Decarboxylative cross coupling reactions are chemical reactions in which a carboxylic acid is reacted with an organic halide to form a new carbon-carbon bond, concomitant with loss of CO2. Aryl and alkyl halides participate. Metal catalyst, base, and oxidant are required.
A significant advantage of this reaction is that it uses relatively inexpensive carboxylic acids (or their salts) and is far less air and moisture sensitive in comparison to typical cross-coupling organometallic reagents. Furthermore, the carboxylic acid moiety is a common feature of natural products and can also be prepared by relatively benign air oxidations. Additional benefits include the broad tolerance of functional groups, as well as the capacity to avoid the use of strong bases. An important elementary step in this reaction is protodecarboxylation or metalation to first convert the C–COOH bond to a C–H or C–M bond respectively. Shang R, Liu, L. Transition metal-catalyzed decarboxylative cross-coupling reactions. Science China-Chemistry, 2011, 11, 54: 1670–1687 DOI: 10.1007/s11426-011-4381-0
History and catalyst development
Copper monometallic systems The first reported decarboxylative cross coupling reaction was an Ullmann reaction, in 1966 by Nilsson et al. Thermal decarboxylation of copper benzoates, in the presence of an aryl halide, was found to produce (both symmetric and unsymmetric) biaryls through aryl-Cu intermediates.Nilsson M. A new biaryl synthesis illustrating a connection between the Ullmann biaryl synthesis and copper-catalyzed decarboxylation. Acta Chem Scand, 1966, 20: 423–426. DOI: 10.3891/acta.chem.scand.20-0423
This monometallic copper system required drastic conditions for complete cross-coupling, and had various intrinsic limitations, both of which prevented development of a catalytic, preparatory version of this reaction.Rodríguez N, Goossen L. Decarboxylative coupling reactions: a modern strategy for C–C-bond formation. Chem Soc Rev, 2011, 40:5030–5048. DOI: 10.1039/C1CS15093F It was not until 2009 that Liu and Shang et al. found that decarboxylative cross-coupling of aryl bromides and iodides with potassium polyfluorobenzoates could be achieved using monometallic copper iodide as a catalyst. The oxidative addition step was determined to be the rate-limiting step in the copper-only catalyst cycle (a contrast with Pd-catalyzed decarboxylative cross-coupling).Shang R, Fu Y, Wang Y, Xu Q, Yu HZ, Liu L. Copper-catalyzed decarboxylative cross-coupling of potassium polyfluorobenzoates with aryl iodides and bromides. Angew Chem Int Ed, 2009, 48: 9350–9354. DOI:10.1002/anie.200904916
Cu(I)-only systems have also been found to promote coupling of alkynyl carboxylic acids with aryl halides (see aryl alkynes below), as well as decarboxylative dehydrogenative cross-coupling of amino acids with alkynes (or similar nucleophiles).Shang R, Fu Y, Li JB, Zhang SL, Guo QX, Liu L. Synthesis of aromatic esters via Pd-catalyzed decarboxylative coupling of potassium oxalate monoesters with aryl bromides and chlorides. J Am Chem Soc, 2009, 131: 5738–5739 DOI: 10.1021/ja900984xBi HP, Zhao L, Liang YM, Li CJ. The copper-catalyzed decarboxylative coupling of the sp3–hybridized carbon atoms of α-amino acids. Angew Chem Int Ed, 2009, 48: 792–795 DOI: 10.1002/anie.200805122
Catalysts for decarboxylative cross-coupling are of the general form ML2, with a wide variety of ligand types optimized for different substrates. Copper (and silver) centers are often complexed with phenanthrolines, and activity is reported to increase with electron-rich substituents on the ligands.
