Dedicated to Prof. Günter Helmchen on the occasion of his 81st birthday
1
Introduction
Cross-coupling reactions, which traditionally involve transition metals, are one of
the most significant chemical processes in synthetic organic chemistry.[1]
[2]
[3]
[4] A cross-coupling reaction is specified as the substitution process of alkyl, vinyl,
and aryl halides or pseudohalides by carbon as well heteroatom-based nucleophiles
under transition-metal (TM) catalysis, leading to the efficient construction of new
C–C and C–X (X = hetero atoms) bonds. Often, an electrophile (e.g., halide) and a
nucleophile (e.g., organometallic regent) serve as coupling partners, forming new
chemical bonds with the loss of activating groups. These routes are considered an
important synthetic tool in various domains of chemistry to prepare a wide range of
organic molecules, ranging from natural and unnatural products of biological relevance
to novel organic materials. Almost for two decades, cross-coupling reactions have
had a significant influence on drug discovery and medicinal chemistry.[5–7] Expanding the spectrum of coupling partners is one of the primary research aims
in the cross-coupling field. For example, an organoborane nucleophile is used in the
Suzuki–Miyaura reaction;[8,9] whereas the Stille reaction employs an organotin nucleophile.[10]
[11]
[12] The significant contribution to palladium cross-coupling reactions was acknowledged
in 2010 with the award of the Nobel Prize in chemistry.[13,14] Over the years, several attempts have been made to activate a substrate with a single
transition metal catalyst to enable a specific transformation. For example, palladium–phosphine-based
complexes, are frequently used in cross-coupling reactions owing to their conventional
oxidative addition, facilitating coupling, and reductive elimination catalytic cycle
mechanism.[15–18]
Scheme 1 Selected examples of boryl-substituted monofluoroalkenes 4 via cis-borylfluoroallylation of alkynes 1
Scheme 2 Proposed mechanism for formation of monofluoroalkenes 4 via cis-borylfluoroallylation of alkynes 1
Scheme 3 Some selected examples of asymmetric alkene hydroalkenylation 12
Scheme 4 Some selected examples of asymmetric alkene hydroalkenylation of unactivated alkenes
to deliver 14 and plausible mechanism
Scheme 5 Selected examples of synthesizing skipped dienes 20 using synergetic Pd/Cu catalysis
Scheme 6 Plausible reaction mechanism for generating skipped dienes 20
For decades, expensive phosphine ligands have been designed with improved reactivity.
On the other hand, considerable attention has also been given to copper catalysis
in the field of cross-coupling reactions during the last decade, owing the low cost
of the catalysts, good functional group tolerance, high abundance, and low toxicity.[19]
[20]
[21]
[22]
[23]
[24]
[25] Besides which, copper plays a crucial role in cross-coupling reactions, and its
scope and practicality in the bond formation processes of C–N, C–O, C–P, and C–C bonds
has substantially grown. Most well-known catalytic processes use a single catalyst
to achieve the desired chemical transformation. On the other side, in a mono-catalytic
approach, one of the reactants is activated by the use of sub-stoichiometric quantities
of the catalyst, whereas the second reactant often needs an extra activation through
a stoichiometric quantity of an activating agent/pre-functional group manipulation
to facilitate the required transformation. Concerning environmental and economic aspects,
it is desirable to develop chemical processes that might improve the chemical utility
and efficiency of catalyst-driven reactions while reducing waste. Chemical space diversity
is generally limited to one-pot reactions catalysed by a single transition metal complex
in order to access a wide range of reactions in a single vessel.
Scheme 7 The C–2 arylation process to obtain azole derivatives 25 via Pd/Cu catalysis
Scheme 8 Plausible reaction mechanism for C2 arylation to give 27
[26]
[27]
[28]
[29]
[30] Thus, dual catalysis, where two catalysts can react with two substrates to produce
active intermediates, has become popular, allowing multi-transformation processes
with high regioselectivity.[31]
[32]
[33] Such types of catalytic systems provide more opportunities, not only because they
allow the successful delivery of a significant percentage of transformations in a
single step, but also allow tailoring of each catalytic cycle to produce selective
and divergent products. In particular, as a result of these factors, dual catalysis
has started to develop as a research methodology of considerable interest, among various
areas.[34]
[35]
[36]
[37] Of late, there has been a surge of interest in combining distinct types of catalysis
to enable novel chemical reactivity.[37]
[38]
[39]
[40]
[41]
[42] In that context, alternative catalytic approaches that go beyond the single-site
method might lead to the discovery of alternative reactivity and selectivity regimes.
