synthesis of biaryls via catalytic decarboxylative...
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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.
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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.
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5
Introduction
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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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Results & Discussion
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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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Results & Discussion
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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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Results & Discussion
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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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Results & Discussion
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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Results & Discussion
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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.
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Results & Discussion
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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Results & Discussion
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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).
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Results & Discussion
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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Results & Discussion
15 Angew. Chem. Int. Ed. 2008, 47, 7103-7106.
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Results & Discussion
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
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Results & Discussion
17 J. Am. Chem. Soc. 2008, 130, 15248-15249.
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Results & Discussion
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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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Results & Discussion
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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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Results & Discussion
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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.
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Results & Discussion
21 Chem. Commun. 2009, 46, 7173-7175.
Main advantage: reaction temperature reduced to 120°C.
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Results & Discussion
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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Results & Discussion
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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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Results & Discussion
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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: