1.4 Antecedentes del Estudio
1.4.2 Investigaciones Internacionales
Cross-coupling reactions are among the most important chemical processes in the fine chemical and
pharmaceutical industries. These reactions represent the key steps in building complex molecules from simple precursors. Recently, there has been a burgeoning of interests in this area, mainly due to interest in coupling challenging substrates, such as electron rich aryl chlorides, triflates, nitriles, etc. Steric effect as well as the presence of sulfur on the substrate can play an adverse role in coupling reactions. One of the key mechanistic steps in coupling reactions is the oxidative addition of the aryl halide, Ar-X to Pd(0) (see below).
Reaction Temperature Pressure Solvent Catalyst
(°C) (bar)
Hydrosilylation of 25–75 1 None or Chloroplatinic acid,
alkenes hydrocarbons Pt–92, Pt–96,
Pt–112, Pt–114, Pt/AI2O3B301013-5,
B301099-5
Hydrosilylation of 25 1 Ethanol or Rh–93, Rh–100
alkyne to cis-alkene propan-2-ol
Hydrosilylation of 25 1 Acetonitrile Rh–93 + PPh3or
alkyne to trans-alkene Rh–100
Ar
General Mechanism of Coupling B
LnPd0 oxidative addition
Mehanism of Heck Coupling Mechanism of Heck Coupling
The ease of C-X bond cleavage is in the order I > Br > Cl.
The relative reactivities of Ar-X can be correlated to their respective bond dissociation energy:
Ph-Cl: 96 kcal/mol Ph-Br: 81 kcal/mol Ph-I: 65 kcal/mol
In some cases, the iodide system is active enough for coupling to occur in the absence of a ligand.Typically, a Ph3P-based Pd complex is suited for Ar-Br coupling, while Ar-Cl coupling is practically impossible, although there has been some success with activated aryl chlorides. Electron withdrawing substituents on the Ar ring activates the Ar-X bond, while electron donating groups have a deactivation effect on the Ar-X bond.
During the late 1990’s several academic groups (eg: Koie, Fu, Buchwald, Hartwig, Beller, etc.) found that electron-rich phosphines (aliphatic) in the presence of a Pd precursor favor the Ar-Cl addition to Pd(0). The bulkiness of the ligand (cone angle measures bulkiness) is also important, as it facilitates the reductive elimination step. In this regard, t-Bu3P acts as an excellent electron rich, bulky
monodentate ligand. However, t-Bu3P is a pyrophoric waxy solid and therefore difficult to handle in a conventional production environment.
Our research indicates that bidentate ligands are equally effective in coupling chemistry. It is well documented that the large bite angle of a bidentate ligand enhances the reductive elimination step. From a handling perspective, a fully formed, relatively air-stable yet active catalyst is a preferred choice.
Johnson Matthey offers advanced technology for coupling reactions. Several examples of these electron rich bulky monodentate and bidentate phosphine based “third generation” catalysts are given below.
4.7.1 Heck Reaction
A Japanese scientist, Mizoroki (1971) and an American scientist, Heck (1972) developed independently a protocol to couple an aryl or alkenyl halide with an olefin in the presence of a Pd based catalyst. These reactions can occur both inter- and intra-molecularly. The application of this chemistry includes the synthesis of hydrocarbons, conducting polymers, light emitting electrodes, dyes and enantioselective synthesis of natural products. An example of classical Heck reaction is demonstrated for the synthesis of anti-inflammatory agent- LTD4 antagonists1,2.
These reactions are promoted by a base, which neutralizes the liberated acid. Pd(0), stabilized with an aromatic phosphine ligand, is the active catalytic species (LnPd) and the favored reaction media are dipolar aprotic solvents such as acetonitrile, DMF, DMSO and DMA.
Recently Heck coupling has been applied to challenging substrates with the aid of the next generation catalysts.