Multicatalytic systems such as cascade catalysis (domino or tandem catalysis),[43]
[44] bifunctional catalysis,[45]
[46] double activation catalysis, and synergistic catalysis have been developed to date.[34]
[37]
,
[47]
[48]
[49] The use of dual-metal catalytic systems in the synthesis of new compounds has increased
significantly during the past twenty years.[50]
[51]
[52] In addition to improving selectivity and reactivity, these novel methods can also
greatly enhance the reaction processes that would not be feasible with a single metal
catalyst, enabling the synthesis of novel compounds and molecular frameworks. Synergistic
catalysis has often been studied by combining a transition metal catalyst with Lewis
acids,[53]
[54] organocatalysts (e.g., Brønsted acids, N-heterocyclic carbenes, chiral amines, and Lewis bases),[55]
[56]
[57]
[58]
[59]
[60]
[61]
[62]
[63]
[64]
[65]
[66]
[67] or Lewis acids with N-heterocyclic carbenes.[68]
[69]
[70] The use of bimetallic catalysts for cross-coupling reactions is one such alternate
strategy emphasized in this review.
2
Cu/Pd-Catalysed Bond Formation
2.1
Cu/Pd-Catalysed C(sp
3)–C(sp
2) Bond Formation
The research group of Gong and Fu has disclosed the synthesis of boryl-substituted
monofluoroalkenes 4 via cis-borofluoroallylation using Pd/Cu dual catalysis, involving alkynes 1, B2pin2
2, and gem-difluorocyclopropanes 3 as starting materials as shown in Scheme [1]. Remarkably, the reported method gives easy and quick entry to a wide array of borylated
monofluoroalkenes 4 with high regio- and stereoselectivities. Besides which, further studies were carried
out to validate the applicability of this three-component coupling reaction, and late-stage
transformations on complex molecules, such as δ-tocopherol, estrone, and canagliflozin derivatives, were examined. Furthermore, the
silylation-fluoroallylation process proceeded efficiently, yielding the appropriate
silyl monofluoroalkene product 4. Notably, the use of Cu catalysts allows for the simple insertion of Cu–B into triple
bonds via the intermediate LCuBpin. Concurrently, the use of palladium catalysts with
sterically hindered phosphine ligands favors the ring-opening coupling of gem-difluorinated cyclopropanes, followed by transmetallation and reductive elimination
to lead to the final monofluorinated alkenes 4 as shown in Scheme [2].[71]
Scheme 9 Regioselective direct C–H arylation of five-membered heterocycles 32–34 via Ru/Pd catalysis
Scheme 10 Stereodivergent synthesis of alkenyl pyridines 42/42′ via pyridinium salts 41
In another report, Buchwald et al. reported an asymmetric olefin hydroalkenylation approach that enables the fabrication
of various α-stereogenic olefins 12 and olefins 14 from easily accessible starting materials as depicted in Schemes 3 and 4.[72] This methodology has successfully coupled vinylarenes 11 and unactivated olefins 13 using CuH and Pd catalysis, from the easily accessible enol triflates 10 as coupling partners. This method made use of an in situ produced Cu(I)–alkyl species as well as readily accessible enol triflates. Notably,
the activated olefins such as vinylarenes successfully delivered the asymmetric Markovnikov
hydroalkenylation products 12 (Scheme [3]), whereas the anti-Markovnikov hydroalkenylation products 14 were obtained from unactivated olefins 13 (Scheme [4], left side); wherein the readily available enol triflates were utilized as alkenyl
coupling partners. The suggested synergism involves the CuH and Pd catalytic cycles
(Scheme [4], right side). Significantly, the combination of CuH and Pd catalysed reactions enabled
access to tri- and tetrasubstituted alkene classes 12 and 14 that are difficult to synthesize using conventional methods.
