JOHNSON MATTHEY TECHNOLOGY REVIEW Johnson Matthey’s international journal of research exploring science and technology in industrial applications www.technology.matthey.com SPECIAL ISSUE 12 ‘PALLADIUM CATALYSED CROSS-COUPLING – PRACTICAL ASPECTS’ APRIL 2017 Published by Johnson Matthey ISSN 2056-5135
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JOHNSON MATTHEY TECHNOLOGY REVIEW
Johnson Matthey’s international journal of research exploring science and technology in industrial applications
www.technology.matthey.com
SPECIAL ISSUE 12 ‘PALLADIUM CATALYSED CROSS-COUPLING – PRACTICAL ASPECTS’ APRIL 2017Published by Johnson Matthey
Johnson Matthey Technology Review is published by Johnson Matthey Plc.
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Contents SPECIAL ISSUE 12 ‘PALLADIUM CATALYSED CROSS-COUPLING – PRACTICAL ASPECTS’ APRIL 2017
JOHNSON MATTHEY TECHNOLOGY REVIEW
Johnson Matthey’s international journal of research exploring science and technology in industrial applications
www.technology.matthey.com
Cleaning Up Catalysis Palladium Impurity Removal from Active Pharmaceutical Ingredient Process
StreamsBy Stephanie Phillips, Duncan Holdsworth, Pasi Kauppinen and Carl Mac NamaraOriginal publication: Johnson Matthey Technol. Rev., 2016, 60, (4), 277
Final Analysis: The Use of Metal Scavengers for Recovery of Palladium Catalyst from Solution By Stephanie Phillips and Pasi KauppinenOriginal publication: Platinum Metals Rev., 2010, 54, (1), 69
Safer, Faster and Cleaner Reactions Using Encapsulated Metal Catalysts and Microwave HeatingBy Mike R. PittsOriginal publication: Platinum Metals Rev., 2008, 52, (2), 64
Catalysis in the Service of Green Chemistry: Nobel Prize-Winning Palladium-Catalysed Cross-Couplings, Run in Water at Room TemperatureBy Bruce H. Lipshutz, Benjamin R. Taft, Alexander R. Abela, Subir Ghorai, Arkady Krasovskiy and Christophe Duplais
Original publication: Platinum Metals Rev., 2012, 56, (2), 62
The Nobel Prize The 2010 Nobel Prize in Chemistry: Palladium-Catalysed Cross-Coupling
By Thomas J. ColacotOriginal publication: Platinum Metals Rev., 2014, 58, (3), 12
Note: all page numbers are as originally published
Contents (continued)
JOHNSON MATTHEY TECHNOLOGY REVIEW
Johnson Matthey’s international journal of research exploring science and technology in industrial applications
www.technology.matthey.com
‘From the Bench’ Tips “Palladium-Catalyzed Coupling Reactions: Practical Aspects and Future Developments” A book review by Robert Hanley Original publication: Platinum Metals Rev., 2014, 58, (2), 93
The Directed ortho Metallation–Cross-Coupling Fusion: Development and Application in SynthesisBy Johnathan Board, Jennifer L. Cosman, Toni Rantanen, Suneel P. Singh and Victor SnieckusOriginal publication: Platinum Metals Rev., 2013, 57, (4), 234
Palladium/Nucleophlic Carbene Catalysts for Cross-Coupling ReactionsBy Anna C. Hillier and Steven P. Nolan
Original publication: Platinum Metals Rev., 2002, 46, (2), 50
A Highly Active Palladium(I) Dimer for Pharmaceutical ApplicationsBy Thomas J. Colacot
Original publication: Platinum Metals Rev., 2009, 53, (4), 183
And Finally...
Final Analysis: Is Gold a Catalyst in Cross-Coupling Reactions in the Absence of Palladium?By Madeleine Livendahl, Pablo Espinet and Antonio M. EchavarrenOriginal publication: Platinum Metals Rev., 2011, 55, (3), 212
Note: all page numbers are as originally published
www.technology.matthey.com JOHNSON MATTHEY TECHNOLOGY REVIEW
http://dx.doi.org/10.1595/205651316X693247 Johnson Matthey Technol. Rev., 2016, 60, (4), 277–286
Palladium Impurity Removal from Active Pharmaceutical Ingredient Process Streams A method for scale-up
By Stephanie Phillips* and Duncan Holdsworth Johnson Matthey Plc, Orchard Road, Royston, Hertfordshire, SG8 5HE, UK
Pasi Kauppinen** Johnson Matthey Finland Oy, Autokatu 6, FI-20380 Turku, Finland
and Carl Mac Namara Johnson Matthey Plc, PO Box 1, Billingham, Cleveland, TS23 1LB, UK
In this article, we will look at palladium impurity removal from active pharmaceutical ingredient (API) process streams using metal scavengers and the drivers for the implementation of such processes. The article will review some of the available scavengers and detail how Johnson Matthey approaches the trial work and the methods used for screening, optimisation and scale-up of the scavenger process. It will outline the steps taken to ensure smooth transfer of the metal impurity removal process from lab to plant. This will include Johnson Matthey data from batch isotherm, kinetic and fixed bed trials and the application of mathematical models for performance characterisation and scale-up, which all feed into the final system design. Performance data for
a number of the Johnson Matthey range of scavengers will be referenced both in batch and cartridge systems and the benefits of using the scavengers in a cartridge system will be presented.