P Pd P
Pd(t-Bu3P)2
P P
Br Pd
Br Pd
[Pd( μ-Br)t-Bu
3P]
2Fe Pd
Cl P Cl
P
Pd
Cl P Cl
P
di-t-bpfPdCl2 FibreCat 1032
Fe
Ph Ph Ph
P(t-Bu)
2Ph
Ph
Q-Phos
N
Cl O CO2Me
N
Cl CO2Me
Me CO2H N
Cl
Br
O CO2Me
3 mol% Pd(OAc)2 9 mol% P(o -Tol)3 Et3N / DMF / 100°C / 1.5 hr
(91%) +
>95% trans -isomer
L-699,392 (Merck-Frosst)
Pd-116
Pd-113
Pd-118
These catalysts have been successfully scaled up and tested in commercial processes.
Pd-catalyst Conversion Selectivity
Pd(0) (t-Bu3P)2can be also used for indole and azaindole syntheses by direct annulation.1 In the following example, enamine formation followed by intra molecular Heck coupling of an aryl chloride is speculated, rather than alpha ketone arylation followed by enamine.
4.7.2 Suzuki-Miyaura Coupling
Currently, Suzuki coupling is the most widely utilized Pd catalyzed coupling reaction in the Pharmaceutical and Fine Chemical industries. The coupling reaction involves the reaction of a substituted aryl boronic acid (nucleophile) with a substituted aryl halide, diazonium salt or triflate (electrophile) to produce biaryls. In general, Suzuki coupling reactions require milder conditions than the Heck reactions and are favored due to the non toxicity of the boron reagents.
Commercial examples include antihypertensive drug Valsartan (Novartis) and the fungicide Boscalid (BASF)2.
For challenging aryl chloride conversions several of Johnson Matthey’s third generation catalysts, including Pd-116, Pd-118 and Pd 119, provide significant advantages.
The di-tert-butylphosphinoferrocene palladium dichloride (Pd-118) is an air stable, yet highly active catalyst, which has been proven to be effective in Suzuki coupling. The following table illustrates the generality of the catalyst in Suzuki coupling towards a wide variety of substrates.3
Entry Substrate Catalyst yield (%)
loading
1 4-chlorotoluene 0.01 equiv 98
2 4-bromoanisole 0.01 equiv 100
3 4-chloroanisole 0.01 equiv 100
4 4-bromo-3-methylanisole 0.01 equiv 96 5 2-chlorothiophene 0.01 equiv 84 6 2-bromo-4-fluoroanisole 0.01 equiv 95 7 2-chloro-4-fluoroanisole 0.01 equiv 95 8 2-chloro-3-methylpyridine 0.01 equiv 89
9 2-chloro-4, 0.01 equiv 100
6-dimethoxytriazine
10 Bromomesitylene 0.01equiv 85
For moderately challenging substrates, such as bromothiophenes, chloropyridines, etc., the polymer supported Pd catalyst, FibreCat 1032 has shown good results. Following our preliminary report4, additional research from Abbott Laboratories 5, indicates that these are practical catalysts for conventional and microwave assisted Suzuki coupling. An example of the microwave assisted Suzuki coupling reaction is given below.
Cl R
1 Nazare, et.al., Angew. Chem. Int. Ed., 2004, 43, 4526-4528.
2 Rouhi, Chemical and Engineering News, 2004, 82, 49-58 3 Colacot & Shea, Org. Lett., 2004, 21, 3731.
4 Colacot et. al., Organometallics, 2002, 21, 3301.
5 Sauer et.al., Org. Lett., 2004, 6, 2793.
4.7.3 Alpha-ketone Arylation
Alpha-ketone arylation is a relatively new type of carbon-carbon coupling reaction, where an aryl halide is added to the alpha position of a carbonyl group by activating the CH. Early studies indicate that catalyst choice is critical in accomplishing this type of coupling. Initial results show that Pd-118 is a very good catalyst for such
transformations. An example is given below.
4.7.4 Carbon-heteroatom Coupling – e.g. Buchwald-Hartwig
Amination
Carbon–heteroatom coupling can be effected by a Pd-catalyzed reaction. This can include forming C-N, C-O, C-S and C-P bonds. The C-N bond forming process (amination) is often referred to as the Buchwald–Hartwig, although initial work was carried out by Koie and co workers in Japan.