Mastrel and his research group have disclosed a three-component coupling reaction
involving alkynes 1, bis(pinacolato)diborane 2, and allyl carbonates 19 for the synthesis of skipped dienes using synergetic Cu/Pd catalysis via allylboration
of alkynes 1 and racemic allyl carbonates 19. Significantly, new C(sp
2)–B and C(sp
3)–C(sp
2) bonds are formed in a single operation as shown in Scheme [5].[73] The addition of a Cu–Bpin complex across the alkyne catalyses the generation of
a β-boryl-alkenylcopper species 22, which undergoes transmetallation with 23 to furnish the intermediate 24. Subsequently, intermediate 24 undergoes reductive elimination to result in the final product 20 as depicted in Scheme [6].
2.2
Cu/Pd-Catalysed C(sp
2)–C(sp
2) Bond Formation
Similarly, the research group of Piou and Slutskyy has demonstrated C2-arylation of
azole derivatives 25 using Pd/Cu dual catalytic systems. The optimization conditions revealed that a dual
catalytic system of Pd(OAc)2, PCy3·HBF4, and Cu(Phen)(PPh3)Br allowed the formation of the coupling products 27 in fair to excellent yields. In addition, the reaction has been explored with alternative
Cu co-catalysts, such as CuCl, CuBr, CuI, or Cu(NCMe)4PF6; however, these combinations resulted in poor yields. Using only 0.5–2 mol% of Pd
catalyst, this dual-catalytic approach showed high catalyst turnover. Furthermore,
control experiments showed that the Pd/Cu co-catalyst plays a crucial role to achieve
maximum reaction efficiency, as both metallic species take part in the reaction cycle.
The suggested mechanism involves a bimetallic catalytic system that operates simultaneously
with Pd(0) and Cu(I) species. A variety of aryl bromides 26 and azoles 25 were examined and found to be amenable as shown in Scheme [7].[74] The key step in the mechanism includes the Cu intermediate 29, which undergoes transmetallation with ArPd(II) complex 30 (generated via oxidative addition of Pd(0) to bromopyridine 26), and liberates the Cu(I) catalyst and 31. Subsequently, intermediate 31 undergoes reductive elimination to result in the final product 27 (Scheme [8]).
Brodnik et al. have reported a direct arylation strategy on thiophenes and furans 32 using aryl bromides 26 as coupling partners, under Ru(II)/Pd(0) dual catalysis. Notably, the reported method
was achieved regioselectively by carrying out the arylation reaction on thiophenes
32a–34a and furans 32b–34b in a sequential manner in a single flask, using nitrogen-based directing groups to
achieve a Ru-catalysed C3 arylation followed by a Pd-catalysed C5 arylation, resulting
in highly conjugated heterocycles 38–40 in excellent yields up to 93% (Scheme [9]). An initial investigation was carried out with quinolone-catalysed C3 arylations
on thiophene/furan derivatives. Following on from the Ru-catalysed functionalization,
Pd-catalysed arylation was investigated, which occurred at C5 of the five-membered
heterocycles. Subsequently, other azine compounds, such as isoquinoline and quinazoline
derivatives were investigated as directing groups. Consequently, isoquinoline derivative
33a was shown to be the most reactive, followed by the quinazoline 34a, with quinoline 32a as the least reactive substrate. Some selected examples are as illustrated in Scheme
[9].[75]
Fu, Chen, and co-workers disclosed the first example of the stereodivergent synthesis
of alkenylpyridines 42 using a Pd/Cu dual catalytic system through the activation of pyridinium salts 41 to alkenylate selectively at C2 of pyridines with internal alkynes 1. Significantly, the configuration of the resulting alkenylpyridines could be tuned
by choosing the appropriate N-alkyl groups of the pyridinium salts, enabling the synthesis of both Z- and E-alkenylpyridines 42 with high regio- and stereoselectivities (Scheme [10]). Notably, the Z-enriched alkenylpyridines 42 were selectively synthesized using N-methylpyridinium salts, whilst the E-enriched alkenylpyridines 42′ were favored using N-benzylpyridinium salts; reportedly due to the differing de-alkylation abilities of
the N-alkylpyridinium salts 41. Overall, this approach has a broad substrate scope, excellent functional group compatibility,
and is easily scalable. A plausible mechanism is depicted in Scheme [11].[76]
Scheme 11 Plausible reaction mechanism for constructing Z and E enriched alkenyl pyridines 42/42′
Scheme 12 Pd/Cu-catalysed cross-coupling of bromoarenes 26 and aryl(trialkyl)silanes 51. a Reaction at 120 °C; b PPh2(2-NMe2C6H4) was used instead of TTMPP; c XPhos was used instead of TTMPP, heated at 120 °C; d JohnPhos was used instead of TTMPP.
