Transition Metal-Catalyzed Coupling Reactions in Library Synthesis
It has been widely recognized that the global pharmaceutical and agrochemical industries are currently experiencing a dynamic change. To increase productivity and efficiency, agro and drug companies have been striving to make improvements in every aspect of the R&D. Consequently, new technologies providing novel chemical cores currently are of great demand at all major companies.
Furthermore, high-throughput screening requires the synthesis of larger and more diverse sets of compounds. High-throughput synthesis of heterocyclic compound libraries utilizes various combinatorial strategies including direct scaffold decoration, linear convergent, and divergent approaches.
Biphenyl frameworks (including heteroaromatic moieties) are found in many biologically active products and thus can be considered as a privileged motif in medicinal chemistry.
The emergence of transition metal-catalyzed coupling reactions readily facilitated library/scaffold diversification with the easy incorporation of aromatic/heteroaromatic rings into various chemotypes that are preferentially directed towards hydrophobic cavities of protein targets. Typically, carbon–halogen bonds are utilized for a variety of transition metal (mostly palladium)-catalyzed reactions, including Suzuki–Miyaura, Sonogashira, Buchwald–Hartwig, Stille, Negishi, and Heck couplings. Most recently, direct C–H activation/arylation protocols were also reported for direct derivatization of heterocyclic cores.
On the other hand, cross-coupling reactions were also implemented into domino and cascade reactions to enable multiple bond-forming and bond-cleaving events in a single synthetic operation yielding efficiently novel ring systems.
KeywordsCatalysis Cross-coupling Library synthesis Palladium metal
Dichloromethane, methylene chloride
1,1′- Bis(diphenylphosphino) ferrocene
Methyl tert-butyl ether
This chapter is dedicated to demonstrate how palladium-catalyzed cross-coupling reactions paved the way for efficient library synthesis and became a privileged tool for today’s chemists in designing novel scaffolds (including highly conjugated and biaromatic systems) and building diversity.
Before palladium, copper was the choice of metal for carbon–carbon bond-forming reactions albeit palladium became more popular in the course of their development. Since the early discoveries of palladium-catalyzed carbon–carbon bond-forming reactions like the Suzuki–Miyaura, Heck, Negishi, Sonogashira, and Stille coupling, substantial effort has been invested into this field to develop a wide range of versatile and useful chemistries in order to gain access to valuable fine chemicals, intermediates, and drug candidates. Undoubtedly, the highest recognition of this endeavor was the Nobel Prize in Chemistry 2010 awarded jointly to Richard F. Heck, Ei-ichi Negishi, and Akira Suzuki “for palladium-catalyzed cross-couplings in organic synthesis” .
It is important to note that these chemical transformations are still under continuous development. As outstanding examples, they proved to be particularly suitable for microwave-assisted transformations  and most recently in continuous-flow methodologies  development, as well.
Contiguous research is ongoing towards the synthesis of new phosphine ligands  and circumstances also to improve catalyst activity, thus improving selectivity and yields while decreasing catalyst loading, reaction temperature, reaction time, and overall cost.
There is no doubt that research in this field will continue on, as state-of-the-art methodologies are currently under close investigation in order to meet the requirements of tomorrow’s research regulations and environmental criteria. These innovative fields involve reactions run in/on water [10, 11, 12], the application of polymer-supported reagents and heterogeneous palladium catalysts [13, 14], and even the use of preformed “ready-to-use” catalyst-incorporated tablets . Besides technology expansion, chemical development of palladium-mediated carbon–carbon bond formation is still an area of high interest nowadays. Direct C–H activation [16, 17] and oxidative palladium-catalyzed C–C bond formation [18, 19] are leading examples of this exciting field without being exhaustive.
Assorted examples that display best the utilization of palladium-catalyzed cross-coupling reactions in library design and synthesis with a focus on carbon–carbon bond-forming reactions from broadly the past decade are presented within this chapter.
2 General Synthetic Strategies
Technically, both scaffold synthesis and decoration could be done in solid and solution phases. In solution phase solid-supported reagents and catalysts could also be used. Numerous solid-phase syntheses are reported for Suzuki–Miyaura (Entries 1 , 2 , 3 , 4 , 5 ) and for Sonogashira couplings (Entry 39 ). Stille coupling-induced ring closure on solid support was described (Entry 43 ) together with solution phase scaffold decoration.
Additionally, fluorous liquid–liquid phase reactions are also employed making use of the advantages of the easy separation and purification. In Entries 27  and 28 , the fluorous tag was employed as the leaving group in Suzuki–Miyaura and in Negishi couplings (Entry 40 ).
