SubscribeSolvias has exclusively licensed a highly efficient CN-coupling technology for aromatic and heteroaromatic chlorides, bromides and sulfonates with amines and imines from Yale University (US patents 5,977,361 and US 6,235,938 B1).
The licensing of this CN-coupling technology represents a natural extension of Solvias' technology portfolio and is immediately available to our customers to sup-port industrial-scale manufacturing.
Introduction
Buchwald-Hartwig Amination reactions (CN-coupling reactions) are widely used in the pharmaceutical, agrochemical and speciality chemicals industry because they are high yielding and utilize relatively inexpensive starting materials such as primary and secondary amines or imines and aryl halides. However previously reported catalyst loadings for this transformation were often quite high (> 0.1 mol%). This resulted in high catalyst cost contributions, which limited the use of the technology for cheaper intermediates and commodity building blocks.
Outstanding performance of Josiphos based catalyst systems in CN-coupling: Lowest catalyst loading, high chemoselectivity
In recent publications, Prof. John F. Hartwig of Yale has described the outstanding performance of Josiphos-type ligands in this transformation. Josiphos, a proprietary chiral ligand from Solvias, has been used primarily for asymmetric transformations such as hydrogenations, allylic alkylations, ring-opening reactions, Grignard additions to á,â-unsaturated ketones, and Cu-catalyzed silane reductions.
Hartwig's publications now show that, for the first time, extremely low catalyst loadings (10 ppm) are sufficient for successful CN-coupling reactions. The use of Josiphos ligands combined with Pd(OAc)2 in CN-coupling reactions results in a very economical and industrially viable process. The scope of this transformation is very broad due to superior functional group tolerance and yields high purity products under very mild reaction conditions.
a) Coupling of aryl chlorides and bromides with 10-100 ppm of catalyst
Catalysts resulting from in situ mixing of Solvias Josiphos Ligand SL-J009-1 (air-stable diphosphine ligand) with Pd(OAc)2 couple primary amines very efficiently and selectively with aryl chlorides to yield secondary aryl amines. Under the described conditions, no tertiary amines are formed. For selected applications, catalyst loadings of only 10 ppm to 100 ppm yield full conversion1.
Typical conditions are 25-100 °C, DME or toluene as a solvent and NaOtBu as the base. Heteroaromatic rings as well as highly functionalized coupling partners work equally well. Even chlorophenols selectively couple to give the corresponding hydroxyanilines. As expected, an even better catalyst performance is obtained with aryl bromides. The catalyst loading depends strongly on the coupling partners and should be individually adjusted for best performance. At Solvias, we have found that high purity reactants are often important to achieve catalyst loadings in the ppm range.
Selected examples using aryl chlorides
Figure 1: Catalyst loading, reaction temperature and yield with Solvias' SL-J009-1.1
Selected examples using heteroaryl chlorides
Figure 2: Catalyst loading, reaction temperature and yield with Solvias' SL-J009-1.1
Selected examples using aryl bromides at 100 °C in DME:
Figure 3: Catalyst loading, reaction time and yield with Solvias' SL-J009-1.1
b) High chemoselectivity
An additional benefit of the Josiphos-based CN-coupling technology is their high chemoselectivity of primary amines over secondary amine coupling partners. Primary amines will couple first, and under optimized conditions no second addition is observed. This results in two key advantages of the Josiphos-based system:
1. Accessing secondary amines by coupling an arylhalide with a primary amine is readily achieved with no contamination with secondary amines. This results in better yields and increased purity.
2. Chemoselective coupling of a primary amine in the presence of a secondary amine. This feature significantly broadens the scope of CN-coupling technology and circumvents the need for protecting groups when assembling complex molecules. This results in lower production costs. The three cases of interest are depicted below:
Selected examples using aryl bromides at 100 °C in DME:
c) Coupling of aryl tosylates
Research by John Hartwig at Yale revealed that catalysts resulting from in situ mixing of Solvias Josiphos ligands SL-J002-1 or SL-J009-1 (air-stable diphosphine ligand) with Pd(OAc)2 or other Pd-based precursors couple primary amines efficiently and selectively with readily available aryl tosylates to give secondary aryl amines.2Catalyst loadings are generally higher than with the corresponding aryl halides.
Selected examples using aryl tosylates at room temperature and at 80°C
Figure 4: Reaction temperature, time and yield with Solvias' SL-J009-1 and SL-J002-1.2
Industrial relevance (stability of catalyst/ligand, availability in bulk)
Catalytic applications with such low catalyst loadings are of key industrial interest. As op-posed to many other novel catalyst systems, where industrial application can be delayed due to the nonavailability of the catalyst in commercial quantities, Solvias Josiphos ligands are available in bulk quantities (>> 50 kg) and are currently used in industrial-scale processes. As required for industrial applications the ligands are fully air-stable, non- hygroscopic crystalline solids.
Cleaning up metal and ligand residuals
Due to the high affinity of ferrocene based ligands to charcoal recovering catalyst (ligand and metal) residues from the bulk product is in most cases conveniently and cost-efficiently achieved with charcoal. No additional scavenging technology is typically required.
