extrude-and-sew" strategy with an unprecedented radical reactivity of 3-aminoindazoles.
Y. Zhou, Y. Wang, Y. Lou, Q. Song, Org. Lett., 2019, 21, 8869-8873.

Regioselective Ni(I)-catalyzed reactions of 2-(cyanomethyl)benzonitriles with arylboronic acids provide atom-economic access to 3-aryl-1-aminoisoquinolines via C-C and C-N cascade coupling reactions.
X. Yang, H. Yu, Y. Xu, L. Shao, J. Org. Chem., 2018, 83, 9682-9695.

A cobalt(III)-catalyzed C-H/N-H bond functionalization for the synthesis of 1-aminoisoquinolines from aryl amidines and diazo compounds proceeds under mild reaction conditions, obviates the need for oxidants, produces only N₂ and H₂O as the byproducts, and features a broad substrate scope.
J. Li, M. Tang, L. Zang, X. Zhang, Z. Zhang, L. Ackermann, Org. Lett., 2016, 18, 2742-2745.

An efficient organoselenium-catalyzed aza-Wacker reaction of olefinic hydrazones and oximes provides isoquinolinium imides and an isoquinoline N-oxides. This transformation involves a direct intramolecular C-H amination.
H. Li, L. Liao, X. Zhao, Synlett, 2019, 30, 1688-1692.