Minami, Hiyami et al. established a dual-metal catalytic system involving Pd/Cu catalysts for the cross-coupling
of bromoarenes 26 with aryl(trialkyl)silanes 51. Significantly, this method enabled the cross-coupling of various aryl(trialkyl)silanes
[e.g., trimethyl, triethyl, triisopropyl, and tert-butyldimethyl aryl silanes] with various aryl bromides 26 to deliver the anticipated coupling products 52. It was found the combination of CuF2, Pd2(dba)3/tris(2,4,6-trimethoxyphenyl)phosphine (TTMPP), and CsF in DMI at 100 °C, gave the
desired biaryl products 52 in excellent yields. Furthermore, a less reactive aryl chloride was also coupled
under the Pd/CuII catalysis, in the presence of the XPhos ligand, and yielded the corresponding product
in 78% yield (Scheme [12]).[77]
2.3
Cu/Pd-Catalysed C(sp)–C(sp
2) Bond Formation
Gandon, Roulland, et al. have reported the synthesis of E-1,3-enynes 55 in a stereoselective manner via alkyne hydrocarbation of allenes (AHA), using terminal
alkynes 54 and allenes 53 under Pd and Cu cooperative dual catalysis. Significantly, the E-1,3-enynes 55 are furnished with high regio-/stereoselectivities, good atomic economy, and high
yields. Based on DFT calculations and experimental observations, the authors suggested
a non-traditional but coherent process. It was proposed that a PdII/PdIV catalytic cycle is involved, as well as transition states tightly structured by H-bonds
with Pd counterions and an oxidative addition triggered by a stereodeterminant H+ transfer (Scheme [13]).[78]
2.4
Cu/Pd-Catalysed C(sp
3)–C(sp
3) Bond Formation
Scheme 13 Selected examples of the synthesis of (E)-1,3-enynes 55 and proposed mechanism
The asymmetric synthesis of products containing a quaternary stereocenter is a key
construct in organic synthesis. Moreover, such prevalent motifs are widely present
in bioactive natural substances. In 2021, Kleij et al. reported a dual metal-catalysed decarboxylative C(sp
3)–C(sp
3) bond-forming approach for the asymmetric synthesis of highly functionalized compounds
bearing quaternary carbon center from cyclic vinyl carbonates 63. In this protocol, the authors screened a broad range of ligands, bases, and chiral
diphosphine ligands, under the influence of different concentrations and reaction
temperatures to generate the cross-coupling products. The required Pd catalyst was
synthesized from (R)-3,5-iPr2-4-NMe2-MeOBIPHEP, which was proved to be effective to achieve good enantiomeric excess (ee), as depicted in Scheme [14].[79]
Scheme 14 Substrate scope for the synthesis of targets 63
2.5
Cu/Pd-Catalysed C–X (X = B, N, P, S, Si) Bond Formation
The research group of Qu and Chen has reported the synthesis of borylated 3,3-disubstituted
oxindoles 66 via domino cyclization/deborylation starting from 1,1-diborylmethane 65 and alkene-tethered carbamoyl chlorides 64 (Scheme [15], left side). Notably, the oxindole derivatives 66 with a C(sp
3)–B bond, could be used for further functionalization via the formation of new C–C
and C–X bonds. Since the products formed are versatile intermediates, they have been
further elaborated synthetically due to the presence of the C(sp
3)–B bond. Thus, transformations, such as halogenations (F, Br, and I), Cham–Lam coupling
with N-methylaniline, and treatment of oxindoles with vinylmagnesium bromide under I2, were successfully employed for late-stage transformations (Scheme [15], right side).[80] The mechanism for the formation of the borylated 3,3-oxindole derivatives 66 is shown in Scheme [16].
