synthesis of biaryls via catalytic decarboxylative...

Synthesis of Biaryls via Catalytic Decarboxylative Coupling L. J. Goossen,* G. Deng, L. M. Levy

Science 2006, 313, 662.

Silver-Catalysed Protodecarboxylation of Carboxylic Acids L. J. Goossen,* C. Linder, N. Rodriguez, P. P. Lange, A. Fromm

Chem. Commun. 2009, 46, 7173-7175.

FB Chemie – Organische Chemie, TU Kaiserslautern, Erwin-Schroedinger-Strasse, Geb. 54, 67663 Kaiserslautern, Germany.

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  The biaryl moiety: important structural motif in a great number of biologically active compounds.

  In 2006: Diovan (Valsartan), Novartis, US $4.2 billion sales.

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Introduction

J. Hassan, M. Sevignon, C. Gozzi, E. Schulz, M. Lemaire, Chem. Rev. 2002, 102, 1359-1469.

  Main drawbacks:

-  Scholl reaction, Gomberg-Bachmann reaction, Ullmann couplings: harsh conditions, low yields for the unsymmetrically substituted biaryls, stoichiometric use of copper.

-  Directed ortho-metalation: limited to a narrow range of substrates.

-  Cross-coupling reactions: the most generally applicable strategy but requires the use of stoichiometric amounts of expensive organometallic compounds which have to be prepared from sensitive precursors under elaborate anaerobic conditions.

4

Introduction

  Main advantage of aromatic carboxylic acids: metal salts are easily available at low cost and air/moisture stable.

  Strategy could be achieved with a bimetallic catalyst:

- A copper complex capable of mediating the strongly endothermic extrusion of CO2.

- A two-electron catalyst capable of catalysing the cross-coupling with an aryl halide.

Why ?:

- Copper: metal of choice for decarboxylation step as it was already widely used in protodecarboxylation procedures, but not the appropriate catalyst for the cross-coupling step (M. B. Smith, J. March, Advanced Organic Chemistry, 4th ed.; Wiley: New-York, 1992; pp 563-564).

- Palladium: seems to be a more promising candidate as it is known to catalyse a large number of two-electron cross-coupling reactions.

5

Introduction

Results & Discussion

6 L. J. Goossen, N. Rodriguez, B. Melzer, C. Linder, G. Deng, L. M. Levy, J. Am. Chem. Soc. 2007, 129, 4824-4833.


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  Both electron-rich and electron-poor derivatives successfully converted.

  Broad range of functional groups tolerated.

  Aryl bromides, iodides, or chlorides suitable.

J. Am. Chem. Soc. 2007, 129, 4824-4833.


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  Variation of the aryl halide is easy.

  Extension to other carboxylic acids is troublesome:

- Stoichiometric amount of copper: notable but limited range of substrates can be converted. - Catalytic amount in copper: limited to 2-nitrobenzoic acids.

→ A good balance of the rates of the decarboxylation and cross-coupling steps is crucial to achieve high yield of the biaryls Need to design effective catalyst systems

Relative activity of carboxylic acids toward decarboxylation studied (CO2 extrusion: rate-determining step).

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  A broad range of carboxylic acids smoothly decarboxylates at a sufficiently high rate.

  Addition of halide salt retards the decarboxylation step: competition with carboxylates for coordination sites at the copper.

  Phenanthroline needed for a sufficient level of activity.

  Carboxylic acids divided in 2 categories:

-  Some only decarboxylate with the phenanthroline copper catalyst in absence of bromide ion. → will require stoichiometric amount of copper.

-  Others tolerate the presence of halides. → catalytic amount of copper should suffice.

Many ortho-substituted or heterocyclic carboxylic acids are least affected by the presence of halides

Coordination to the copper in a bidentate fashion which helps to

compete successfully with the halide for the required coordination site at the copper.

J. Am. Chem. Soc. 2007, 129, 4824-4833.

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10 L. J. Goossen, W. R. Thiel, N. Rodriguez, C. Linder, B. Melzer, Adv. Synth. Catal. 2007, 349, 2241-2246.

  DFT calculations on the decarboxylation step:

Decarboxylation is endothermic and endergonic at 298 K and ortho-substituents able to withdraw electron-density through the σ-backbone significantly reduce the free reaction energy

Reactivity of benzoic acids dominated by short-range inductive effects transmitted by the σ-backbone while long-range mesomeric effects through π-system play a minor role.

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  Key: to achieve a general process catalytic in both metals by inducing a stonger preference of the copper for the carboxylate over bomide ions by tuning its ligand environment.

  10% CuBr/phenanthroline + 3% PdBr2: applicable for a wide range of derivatives.

  Catalytic system in copper: limited to ortho-substituted or heterocyclic carboxylic acids → coordination to copper in a chelating fashion → successful competition with halides for coordination sites.

  Nevertheless stoichiometric amounts of copper still needed for some other substrates.

J. Am. Chem. Soc. 2007, 129, 4824-4833.


12 L. J. Goossen, B. Melzer, J. Org. Chem. 2007, 72, 7473-7476.

  Novartis patent literature syntheses via Suzuki-Miyaura cross-coupling:


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J. Org. Chem. 2007, 72, 7473-7476.

