Transition Metal-Catalyzed Coupling Reactions in Library Synthesis

  • János Gerencsér
  • Árpád Balázs
  • György Dormán
Chapter
Part of the Topics in Heterocyclic Chemistry book series (TOPICS, volume 45)

Abstract

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.

Keywords

Catalysis Cross-coupling Library synthesis Palladium metal 

Abbreviations

BEMP

2-Tert-Butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine

DavePhos

2-Dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl

dba

Dibenzylideneacetone

DBU

1,8-Diazabicycloundec-7-ene

DCM

Dichloromethane, methylene chloride

DDQ

2,3-Dichloro-5,6-Dicyanobenzoquinone

DIC

N,N'-Diisopropylcarbodiimide

DIPEA

N,N-Diisopropylethylamine

DME

Dimethoxyethane

DMF

N,N-Dimethylformamide

dppf

1,1′- Bis(diphenylphosphino) ferrocene

DVB

Divinylbenzene

Fmoc

Fluorenylmethyloxycarbonyl

HMBA

10-[(3-Hydroxy-4-methoxybenzylidene)]-9(10H)-anthracenome

HOBt

Hydroxybenzotriazole

mCPBA

Meta-chloroperbenzoic acid

MeCN

Acetonitrile

MIDA

N-Methyliminodiacetic acid

MTBE

Methyl tert-butyl ether

MWI

Microwave irradiation

NBS

N-Bromosuccinic imide

NEM

N-Ethylmorpholine

NIS

N-Iodosuccinic imide

NMP

N-Methylpyrrolidone

POPd

Dihydrogendichlorobis(di-tert-butylphosphinito-kP)palladate(−2)

PS

Polystyrene

PTSA

4-Toluenesulfonic acid

rt

Room temperature

SPhos

2-Dicyclohexylphosphino-2′,6′-dimethoxybiphenyl

TBAB

Tetrabutylammonium bromide

TBAC

Tetrabutylammonium chloride

TBAI

Tetrabutylammonium iodide

TBS

Tert-butyl dimethyl

TBTU

N,N,N′,N′-Tetramethyl-O-(benzotriazol-1-yl)uronium tetrafluoroborate

TEA

Triethylamine

TFA

Trifluoroacetic acid

THF

Tetrahydrofuran

TosMIC

Toluenesulfonylmethyl isocyanide

TPP

Triphenylphosphine

Ts

Tosyl, 4-methylsulfonyl

Xantphos

4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene

XPhos

2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl

1 Introduction

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” [1].

As a result of decades of fundamental research and the deeper understanding of this type of chemistry, nowadays, palladium-catalyzed cross-couplings became suitable not only for scaffold and target (overall library) synthesis but also to be incorporated into multicomponent [2, 3] and domino [4, 5] processes, as well, that greatly increased diversity and step economy. Today, classical palladium-mediated C–C bond-forming “name” reactions are standard instruments in the toolkit of bench chemists all around the globe, and the well-known catalytic cycle [6] (Scheme 1) of these types of reactions is indispensable from every chemistry textbook.
Scheme 1

General catalytic cycle for palladium catalyzed C–C bond formation (stereochemistry and ligands omitted)

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 [7] and most recently in continuous-flow methodologies [8] development, as well.

Contiguous research is ongoing towards the synthesis of new phosphine ligands [9] 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 [15]. 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

There are two main different types of synthetic strategies:
  1. a.
    Scaffold synthesis with the involvement of cross-coupling reactions (Scheme 2)
    Scheme 2

    Scaffold synthesis with the involvement of cross-coupling reactions

     
  2. b.
    Scaffold decoration and library diversification with cross-coupling reactions (Scheme 3)
    Scheme 3

    Scaffold decoration and library diversification with cross-coupling reactions

     

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 [20], 2 [21], 3 [22], 4 [23], 5 [24]) and for Sonogashira couplings (Entry 39 [25]). Stille coupling-induced ring closure on solid support was described (Entry 43 [26]) 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 [27] and 28 [28], the fluorous tag was employed as the leaving group in Suzuki–Miyaura and in Negishi couplings (Entry 40 [29]).

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 [30], 59 [31], 60 [32], 62 [33], 63 [34]).

Suzuki–Miyaura coupling is generally performed on aromatic systems. However, there are two examples where only partially unsaturated rings are subjected to C–C coupling (Entries 22 [35], 32 [36]).

In a one-pot cross-coupling and amination reaction, aryl and unsaturated boronates were used in Entry 12 [37] 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 [38]). However, one-pot sequential double scaffold decoration was applied in Entry 24 [39] with different aromatic species making use of the different reactivity of the I and Br leaving groups or similarly triflate and Br (Entry 53 [40]). 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 [38]).

Sequential Suzuki coupling was also reported leading to a chain of tiophenes (Entry 3 [22]) or thienylpyridyl garlands (Entry 16 [41]). 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 [41]). Few examples lack any heteroatoms (Entries 12 [37], 13 [42], 58 [30]). Apart from some O-heterocycles (Entries 1 [20], 3 [22], 4 [23], 26 [43], 31 [44], 33 [45], 39 [25], 43 [26], 45 [46], 46 [47], 47 [48], 52 [49]), few S-heterocycles are reported (Entries 1 [20], 3 [22], 48 [50], 49 [51]).

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 [52]), 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 [53]).

Multicomponent or tandem scaffold synthesis was reported in Entry 35 [54], which includes Heck reaction and tin-induced ring closure leading to dihydroindenoisoquinoline.

Only two examples were reported when Negishi coupling was employed in scaffold synthesis (Entries 40 [29], 41 [55]).

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 [56]).

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 [57], 43 [26], 44 [58], 45 [46], 46 [47], 47 [48], 48 [50], 49 [51], 50 [59], 51 [60], 52 [49], 53 [40], 54 [61], 55 [62], 56 [63]).

Finally, there are so-called domino or tandem transformations that combine two cross-coupling reactions in one pot. In Entry 58 [30] 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 [31]), pyrrolopyridazines (Entry 60 [32]), indoles (Entry 62 [33]), and quinolinones (Entry 63 [34]) has been reported. In Entry 61 [64] and Entry 34 [65], Heck reaction was followed by an aza-Michael-type ring closure.

Tandem Suzuki–Miyaura coupling–cyclization is reported in Entry 64 [66]. In Entry 65 [67] 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.

