Abstract
Negishi cross-coupling reaction is a familiar reaction for the formation of carbon–carbon bonds that couples organic halides or triflates with organozinc compounds. Palladium is used as a metal catalyst, sometimes nickel can also be used, e.g. Pd2(dba)3, PdCl2(P(otol)3)2, Pd(DPEPhos)Cl2, Ni(PPh3)2Cl2, etc. This reaction has vast applications in organic synthesis as many natural products and biologically active compounds can be obtained through this reaction. The main aim of this review is to summarize the recent synthetic applications of the Negishi reaction reported since 2011 which may be helpful to the researchers working on the development of mild and sustainable strategies regarding the synthesis of pharmaceutically important scaffolds.
Similar content being viewed by others
References
Aarhus TI, Teksum V, Unger A, Habenberger P, Wolf A, Eickhoff J, Klebl B, Wolowczyk C, Biorkoy G, Sundby E, Hoff BH (2023) Negishi cross-coupling in the preparation of benzyl substituted pyrrolo[2,3-d]pyrimidine based CSF1R inhibitors. Eur J Org Chem 26:e202300052. https://doi.org/10.1002/ejoc.202300052
Achelle S, Ramondenc Y, Dupas G, Plé N (2008) Bis- and tris(arylethynyl)pyrimidine oligomers: synthesis and light-emitting properties. Tetrahedron 64:2783–2791. https://doi.org/10.1016/j.tet.2008.01.037
Ahmed SA, Khairou KS, Abdel-Wahab AMA, Hozien ZA, Dürr H (2012) Photochromism of dihydroindolizines. Part XVIII: palladium-catalyzed Negishi coupling for the synthesis of photochromic dihydro 5-azaindolizine-linker-conjugates with a terminal ethylene anchoring group. Tetrahedron Lett 53:4397–4401. https://doi.org/10.1016/j.tetlet.2012.06.039
Akhtar R, Zahoor AF (2020) Transition metal-catalyzed Glaser and Glaser-Hay coupling reactions: scope, classical/green methodologies, and synthetic applications. Synth Commun 50:3337–3368. https://doi.org/10.1080/00397911.2020.1802757
Akhtar R, Zahoor AF, Parveen B, Suleman M (2019a) Development of environmental friendly synthetic strategies for Sonogashira cross coupling reaction: an update. Synth Commun 49:167–192. https://doi.org/10.1080/00397911.2018.1514636
Akhtar R, Zahoor AF, Rasul A, Ahmad M, Anjum MN, Ajmal M, Raza Z (2019b) Design, synthesis, in-silico study and anticancer potential of novel n-4-piperazinyl-ciprofloxacin-aniline hybrids. Pak J Pharm Sci 32:2215–2222
Akin A, Barrila MT, Brandt TA, Dechert-Schmitt AMR, Dube P, Ford DD, Kamlet AS, Limberakis C, Pearsall A, Piotrowski DW, Quinn B, Rothstein S, Salan J, Wei L, Xiao J (2017) A scalable route for the regio- and enantioselective preparation of a tetrazole prodrug: application to the multi-gram-scale synthesis of a PCSK9 inhibitor. Org Process Res Dev 21:1990–2000. https://doi.org/10.1021/acs.oprd.7b00304
Augustyn E, Finke K, Zur AA, Hansen L, Heeren N, Chien HC, Lin L, Giacomini KM, Colas C, Schlessinger AA, Thomas AA (2016) LAT-1 activity of meta-substituted phenylalanine and tyrosine analogs. Bioorg Med Chem Lett 26:2616–2621. https://doi.org/10.1016/j.bmcl.2016.04.023
Babar K, Zahoor AF, Ahmad S, Akhtar R (2021) Recent synthetic strategies toward the synthesis of spirocyclic compounds comprising six-membered carbocyclic/heterocyclic ring systems. Mol Divers 25:2487–2532. https://doi.org/10.1007/s11030-020-10126-x
