Reaction

The Heck reaction is the palladium catalyzed cross-coupling reaction between alkenes, and aryl or vinyl halides (or triflates) to afford substituted alkenes.1,2 It is a useful carbon–carbon bond forming reaction with synthetic importance. The reaction proceeds in the presence of base and it is highly stereoselective in nature. The Heck reaction, discovered by Tsutomu Mizoroki and Richard F. Heck, is also referred to as the Mizoroki–Heck reaction.3 The Pd-catalyzed Mizoroki–Heck reaction of olefins with aryl halides has been recognized with a Nobel Prize in chemistry in 2010.4

An example of the Heck reaction
An example of the Heck reaction

Examples of the Heck reaction

Precautions

Please consult the Safety Data Sheet for information regarding hazards and safe handling practices.

Materials
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Applications

The Heck reaction is useful for the synthesis of:

  • Isomeric 2-aryl-2,5-dihydrofurans, via Heck coupling of aryl bromides with alkenes using neopentyl phosphine ligands. Use of DTBNpP (Di-tert-butylneopentylphosphine) provides high selectivity for 2-aryl-2,3-dihydrofuran while TNpP (trineopentylphosphine) provided high selectivity for the isomeric 2-aryl-2,5-dihydrofuran. Bis(dibenzylideneacetone)palladium(0) (Pd(dba)2) was employed as catalyst.5

    Scheme of the above syntheses:
syntheses
  • Various γ-keto acid derivatives, useful compounds in organic synthesis. Heck coupling reaction of pthalides with different alkenes using Pd(Ac)2 (Palladium(II) acetate) catalyst and TEA (Triethylamine) in dioxane solvent.6

    Scheme of the above synthesis:
syntheses
  • Indolines, biologically significant compounds of considerable importance in synthetic chemistry.7
  • Variety of ortho-trifluoroethyl-substituted styrenes.8
  • Chromenone derivatives such as flavones and neoflavones.9
  • Styrene derivatives.10
  • Bioactive natural products, drugs and functional materials.11
  • Taxol®, a mitotic inhibitor used in cancer chemotherapy; Singulair®, an asthma drug; the herbicide prosulfuron, and Cyclotene®, a monomer for high performance electronic resins.12

Recent Research and Trends

  • Neopentyl phosphine ligands were investigated for promoting the Heck coupling of aryl bromides with alkenes.5
  • Asymmetric Mizoroki−Heck reactions of benzyl electrophiles using a new phosphoramidite as an effective chiral ligand have been reported. Heck reaction of benzyl trifluoroacetate and 2,3-dihydrofuran phosphoramidite ligand affords 2-benzyl-2,5-dihydrofuran as major product in good yield and excellent stereoselectivity.11
  • Scheme of the above synthesis:
Asymmetric Mizoroki Heck Reactions

Asymmetric Mizoroki Heck Reactions

  • Dichloro{bis[1,1',1''-(phosphinetriyl)tripiperidine]}palladium [(P(NC5H10)3)2Pd(Cl)2] has been reported as a cheap, air stable, but highly active catalyst with an excellent functional group tolerance for Heck reactions.12
  • Palladium (Pd)-catalyzed endo-selective Heck reaction of iodomethylsilyl ethers of phenols and aliphatic alkenols has been reported.13
  • The mechanism of the redox-relay Heck reaction has been studied using deuterium-labeled substrates.14
  • Organic cyclic carbonates have been proposed as suitable greener solvents for use in Heck reactions. They are effective alternatives to traditionally used dipolar aprotic solvents that are associated with high toxicity and risk.15
  • Dehydrogenative Heck reaction controlled by redox process of ferrocene affords planar-chiral ferrocene derivatives with excellent enantioselectivity.16
  • Two novel complexes of Pd(II) and Cu(II) with a simple bidentate ligand, 2-(2′-hydroxyphenyl)-5,6-dihydro-1,3-oxazine, have been prepared. These complexes were reported to efficiently catalyze the Heck reaction of aryl halides with olefins at 120 °C.17
  • Phosphine-free palladium-catalyzed Mizoroki–Heck reaction using ball-milling in polyethylene glycol under mild conditions affords excellent yields of coupling products.18