Boronates are typically used as boronic acids (RB(OH)2), boronate esters (RB(OR′)2, and organoboranes (R3B). Besides the common boronates, pinacol boronate is employed in Entry 10 [68]. Organotrifluoroborates are used in Entry 8 [69] that are tolerant to air and moisture and easy to handle and purify. An example of solid-supported boronate reagent (Fig. 1) is reported in Entry 6 [70]. This boronate is a variant of the MIDA boronate [71] (trivalent N-methyliminodiacetic acid (MIDA) ligand).
Fig. 1

Solid-supported boronate reagent for Suzuki coupling

Regarding the Pd catalysts there are many variations employed (Fig. 2.): Pd(PPh3)4; Pd(PPh3)Cl2; Pd3(OAc)6 (Entry 13 [42]), the trimeric form of Pd(OAc)2; POPd (Entry 17 [72]); Pd2(dba)3, (tris(dibenzylideneacetone)dipalladium(0)] (Entry 14 [73]); and Pd(dppf)Cl2•CH2Cl2 [1,1′-Bis(diphenylphosphino)ferrocene]dichloro-palladium(II)] (Entries 18 [74], 27 [27], 28 [28], 65 [67]).
Fig. 2

Palladium catalysts

Heat- and air-stable compound Pd(η3-1-PhC3H4)(η5-C5H5) [75] 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.

Polymer-supported PS-Pd(PPh3)4 is used in Entries 11 [76], 32 [36] under MW heating.

Organophosphine ligands increase the activity and stability of the Pd catalysts reducing its loading; therefore, many different forms were reported (Fig. 3): DavePhos (Suzuki, Entry 8 [69]; Buchwald, Entry 36 [77]); SPhos (Entries 13 [42], 55 [62], 64 [66]); XPhos (Buchwald: Entry 37 [78]); Xantphos (Buchwald: Entry 38 [79]); dppf (direct CH activation: Entry 42 [56]; palladium-catalyzed aminocarbonylation, Entry 47 [48]); BINAP (Buchwald: Entry 52 [49]); and dimethoxy-triphenylphosphine (Heck: Entry 53 [40]).
Fig. 3

Organophosphine ligands

Inorganic salts are generally applied as bases in the Suzuki reaction to facilitate transmetallation [80] – 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 [36]). In the Sonogashira reaction, copper salts are typically used to activate the alkyne partner beside the Pd catalyst (CuI, e.g., in Entry 39 [25]).

Cross-coupling reactions often require high reaction temperature. Microwave-assisted rate acceleration is used in Entries 8 [69], 11 [76], 12 [37], 18 [74], 19 [81], 20 [82], 23 [83], 27 [27], 28 [28], 31 [44], and 55 [62] for Suzuki–Miyaura couplings, in Entry 33 [45] for Heck couplings, and in Entry 38 [79] 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

One-Ring Systems
Entry 1

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Core: Furan, thiophene

Library size: 33 examples (2 × 19, 6 unsuccessful)

Key step: scaffold synthesis and decoration

Method: solid phase – ionic immobilization

Yields: 33–80%

Biology: methionine aminopeptidase inhibitors

Comments:

[20]

Entry 2

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Core: distamycin analogs

Library size: 72 examples

Key step: scaffold decoration (last step)

Method: solid phase – Rink Amide Linker (RAM) SynPhase lantern

Yields: n/d

Biology: n/d

Comments:

[21]

Entry 3

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Core: quarter(3-arylthiophene)

Library size: 256 examples

Key step: scaffold decoration (last step)

Method: solid phase

Yields: 12–45%

Biology: n/d

Comments: sequential Suzuki coupling, organic electron transport materials

[22]

Two-Ring Systems
Entry 4

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Core: benzo[b]thiophene, benzo[b]selenophene

Library size: 53 + 47 examples

Key step: scaffold synthesis and decoration

Method: solid phase

Yields: n/d

Biology: n/d

Comments:

[23]

Three-Ring Systems
Entry 5

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Core: thienoindolizine

Library size: 41 examples

Key step: scaffold decoration

Method: solid phase

Yields: n/d

Biology: n/d

Comments:

[24]

3.1.2 Solution Phase

One-Ring Systems
Entry 6

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Core: pyridine

Library size: 11 examples

Key step: scaffold decoration

Method: solid-supported reagent

Yields: 50–87%

Biology: n/d

Comments: methodology for 2-pyridylboronates

[70]

Entry 7

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Core: pyrazole

Library size: 9 examples

Key step: scaffold decoration

Method: solution phase

Yields: 74–95%

Biology: COX-2 inhibitor

Comments:

[84]

Entry 8

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Core: oxazole

Library size: 7 examples

Key step: scaffold decoration

Method: solution phase

Yields: 44–73%

Biology: n/d

Comments:

[69]

Entry 9

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Core: triazole

Library size: 14 examples

Key step: scaffold decoration (last step)

Method: solution phase – reversed strategy!

Yields: 57–94%

Biology: n/d

Comments:

[52]

Entry 10

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Core: triazole

Library size: 23 + 13

Key step: scaffold decoration (last step)

Method: solution phase

Yields: 43–99%, 72–96%

Biology: n/d

Comments:

[68]

Entry 11

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Core: triazole

Library size: 458 + 192 examples

Key step: scaffold decoration

Method: solution phase with solid-supported catalyst

Yields: n/d

Biology: n/d

Comments: flow hydrogenation

[76]

Entry 12

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Core: biaryl and styrene

Library size: 41 examples

Key step: scaffold decoration

Method: solution phase

Yields: n/d

Biology: acetylcholine receptor agonists and antagonists nAChR

Comments: scavengers, catch and release

[37]

Entry 13

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Core: o-,m-, and p-terphenyls

Library size: 33 examples

Key step: scaffold decoration (last step)

Method: solid phase

Yields: 23–99%

Biology: n/d

Comments: potential photochemical properties used in organic electroluminescent (OEL) devices

[42]

Entry 14

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Core: Pyridine

Library size: 14 examples

Key step: scaffold decoration

Method: solution phase

Yields: 13–90%

Biology: n/d

Comments: sequential diarylation

[73]

Entry 15

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Core: pyrimidine

Library size: 160 examples

Key step: scaffold decoration

Method: solution phase

Yields: 59–94%

Biology: A3 adenosine receptor antagonist

Comments:

[57]

Entry 16

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Core: thienylpyridyl garlands

Library size: 8 examples

Key step: scaffold decoration

Method: solution phase

Yields: 5–68%

Biology: non-peptidic alpha helix mimetics with potential PPI inhibitors

Comments: mono- and bisarylation

[41]

Entry 17

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Core: pyridine

Library size: 7 examples

Key step: scaffold decoration

Method: solution phase

Yields: 74–98%

Biology: potential COX-2 inhibitors

Comments: methodology for sterically hindered pyridyl halides/air-stable catalyst POPd

[72]

Entry 18

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Core: 5-thio-xylopyranoside

Library size: 23 examples

Key step: scaffold decoration

Method: solution phase

Yields: 28–92%

Biology: antithrombotic effect

Comments:

[74]

Entry 19

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Core: pyridazine

Library size: two sublibraries as mixtures – 4 × 5 × 3 = 60

Key step: scaffold decoration

Method: solution phase

Yields: 40–70%, 60–80%

Biology: n/d

Comments: sequential amination and Suzuki coupling (mixture synthesis)

[81]

Two-Ring Systems
Entry 20

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Core: pyrazolopyrimidine

Library size: 29 examples

Key step: scaffold synthesis in three steps

– 14 upper route + 15 lower route

Method: solution phase

Yields: 51–93%, (60–86%)

Biology: n/d

Comments:

[82]

Entry 21

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Core: thienopyrimidine

Library size: 72 examples + 2 unsuccessful

Key step: scaffold decoration (last step)

Method: solution phase

Yields: 71–94%

Biology: n/d

Comments:

[85]

Entry 22

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Core: 5,6-dihydroindol-2-one

Library size: 11 examples

Key step: scaffold decoration

Method: solution phase

Yields: 52–91%

Biology: n/d

Comments:

[35]

Entry 23

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Core: benzothiazole

Library size: 13 examples

Key step: scaffold decoration

Method: solution phase

Yields: 59–79%

Biology: n/d

Comments:

[83]

Entry 24

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Core: quinolinone

Library size: 13 examples

Key step: scaffold decoration

Method solution phase

Yields: 47–99%

Biology: n/d

Comments: One-pot sequential double scaffold decoration

[39]

Entry 25

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Core: isoquinoline

Library size: 6 examples

Key step: scaffold decoration

Method: solution phase

Yields: 75–98%

Biology: protein tyrosine phosphatase 1B (PTP1B)

Comments:

[86]

Entry 26

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Core: cumarine

Library size: 11 examples

Key step: scaffold decoration

Method: solution phase

Yields: 51–91%

Biology: n/d

Comments:

[43]

Entry 27

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Core: benzodiazepinedione

Library size: 31 examples

Key step: scaffold decoration

Method: fluorous synthesis

Yields: 20–67%

Biology: n/d

Comments: cyclohexyl and methyl 2-isocyanoacetate as convertible isonitriles

[27]

Entry 28

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Core: benzodiazepinedione 2

Library size: 36 examples

Key step: scaffold decoration

Method: fluorous synthesis

Yields: 10–76% (generally 20–40%)

Biology: n/d

Comments:

[28]

Three-Ring Systems
Entry 29

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Core: pyrazole-isoquinoline

Library size: 7 examples

Key step: scaffold decoration

Method: solution phase

Yields: 76–99%

Biology: n/d

Comments:

[87]

Entry 30

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Core: pyrroloisoquinoline

Library size: 45 examples; 9 sublibraries

Key step: scaffold decoration

Method: solution phase

Yields: n/d

Biology: cytotoxicity data given

Comments: double and sequential scaffold decorations, Lamellarin D analogs

[38]

Entry 31

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Core: dibenzopyranones

Library size: 32 examples

Key step: scaffold synthesis

Method: solution phase

Yields: 68–98%

Biology: n/d

Comments:

[44]

Entry 32

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Core: pyrrolobenzodiazepine

Library size: 66 examples

Key step: scaffold decoration (last step)

Method: solution phase, solid-supported Pd

Yields: 4–57%

Biology: n/d

Comments:

[36]

3.2 Heck Reaction

Entry 33

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Core: chromanone, flavone

Library size: 24 + 24 examples

Key step: scaffold decoration

Method: solution phase

Yields: 8–94%, 40–85%

Biology: n/d

Comments: phosphine-free Heck

[45]

Entry 34

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Core: tetrahydroisoquinoline and dihydroisoindoline containing tricyclic sultams

Library size: 120 members (40 + 40 + 40)

Key step: scaffold synthesis

Method: solution phase

Yields: 50–99%, 53–99%, 35–99%, 22–88%

Biology: n/d

Comments:

[65]

Entry 35

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Core: dihydroindenoisoquinoline

Library size: 111 members

Key step: scaffold synthesis

Method: solution phase

Yields: 6–71% for two steps (generally 20–30%)

Biology: n/d

Comments: multicomponent or tandem scaffold synthesis (Heck, and tin-induced ring closure)

[54]

3.3 Buchwald–Hartwig Amination

Entry 36

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Core: piperazine

Library size: 17 examples

Key step: scaffold decoration

Method: solution phase

Yields: 13–85%

Biology: potential 5-HT2a

Comments: Ligand = DavePhos

[77]

Entry 37

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Core: bis-(het)arylamine

Library size: 39 examples

Key step: scaffold decoration (last step)

Method: solution phase

Yields: 45–95%

Biology: n/d

Comments: in situ generated Pd catalyst Pd(η3-1-PhC3H4)(η5-C5H5)

[78]

Entry 38

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Core: quinoxalinone

Library size: 21 examples

Key step: scaffold decoration

Method: solution phase

Yields: 58–93%

Biology: cannabinoid CB2 receptor agonist

Comments:

[79]

3.4 Sonogashira Reaction

Entry 39

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Core: isocoumarines and heterocyclic derivatives

Library size: 51 examples

Key step: scaffold synthesis

Method: solid phase

Yields: 28–99%

Biology: n/d

Comments:

[25]

3.5 Negishi Coupling

Entry 40

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Core: pyrazole

Library size: 11 examples

Key step: scaffold decoration suitable for library synthesis

Method: fluorous synthesis

Yields: 26–99%

Biology: n/d

Comments: fluorous tag was used as a leaving group

[29]

Entry 41

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Core: pyridazine

Library size: 13 examples

Key step: scaffold synthesis suitable for library synthesis

Method: solid phase

Yields: 37–92%

Biology: n/d

Comments:

[55]

3.6 Direct CH Activation

Entry 42

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Core: quinolinone

Library size: 20 examples

Key step: scaffold decoration (last step)

Method: solution phase

Yields: 78–98%

Biology: n/d

Comments: Direct CH activation

[56]

3.7 Multiple Cross-Couplings

3.7.1 Solid Phase

Entry 43

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Core: benzopyrane

Library size: 424 examples

Key step: scaffold decoration

Method: solid phase

Yields: n/d

Biology: n/d

Comments: multiple cross-coupling Suzuki, Stille, Negishi

[26]

3.7.2 Solution Phase

One-Ring Systems
Entry 44

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Core: isoxazole

Library size: 64 examples

Key step: scaffold decoration

Method: solution phase

Yields: 8–85%

Biology: n/d

Comments: multiple cross-coupling Suzuki, Sonogashira, Heck, Pd-catalyzed aminocarbonylation

[58]

Two-Ring Systems
Entry 45

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Core: furane

Library size: 163 examples, 46 (Suzuki) +53 (Sonogashira) +3 (Heck) +6 (amides) +55 (esters)

Key step: scaffold decoration

Method: solution phase

Yields: 6–88%

Biology: n/d

Comments: multiple type cross-couplings Suzuki, Sonogashira, Heck

[46]

Entry 46

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Core: cyclic imidate, isobenzofurane

Library size: 75 examples

Key step: scaffold decoration

Method: solution phase

Yields: 4–92%

Biology: n/d

Comments: multiple type cross-couplings Suzuki, Sonogashira, Heck, Pd-amino carbonylation

[47]

Entry 47

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Core: benzofurane

Library size: 121 examples

Key step: scaffold synthesis and decoration

Method: solution phase

Yields: 18–88%

Biology: n/d

Comments: scaffold synthesis (Sonogashira); multiple cross-coupling Suzuki, Suzuki carbonylation., Sonogashira, Heck, Pd-catalyzed alkoxycarbonylation

[48]

Entry 48

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Core: benzothiophene

Library size: 72 examples – 21 (Suzuki) + 17 (Sonogashira) + 7 (Heck) + 11 (alkoxycarbonylation) + 16 (aminocarbonylation)

Key step: scaffold decoration

Method: solution phase

Yields: n/d

Biology: n/d

Comments: multiple cross-coupling Suzuki, Sonogashira, Heck, Pd-cat. amino- and alkoxycarbonylation

[50]

Entry 49

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Core: benzothiophene

Library size: 165 examples

Key step: scaffold decoration

Method: solution phase

Yields: n/d

Biology: n/d

Comments: multiple cross-coupling Suzuki, Sonogashira, Heck, Pd-catalyzed alkoxycarbonylation

[51]

Entry 50

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Core: indole

Library size: 38 examples (11 Suzuki + 27 Sonogashira)

Key step: scaffold synthesis and decoration

Method: solution phase – few solid-phase examples also discussed

Yields: 2–84%, 3–94%

Biology: n/d

Comments: multiple cross-coupling Suzuki, Sonogashira

[59]

Entry 51

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Core: 9-deazaxanthine

Library size: 9 examples

Key step: scaffold decoration

Method: solution phase

Yields: 23–98%

Biology: n/d

Comments: multiple cross-coupling Suzuki, Sonogashira, Heck, etc.

[60]

Entry 52

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Core: isocoumarin

Library size: 82 examples – 26 (Suzuki) + 25 (Sonogashira) + 8 (Heck) + 23 (isocoumarin)

Key step: scaffold synthesis and decoration

Method: solution phase

Yields: n/d

Biology: n/d

Comments: scaffold synthesis (Sonogashira); multiple coupling Suzuki, Sonogashira, Heck

[49]

Entry 53

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Core: quinoline

Library size: 23 examples

Key step: sequential double scaffold decoration

Method: solution phase

Yields: 60–81%, 72–92%

Biology: n/d

Comments: multiple cross-coupling Buchwald, Heck

[40]

Entry 54

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Core: dihydroisoquinoline

Library size: 75 examples

Key step: scaffold decoration

Method: solution phase

Yields: 11–99%

Biology: n/d

Comments: multiple cross-coupling: Suzuki, Sonogashira

[61]

Three-Ring Systems
Entry 55

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Core: indole-based NPL

Library size: 93 examples – 51 Suzuki, 42 Buchwald

Key step: scaffold decoration

Method: solution phase

Yields: 4–76%, 5–83%

Biology: n/d

Comments: multiple type cross-couplings – Suzuki, Buchwald–Hartwig

[62]

Entry 56

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Core: pyranoquinolines

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%

Biology: n/d

Comments: scaffold synthesis (Sonogashira); multiple type cross-couplings – Suzuki, Heck, Sonogashira

[63]

3.8 Domino–Tandem Cross-Coupling Reactions

3.8.1 One-Ring Systems

Entry 57

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Core: pyrimidine

Library size: 30 examples

Key step: scaffold synthesis

Method: solution phase

Yields: 40–61%

Biology: human hepatocellular carcinoma BEL-7402 cells

Comments: two-step one-pot Suzuki–cyclization

[53]

3.8.2 Two-Ring Systems

Entry 58

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Core: indene

Library size: 20 examples

Key step: one-pot scaffold synthesis and decoration

Method: solution phase

Yields: 67–98%

Biology: n/d

Comments: tandem Suzuki–Heck

[30]

Entry 59

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Core: Indolizine

Library size: 25 members (5 × 5)

Key step: one-pot scaffold synthesis and decoration

Method: solution phase

Yields: 28–78%

Biology: n/d

Comments: tandem Sonogashira–cycloisomerization, flow chemistry

[31]

Entry 60

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Core: pyrrolo-pyridazine

Library size: 20 examples

Key step: one-pot scaffold synthesis and decoration

Method: solution phase

Yields: 11–91%

Biology: n/d

Comments: Sonogashira coupling–isomerization–condensation

[32]

Entry 61

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Core: sultam; 1,1-dioxido-1,2-benzisothiazoline

Library size: 92 examples

Key step: one-pot scaffold synthesis and decoration

Method: solution phase

Yields: 5–93%

Biology: n/d

Comments: tandem Heck–aza-Michael

[64]

Entry 62

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Core: indole

Library size: 15 examples

Key step: one-pot scaffold synthesis and decoration

Method: solution phase

Yields: 60–85%

Biology: SIRT1

Comments: Sonogashira–desilylation–Sonogashira–cyclization

[33]

Entry 63

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Core: quinolinone

Library size: 8 examples

Key step: one-pot scaffold synthesis and decoration

Method: solution phase

Yields: 65–88%

Biology: n/d

Comments: Suzuki, Sonogashira, cyclization

[34]

3.8.3 Three-Ring Systems

Entry 64

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Core: phenanthridinone

Library size: 10 examples

Key step: one-pot scaffold synthesis and decoration

Method: solid phase

Yields: 65–96%

Biology: n/d

Comments: tandem Suzuki–cyclization

[66]

3.8.4 Four-Ring Systems

Entry 65

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Core: dihydroindolo-benzazepinone (paullone)

Library size: 12 examples

Key step: one-pot scaffold synthesis, joining two diversity holding fragments

Method: solution phase

Yields: 44–99%

Biology: SIRT1 inhibitors

Comments: tandem Suzuki–intramolecular amide formation

[67]

Conclusion

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 [88]; 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.

References

  1. 1.
    Nobel Media AB (2013) The Nobel prize in chemistry 2010. www.Nobelprize.org
  2. 2.
    Balme G, Bouyssi D, Monteiro N (2006) Palladium-mediated cascade or multicomponent reactions: a new route to carbo- and heterocyclic compounds. Pure Appl Chem 78(2):231–239CrossRefGoogle Scholar
  3. 3.
    Zhu J, Bienayme H (2006) Multicomponent reactions. Wiley-VCH, WeinheimGoogle Scholar
  4. 4.
    de Meijere A, von Zezschwitz P, Bräse S (2005) The virtue of palladium-catalyzed domino reactions − diverse oligocyclizations of acyclic 2-bromoenynes and 2-bromoenediynes. Acc Chem Res 38(5):413–422CrossRefGoogle Scholar
  5. 5.
    Pellissier H (2013) Asymmetric domino reactions. RSC Publishing, LondonGoogle Scholar
  6. 6.
    Schröter S, Stock C, Bach T (2005) Regioselective cross-coupling reactions of multiple halogenated nitrogen-, oxygen-, and sulfur-containing heterocycles. Tetrahedron 61(9):2245–2267CrossRefGoogle Scholar
  7. 7.
    de la Hoz A, Loupy A (2012) Microwaves in organic synthesis. Wiley-VCH, WeinheimGoogle Scholar
  8. 8.
    Noël T, Buchwald SL (2011) Cross-coupling in flow. Chem Soc Rev 40(10):5010–5029CrossRefGoogle Scholar
  9. 9.
    Martin R, Buchwald SL (2008) Palladium-catalyzed Suzuki−Miyaura cross-coupling reactions employing dialkylbiaryl phosphine ligands. Acc Chem Res 41(11):1461–1473CrossRefGoogle Scholar
  10. 10.
    Li B, Dixneuf PH (2013) sp2 C–H bond activation in water and catalytic cross-coupling reactions. Chem Soc Rev 42(13):5744–5767Google Scholar
  11. 11.
    Lipshutz BH, Taft BR, Abela AR, Ghorai S, Krasovskiy A, Duplais C (2012) Catalysis in the service of green chemistry: Nobel prize-winning palladium-catalysed cross-couplings, run in water at room temperature. Platinum Metals Rev 56(2):62–74CrossRefGoogle Scholar
  12. 12.
    Dixneuf PH, Cadierno V (2013) Metal-catalyzed reactions in water. Wiley-VCH, WeinheimGoogle Scholar
  13. 13.
    Yin L, Liebsche J (2007) Carbon−carbon coupling reactions catalyzed by heterogeneous palladium catalysts. Chem Rev 107(1):133–173CrossRefGoogle Scholar
  14. 14.
    Molnár Á (2013) Palladium-catalyzed coupling reactions. Wiley-VCH, WeinheimGoogle Scholar
  15. 15.
    Ruhland T, Nielsen SD, Holm P, Christensen CH (2007) Nanoporous magnesium aluminometasilicate tablets for precise, controlled, and continuous dosing of chemical reagents and catalysts: applications in parallel solution-phase synthesis. J Comb Chem 9(2):301–305CrossRefGoogle Scholar
  16. 16.
    Lyons TW, Sanford MS (2010) Palladium-catalyzed ligand-directed C−H functionalization reactions. Chem Rev 110(2):1147–1169CrossRefGoogle Scholar
  17. 17.
    Mousseau JJ, Charette AB (2013) Direct functionalization processes: a journey from palladium to copper to iron to nickel to metal-free coupling reactions. Acc Chem Res 46(2):412–424CrossRefGoogle Scholar
  18. 18.
    Chen X, Engle KM, Wang D-H, Yu J-Q (2009) Palladium(II)-catalyzed C–H activation/C–C cross-coupling reactions: versatility and practicality. Angew Chem Int Ed 48(28):5094–5115Google Scholar
  19. 19.
    Wu Y, Wang J, Mao F, Kwong FY (2014) Palladium-catalyzed cross-dehydrogenative functionalization of C(sp2)-H bonds. Chem Asian J 9(1):26–47CrossRefGoogle Scholar
  20. 20.
    Vedantham P, Guerra JM, Schoenen F, Huang M, Gor PJ, Georg GI, Wang JL, Neuenswander B, Lushington GH, Mitscher LA, Ye Q-Z, Hanson PR (2008) Ionic immobilization, diversification, and release: application to the generation of a library of methionine aminopeptidase inhibitors. J Comb Chem 10(2):185–194CrossRefGoogle Scholar
  21. 21.
    Brucoli F, Howard PW, Thurston DE (2009) Efficient solid-phase synthesis of a library of distamycin analogs containing novel biaryl motifs on synphase lanterns. J Comb Chem 11(4):576–586CrossRefGoogle Scholar
  22. 22.
    Briehn CA, Bäuerle P (2002) Design and synthesis of a 256-membered ð-conjugated oligomer library of regioregular head-to-tail coupled quater(3-arylthiophene)s. J Comb Chem 4(5):457–469CrossRefGoogle Scholar
  23. 23.
    Bui CT, Flynn BL (2006) Solid-phase synthesis of 2,3-disubstituted Benzo[b]thiophenes and benzo[b]selenophenes. J Comb Chem 8(2):163–167CrossRefGoogle Scholar
  24. 24.
    Le Quement ST, Nielsen TE, Meldal M (2008) Solid-phase synthesis of aryl-substituted thienoindolizines: sequential pictet-spengler, bromination and Suzuki cross-coupling reactions of thiophenes. J Comb Chem 10(3):447–455CrossRefGoogle Scholar
  25. 25.
    Peuchmaur M, Lisowski V, Gandreuil C, Maillard LT, Martinez J, Hernandez J-F (2009) Solid-phase synthesis of isocoumarins: a traceless halocyclization approach. J Org Chem 74(11):4158–4165CrossRefGoogle Scholar
  26. 26.
    Oh S, Jang HJ, Ko SK, Ko Y, Park SB (2010) Construction of a polyheterocyclic benzopyran library with diverse core skeletons through diversity-oriented synthesis pathway. J Comb Chem 12(4):548–558CrossRefGoogle Scholar
  27. 27.
    Zhou H, Zhang W, Yan B (2010) Use of cyclohexylisocyanide and methyl 2-isocyanoacetate as convertible isocyanides for microwave-assisted fluorous synthesis of 1,4-benzodiazepine-2,5-dione library. J Comb Chem 12(1):206–214CrossRefGoogle Scholar
  28. 28.
    Liu A, Zhou H, Su G, Zhang W, Yan B (2009) Microwave-assisted fluorous synthesis of a 1,4-benzodiazepine-2,5-dione library. J Comb Chem 11(6):1083–1093CrossRefGoogle Scholar
  29. 29.
    Zhang T, Gao X, Wood HB (2011) Pd-catalyzed Negishi coupling of pyrazole triflates with alkyl zinc halides. Tetrahedron Lett 52(2):311–313CrossRefGoogle Scholar
  30. 30.
    Ye S, Ren H, Wu J (2010) Efficient assembly of 1-methylene-1H-indenes via palladium-catalyzed tandem reaction of 1-(2,2-dibromovinyl)-2-alkenylbenzene with arylboronic acid. J Comb Chem 12(5):670–675CrossRefGoogle Scholar
  31. 31.
    Lange PP, James K (2012) Rapid access to compound libraries through flow technology: fully automated synthesis of a 3-aminoindolizine library via orthogonal diversification. ACS Comb Sci 14(10):570–578CrossRefGoogle Scholar
  32. 32.
    Wang M, Tan C, He Q, Xie Y, Yang C (2013) A novel convenient approach towards pyrrolo[1,2-b]pyridazines through a domino coupling–isomerization–condensation reaction. Org Biomol Chem 11:2574–2577CrossRefGoogle Scholar
  33. 33.
    Rao RM, Reddy U, Alinakhi CH, Mulakayala N, Alvala M, Arunasree MK, Poondra RR, Javed J, Pal M (2011) Sequential coupling/desilylation–coupling/cyclization in a single pot under Pd/C–Cu catalysis: synthesis of 2-(hetero)aryl indoles. Org Biomol Chem 9:3808–3816CrossRefGoogle Scholar
  34. 34.
    Wang Z, Wu J (2008) Synthesis of 1H-indol-2-yl-(4-aryl)-quinolin-2(1H)-ones via Pd-catalyzed regioselective cross-coupling reaction and cyclization. Tetrahedron 64(8):1736–1742CrossRefGoogle Scholar
  35. 35.
    Goh WK, StC Black D, Kumar N (2007) Synthesis of novel 7-substituted 5,6-dihydroindol-2-ones via a Suzuki–Miyaura cross-coupling strategy. Tetrahedron Lett 48(51):9008–9011CrossRefGoogle Scholar
  36. 36.
    Antonow D, Cooper N, Howard PW, Thurston DE (2007) Parallel synthesis of a novel C2-aryl pyrrolo[2,1-c][1,4]benzodiazepine (PBD) library. J Comb Chem 9(3):437–445CrossRefGoogle Scholar
  37. 37.
    Organ MG, Mayer S, Lepifre F, N’Zemba B, Khatri J (2003) Combining the use of solid-supported transition metal catalysis with microwave irradiation in solution-phase parallel library synthesis. Mol Divers 7:211–227CrossRefGoogle Scholar
  38. 38.
    Pla D, Marchal A, Olsen CA, Francesch A, Cuevas C, Albericio F, Álvarez M (2006) Synthesis and structure−activity relationship study of potent cytotoxic analogues of the marine alkaloid lamellarin D. J Med Chem 49(11):3257–3268CrossRefGoogle Scholar
  39. 39.
    Mugnaini C, Falciani C, De Rosa M, Brizzi A, Pasquini S, Corelli F (2011) Regioselective functionalization of quinolin-4(1H)-ones via sequential palladium-catalyzed reactions. Tetrahedron 67(32):5776–5783CrossRefGoogle Scholar
  40. 40.
    Wang Z, Wang B, Wu J (2007) Diversity-oriented synthesis of functionalized quinolin-2(1H)-ones via Pd-catalyzed site-selective cross-coupling reactions. J Comb Chem 9(5):811–817CrossRefGoogle Scholar
  41. 41.
    De Giorgi M, Voisin-Chiret AS, Sopková-de Oliveira Santos J, Corbo F, Franchini C, Rault S (2011) Design and synthesis of thienylpyridyl garlands as non-peptidic alpha helix mimetics and potential protein–protein interactions disruptors. Tetrahedron 67(34):6145–6154Google Scholar
  42. 42.
    Miguez JMA, Adrio LA, Sousa-Pedrares A, Vila JM, Hii KK (2007) A practical and general synthesis of unsymmetrical terphenyls. J Org Chem 72(20):7771–7774CrossRefGoogle Scholar
  43. 43.
    Wu J, Wang L, Fathi R, Yang Z (2002) Palladium-catalyzed cross-coupling reactions of 4-tosylcoumarin and arylboronic acids: synthesis of 4-arylcoumarin compounds. Tetrahedron Lett 43(24):4395–4397CrossRefGoogle Scholar
  44. 44.
    Vishnumurthy K, Makriyannis A (2010) Novel and efficient one-step parallel synthesis of dibenzopyranones via Suzuki–Miyaura cross coupling. J Comb Chem 12(5):664–669CrossRefGoogle Scholar
  45. 45.
    Zhang Y, Lv Z, Zhong H, Zhang M, Zhang T, Zhang W, Li K (2012) Efficient Heck cross-coupling of 3-iodo-benzopyrones with olefins under microwave irradiation without phosphine. Tetrahedron 68(47):9777–9787CrossRefGoogle Scholar
  46. 46.
    Cho C-H, Shi F, Jung D-I, Neuenswander B, Lushington GH, Larock RC (2012) Solution-phase synthesis of a highly substituted furan library. ACS Comb Sci 14(7):403–414CrossRefGoogle Scholar
  47. 47.
    Mehta S, Waldo JP, Neuenswander B, Lushington GH, Larock RC (2013) Solution-phase parallel synthesis of a multisubstituted cyclic imidate library. ACS Comb Sci 15(5):247–254CrossRefGoogle Scholar
  48. 48.
    Cho C-H, Neuenswander B, Lushington GH, Larock RC (2008) Parallel synthesis of a multi-substituted benzo[b]furan library. J Comb Chem 10(6):941–947CrossRefGoogle Scholar
  49. 49.
    Roy S, Roy S, Neuenswander B, Hill D, Larock RC (2009) Solution-phase synthesis of a diverse isocoumarin library. J Comb Chem 11(6):1128–1135CrossRefGoogle Scholar
  50. 50.
    Cho C-H, Neuenswander B, Larock RC (2010) Diverse methyl sulfone-containing benzo[b]thiophene library via iodocyclization and palladium-catalyzed coupling. J Comb Chem 12(2):278–285CrossRefGoogle Scholar
  51. 51.
    Cho C-H, Neuenswander B, Lushington GH, Larock RC (2009) Solution-phase parallel synthesis of a multi-substituted benzo[b]thiophene library. J Comb Chem 11(5):900–906CrossRefGoogle Scholar
  52. 52.
    Davey PRJ, Delouvrié B, Dorison-Duval D, Germain H, Harris CS, Magnien F, Ouvry G, Tricotet T (2012) Facile preparation and Suzuki–Miyaura cross-coupling of N-2-alkylated 2H-1,2,3-triazole 4-boronates. Tetrahedron Lett 53(50):6849–6852CrossRefGoogle Scholar
  53. 53.
    Xie F, Li S, Bai D, Lou L, Hu Y (2007) Three-component, one-pot synthesis of 2,4,5-substituted pyrimidines library for screening against human hepatocellular carcinoma BEL-7402 cells. J Comb Chem 9(1):12–13CrossRefGoogle Scholar
  54. 54.
    Kumar S, Painter TO, Pal BK, Neuenswander B, Malinakova HC (2011) Application of sequential Cu(I)/Pd(0)-catalysis to solution-phase parallel synthesis of combinatorial libraries of dihydroindeno[1,2-c]isoquinolines. ACS Comb Sci 13(5):466–477CrossRefGoogle Scholar
  55. 55.
    Chekmarev DS, Stepanov AE, Kasatkin AN (2005) Highly selective mono-substitution in Pd-catalyzed cross-coupling reactions of 3,6-dichloropyridazine with organozinc compounds. Tetrahedron Lett 46(8):1303–1305CrossRefGoogle Scholar
  56. 56.
    Ma Z, Xiang Z, Luo T, Lu K, Xu Z, Chen J, Yang Z (2006) Synthesis of functionalized quinolines via Ugi and Pd-catalyzed intramolecular arylation reactions. J Comb Chem 8(5):696–704CrossRefGoogle Scholar
  57. 57.
    Yaziji V, Coelho A, El Maatougui A, Brea J, Loza MI, Garcia-Mera X, Sotelo E (2009) Divergent solution-phase synthesis of diarylpyrimidine libraries as selective A3 adenosine receptor antagonists. J Comb Chem 11(4):519–522CrossRefGoogle Scholar
  58. 58.
    Waldo JP, Mehta S, Neuenswander B, Lushington GH, Larock RC (2008) Solution phase synthesis of a diverse library of highly substituted isoxazoles. J Comb Chem 10(5):658–663CrossRefGoogle Scholar
  59. 59.
    Worlikar SA, Neuenswander B, Lushington GH, Larock RC (2009) Highly substituted indole library synthesis by palladium-catalyzed coupling reactions in solution and on a solid support. J Comb Chem 11(5):875–879CrossRefGoogle Scholar
  60. 60.
    Bartoccini F, Piersanti G, Mor M, Tarzia G, Minetti P, Cabri W (2012) Divergent synthesis of novel 9-deazaxanthine derivatives via late-stage cross-coupling reactions. Org Biomol Chem 10:8860–8867CrossRefGoogle Scholar
  61. 61.
    Markina NA, Mancuso R, Neuenswander B, Lushington GH, Larock RC (2011) Solution-phase parallel synthesis of a diverse library of 1,2-dihydroisoquinolines. ACS Comb Sci 13(3):265–271CrossRefGoogle Scholar
  62. 62.
    Thornton PD, Brown N, Hill D, Neuenswander B, Lushington GH, Santini C, Buszek KR (2011) Application of 6,7-indole aryne cycloaddition and Pd(0)-catalyzed Suzuki–Miyaura and Buchwald–Hartwig cross-coupling reactions for the preparation of annulated indole libraries. ACS Comb Sci 13(5):443–448CrossRefGoogle Scholar
  63. 63.
    Aggarwal T, Imam M, Kaushik NK, Chauhan VS, Verma AK (2011) Pyrano[4,3-b]quinolines library generation via iodocyclization and palladium-catalyzed coupling reactions. ACS Comb Sci 13(5):530–536CrossRefGoogle Scholar
  64. 64.
    Rolfe A, Young K, Volp K, Schoenen F, Neuenswander B, Lushington GH, Hanson PR (2009) One-pot, three-component, Domino Heck-aza-Michael approach to libraries of functionalized 1,1-dioxido-1,2-benzisothiazoline-3-acetic acids. J Comb Chem 11(4):732–738CrossRefGoogle Scholar
  65. 65.
    Zang Q, Javed S, Porubsky P, Ullah F, Neuenswander B, Lushington GH, Basha FZ, Organ MG, Hanson PR (2012) Synthesis of a unique isoindoline/tetrahydroisoquinoline-based tricyclic sultam library utilizing a Heck-aza-Michael strategy. ACS Comb Sci 14(3):211–217CrossRefGoogle Scholar
  66. 66.
    Tanimoto K, Nakagawa N, Takeda K, Kirihata M, Tanimori S (2013) A convenient one-pot access to phenanthridinones via Suzuki–Miyaura cross-coupling reaction. Tetrahedron Lett 54(28):3712–3714CrossRefGoogle Scholar
  67. 67.
    Soto S, Vaz E, Dell'Aversana C, Álvarez R, Altucci L, de Lera ÁR (2012) New synthetic approach to paullones and characterization of their SIRT1 inhibitory activity. Org Biomol Chem 10:2101–2112CrossRefGoogle Scholar
  68. 68.
    Katkevica S, Salun P, Jirgensons A (2013) Synthesis of 5-substituted 3-mercapto-1,2,4-triazoles via Suzuki–Miyaura reaction. Tetrahedron Lett 54(34):4524–4525CrossRefGoogle Scholar