  Optimisation of the catalyst system and conditions for the key coupling step:

NC

HO2C+

R

Br

catalyst, ligand

base

R

NC

R= Me CHO 1,3-dioxolane CH(OMe)2

R= Me CHO

➭ NC

HO2C+

Br NC

OMeMeO

HO

2% PdBr2, 15% CuOKF, PPh3

quinoline170°C, 24h00

80%

Acetal hydrolyzed during acidic work-up

  Completion of the synthesis:

➭ Overall yield 39% (4 steps).


14 L. J. Goossen, B. Zimmermann, T. Knauber, Angew. Chem. Int. Ed. 2008, 47, 7103-7106.

NO2

O

O

K+

OMe

Cl

NO2OMeCuI

1,10-phenanthrolinePd source, phosphane

NMP, 160°C

Need to facilitate insertion in the C-Cl bond

Use of bulky and electron-rich phosphane to increase electron-density at the palladium center

Catalyst system: 2 mol% CuI, 2 mol% PdI2, 2 mol% 1,10-phenanthroline, 2 mol% (o-biphenyl)PtBu2.

First-generation catalyst system (1 mol% CuI, 1,10-phenanthroline, 0.5 mol% Pd(acac)2) inactive (0% yield)

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15 Angew. Chem. Int. Ed. 2008, 47, 7103-7106.


16 L. J. Goossen, N. Rodriguez, C. Linder, J. Am. Chem. Soc. 2008, 130, 15248-15249.

  First-generation catalytic system: limited to complexing substrates such as heterocyclic or ortho-substituted benzoic acid due to thermodynamically unfavorable exchange of a halide for a nonortho-substituted benzoate derivative at the copper center.

  Solution: replace aryl halides by aryl triflates → triflate ions: weakly coordinating to the copper.

First-generation catalyst system (1 mol% CuI, 1,10-phenanthroline, 0.5 mol% Pd(acac)2) not effective (34% yield)

Use of sterically demanding /moderately electron-rich chelating phosphine

Catalyst system: 7.5 mol% Cu2O, 3 mol% PdI2, 15 mol% 1,10-phenanthroline, 4.5 mol% Tol-BINAP.

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➭

O

O

K+

TfO

Cu- and Pd-sourceN-ligand, phosphine

NMP, 170°C

O2NO2N


17 J. Am. Chem. Soc. 2008, 130, 15248-15249.


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  Protodecarboxylation can be made catalytic in copper and extended to the full range of benzoic acids.

  Direct insertion of copper catalyst into the aryl carboxylate bond without previous formation of a π-coordinated intermediate: both CO2 and [(phen)Cu]+ bound through the lone pair of the phenyl anion.

  Proposed mechanism:

Adv. Synth. Catal. 2007, 349, 2241-2246.

Molecular structure of the transition state


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N N

N N

Ph Ph

3a

3c

Adv. Synth. Catal. 2007, 349, 2241-2246.

  Protodecarboxylation also promoted by microwave irradiation → reduction of reaction times, higher yields, lower loading of catalyst (J. Org. Chem. 2009, 74, 2620-2623).


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  Compared DFT calculations on the decarboxylation step:

With silver(I) carboxylate: extrusion of CO2 is exergonic and has a lower activation barrier of ΔG≠

298 = 29.6 kcal/mol compared to copper carboxylate.

  Calculated reaction path for Ag(I)-catalysed protodecarboxylation: formation of the NMP-stabilised 2-fluorophenyl silver complex also exergonic with ΔG≠

298 = 28.8 kcal/mol.

  Until now, silver was only known as an untypical mediator for protodecarboxylations and used in overstoichiometric amounts as co-mediator.

L. J. Goossen, C. Linder, N. Rodriguez, P. P. Lange, A. Fromm, Chem. Commun. 2009, 46, 7173-7175.


21 Chem. Commun. 2009, 46, 7173-7175.

  Main advantage: reaction temperature reduced to 120°C.


22 Chem. Commun. 2009, 46, 7173-7175.

  Broad scope with Ag-catalyst system.

  Ag-catalyst system complements the results obtained with Cu-catalyst system.

  New opportunities for low-temperature decarboxylative cross-coupling:


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J. Cornella, C. Sanchez, D. Banawa, I. Larrosa, Chem. Commun. 2009, 46, 7176-7178.

  Simple and convenient procedure to decarboxylate ortho-substituted benzoic acids (published the same day as Goossen’s one !!!): Cl

CO2H

NO2

Cl

NO2

+ CO2

10 mol% Ag2CO3DMSO

120°C, 16h00

  Substrate scope:

  Main drawback: limited to ortho-substituted benzoic acids.

  Main advantage: not air/moisture sensitive.


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P. Liu, C. Sanchez, J. Cornella, I. Larrosa, Org. Lett. 2009, 11 (24), 5710-5713.

  Ag-catalyst system can also promote decarboxylation of heteroaromatic carboxylic acids: 10 mol% Ag2CO3, 5 mol% AcOH, DMSO, 120°C.

→ Substrates with a carboxylic acid in α-position of the heteratom (furans, thiophenes, pyridines, quinolines, benzofurans...).

→ Regioselective monoprotodecarboxylation of aromatic dicarboxylic acids:

synthesis of biaryls via catalytic decarboxylative...

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