Palladium monometallic systems In 2000, Steglich et al. reported an intramolecular Pd(II)-mediated decarboxylative cross-coupling reaction in their synthesis of lamellarin L.Peschko C, Winklhofer C, Steglich W. Biomimetic total synthesis of lamellarin l by coupling of two different arylpyruvic acid units. Chem Eur J, 2000, 6: 1147–52 DOI: 10.1002/(SICI)1521-3765(20000403)6:7<1147::AID-CHEM1147>3.0.CO;2-1 Myers et al. reported decarboxylative olefination of ortho-substituted arene carboxylates in the presence of an oxidant (Ag2CO3) in 2002.Myers AG, Tanaka D, Mannion MR. Development of a decarboxylative palladation reaction and its use in a Heck-type olefination of arene carboxylates. J Am Chem Soc, 2002, 124: 11250–51 DOI: 10.1021/ja027523m
Subsequent studies showed that homogeneous Pd catalysts were able to decarboxylate acids at lower temperatures than their Cu and Ag counterparts, but were limited to electron rich ortho-substituted aromatic carboxylic acids.Dickstein JS, Mulrooney CA, O’Brien EM, Morgan BJ, Kozlowski MC. Development of a catalytic aromatic decarboxylation reaction. Org Lett, 2007, 9: 2441–44 DOI: 10.1021/ol070749fMeyers et al. On the Mechanism of the Palladium(II)-Catalyzed Decarboxylative Olefination of Arene Carboxylic Acids. Crystallographic Characterization of Non-Phosphine Palladium(II) Intermediates and Observation of Their Stepwise Transformation in Heck-like Processes JACS, 2005, 127, 10323–33 DOI: 10.1021/ja052099l Despite this, palladium catalysts are able to promote a wide variety of cross-coupling reactions including biaryl formation and aryl alkyne formation, along with a variety of cross-coupling reactions in which the carboxylic acid is not bonded to an aromatic.Zhang WW, Zhang XG, Li JH. Palladium-catalyzed decarboxylative coupling of alkynyl carboxylic acids with benzyl halides or aryl halides. J Org Chem, 2010, 75: 5259–5264 DOI: 10.1021/jo1010284Yeung PY, Chung KH, Kwong FY. Palladium-catalyzed decarboxylative arylation of potassium cyanoacetate: Synthesis of α-diaryl nitriles from aryl halides. Org Lett, 2011, 13: 2912–15 DOI: 10.1021/ol2009522 Other Pd-catalyzed decarboxylation cross-coupling reactions include conjugated diene preparation (see dienes and trienes below) and dehydrogenative reactions (with a variety of substrate and catalyst combinations).Yamashita M, Hirano K, Satoh T, Miura M. Synthesis of α,ω-diarylbutadienes and hexatrienes via decarboxylative coupling of cinnamic acids with vinyl bromides under palladium catalysis. Org Lett, 2010, 12: 592–95 DOI: 10.1021/ol9027896
Contrarily to Cu-only systems, decarboxylative palladation is the rate-limiting step in the palladium catalytic cycle.
Palladium-–copper bimetallic systems A Pd–Cu bimetallic system was not discovered until 2006 when Goossen et al. reported a decarboxylative cross-coupling of aryl halides with ortho-substituted aromatic carboxylic acids.Goossen LJ, Deng GJ, Levy LM. Synthesis of biaryls via catalytic decarboxylative coupling. Science, 2006, 313: 662–64 DOI: 10.1126/science.1128684 Through subsequent studies it was found that the use of aryl triflates allowed substrate scope for cross-coupling to be extended to some aromatic carboxylates lacking any ortho-substitution (less reactive). This was a result of the fact that any halide anion generated in the reaction inhibited the Cu-catalyzed decarboxylation process.Goossen LJ, Rodriǵ uez N, Linder C. Decarboxylative biaryl synthesis from aromatic carboxylates and aryl triflates. J Am Chem Soc, 2008, 130: 15248–49 DOI: 10.1021/ja8050926 Further optimization of the system and catalyst conditions has made decarboxylative cross-coupling using bimetallic Pd–Cu systems applicable to organic synthesis, most predominantly in the formation of biaryls. As well, the variability of this combined catalytic system allows for promotion of a large spectrum of reactions, including aryl ketone formation, c-heteroatom cross-coupling, and many others.
Palladium–silver bimetallic systems Silver being in the same group as copper, Pd–Ag(I) bimetallic systems are inherently similar to Pd–Cu catalytic systems. However, silver salts are better suited for protodecarboxylation of carboxylic acids than their copper equivalents, allowing milder reaction conditions in Pd–Ag cycles relative to Pd–Cu cycles.Goossen LJ, Rodríguez N, Linder C, Lange PP, Fromm A. Comparative study of copper- and silver-catalyzed protodecarboxylations of carboxylic acids. ChemCatChem, 2010, 2: 430–42 DOI: 10.1002/cctc.200900277 Ag(I) catalyzed monometallic systems have also been reported. Their proficiency (relative to copper) is likely attributed to lower electronegativity and greater expansion of d-orbitals, which promote decarboxylation of the substrate.Lu P, Sanchez C, Cornella J, Larrosa I. Silver-catalyzed protodecarboxylation of heteroaromatic carboxylic acids. Org Lett, 2009, 11: 5710–5713 DOI:10.1021/ol902482p One limitation of this catalyst combination is that the silver salts will form insoluble silver halides, forcing the reaction to require a stoichiometric amount of Ag if halides are present. This obstacle was overcome by Goossen et al. in 2010 by using aryl triflates, and catalytic reaction with aryl sulfonates has also been reported.Goossen LJ, Lange PP, Rodríguez N, Linder C. Low-temperature Ag/Pd-catalyzed decarboxylative cross-coupling of aryl triflates with aromatic carboxylate salts. Chem Eur J, 2010, 16: 3906–09 DOI: 10.1002/chem.200903319
Product scope via variation of substrates The product scope of this reaction is extremely broad with the use of different substrates; however development of different functionalities has required accompanied studies to determine the proper catalyst system. The most typical class of reactions involves coupling between C–COOH and C–X bonds, however C–COOH and C–M cross-coupling, homo-coupling of carboxylic acids, heck coupling, and dehydrogenative cross-coupling can also be including in this class as they release CO2. Heteroatom cross coupling reactions involving formation of C–N, C–S, C–P, and C–X bonds have also been demonstrated.
Biaryl formation Per IUPAC, the term biaryl refers to an assembly of two aromatic rings joined by a single bond, starting with the simplest, biphenyl. Biaryls constitute an important structural motif of physical organic, synthetic, and catalytic interest—for instance, underlying the area of atropisomers in enantioselective synthesis—and they appear in many pharmaceutical, agrochemical, and materials (e.g. LCD) applications. The example of a coupling reaction reaction used in their preparation is an alternative to the traditional Suzuki and Stille cross-coupling reactions, and various catalysts have been employed for this transformation; Goossen et al. reported the formation of biaryls from palladium and copper-catalzyed cross-coupling reactions of an aryl or heteroaryl carboxylic acid and an aryl halide (I, Br, or Cl) in the presence of a base.Goossen LJ, Rodríguez N, Melzer B, Linder C, Deng GJ, Levy LM. Biaryl synthesis via Pd-catalyzed decarboxylative coupling of aromatic carboxylates with aryl halides. J Am Chem Soc, 2007, 129: 4824–33 DOI: 10.1021/ja068993+
Aryl alkynes Aryl alkynes are typically made utilizing the Sonogashira reaction which is the palladium catalyzed cross-coupling reaction of terminal alkynes and aryl halides. Instead of the terminal alkynes, alkyne carboxylic acids has advantages, easy handling and storage. The first decarboxylative coupling of alkyne carboxylic acids was reported in 2008 by S. Lee. They employed propiolic acid as an alkyne source. One year later, S. Lee applied the decarboxylative coupling reactions toward 2-octynoic acid and phenylpropiolic acid. In 2010, Xue et al. reported the coupling of an aryl halide and alkynyl carboxylic acid under mild reactions conditions and a copper-only catalyst to obtain aryl alkynes.
Park, K. Lee, S. Transition metal-catalyzed decarboxylative coupling reactions of alkynyl carboxylic acids RSC Advances 2013, 3: 14165-14182 DOI: 10.1039/C3RA41442F Moon, J. Jeong, M. Nam, H. Ju, J. Moon, J. H. Jung H. M. Lee, S. One-Pot Synthesis of Diarylalkynes Using Palladium-Catalyzed Sonogashira Reaction and Decarboxylative Coupling of sp Carbon and sp2 Carbon Org. Lett., 2008, 10: 945–948. DOI: 10.1021/ol703130y