  69. 69.
    Molander GA, Febo-Ayala W, Jean-Gérard L (2009) Condensation reactions to form oxazoline-substituted potassium organotrifluoroborates. Org Lett 11(17):3830–3833CrossRefGoogle Scholar
  70. 70.
    Gros P, Doudouh A, Fort Y (2004) New polystyrene-supported stable source of 2-pyridylboron reagent for Suzuki couplings in combinatorial chemistry. Tetrahedron Lett 45(33):6239–6241CrossRefGoogle Scholar
  71. 71.
    Lee SJ, Gray KC, Paek JS, Burke MD (2008) Simple, efficient, and modular syntheses of polyene natural products via iterative cross-coupling. J Am Chem Soc 130(2):466–468CrossRefGoogle Scholar
  72. 72.
    Khanapure SP, Garvey DS (2004) Use of highly reactive, versatile and air-stable palladium–phosphinous acid complex [(t-Bu)2P(OH)]2PdCl2 (POPd) as a catalyst for the optimized Suzuki–Miyaura cross-coupling of less reactive heteroaryl chlorides and arylboronic acids. Tetrahedron Lett 45(27):5283–5286CrossRefGoogle Scholar
  73. 73.
    Daykin LM, Siddle JS, Ankers AL, Batsanov AS, Bryce MR (2010) Iterative and regioselective cross-couplings of 2-chloro-3,4-diiodopyridine leading to 2,3,4-triheteroarylpyridines. Tetrahedron 66(3):668–675CrossRefGoogle Scholar
  74. 74.
    Bondoux M, Mignon L, Ou K, Renaut P, Thomas D, Barberousse V (2009) Palladium-catalyzed C–C coupling: efficient preparation of new 5-thio-β-D-xylopyranosides as oral venous antithrombotic drugs. Tetrahedron Lett 50(27):3872–3876CrossRefGoogle Scholar
  75. 75.
    Fraser AW, Besaw JE, Hull LE, Baird MC (2012) Pd(η3–1-PhC3H4)(η5-C5H5), an unusually effective catalyst precursor for Suzuki–Miyaura cross-coupling reactions catalyzed by bis-phosphine palladium(0) compounds. Organometallics 31(6):2470–2475CrossRefGoogle Scholar
  76. 76.
    Szommer T, Lukács A, Szabó MJ, Hoffmann MG, Schmitt MH, Gerencsér J (2012) Parallel synthesis of 1,2,4-triazole derivatives using microwave and continuous-flow techniques. Mol Divers 16:81–90CrossRefGoogle Scholar
  77. 77.
    Michalik D, Kumar K, Zapf A, Tillack A, Arlt M, Heinrich T, Beller M (2004) A short and efficient synthesis of N-aryl- and N-heteroaryl-N′-(arylalkyl)piperazines. Tetrahedron Lett 45(10):2057–2061CrossRefGoogle Scholar
  78. 78.
    Hanthorn JJ, Valgimigli L, Pratt DA (2012) Preparation of highly reactive pyridine- and pyrimidine-containing diarylamine antioxidants. J Org Chem 77(16):6908–6916CrossRefGoogle Scholar
  79. 79.
    Brachet E, Peyrat J-F, Brion J-D, Messaoudi S, Alami M (2013) A palladium-catalyzed coupling of 3-chloroquinoxalinones with various nitrogen-containing nucleophiles. Org Biomol Chem 11:3808–3816CrossRefGoogle Scholar
  80. 80.
    Amatore C, Jutand A, LeDuc G (2011) Kinetic data for the transmetalation/reductive elimination in palladium-catalyzed Suzuki–Miyaura reactions: unexpected triple role of hydroxide ions used as base. Chem Eur J 17(8):2492–2503CrossRefGoogle Scholar
  81. 81.
    Schmitt M, de Araújo-Júnior JX, Oumouch S, Bourguignon J-J (2006) Use of 4-bromo pyridazine 3,6-dione for building 3-amino pyridazine libraries. Mol Divers 10:429–434CrossRefGoogle Scholar
  82. 82.
    Liu J, Wang X (2011) Microwave-assisted, divergent solution-phase synthesis of 1,3,6-trisubstituted pyrazolo[3,4-d]pyrimidines. ACS Comb Sci 13(4):414–420CrossRefGoogle Scholar
  83. 83.
    Heo Y, Song YS, Kim BT, Heo J-N (2006) A highly regioselective synthesis of 2-aryl-6-chlorobenzothiazoles employing microwave-promoted Suzuki–Miyaura coupling reaction. Tetrahedron Lett 47(18):3091–3094CrossRefGoogle Scholar
  84. 84.
    Organ MG, Mayer S (2003) Synthesis of 4-(5-Iodo-3-methylpyrazolyl) phenylsulfonamide and its elaboration to a COX II inhibitor library by solution-phase Suzuki coupling using Pd/C as a solid-supported catalyst. J Comb Chem 5(2):118–124CrossRefGoogle Scholar
  85. 85.
    Peng J, Lin W, Jiang D, Yuan S, Chen Y (2007) Preparation of a 7-arylthieno[3,2-d]pyrimidin-4-amine library. J Comb Chem 9(3):431–436CrossRefGoogle Scholar
  86. 86.
    Ye C, Chen Z, Wang H, Wu J (2012) Generation of diverse 1-(isoquinolin-1-yl)guanidines via a sequential multi-component/cross-coupling reaction. Tetrahedron 68(26):5197–5202CrossRefGoogle Scholar
  87. 87.
    Yu X, Pan X, Wu J (2011) An efficient route to diverse H-pyrazolo[5,1-a]isoquinolines via sequential multi-component/cross-coupling reactions. Tetrahedron 67(6):1145–1149CrossRefGoogle Scholar
  88. 88.
    Welsch ME, Snyder SA, Stockwell BR (2010) Privileged scaffolds for library design and drug discovery. Curr Op Chem Biol 14:1–15Google Scholar

Copyright information

© Springer International Publishing Switzerland 2014

Authors and Affiliations

  • János Gerencsér
    • 1
  • Árpád Balázs
    • 1
  • György Dormán
    • 2
  1. 1.ComInnex Inc.BudapestHungary
  2. 2.ThalesNano Inc.BudapestHungary

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