There are many instances where scaffold synthesis, as well as scaffold decoration, employs cross-coupling reactions. Sonogashira reaction is particularly popular in scaffold synthesis since the inserted triple bond can be used in subsequent cyclization reactions in many ways. (Entries 58 , 59 , 60 , 62 , 63 ).
In a one-pot cross-coupling and amination reaction, aryl and unsaturated boronates were used in Entry 12  at high temperatures (160°C) under MW heating. The ring halogen reacted with the boronates, while the aliphatic chloride was replaced with various amines; thus, two diversity elements were introduced selectively in one reaction. In this reaction the desired compounds were purified with scavengers using a “catch-to-release” technique.
Two identical aromatic groups can be introduced in double scaffold decoration if two identical halogens are present in the precursor structure (Entry 30 ). However, one-pot sequential double scaffold decoration was applied in Entry 24  with different aromatic species making use of the different reactivity of the I and Br leaving groups or similarly triflate and Br (Entry 53 ). In another example (“sandwich sequence”), selective introduction of a bromine leaving group is followed by the first Suzuki coupling and facilitated the second Suzuki coupling (Entry 30 ).
Sequential Suzuki coupling was also reported leading to a chain of tiophenes (Entry 3 ) or thienylpyridyl garlands (Entry 16 ). Large majority of the synthetic targets are N- or N,O-/N,S/heterocyclic ring systems. The heterocyclic rings are either condensed ring systems or contain a chain of isolated rings (e.g., Entry: 16 ). Few examples lack any heteroatoms (Entries 12 , 13 , 58 ). Apart from some O-heterocycles (Entries 1 , 3 , 4 , 26 , 31 , 33 , 39 , 43 , 45 , 46 , 47 , 52 ), few S-heterocycles are reported (Entries 1 , 3 , 48 , 49 ).
Normally, the preformed scaffold contains the halogen or pseudohalogen (e.g., triflate) leaving group in the reaction. In one reported case a “reversed strategy” was used (Entry 9 ), namely, the triazole motif of the scaffold was converted to a boronate ester and reacted with various aryl bromides. The striking advantage of this strategy is that aryl halides are available on the market more readily and in higher numbers compared with boronates. Moreover, aryl halides are generally more reasonably priced.
In an interesting reaction sequence chromones were subjected to Suzuki coupling which was followed by subsequent ring opening and closure to pyrimidine ring (Entry: 57 ).
Multicomponent or tandem scaffold synthesis was reported in Entry 35 , which includes Heck reaction and tin-induced ring closure leading to dihydroindenoisoquinoline.
When a certain spatial distance is set between the aryl fragments, intramolecular direct CH activation is possible without using activating groups like boronates to induce coupling leading to fused ring systems (Entry 42 ).
The intermediate scaffolds having the proper leaving groups I, Br, or the pseudo halide triflates are suitable for conversion to decorated scaffolds with Suzuki–Miyaura, Negishi, Sonogashira, Heck, and Pd-catalyzed carbonylation reactions. There are several examples where many of these cross-coupling reactions were used for increasing the diversity around the scaffold or core structure (Entries 15 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 ).
Finally, there are so-called domino or tandem transformations that combine two cross-coupling reactions in one pot. In Entry 58  intramolecular Heck reaction and Suzuki couplings lead to indenes. In this case, the scaffold synthesis and decoration take place in one single step and pot. Similarly, Sonogashira reaction followed by intramolecular ring closure leading to an indolizine library (Entry 59 ), pyrrolopyridazines (Entry 60 ), indoles (Entry 62 ), and quinolinones (Entry 63 ) has been reported. In Entry 61  and Entry 34 , Heck reaction was followed by an aza-Michael-type ring closure.
Tandem Suzuki–Miyaura coupling–cyclization is reported in Entry 64 . In Entry 65  two scaffold fragments possessing diversity elements were merged in a Suzuki–Miyaura coupling, which was followed by intramolecular lactamization.
2.1 Components in the Suzuki Coupling
Since the Suzuki–Miyaura coupling is the most frequently used C–C bond-forming reaction in library synthesis, this subsection is primarily focused on the main factors of this type of cross-coupling reaction. There are four key components of the Suzuki coupling: boronates, Pd catalysts, organophosphine ligands, and inorganic salts or bases.
