Suzuki and Related Cross-Coupling Reactions

Cross-coupling reactions, and the Suzuki reaction in particular, are  among widely used synthetic methods for creating new C-C bonds to form more complex molecules from smaller molecule.  In the Suzuki reaction, or Suzuki–Miyaura reaction, an organoboron compound and an organohalide are cross-coupled in the presence of a base using a palladium complex as a catalyst. The reaction is used in the pharmaceutical industry to link, for example, aromatic ring structures to create more complex intermediate compounds used in API synthesis. Related coupling reactions include Negishi and Heck, which also use transition metals complexes as catalysts in cross coupled reactions.  The Negishi reaction couples organohalides with organozinc compounds to form C-C bonds, while the Heck reaction uses a palladium catalyst to couple an unsaturated halide with an alkene, forming a substituted alkene. 

There are a number of other reactions that form C-C bonds in cross-coupled products.  In Kumada-Corriu coupling, a Grignard reagent, and an organic halide are coupled using palladium or nickel. The Sonogashira reaction uses a palladium catalyst and a copper co-catalyst to cross couple an alkyne and an aryl or vinyl halide.  

Generally, commonly used cross-coupling reactions can be classified as either catalyzed reactions or non-catalyzed.  Catalyzed cross-coupling reactions typically use a transition metal such as palladium, zinc, nickel complexed with a variety of ligands. The Grignard reaction is an example of a non-catalyzed C-C bond forming synthesis.

Catalyzed cross-coupling reactions include:

• Suzuki–Miyaura – Couples boronic acids, boron esters, borane with alkyl or aryl halides
• Negishi – Couples organozinc compounds with organohalides
• Heck – Couples unsaturated halide with an alkene
• Kumada-Corriu – Couples Grignard reagent with organohalides
• Stille – Couples organic halides with organotin compounds 
• Sonogashira – Couples terminal alkyne and an aryl or vinyl halide.
• Hayashi-Miyaura - couples bis(pinacolato)diboron (B2pin2) with aryl halides and vinyl halides

In the Suzuki - or Suzuki–Miyaura - reaction, an organoboronic acid and an organohalide are cross-coupled using a palladium complex as a catalyst in the presence of a base. The reaction is used in the pharmaceutical industry to link, for example, aromatic ring structures to create more complex intermediate compounds used in API synthesis.

There are three basic processes that occur in a Suzuki coupling reaction. In the first step, a Pd(II) intermediate compound is formed via oxidative addition of a Pd(0) complex by an aryl halide species. Next, in the presence of a base, the organoborane compound reacts with the Pd(II) intermediate species and forms a second intermediate complex via transmetalation. Finally, the product is formed via reductive elimination and the original Pd(0) complex is reestablished. 

Cross-coupl reactions are among the most proinglifically used methods to achieve C-C bonding as well as C-H, C-N, C-O, etc bond formation.  For this reason, cross coupling reactions are important in pharmaceutical, polymer, and natural synthesis applications. In the case of the widely adapted Suzuki reaction, there are numerous advantages of this synthesis method:

• Mild reaction conditions with good yields
• Stable in air and water
• Low toxicity; supports “green” chemistry
• Useful with a broad range of functional groups
• High reaction stereoselectivity
• Can readily be used in telescoped reactions 
• Wide diversity of available organoboron compounds
• Palladium complexes available with an array of ligands 

The Heck reaction is important in commercial applications as well. As examples, the pharmaceuticals montelukast (Asthma), naproxen (NSAID), eletriptan (migraines), and rilpivirine (HIV) all used Heck reactions in their synthesis. The Sonogashira reactions was used in the synthesis of terbinafine (fungicide). The Negishi reaction in not typically used for large scale synthesis due to the toxicity associated with stannanes and water/oxygen sensitivity, but it has proven very useful in natural product synthesis. 

Part of the reason for the ever-widening scope of Suzuki coupling and related reactions is the expanding research, development and availability of novel organoboron compounds and transition metal catalyst complexes.   In situ vibrational is providing important information in the synthesis of these reagents and catalysts with regard to activity and structure, such as how ligands are bonded.    Furthermore intermediates that form during coupling reactions are observed and identified by in situ vibrational spectroscopy.   In process development and scale-up,  investigating the effect of reaction variables such as temperature, dosing rate and stirring on coupling reactions lead to optimized syntheses.

For these reasons, ReactIR and ReactRaman in situ vibrational spectroscopy are valuable tools in the study of Suzuki and related coupling reactions.  Also, to ensure process safety and to support studies on the effect of reaction variables, EasyMax and EasyMax HFCal are important in quantifying reaction kinetics and thermodynamics.  In situations where reaction samples are required for offline testing,  EasySampler provides unattended, automated sample removal, and dilution - without disturbing the reaction.

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The authors report the use of Grignard reagents (RMgX) generated in situ from Knochel-Hauser derivative arylmagnesium halides TMPMgCl•LiCl and TMP2Mg•2LiCl in a telescoped Kumada-Corriu C-C coupling of heterocycles with iodo- or bromobenzene compounds.  This rapid reaction is performed under mild conditions, including  ambient temperatures, and is an effective alternative to transmetalation with zinc salts under Negishi coupling conditions. 

ReactIR tracked the deprotonation of a pyrazolopiperidine compound to form a metallo-pyrazolopiperidine intermediate and showed that this intermediate compound had good stability over a 14 hour period.  ReactIR then was used to track the conversion of the intermediate to the Kumada-Corriu coupled product compound.  The in situ FTIR information indicated that both the deprotonation and the coupling is occurs rapidly.

Kyle Clagg, Sara Hold, Archana Kumar, Stefan G. Koeniga, Remy Angelaud, “A Telescoped Knochel-Hauser / Kumada-Corriu Coupling Strategy to Functionalized Aromatic Heterocycles”, Tetra. Let.,  2019,  60(1), 5-7

The authors investigated safety hazards resulting from Suzuki−Miyaura cross-coupling of aryl bromides with vinylboron compounds.  Specifically, the thermal profile recorded for the cross-coupling of 1-bromo-3-(trifluoromethyl)benzene with potassium vinyltrifluoroborate under specific conditions revealed a significant exotherm upon the addition of catalytic 1,1′-bis(diphenylphosphino)ferrocene palladium(II) dichloride [Pd(dppf)Cl2].  Via calorimetric investigation with EasyMax, they determined that both the reaction rate and the exotherm were greater in aqueous systems relative to anhydrous conditions, but that even in the absence of water, the exotherm size and rate was highly dependent on reactants, reagents, solvents and catalysts.  In some cases the maximum temperature of the reaction was greater than boiling point of the solvent or conducive to reaction mixture decomposition.

Further investigations into the specific source of the exotherm were performed.  In earlier work, it was shown that polymerization of the styrene products can be related to exotherms.  To determine if polymerization might be the cause, ReactIR measurements were employed to track the consumption of starting material after the Pd(dppf)Cl2 was added and this was found to correlate with the observed heat conversion.  The mixture was then held under the reaction conditions for an extended period and ReactIR tracking showed no product polymerization, eliminating that potential cause.

Qiang Yang, Belgin Canturk, Kaitlyn Gray, Elizabeth McCusker, Min Sheng, and Fangzheng Li, Organic Process Research & Development 2018 22 (3), 351-359

The authors report the use of in situ FTIR spectroscopy in optimizing the Heck-Matsuda reaction, a palladium catalyzed synthesis that cross couples olefins with aryl groups.  In contrast to reactions that use alkyl halides, the Heck-Matsuda reaction uses arene diazonium salts that are reacted with the respective olefins.  These reactions are performed under mild reaction conditions, however insufficient monitoring of  diazonium salt formation can lead to safety issues.  Thus, the ReactIR tracks the telescoped reaction in which the arene diazonium salt is synthesized in situ, followed by addition of the olefin and palladium acetate catalyst to form the coupled product.  IR bands at 1020 cm-1 (C-O) and 1640 cm-1 (C=C) were assigned to the palladium complex Upon addition of water, those bands disappeared and a new band at 1740 cm-1 (C=O) appeared, indicating that the alkene-palladium complex was transformed to the aldehyde product via keto enol tautomerization.

K. Sateesh Reddy, Bandi Siva, S. Divya Reddy, N. Reddy Naresh, T. V. Pratap, B. Venkateswara Rao, Yi-An Hong, B. Vijaya Kumar, A. Krishnam Raju, P. Muralidhar Reddy, Anren Hu, “In Situ FTIR Spectroscopic Monitoring of the Formation of the Arene Diazonium Salts and Its Applications to the Heck–Matsuda Reaction”, Molecules 2020, 25, 2199

Erran Song, Jiong Wang, Tiesheng Li, Wuduo Zhao Minghua Liu, Yangjie, Wu, “Novel ordered cyclopalladated aryl imine monolayers—Structure Designing for Enhancing Catalytic Performance”, Molecular Catalysis, 2020, 482, 110671

K. Sateesh Reddy, Bandi Siva, S. Divya Reddy, N. Reddy Naresh, T. V. Pratap, B. Venkateswara Rao, Yi-An Hong, B. Vijaya Kumar, A. Krishnam Raju, P. Muralidhar Reddy, Anren Hu, “In Situ FTIR Spectroscopic Monitoring of the Formation of the Arene Diazonium Salts and Its Applications to the Heck–Matsuda Reaction”, Molecules 2020, 25, 2199

 Matelienė (née Dauksaîtė), Jan Knaup, Frank von Horsten, Xiaoting Gu, Heiko Brunner,“Benign Arylations of Dimethyl Itaconate via Heck–Matsuda Reaction Utilizing in‐Situ Generated Palladium on Aluminum Oxide”, EurJOC, 2020, 1, 127-135