Scheme 15 Selected examples of borylated 3,3-disubstituted oxindole derivatives 66
Scheme 16 Plausible mechanism for the synthesis of borylated 3,3-disubstituted oxindoles 66
Scheme 17 Synthesis of phosphorated 2H-indazoles 74 using Cu/Pd cooperative catalysis
Lin et al. disclosed a protocol for the synthesis of phosphorated 2H-indazoles 74 via domino C–N and C–P bond formation using a Cu/Pd cooperative dual catalytic system,
involving 2-alkynyl azobenzenes 72 and diarylphosphine oxides or phosphonates 73 (Scheme [17]).[81] This method offered a practical approach to obtain several phosphorus 2H-indazoles 74 in moderate to good yields, and with good tolerance of functional groups. Based on
control experiments, the mechanism is proposed to proceed via a copper carbene intermediate
75, which further undergoes transmetallation with the palladium catalyst to deliver
palladium carbene intermediate 76. Subsequently, phosphinous acid 73′ (the tautomeric form of H-phosphonate) reacts with 76 to offer Pd(II) intermediate 77 in the presence of a base, which further undergoes migratory insertion and delivers
the intermediate 78. Finally, the target product 74 is formed via protonation of the intermediate 78 as shown in Scheme [18].
An efficient dual catalysis strategy for the construction of unsymmetrical aryl sulfides
81 has been reported by Khakyzadeh et al. This method uses phenols 79, arylboronic acids 80, and S8(II) as starting materials (Scheme [19]). The designed palladium encapsulated on nano-silica-based (SiO2@OL@Pd) catalyst and CuI were employed for this purpose. This method converted the
free hydroxyl group of phenols 79 into phenolic compounds 82 (Scheme [20]), which are more active as coupling partners in C–S bond-forming processes than
aryl halides. Notably, nanomaterial-based catalysts have a relatively high surface
area to volume ratio, which increases the interaction between the reactants and the
catalyst and, as a result, increases catalytic activity.
After synthesizing and characterizing SiO2@OL@Pd(II), the authors shifted their attention to developing and improving a dual
metal catalytic system involving Pd and Cu for C–O bond cleavage and subsequent C–S
bond formation under mild and efficient conditions. Initially, when the reaction is
carried out in the absence of [SiO2@OL@Pd(II)], a poor yield of the desired product (21%) was isolated. Similar results
(25%) were obtained when the reaction was carried out in the absence of CuI. The reaction
was further studied with activating groups such as toluenesulfonyl chloride and acetic
anhydride. In general, the reactions proceeded smoothly and furnished the final products
in good to excellent yields (70–96%) after activating the phenols 79 to form their active tosylates/acetates/triflates 82. The studies revealed that the electronic properties of substituents flanking the
phenols/arylboronic acids and steric effects pertaining to ortho-substituted substrates had a considerable impact on yields. Notably, most aromatic
rings substituted with electron-withdrawing groups, such as CHO, CH3CO, and NO2, groups were effective in furnishing the desired products.[82]
Scheme 18 Proposed mechanism for synthesis of 74
The proposed reaction mechanism is as demonstrated in Scheme [20]. Initially, the free phenol interacts with the activating agent (trifluoromethanesulfonyl
chloride, toluenesulfonyl chloride, or acetic anhydride) to yield the phenolic intermediate
82. Following the reaction of 82 with palladium, driven by oxidative addition and C–O bond dissociation, an aryl palladium
species 83 is produced. Simultaneously, in another cycle, the reaction of arylboronic acid 80 with S8 in the presence of CuI produces the organocopper thiolate intermediate 87. Subsequently, intermediate 87 undergoes transmetallation with intermediate 83 to give intermediate 84. In the final step, the targeted products 81 are obtained via reductive elimination of the intermediate 84, thus, completing the catalytic cycle.
