The 2-Pyridyl Problem: Challenging Nucleophiles in Cross-Coupling Arylations

Abstract

Azine-containing biaryls are ubiquitous scaffolds in many areas of chemistry, and efficient methods for their synthesis are continually desired. Pyridine rings are prominent amongst these motifs. Transition-metal-catalysed cross-coupling reactions have been widely used for their synthesis and functionalisation as they often provide a swift and tuneable route to related biaryl scaffolds. However, 2-pyridine organometallics are capricious coupling partners and 2-pyridyl boron reagents in particular are notorious for their instability and poor reactivity in Suzuki-Miyaura cross-coupling reactions. The synthesis of pyridine-containing biaryls is therefore limited, and methods for the formation of unsymmetrical 2,2'-bis-pyridines are scarce. This Review focuses on the methods developed for the challenging coupling of 2-pyridine nucleophiles with (hetero)aryl electrophiles, and ranges from traditional cross-coupling processes to alternative nucleophilic reagents and novel main group approaches.

Keywords: biaryl; catalysis; palladium; pyridine; synthetic methods.

Figure 1

Pyridine‐derivatives across various applications.

Scheme 1

Synthesis of 2‐pyridine‐containing biaryls: scope of this Review.

Scheme 2

Selected examples of Negishi cross‐couplings catalysed by Pd(PPh₃)₄. rt=room temperature; THF=tetrahydrofuran; SPhos=2‐dicyclohexylphosphino‐2′,6′‐dimethoxybiphenyl.

Scheme 3

Use of XPhos Pd G3‐amido precatalyst for Negishi couplings under mild reaction conditions.

Scheme 4

Copper‐catalysed coupling of electron‐deficient (hetero)arenes via direct zincation. tmp=2,2,6,6‐tetramethylpiperidine. EWG=electron withdrawing group.

Scheme 5

SPO ligands enabling the Kumada coupling of 2‐pyridyl Grignard reagents.

Scheme 6

Sequential assembly with two Grignard reagents, titanium as the coupling agent and under Fe or Co catalysis. TMEDA=tetramethylethylenediamine; DMPU=N,N′‐dimethylpropyleneurea.

Scheme 7

Selected scope examples, featuring sensitive functionality, of organogermane cross‐couplings to aryl iodides. dba=dibenzylideneacetone.

Scheme 8

The 2‐pyridyl alane cross‐coupling with scope examples.

Scheme 9

Developments of the Hiyama coupling to 2‐pyridyl substrates.

Scheme 10

Novel catalytic systems for the coupling of aryltriethylsilanes with aryl bromides.

Figure 2

Schematic of the Suzuki–Miyaura cross‐coupling.

Figure 3

Boron‐reagents unstable towards protodeboronation (according to pH studies by Lloyd‐Jones and co‐workers).

Scheme 11

Proposed mechanism for the protodeboronation of 2‐pyridyl boronic acid.

Scheme 12

Copper‐assisted SMC of 2‐pyridyl Bpin. [a] No CuCl.

Figure 4

Proposed roles of copper in the SMC of 2‐pyridyl boronates. 1) Irreversible transmetalation. 2) Reversible coordination.

Figure 5

Boron‐derived 2‐pyridyl reagents.

Scheme 13

Use of TBA 2‐pyridyltriolborate salts in SMC. dcpp=1,3‐bis(dicyclohexylphosphino)propane.

Scheme 14

Selected scope from the SMC of lithium 2‐pyridyl−B(OⁱPr)₃ reagents.

Scheme 15

Selected examples of the coupling of PDEA boronates.

Scheme 16

Use of 2‐pyridyl−B(MIDA) in SMC reactions.

Figure 6

The proposed “attenuation” strategy.

Scheme 17

Micelle‐catalysed coupling of 6‐substituted pyridyl−B(MIDA).

Scheme 18

The coupling of 2‐pyridyl−BF₃K reagents.

Scheme 19

The slow‐release mechanism of aryl−BF₃K reagents.

Scheme 20

Direct SMC reaction of 2‐pyridyl−B(aam) reagents.

Figure 7

Coupling of Aryl−B(dan) and the role of KO^tBu.

Scheme 21

Direct coupling of 2‐pyridyl−B(dan).

Scheme 22

Representative picolinic acid decarboxylative cross‐coupling catalytic cycle with competing pathways.

Scheme 23

Decarboxylative cross‐coupling scope. BINAP=2,2′‐bis(diphenylphosphino)‐1,1′‐binaphthalene.

Scheme 24

N‐oxide decarboxylative cross‐coupling examples showing that [Ag] outperformed [Cu]. Transition states investigated by DFT calculations for the decarboxylative‐metalation step.

Scheme 25

Selected scope examples. [a] Ag₂CO₃ (5 mol %) used instead of Cu₂O.

Scheme 26

Extrusion of SO₂ from 2‐pyridyl sulfinate palladium complexes.

Scheme 27

Simplified 2‐pyridyl allylsulfone desulfinative cross‐coupling mechanism.

Scheme 28

Summary of Willis group desulfinative cross‐coupling reactions.

Scheme 29

Heterobiaryl three‐step synthetic sequence via phosphorus ligand coupling. DBU=1,8‐diazabicyclo[5.4.0]undec‐7‐ene.

Scheme 30

Scope examples of 2,2′‐bipyridines formed by P^V contractive methodology. [a] Alternative conditions were used for quinolines/diazines (6 examples, 62–95 % yield). [b] Yields after coupling (steps 1 and 2).

Scheme 31

Sulfur(IV)‐mediated unsymmetrical heterocycle cross‐couplings with selected 2‐pyridyl scope examples.

Scheme 32

C−H activation to solve the 2‐pyridyl problem.

Scheme 33

Pd‐catalysed CDC to heterobiaryl products.

Scheme 34

Rh‐catalysed C−H activation of pyridines with electrophiles.

Scheme 35

Pd‐catalysed CDC of pyridine N‐oxides.

Scheme 36

Cu‐mediated CDC of pyridine N‐oxides.

Scheme 37

Alternative routes to pyridine N‐oxide C−H activation.

Scheme 38

Pd‐catalysed C−H activation of pyridine N‐oxides with electrophiles.

Scheme 39

Catalytic cycle for the C−H activation of pyridine N‐oxides with electrophiles.

Scheme 40

Cu‐catalysed C−H activation of pyridines.

Scheme 41

Coupling N‐iminopyridinium ylides to electrophiles.

Scheme 42

Coupling N‐phenacylpyridinium halides with electrophiles.

Scheme 43

Coupling in situ generated N‐methyl pyridinium salts with electrophiles.