Pingping Huang, Erran Song, Yimeng Sun, Tiesheng Li, Donghui Wei, Minghua Liu, Yangjie Wu, “Schiff-based Pd(II)/Fe(III) bimetallic self-assembly monolayer---preparation, structure, catalytic dynamic and synergistic, Molecular Catalysis, 2019, 469, 75-86

Qiang Yang, Nicholas R. Babij, Steffen Good, “Potential Safety Hazards Associated with Pd-Catalyzed Cross-Coupling Reactions”, Org. Process Res. Dev. 2019, 23, 12,  2608–2626

 Weili Shang, Xiangfeng Zeng, Tiesheng Li, Wenjian Xu, Donghui Wei, Minghua Liu, Yangjie Wu“Controlled distribution of active centre to enhance catalytic activity of ordered Pd/Co catalytic nano-monolayer”, J. Catalysis, 2019, 376, 228-237

 Qiang Yang, Neeraj Sane, Daniel Klosowski, Melissa Lee, Tay Rosenthal, Nick X. Wang, Eric Wiensch, “Mizoroki–Heck Cross-Coupling of Bromobenzenes with Styrenes: Another Example of Pd-Catalyzed Cross-Coupling with Potential Safety Hazards”, Org. Process Res. Dev. 2019, 23, 10, 2148–2156

 Kyle Clagg, Sara Hold, Archana Kumar, Stefan G. Koeniga, Remy Angelaud, “A Telescoped Knochel-Hauser / Kumada-Corriu Coupling Strategy to Functionalized Aromatic Heterocycles”, Tetra. Let., 2019,  60(1), 5-7

 Satoshi Nakane, Sho Yoshinaka, Shoutaro Iwase, Yoshihiro Shuto, Paul Bunse, Bernhard Wunsch, Shinji Tanaka, Masato Kitamura, “Synthesis of fluspidine via asymmetric NaBH4 reduction of silicon enolates of β-keto esters”, Tetrahedron 2018, 74(38), 5069-5084

 Qiang Yang, Belgin Canturk, Kaitlyn Gray, Elizabeth McCusker, Min Sheng, Fangzheng Li, “Evaluation of Potential Safety Hazards Associated with the Suzuki− Miyaura Cross-Coupling of Aryl Bromides with Vinylboron Species”,  Org. Process Res. Dev. 2018, 22, 351−359

Indrek Kalvet, Gulliaume Magnin, Franziska Schoenebeck, “Rapid Room-Temperature, Chemoselective Csp2  - Csp2  Coupling of Poly(pseudo)halogenated Arenes Enabled by Palladium(I) Catalysis in Air”, Angew. Chem. Int. Ed. , 2017, 56, 1581-1585

 Jesús A. Molina de la Torre, Ana C. Albéniz, “α-Diimine–Palladium Complexes Incorporated in Vinylic Addition Polynorbornenes: Synthesis and Catalytic Activity”, Eur. J. Inorg. Chem. 2017, 2911–2919

 Ziqian Xue, Pingping Huang, Tiesheng Li, Pengxiao Qin, Dan Xiao, Minghua Liu, Penglei Chen, Yangjie Wu, “A novel “tunnel-like” cyclopalladated arylimine catalyst immobilized on graphene oxide nano-sheet”, Nanoscale, 2017, 9, 781

 Jesús A. Molina de la Torre, Ana C. Albéniz, “Vinylic Addition Polynorbornene as a Support for N-Heterocyclic Carbene Palladium Complexes: Catalytic Activity in C–C Cross– Coupling Reactions”, ChemCatChem, 2016, 8(13), 2241–2248

Chengxi Li, Tianyu Chen, Bowen Li, Guolan Xiao, Wenjun Tang, “Efficient Synthesis of Sterically Hindered Arenes Bearing Acyclic Secondary Alkyl Groups by Suzuki–Miyaura Cross‐Couplings”, Angew. Chem, 2015, 54(12), 3792-3796

 Josep Llaveria, Daniele Leonori ,Varinder K. Aggarwal, “Stereospecific Coupling of Boronic Esters with N-Heteroaromatic Compounds”, J. Am. Chem. Soc. 2015, 137(34), 10958–10961

 Chengxi Li, Guolan Xiao, Qing Zhao, Huimin Liu, Tao Wang, and Wenjun Tang, ” Sterically Demanding Aryl-Alkyl Suzuki-Miyaura Coupling”, Org. Chem. Front., 2014, 1, 225-229

 Ciril Jimeno, Ute Christmann, Eduardo C. Escudero-Adn, Ramon Vilar, Miquel A. Perics, “Studies on the Amination of Aryl Chlorides with a Monoligated Palladium Catalyst: Kinetic Evidence for a Cooperative Mechanism”,  Chem. Eur. J. 2012, 18, 16510 – 16516

 A. Stephen K. Hashmi, Christian Lothschütz, Constantin Böhling, Frank Rominger, “From Isonitriles to Carbenes: Synthesis of New NAC− and NHC−Palladium(II) Compounds and Their Catalytic Activity”, Organometallics 2011, 30(8), 2411–2417