A general scheme of amination and ether formation is shown below. As there is an acid by-product, a base is used, often a strong organic base such as NaOtBu to drive the reaction.
A wide variety of homogeneous Pd(0) catalysts can be used for the above reactions.
The new range of highly active Pd-catalysts are very suitable for this difficult coupling reaction. 113 and Pd-116 have been shown to catalyze a wide range of substrates including aryl chlorides and triflates. Air stable catalysts such as Pd-118 (Pd(dtbpf)Cl2) and Pd-107 (Pd(dppf)Cl2) show good activity for aryl chlorides and bromides, respectively.
The following example show the fast rates achieved with
Simple Pd(0) compounds such as Pd-101 Pd(PPh3)4or catalysts made from precursors such as Pd-111
[Pd(OAc)2]3, Pd-110 [Pd(allyl)Cl]2and Pd-94 Pd2(dba)3with suitable phosphine ligands can also be used, depending on the substrate.
4.7.5 Organometallic Reactions
In some reactions, a prerequisite is the production of an organometallic intermediate containing metals such as magnesium, tin, zinc or lithium.
These organometallic compounds can react with an aryl halide with the elimination of the metal halide and the subsequent formation of a coupled product. The best known general example of this type of reaction is probably the Grignard reaction.
In some cases these reactions proceed satisfactorily.
However, in other cases, the presence of a homogeneous palladium catalyst may dramatically improve the yield of the coupled product.
The relative positions of the substituents on the aromatic rings determine the point at which coupling occurs, i.e.
Heterocyclic ring coupling is also possible, e.g.
The organometallic reagent may in some cases be completely aliphatic, but coupling can still occur, e.g.
Palladium-catalyzed reactions of this type, involving the O
4.7.6 Sonogashira Reaction
Palladium catalysts can also be employed in the coupling of terminal alkynes with aryl or alkyl halides. The reaction, known as the Sonogashira reaction, generally involves the use of a palladium catalyst in conjunction with copper iodide, the copper reacting with the alkyne to form an alkynylcuprate.
Mild conditions are usually used for this reaction, often room temperature, allowing a large number of functional groups to be tolerated.
If the reaction is performed on an alkene, the geometry about the double bond is usually preserved, making this an extremely useful reaction for the synthesis of ene-yne molecules with specific geometry.
4.7.7 Palladacycles
The use and versatility of coupling reactions has increased recently with the advent of new Pd catalysts known as palladacycles.
The generic structure of such species is
Many of these complexes show not only increased activity over the more traditional catalysts, but also exhibit very good thermal and air stability. In the case of the phosphite catalysts developed by Bedford1(see below) these reactions can be performed in air without the drying of solvents or reagents – a major advance over the more conventional catalysts.
Their main advantage is activity – catalyst loadings as low as 10-4 mol % have been successfully used in reactions of aryl bromides.
1 D.A. Aldisson, R.B. Bedford, S.E. Lawrence and P.N. Scully 2 Chem. Comm. (1998) 2095
X = halide, acetate L = P or N
The Bedford bridging chloro palladacycle containing the tris (2,4-di-t-butyl phenyl) phosphite ligand – Pd 109.
O P Cl
Reaction Temperature Solvent Catalyst
(°C)
Heck 25–100 Various (e.g. toluene, THF) Pd–62, Pd–100, Pd–101,
Pd–106, Pd–108, Pd–109, Pd–111, Pd-116, Pd-119 FibreCat®–1001, 1002 Pd/C A109047-5, A405028-5,
A503023-5, A102023-5, A470085-5
Suzuki 25–100 Various Pd–101, Pd–109, Pd–111, Pd-113
Pd-118
FibreCat®–1001, 1002, 1032
Buchwald–Hartwig 80–100 THF or toluene Pd–106, Pd–107, Pd–113
Pd–111, Pd–116, Pd–118 FibreCat®–1001, 1002
Organometallic reactions 25–100 THF, dioxane, toluene or DMF Pd-62, Pd-100, Pd–101, Pd-103, Pd-106
Sonogashira reaction 25–120 THF or DMF Pd-100, Pd-101
FibreCat®1032