„Win-win" IP solutions
Companies wanting to utilize this technology will benefit from Solvias' simple "IP-included" per kilogram licensing model. With the purchase of the ligand/catalyst from Solvias, the client receives all rights to use the ligand/catalyst(s) in his CX-coupling reactions3.
Where to obtain screening amounts and bulk quantities
For immediate evaluation of the relevant Josiphos catalysts, Solvias Cat. No. SL-J009-1 (SIAL No# 88733; Strem No# 26-0975; CAS No# 158923-11-6 ) and SL-J002-1 (SIAL No# 88719; Strem No# 26-1200; CAS No# 155830-69-6) are sold in quantities up to 10 g from Sigma-Aldrich and Strem Chemicals. Quantities > 10 g to multi-kilograms can be purchased directly from Solvias.
New CX-Coupling Kit: SL-J009-1 and SL-J002-1 are also included in the new CX-Coupling Kit co-developed by Solvias and Umicore, which is distributed by Wako Chemicals (Japan), Solvias and Umicore. It contains a selection of the most important air- and moisture-stable coupling catalysts from both companies' portfolios: Solvias' Pd-cycle- 4 and diphosphine ligand catalysts, and Umicore's carbene-based Pd catalysts 5.
CX-Coupling Kit:
Pricing information CX-Coupling Kit:
660 EUR, 1010 CHF, 780 US$
Kit content: All vials contain 250 mg
- 8 Catalysts for Successful, Scalable Coupling Reactions with Aryl Chlorides, Bromides and Sulfonates
- CN-Coupling (Buchwald-Hartwig Amination Type)
- CC-Coupling (Suzuki, Heck, Kumada, Ketone Arylation, Negishi Type)
Kit contains 250mg of catalysts shown below plus Pd(dba)2 and Pd(OAc)2
L-J002-1 
SL-J009-1 SK-CC01-A 4 SK-CC02-A 4
(IPr)Pd(allyl)Cl 5 (IMes)Pd(allyl)Cl 5 (IPr)Pd(NQ)]2 5 [(IMes)Pd(NQ)]2 5
From mg to multi-kg using Solvias sophisticated kilolab
Solvias CX-Coupling screening and development services
Solvias has a team of research and development chemists dedicated to the area of CX-coupling. This highly experienced team is responsible for ligand R&D tasks ranging from initial screening to industrial troubleshooting of CX-coupling reactions.
Solvias has an excellent track record in the pharmaceutical and agrochemical industry, having successfully tackled catalytic coupling tasks that required sophisticated methods and broad screening capabilities. The portfolio of catalysts available at Solvias includes all industrially relevant systems, including both Solvias' proprietary catalysts as well as foreign and patent-free catalyst systems.
In our vessels ranging from 0.4 ml screening reactors to 50 l kilolab equipment the new systems are readily scaled to prove of concept level (multi-kg scale). Solvias' detailed laboratory procedures and technology transfer packages ensure that further scale-up of the process can be performed timely and success-fully in the customer's production facilities.
To further increase the capacity of Solvias' ligand screening services, we have recently add-ed a state-of-the-art automated High Through-put Screening System (Symyx Technologies, Inc.) capable of screening up to 200 high pressure reactions (homogeneous hydrogena-tions) per day. This HTS robot will also be avail-able for CX-coupling and carbonylation screening studies beginning in Q4 2006. (See article: Solvias to Introduce High Throughput Catalyst Screening Services)
Conclusions
This performance enhanced CN-coupling technology developed by John F. Hartwig at Yale University is a natural extension of Solvias' technology portfolio and enables high yielding transformations with outstanding functional group tolerance and selectivities. The catalysts required consist of a simple assembly of a commodity Pd precursor and already industrially proven Solvias ligands that are available in bulk quantities. Customer in the pharmaceutical, finechemical, and agrochemical industry benefit from a straight forward "IP-included" catalyst pricing.
The incorporation of SL-J002-1 and SL-J009-1 into the CX-coupling kit developed by Umicore and Solvias provides customers with a collection of industrially relevant coupling catalysts for the most common coupling reactions such as: Suzuki, Heck, Kumada, CN-coupling, and ketone-arylation.
References
1 Q. Shen, S. Shekar, J. P. Stambuli, J. F. Hartwig, Angew. Chem. Int. Ed., 2005, 44, 1371.2
2 A. H. Roy, J. F. Hartwig, J. Am. Chem. Soc., 2003, 125, 8704.
3 M. Thommen, "Intellectual Property: Problems and Solutions", Spec. Chem. Mag., March 2003, 13.
4 (a) A. F. Indolese, A. Schnyder EP1132361 2000 (assigned to Solvias AG).
b) A. Schnyder, A. F. Indolese, M. Studer, H.U. Blaser, Angew. Chem. Int. Ed. 2002, 41, 3668.
c) U. Nettekoven, F. Naud, A. Schnyder, H. U. Blaser, Synlett, 2004, 14, 2549.
5 O. Navarro, Y. Oonishi, R. A. Kelly, E. D. Stevens, O. Briel, S. P. Nolan, J. Organomet. Chem., 2004, 689, 3722. L. J. Goossen, J. Paetzold, O. Briel, A. Rivas-Nass, R. Karch, B. Kayser, Synlett, 2005, 2, 275.