Barbero M, Cadamuro S, Dughera S (2014) Negishi cross-coupling of arenediazonium o-benzenedisulfonimides. Tetrahedron 70:8010–8016. https://doi.org/10.1016/j.tet.2014.08.035
Bender AM, Griggs NW, Gao C, Trask TJ, Traynor JR, Mosberg HI (2015) Rapid synthesis of boc-2′,6′-dimethyl-L-tyrosine and derivatives and incorporation into opioid peptidomimetics. ACS Med Chem Lett 6:1199–1203. https://doi.org/10.1021/acsmedchemlett.5b00344
Bernhardt S, Manolikakes G, Kunz T, Knochel P (2011) Preparation of solid salt-stabilized functionalized organozinc compounds and their application to cross-coupling and carbonyl addition reactions. Angew Chem Int Ed 50:9205–9209. https://doi.org/10.1002/anie.201104291
Berretta G, Coxon GD (2012) Synthesis of cis, cis-diunsaturated α-meromycolic acid by a palladium-catalysed alkyl-alkyl Negishi reaction. Tetrahedron Lett 53:214–216. https://doi.org/10.1016/j.tetlet.2011.11.021
Brown AN, Li B, Liu SY (2019) Expanding the functional group tolerance of cross-coupling in 1,2-dihydro-1,2-azaborines: installation of alkyl, alkenyl, aryl, and heteroaryl substituents while maintaining a B-H bond. Tetrahedron 75:580–583. https://doi.org/10.1016/j.tet.2018.12.039
Burley SD, Lam VV, Lakner FJ, Bergdahl BM, Parker MA (2013) New route to the Ergoline skeleton via cyclization of 4-unsubstituted indoles. Org Lett 15:2598–2600. https://doi.org/10.1021/ol400620a
Cao Q, Howard JL, Wheatley E, Browne DL (2018) Mechanochemical activation of zinc and application to Negishi cross-coupling. Angew Chem 130:11509–11513. https://doi.org/10.1002/ange.201806480
Čarný T, Peňaška T, Andrejčák S, Šebesta R (2022) Mechanochemical Pd-catalyzed cross-coupling of arylhalides and organozinc pivalates. Chem Eur J 28:e202202040. https://doi.org/10.1002/chem.202202040
Chandrasoma N, Pathmanathan S, Buszek KR (2015) A practical, multi-gram synthesis of (±)-herbindole A, (±)-herbindole B, and (±)-herbindole C from a common intermediate via 6,7-indole aryne cycloaddition and Pd(0)-catalyzed cross-coupling reactions. Tetrahedron Lett 56:3507–3510. https://doi.org/10.1016/j.tetlet.2015.02.064
Chen Y-H, Ellwart M, Malakhov V, Knochel P (2017) Solid organozinc pivalates: a new class of zinc organometallics with greatly enhanced air- and moisture-stability. Synthesis 49:3215–3223. https://doi.org/10.1055/s-0036-1588843
Cherney AH, Hedley SJ, Mennen SM, Tedrow JS (2018) Xantphos as a branch-selective ligand for the acyclic sec-alkyl Negishi cross-coupling of heteroaryl halides. Organometallics 38:97–102. https://doi.org/10.1021/acs.organomet.8b00590
Clarkson GJ, Roesner S (2023) Synthesis of benzofuropyridines and dibenzofurans by a metalation/Negishi cross-coupling/SNAr reaction sequence. J Org Chem 88:684–689. https://doi.org/10.1021/acs.joc.2c02111
Coleridge BM, Bello CS, Ellenberger DH, Leitner A (2010) Negishi coupling of 2-pyridylzinc bromide-paradigm shift in cross-coupling chemistry? Tetrahedron Lett 51:357–359. https://doi.org/10.1016/j.tetlet.2009.11.036
Dennis EG, Jeffery DW, Perkins MV, Smith PA (2011) Pd(DPEPhos)Cl2-catalyzed Negishi cross-couplings for the formation of biaryl and diarylmethane phloroglucinol adducts. Tetrahedron 67:212–2131. https://doi.org/10.1016/j.tet.2011.01.030
Dorval C, Stetsiuk O, Gaillard S, Dubois E, Gosmini C, Danoun G (2022) Cobalt bromide-catalyzed Negishi-type cross-coupling of amides. Org Lett 24:2778–2782. https://doi.org/10.1021/acs.orglett.2c00940
Ellwart M, Chen Y-H, Tüllmann CP, Malakhov V, Knochel P (2018) Preparation of solid organozinc pivalates and their reaction in Pd-catalyzed cross-couplings. Org Synth 95:127–141. https://doi.org/10.1002/0471264229.os095.09
Featherston AL, Miller SJ (2016) Synthesis and evaluation of phenylalanine-derived trifluoromethyl ketones for peptide-based oxidation catalysis. Bioorg Med Chem 24:4871–4874. https://doi.org/10.1016/j.bmc.2016.07.012
Genov M, Fuentes B, Espinet P, Pelaz B (2006) Asymmetric Negishi reaction for sterically hindered couplings: synthesis of chiral binaphthalenes. Tetrahedron Asymmetry 17:2593–2595. https://doi.org/10.1016/j.tetasy.2006.10.008
Grob MA, Mereiter K, Wang Y, Weissensteiner W (2012) En route to biferrocene based Walphos ligands: the synthesis of unsymmetrically 2,2″-disubstituted biferrocenes by Negishi coupling. J Organometal Chem 716:32–38. https://doi.org/10.1016/j.jorganchem.2012.05.041
Guo P, Jin H, Han J, Xu L, Li P, Zhan M (2023) Nickel-catalyzed Negishi cross-coupling of alkyl halides, including unactivated tertiary halides, with a boron-stabilized organozinc reagent. Org Lett 25:1268–1273. https://doi.org/10.1021/acs.orglett.3c00051
Haas D, Hammann JM, Greiner R, Knochel P (2016) Recent developments in Negishi cross-coupling reactions. ACS Catal 6:1540–1552. https://doi.org/10.1021/acscatal.5b02718
Harris CF, Ravindranathan D, Huo S (2012) Oxidative addition of heteroaromatic halides to Negishi reagent and subsequent cross-coupling reactions. Tetrahedron Lett 53:5389–5392. https://doi.org/10.1016/j.tetlet.2012.07.105
Haut FL, Speck K, Wildermuth R, Möller K, Mayer P, Magauer T (2018) A Negishi cross-coupling reaction enables the total synthesis of (+)-stachyflin. Tetrahedron 74:3348–3357. https://doi.org/10.1016/j.tet.2018.02.048
Hebbar N, Fiol-Petit C, Ramondenc Y, Plé G, Plé N (2011) A new series of rod-like conjugated molecules with a pyrazine or a bipyrazine core. Synthesis and light emitting properties. Tetrahedron 67:2287–2298. https://doi.org/10.1016/j.tet.2011.01.068
Hyodo K, Nonobe H, Nishinaga S, Nishihara Y (2014) Synthesis of 2,9-dialkylated phenanthro[1,2-b:8,7-b′]dithiophenes via cross-coupling reactions and sequential Lewis acid-catalyzed regioselective cycloaromatization of epoxide. Tetrahedron Lett 55:4002–4005. https://doi.org/10.1016/j.tetlet.2014.05.035
Joo SR, Kim JS, Kim SH (2017) Direct preparation of arylethynylzinc bromides and their application to cross-coupling reactions. Tetrahedron Lett 58:3267–3270. https://doi.org/10.1016/j.tetlet.2017.07.020
Jung HS, Kim SH (2015) Direct preparation of new organozinc reagents, aminophenylzinc iodides, and their applications. Tetrahedron Lett 56:1004–1006. https://doi.org/10.1016/j.tetlet.2015.01.053
Kim SH, Rieke RD (2011) Preparation of aryl ketones via Ni-catalyzed Negishi-coupling reactions with acid chlorides. Tetrahedron Lett 52:1523–1526. https://doi.org/10.1016/j.tetlet.2011.01.135
King AK, Brar A, Findlater M (2023) A tertiary phosphine oxide ligand-based recyclable system for the Suzuki-Miyaura and Negishi reactions: evidence for pseudo-homogeneous catalysis. Catal Sci Technol 13:301–304. https://doi.org/10.1039/D2CY01734B
Krasovskiy A, Thomé I, Graff J, Krasovskaya V, Konopelski P, Duplais C, Lipshutz BH (2011) Cross-couplings of alkyl halides with heteroaromatic halides, in water at room temperature. Tetrahedron Lett 52:2203–2205. https://doi.org/10.1016/j.tetlet.2010.11.160
Lim C, Burton DJ (2014) Stereospecific synthesis of (E)- and (Z)-1-chloro-1,2-difluorostyrenes. J Fluor Chem 167:61–73. https://doi.org/10.1016/j.jfluchem.2014.07.032
Lipshutz BH, Amorelli B (2009) Carboalumination/Ni-catalyzed couplings. A short synthesis of verticipyrone. Tetrahedron Lett 50:2144–2146. https://doi.org/10.1016/j.tetlet.2009.02.167
Lutter FH, Graßl S, Grokenberger L, Hofmayer MS, Chen Y-H, Knochel P (2019) Cobalt-catalyzed cross-couplings and electrophilic aminations using organozinc pivalates. ChemCatChem 11:5188–5197. https://doi.org/10.1002/cctc.201900070
Malig TC, Kumar A, Kurita KL (2022) Online and in situ monitoring of the exchange, transmetalation, and cross-coupling of a Negishi reaction. Org Process Res Dev 26:1514–1519. https://doi.org/10.1021/acs.oprd.2c00081
Mešková M, Putala M (2011) The development of an approach toward sterically-hindered chiral 2′-aryl-1,1′-binaphthalenes functionalized at position 2. Tetrahedron Lett 52:53795383. https://doi.org/10.1016/j.tetlet.2011.08.046
Miller DK (2013) Facile conversion of chromane-6-triflate to chromane-6-alanines under palladium conditions. Tetrahedron Lett 54:811–813. https://doi.org/10.1016/j.tetlet.2012.11.115
Mišicák R, Ríteský S, Vala M, Weiter M, Cigán M, Gmucová K, Végsö K, Weis M, Kožíšek J, Pavúk M, Putala M (2016) Effect of the ethynylene linker on the properties and carrier mobility of naphthalene derivatives with hexylbithienyl arms. Synth Met 217:156–171. https://doi.org/10.1016/j.synthmet.2016.03.034
Miyagi S, Yokoo R, Tanigawa T, Pitna DB, Hirose M, Usuki T (2022) Synthesis of desmosine-BSA/KLH conjugates via Sonogashira/Negishi cross-coupling reactions. Tetrahedron Lett 90:153616. https://doi.org/10.1016/j.tetlet.2021.153616
Murphy-Benenato KE, Gingipalli L, Boriack-Sjodin PA, Martinez-Botella G, Carcanague D, Eyermann CJ, Gowravaram M, Harang J, Hale MR, Ioannidis G, Jahic H, Jhonstone M, Kutsche A, Laganas MA, Loch JT, Miller MD, Oguto H, Patel SJ (2015) Negishi cross-coupling enabled synthesis of novel NAD+-dependent DNA ligase inhibitors and SAR development. Bioorg Med Chem Lett 25:5172–5177. https://doi.org/10.1016/j.bmcl.2015.09.075
Natori Y, Imahori T, Murakami K, Yoshimura Y, Nakagawa S, Kato A, Adachi I, Takahata H (2011) The synthesis and biological evaluation of 1-C-alkyl-L-arabinoiminofuranoses, a novel class of α-glucosidase inhibitors. Bioorg Med Chem Lett 21:738–741. https://doi.org/10.1016/j.bmcl.2010.11.112
Natori Y, Sakuma T, Yoshimura Y, Kinami K, Hirokami Y, Sato K, Adachi I, Kato A, Takahata H (2014) Synthesis and biological evaluation of α-1-C-4′-arylbutyl-l-arabinoiminofuranoses, a new class of α-glucosidase inhibitors. Bioorg Med Chem Lett 24:3298–3301. https://doi.org/10.1016/j.bmcl.2014.06.001
O’Keefe BM, Simmons N, Martin SF (2011) Facile access to sterically hindered aryl ketones via carbonylative cross-coupling: application to the total synthesis of luteolin. Tetrahedron 67:4344–4351. https://doi.org/10.1016/j.tet.2011.03.074
Ogawa K, Hayashi T, Lin YY, Usuki T (2017) Synthesis of desmosine-containing cyclic peptide for the possible elucidation of elastin crosslinking structure. Tetrahedron 73:3838–3847. https://doi.org/10.1016/j.tet.2017.05.045
Oshita J, Noguchi Y, Watanabe A, Sennari G, Sato S, Hirose T, Oikawa D, Inahashi Y, Iwatsuki M, Ishiyama A, Ōmura S, Sunazuka T (2016) Towards the total synthesis of the anti-trypanosomal macrolide, actinoallolides: construction of a key linear intermediate. Tetrahedron Lett 57:357–360. https://doi.org/10.1016/j.tetlet.2015.12.022
Paju A, Kostomarova D, Matkevits K, Laos M, Pehk T, Kanger T, Lopp M (2015) 3-Alkyl-1,2-cyclopentanediones by Negishi cross-coupling of a 3-bromo-1,2-cyclopentanedione silyl enol ether with alkylzinc reagents: an approach to 2-substituted carboxylic acid γ-lactones, homocitric and lycoperdic acids. Tetrahedron 71:9313–9320. https://doi.org/10.1016/j.tet.2015.10.014
Pierige M, Iuliano A, Angelici G, Casotti G (2022) Stabilized arylzinc iodides in Negishi acylative cross-coupling: a modular synthesis of chalcones. Organics 3:87–94. https://doi.org/10.3390/org3020006
Placzek M, LaBeaume P, Harris L, Ng P, Daniels M, Kallmerten A, Jones GB (2011) Microwave accelerated three-component fluoroalkylations: expeditious routes to fluoropharmaceuticals and PET ligands. Tetrahedron Lett 52:332–335. https://doi.org/10.1016/j.tetlet.2010.11.056
Sakata K, Urabe D, Inoue M (2013) Preparation and palladium-mediated cross-coupling of α-benzoyloxyalkylzinc bromides. Tetrahedron Lett 54:4189–4192. https://doi.org/10.1016/j.tetlet.2013.05.114
Sathiyalingam S, Roesner S (2022) Synthesis of α- and β-carbolines by a metalation/Negishi cross-coupling/SNAr reaction sequence. Adv Synth Catal 364:1769–1774. https://doi.org/10.1002/adsc.202200127
Sato H, Sato K, Iida M, Yamanaka H, Oishi T, Chida N (2008) Total synthesis of mycestericin A. Tetrahedron Lett 49:1943–1947. https://doi.org/10.1016/j.tetlet.2008.01.105
Shah P, Santana MD, Garcia J, Serrano JL, Naik M, Pednekar S, Kapdi AR (2013) [Pd(PPh3)2(saccharinate)2]-general catalyst for Suzuki–Miyaura, Negishi cross-coupling and C–H bond functionalization of coumaryl and pyrone substrates. Tetrahedron 69:1446–1453. https://doi.org/10.1016/j.tet.2012.12.030
Shen J, Wong B, Gu C, Zhang H (2015) Negishi approach to 1,5-disubstituted 3-amino-1H-1,2,4-triazoles. Org Lett 17:4678–4681. https://doi.org/10.1021/acs.orglett.5b02021
Stefani HA, Pena JM, Manarin F, Ando RA, Leal DM, Petragnani N (2011) Negishi cross-coupling of organotellurium compounds: synthesis of biaryls, aryl-, and diaryl acetylenes. Tetrahedron Lett 52:4398–4401. https://doi.org/10.1016/j.tetlet.2011.06.025
Stefani HA, Leal DM, Manarin F (2012) 4-Organochalcogenoyl-1H-1,2,3-triazoles: synthesis and functionalization by a nickel-catalyzed Negishi cross-coupling reaction. Tetrahedron Lett 53:6495–6499. https://doi.org/10.1016/j.tetlet.2012.09.062
Stempel E, Kaml RFX, Budisa N, Kalesse M (2018) Painting argyrins blue: Negishi cross-coupling for synthesis of deep-blue tryptophan analogue β-(1-azulenyl)-l alanine and its incorporation into argyrin C. Bioorg Med Chem 26:5259–5269. https://doi.org/10.1016/j.bmc.2018.03.037
Suzuki R, Yanuma H, Hayashi T, Yamada H, Usuki T (2015) Syntheses of natural and deuterated desmosines via palladium-catalyzed cross-coupling reactions. Tetrahedron 71:1851–1862. https://doi.org/10.1016/j.tet.2015.01.064
Tabassum S, Zahoor AF, Ahmad S, Noreen R, Khan SG, Ahmad H (2022) Cross-coupling reactions towards the synthesis of natural products. Mol Divers 26:647–689. https://doi.org/10.1007/s11030-021-10195-6
Tanaka M, Hikawa H, Yokoyama Y (2011) Convenient synthesis of chiral tryptophan derivatives using Negishi cross-coupling. Tetrahedron 67:5897–5901. https://doi.org/10.1016/j.tet.2011.06.053
Thakur SK, Kaur M, Manar KK, Adhikari M, Choudhury AR, Singh S (2022) Well-defined Ni(0) and Ni(II) complexes of bicyclic (alkyl)(amino)carbene (MeBICAAC): catalytic activity and mechanistic insights in Negishi cross-coupling reaction. Chem Eur J 28:e202202237. https://doi.org/10.1002/chem.202202237
Thomas E, Brion JD, Peyrat JF (2014) Synthesis and preliminary biological evaluation of new antiproliferative aromatic analogues of 1α,25-dihydroxyvitamin D3. Eur J Med Chem 86:381–393. https://doi.org/10.1016/j.ejmech.2014.07.037
Tissot M, Body N, Petit S, Claessens J, Genicot C, Pasau P (2018) Synthesis of electron-deficient heteroaromatic 1,3-substituted cyclobutyls via zinc insertion/Negishi coupling sequence under batch and automated flow conditions. Org Lett 20:8022–8025. https://doi.org/10.1021/acs.orglett.8b03588
Tuttle JB, Azzarelli JM, Bechle BM, Dounay AB, Evrard E, Gan X, Ghosh S, Henderson J, Kim JY, Parikh VD, Verhoest PR (2011) Synthesis of ortho-substituted nitroaromatics via improved Negishi coupling conditions. Tetrahedron Lett 52:5211–5213. https://doi.org/10.1016/j.tetlet.2011.07.083
Wang L, Liu G (2019) One-pot Negishi cross-coupling reaction of aryldiazonium salts via Ni catalysis induced by visible-light. Catal Commun 131:105785. https://doi.org/10.1016/j.catcom.2019.105785
Wong B, Linghu X, Crawford JJ, Drobnick J, Lee W, Zhang H (2014) A chemoselective Reformatsky–Negishi approach to α-haloaryl esters. Tetrahedron 70:1508–1515. https://doi.org/10.1016/j.tet.2013.12.053
Yan M, Zhou Q, Lu P (2022) Collective synthesis of chiral tetrasubstituted cyclobutanes enabled by enantioconvergent Negishi cross-coupling of cyclobutenones. Angew Chem 135:e202218008. https://doi.org/10.1002/ange.202218008
Yanuma H, Usuki T (2012) Total synthesis of the COPD biomarker desmosine via Sonogashira and Negishi cross-coupling reactions. Tetrahedron Lett 53:5920–5922. https://doi.org/10.1016/j.tetlet.2012.08.084
Yousaf M, Zahoor AF, Akhtar R, Ahmad M, Naheed S (2020) Development of green methodologies for Heck, Chan-Lam, Stille and Suzuki cross-coupling reactions. Mol Divers 24:821–839. https://doi.org/10.1007/s11030-019-09988-7
Zhang T, Gao X, Harold BW (2011) Pd-catalyzed Negishi coupling of pyrazole triflates with alkyl zinc halides. Tetrahedron Lett 52:311–313. https://doi.org/10.1016/j.tetlet.2010.11.037
Acknowledgements
The authors are thankful to GC University, Faisalabad, for providing the facilities to carry out this work.
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Conflict of interest
The authors declare no conflict of interest.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Muzammil, Zahoor, A.F., Parveen, B. et al. Recent developments in the chemistry of Negishi coupling: a review. Chem. Pap. (2024). https://doi.org/10.1007/s11696-024-03369-7
Received:
Accepted:
Published:
DOI: https://doi.org/10.1007/s11696-024-03369-7