A synergistic Pd/Cu dual catalysis-controlled regioselective and stereospecific ring-opening
C(sp
3)–Si cross-coupling of 2-arylaziridines 88 using silylborane 89 was demonstrated for the synthesis of differently functionalized products 90 by Minakata et al. in 2019. The regioselectivity of the coupling is effectively controlled by choosing
an appropriate combination of catalysts to produce two regioisomers of β-silylamines 90, such as β-silyl-α-phenethylamines (condition A) and β-silyl-β-phenethylamines (condition C), in good to high yields. Furthermore, a slight variation
in reaction conditions (conditions B) resulted in a significant shift in the reaction
pathways, giving in an efficient and selective tandem reaction to yield α-silyl-β-phenethylamines. The detailed conditions and conversions are presented in Scheme
[21].[83]
Scheme 19 Substrate scope for diaryl sulfide preparation
Scheme 20 Proposed mechanism for the synthesis of diaryl sulfides 81
Scheme 21 Substrate scope of aziridines 88
An efficient cooperative copper and palladium dual-catalysed (Cu/Pd) four-component
borocarbonylation from readily available aryl iodides 92 or aryl triflates 93, vinylarenes 91, CO, and B2Pin2
2 for the formation of β-boryl ketones 94 and β-boryl vinyl esters 95 was demonstrated by Wu and co-workers in 2020. Incorporating a variety of electron-withdrawing
or electron-donating groups at the meta/para-positions, aryl iodides were effectively converted into the required products 94/95 depending on the substrate and the conditions applied. This strategy enables the
formation of various synthetically essential β-boryl ketones 94 with good to excellent yields. Furthermore, by applying appropriate p-tolyl triflates as the substrates instead of aryl halides, the reaction surprisingly
generated β-boryl vinyl esters 95, along with a trace of β-boryl ketone. The authors further optimized the reaction conditions for synthesizing
β-boryl vinyl esters 95. The substrate scope was investigated using the optimized reaction conditions for
four-component borocarbonylation. As described in Scheme 22[84]
the reaction proceeded readily with a wide range of aryl triflates 93, yielding the anticipated β-boryl vinyl esters 95 in moderate to excellent yields. Aryl triflates having either electron-withdrawing
or electron-donating groups on the para position of the aromatic ring were amenable substrates and produced the products
in 47–71% yields. Significantly, aryl triflates with ortho- or meta-substituents and more sterically hindered substituents such as isopropyl and tert-butyl groups provided the desired products in high yields. The triflate produced
from estrone also resulted in the desired product in 62% yield.
Scheme 22 Substrate scope of styrenes 91 and aryl iodides/triflates 92/93
Scheme 23 The substrate scope of alkyne 54, nitrones 96, and allyl Boc carbonates 97/98. a
98 was used.
The Kinugasa reaction provides a nitrone-alkene, which results in isoxazolines or
isoxazolidines through a [3+2] cycloaddition reaction.[85]
[86]
[87] Kinugasa and Hashimoto discovered the direct synthesis of β-lactams 99 in 1972 when they reported that reacting a copper acetylide with a nitrone delivered
β-lactams 99. The Kinugasa reaction is an appealing alternative for the synthesis of β-lactams due to its efficient atom economy, and readily available starting materials.
In this context, in 2021, Xu et al. demonstrated a synergistic Cu-catalysed Kinugasa mechanism and a Pd-catalysed allylic
alkylation reaction for the synthesis of chiral β-lactams 99. This asymmetric multicomponent, interrupted Kinugasa allylic alkylation (IKAA) protocol
successfully delivered chiral β-lactams 99 with a quaternary carbon center starting from 54, 96, and 97/98 in high yields and stereoselectivity; difficult to achieve using alternative synthetic
approaches. An essential aspect of this reaction is the stereoselective coupling of
two catalytic quantities of transitory organometallic intermediates produced in situ. The detailed reaction conditions and substrate scope for the selected examples are
shown in Scheme [23].[88]
Alkene difunctionalization allows rapid generation of molecular complexity from simple
alkene precursors, with control of diastereo-, regio-, and enantioselectivity an inherent
problem. In that context, Brown and Dorn reported a Pd/Cu-catalysed approach to alkene
arylboration from alkenes 100 with (Bpin)2
2 and aryl halides 26. In this protocol, the authors screened various alkene substrates, such alkenylarenes
100 (Scheme [24], left side), 1,3-dienes 103 (Scheme [24], right side), and 1-substituted alkenylarenes 106 (Scheme [25], left side) resulting in good yields with excellent diastereoselectivities.[89] The authors proposed a reaction mechanism based on the literature and their previous
experience with reactions of 1,1- and 1,2-disubstituted derivatives; the plausible
mechanism has been presented in Scheme [25] (right side).
Scheme 24 Arylboration of alkenyl arenes 100 and 1,3-dienes 103
Scheme 25 Arylboration of 1-substituted alkenyl arenes 106 and arylboration reaction mechanism