Heat- and air-stable compound Pd(η3-1-PhC3H4)(η5-C5H5)  reacts rapidly with a wide variety of tertiary phosphines (L) to produce near-quantitative yields of the corresponding Pd(0) compounds PdL2. This moiety is believed to be the active species in many often-used cross-coupling catalyst systems including Pd(PPh3)4, Pd2(dba)3, PdCl2, and Pd(OAc)2.
Inorganic salts are generally applied as bases in the Suzuki reaction to facilitate transmetallation  – CsF, KF, Cs, Na and K carbonates, bicarbonates, phosphates and hydroxides – while TEA is often used as an acid scavenging base (e.g., Entry 32 ). In the Sonogashira reaction, copper salts are typically used to activate the alkyne partner beside the Pd catalyst (CuI, e.g., in Entry 39 ).
Cross-coupling reactions often require high reaction temperature. Microwave-assisted rate acceleration is used in Entries 8 , 11 , 12 , 18 , 19 , 20 , 23 , 27 , 28 , 31 , and 55  for Suzuki–Miyaura couplings, in Entry 33  for Heck couplings, and in Entry 38  for Buchwald–Hartwig couplings.
Nevertheless, the choice of solvent is an important factor in transition metal-catalyzed cross-couplings. While as an exception, the Suzuki reaction tolerates water as the reaction medium, other cross-coupling reactions often require the rigorous exclusion of even moisture. Typical reaction media for palladium-catalyzed coupling reactions are toluene, THF, dioxane, and DMF, although unique transformations can be run under solvent-free conditions.
3 Reaction Summaries
3.1 Suzuki Coupling
3.1.1 Solid-Phase Synthesis
3.1.2 Solution Phase
3.2 Heck Reaction
3.3 Buchwald–Hartwig Amination
3.4 Sonogashira Reaction
3.5 Negishi Coupling
3.6 Direct CH Activation
3.7 Multiple Cross-Couplings
3.7.1 Solid Phase
3.7.2 Solution Phase
Library size: 121 examples
Key step: scaffold synthesis and decoration
Method: solution phase
Comments: scaffold synthesis (Sonogashira); multiple cross-coupling Suzuki, Suzuki carbonylation., Sonogashira, Heck, Pd-catalyzed alkoxycarbonylation
Library size: 72 examples – 21 (Suzuki) + 17 (Sonogashira) + 7 (Heck) + 11 (alkoxycarbonylation) + 16 (aminocarbonylation)
Key step: scaffold decoration
Method: solution phase
Comments: multiple cross-coupling Suzuki, Sonogashira, Heck, Pd-cat. amino- and alkoxycarbonylation
Library size: 82 examples – 26 (Suzuki) + 25 (Sonogashira) + 8 (Heck) + 23 (isocoumarin)
Key step: scaffold synthesis and decoration
Method: solution phase
Comments: scaffold synthesis (Sonogashira); multiple coupling Suzuki, Sonogashira, Heck
Library size: 65 examples – 40 Suzuki, 20 Heck, 5 Sonogashira
Key step: scaffold synthesis and decoration
Method: solution phase
Yields: 65–84%, 65–80%, 65–75%
Comments: scaffold synthesis (Sonogashira); multiple type cross-couplings – Suzuki, Heck, Sonogashira
3.8 Domino–Tandem Cross-Coupling Reactions
3.8.1 One-Ring Systems
3.8.2 Two-Ring Systems
3.8.3 Three-Ring Systems
3.8.4 Four-Ring Systems
In the last decade cross-coupling reactions became a standard laboratory technique in library synthesis. In the meantime biphenyl frameworks (including heteroaromatic ring systems) have extensively been reported in many biologically active products and have been considered as a privileged motif in medicinal chemistry ; thus, the importance of the cross-coupling reactions was further justified.
While there are some examples for solid-phase synthesis, mostly solution phase parallel synthesis is employed including the application of solid-supported reagents and fluorous two-phase reactions. Suzuki–Miyaura coupling is the most widely used C–C coupling reaction, while Sonogashira reaction is favorably used in scaffold synthesis followed by ring closure involving alkynes. Apart from the Suzuki and Sonogashira coupling, additional Pd-catalyzed reactions (Heck, Negishi, Buchwald–Hartwig amination, etc.) were used to increase the diversity around the core structure. Typically such diversity enhancement can be realized through C–C and C–N single bonds (Suzuki–Miyaura and Buchwald–Hartwig amination), double bonds (Heck), triple bonds (Sonogashira), etc. In summary, these techniques greatly increase the toolbox of the organic and medicinal chemists and contribute to afford novel chemotypes for the early phase of drug discovery.
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