References

1.
Biffis A, Zecca M, Basato M. 2001. Palladium metal catalysts in Heck C?C coupling reactions. Journal of Molecular Catalysis A: Chemical. 173(1-2):249-274. http://dx.doi.org/10.1016/s1381-1169(01)00153-4
2.
Li JJ. 2009. Name Reactions. http://dx.doi.org/10.1007/978-3-642-01053-8
3.
Oestreich M. 2009. The Mizoroki?Heck Reaction. http://dx.doi.org/10.1002/9780470716076
4.
Ruan J, Xiao J. 2011. From ?-Arylation of Olefins to Acylation with Aldehydes: A Journey in Regiocontrol of the Heck Reaction. Acc. Chem. Res.. 44(8):614-626. http://dx.doi.org/10.1021/ar200053d
5.
Lauer MG, Thompson MK, Shaughnessy KH. 2014. Controlling Olefin Isomerization in the Heck Reaction with Neopentyl Phosphine Ligands. J. Org. Chem.. 79(22):10837-10848. http://dx.doi.org/10.1021/jo501840u
6.
Shashikumar ND, Krishnamurthy G, Bhojyanaik HS. 2014. A Facile Synthesis of Novel Cyclic Esters of ?-Keto Acid Derivatives by Heck Coupling Reaction. J. Heterocyclic Chem.. 51(S1):E354-E357. http://dx.doi.org/10.1002/jhet.1898
7.
Zheng H, Zhu Y, Shi Y. 2014. Palladium(0)-Catalyzed Heck Reaction/C?H Activation/Amination Sequence with Diaziridinone: A Facile Approach to Indolines. Angew. Chem.. 126(42):11462-11466. http://dx.doi.org/10.1002/ange.201405365
8.
Zhang H, Chen P, Liu G. 2014. Palladium-Catalyzed Cascade C?H Trifluoroethylation of Aryl Iodides and Heck Reaction: Efficient Synthesis ofortho-Trifluoroethylstyrenes. Angew. Chem. Int. Ed.. 53(38):10174-10178. http://dx.doi.org/10.1002/anie.201403793
9.
Khoobi M, Alipour M, Zarei S, Jafarpour F, Shafiee A. 2012. A facile route to flavone and neoflavone backbones via a regioselective palladium catalyzed oxidative Heck reaction. Chem. Commun.. 48(24):2985. http://dx.doi.org/10.1039/c2cc18150a
10.
Shirakawa E, Zhang X, Hayashi T. 2011. Mizoroki-Heck-Type Reaction Mediated by Potassium tert-Butoxide. Angew. Chem.. 123(20):4767-4770. http://dx.doi.org/10.1002/ange.201008220
11.
Yang Z, Zhou J(. 2012. Palladium-Catalyzed, Asymmetric Mizoroki?Heck Reaction of Benzylic Electrophiles Using Phosphoramidites as Chiral Ligands. J. Am. Chem. Soc.. 134(29):11833-11835. http://dx.doi.org/10.1021/ja304099j
12.
Oberholzer M, Frech CM. Mizoroki-Heck Cross-coupling Reactions Catalyzed by Dichloro{bis[1,1',1''-(phosphinetriyl)tripiperidine]}palladium Under Mild Reaction Conditions. JoVE.(85): http://dx.doi.org/10.3791/51444
13.
Parasram M, Iaroshenko VO, Gevorgyan V. 2014. Endo-Selective Pd-Catalyzed Silyl Methyl Heck Reaction. J. Am. Chem. Soc.. 136(52):17926-17929. http://dx.doi.org/10.1021/ja5104525
14.
Hilton MJ, Xu L, Norrby P, Wu Y, Wiest O, Sigman MS. 2014. Investigating the Nature of Palladium Chain-Walking in the Enantioselective Redox-Relay Heck Reaction of Alkenyl Alcohols. J. Org. Chem.. 79(24):11841-11850. http://dx.doi.org/10.1021/jo501813d
15.
Parker HL, Sherwood J, Hunt AJ, Clark JH. 2014. Cyclic Carbonates as Green Alternative Solvents for the Heck Reaction. ACS Sustainable Chem. Eng.. 2(7):1739-1742. http://dx.doi.org/10.1021/sc5002287
16.
Pi C, Li Y, Cui X, Zhang H, Han Y, Wu Y. 2013. Redox of ferrocene controlled asymmetric dehydrogenative Heck reaction via palladium-catalyzed dual C?H bond activation. Chem. Sci.. 4(6):2675. http://dx.doi.org/10.1039/c3sc50577d
17.
Bagherzadeh M, Amini M, Ellern A, Keith Woo L. 2012. Palladium and copper complexes with oxygen?nitrogen mixed donors as efficient catalysts for the Heck reaction. Inorganica Chimica Acta. 38346-51. http://dx.doi.org/10.1016/j.ica.2011.10.040
18.
Declerck V, Colacino E, Bantreil X, Martinez J, Lamaty F. 2012. Poly(ethylene glycol) as reaction medium for mild Mizoroki?Heck reaction in a ball-mill. Chem. Commun.. 48(96):11778. http://dx.doi.org/10.1039/c2cc36286d

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