Introduction
The need to remove palladium (Pd) from API process streams is driven by International Conference on Harmonisation (ICH) Q3D guidelines which dictate the permissible levels of Pd allowed in the final drug product. The platinum group metals (pgms), including Pd as well as platinum, rhodium and ruthenium are generally considered as route-dependent human toxicants (ICH Classification 2b), (1), therefore the limits for these metals are low – 10 µg g–1 as an oral concentration in the drug product, drug substance or excipient. This oral concentration is conver ted into a permitted daily exposure limit for each platinum group metal of 100 µg d–1, which is based on an assumed worst-case dosage level of 10 g d–1. If the dosage rate is known to be lower, the permitted oral concentration may be increased. For the pgms, it may also be an option to use a component approach, whereby the overall level of the element in the excipient would be considered. As the pgms would only come from a catalyst source, the overall level of the element in the excipient could then be determined. For a chemist developing or manufacturing the API, a target of 10 µg g–1 or even lower may still be put in place to avoid process re-works (1).
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Despite the challenges of removal, the use of homogeneous Pd catalysts offers many benefits over classical, often stoichiometric reaction protocols (2–4). It is often possible to achieve a reduction of the number of steps in a multi-step synthesis of a target compound, as well as increasing overall yields, by employing Pd catalysis. In order to achieve the benefits offered by the catalysts, there will be a subsequent need for Pd removal (4–10).
Numerous Pd removal methods are available to the chemist and the optimal method is typically selected based on cost, time, quality and ease of implementation. When considering which Pd removal method to use, the default is often to use standard methods such as distillation, crystallisation or carbon adsorption to remove the Pd (10, 11). All are efficient methods of separation; however, the process costs, and their robustness, may be challenged during scale-up. Equally, consideration needs to be given to the time taken to run the process and any impacts that the removal method may have on product yield.
Scavengers provide an excellent solution for Pd removal issues, particularly at low metal levels (6, 8). Johnson Matthey’s screening programme ensures that the best scavenger is selected based on the reaction conditions, but also that the process is robust and that consistent removal of Pd is achieved, irrespective of process scale.
Scavenger Products
There are a range of different scavengers available on the market for product purification (5–8). A significant portion of these are based on a silica support, however others, such as those based on polymer resins and polymer fibres (5, 7) are also available. The Johnson Matthey range includes all three classes of support materials and details of the core product types are listed in Table I, with specific product details provided in Table II.
Screening Method
Below is an outline of the steps involved in achieving a robust, long-term metal removal solution. This full screening package can be completed by Johnson Matthey or at the customer site with technical support provided.
The extent to which a scavenger can remove Pd to the required levels is critical. The initial trials within the screening programme look at a number of scavengers for Pd removal efficiency. Conditions can then be optimised with respect to the amount of scavenger, the temperature and whether a mix of scavengers with different functionalities should be used together. Time taken for Pd removal is considered within the batch isotherm, and kinetic and fixed bed studies are
Table I Overview of Johnson Matthey Scavenging Product Types
Product type Support material Key benefits Processing options
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Table II Chemical Functionalisation of the Core Scavenger Range
Scavenger Abbreviation Functionality
MercaptoQuadraSil® MP QS-MP SH
Primary amineQuadraSil® AP QS-AP NH2
QuadraSil® TA QS-TA H Triamine
NH2N H
N
QuadraPure® TU QP-TU S Thiourea
NH2N H
NH2 BenzylamineQuadraPure® BZA QP-BZA
Tertiary amine QuadraPure® DMA QP-DMA N
MercaptoSmopex®-234 S-234 SH
MercaptoSmopex®-111 S-111
SH
O
O
N
PyridineSmopex®-105 S-105
carried out to generate the performance data required to model, scale-up and design an optimised process for full-scale application.
The Screening Programme: Initial Screening
The initial screen is used as a feasibility study to determine the most suitable scavenger for Pd impurity removal from a particular sample or application. All scavengers used in the screen are commercially
available and all screening is completed on representative process samples. Where solid samples are provided, these are dissolved in an appropriate solvent.
Prior to carrying out any screening, customer process data is required to ensure optimal results taking into account any constraints relating to operating conditions.
Initial screening can be carried out using a variety of equipment, with the two preferred options being: (a) roller mixer machine; or (b) flask with overhead
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stirrer to allow best mixing of and contact with the scavengers. A hot plate, with a magnetic stirrer or a Radleys CarouselTM , have also been used, with care being taken to ensure suitable contact with the scavenger material.
Initial Screening: Experimental
All solutions are filtered prior to screening to ensure homogeneous sampling. A sample of mother liquor is retained for analysis. Typically 1 w/v% scavenger is allowed for Pd concentrations up to 500 mg l–1 . However, if a single element (or the total pgm concentration) has a higher concentration than this, the amount of scavenger is increased. For solutions with a pgm concentration in the region of 500–1000 ppm, for example, 3 w/v% is recommended for initial screening. During optimised screening, the amount of scavenger will be adjusted based on knowledge of the API process and the type of Pd catalyst used during it. Consideration will also be given to the presence of other reagents and metals which may be present and could compete for sites on the scavenger.
Initial screening is completed at room temperature for 2 h. Approximately six to eight scavengers are included in the initial screening. All solution samples are analysed using inductively coupled plasma-optical emission spectroscopy (ICP-OES) or atomic absorption spectroscopy (AAS) to determine the Pd concentration pre- and post-screening (12).
In the examples shown below, an organic process solution used in an API manufacturing process with an oncology indication was the selected material for the screening programme. This was a more
challenging Pd removal project, both in terms of the ease with which the Pd was removed and the low initial concentrations of the Pd in solution. The final target level was 10 µg g –1 in the API, equating to >1 mg l–1 in the solution.
Initial Screening: Results
Results from this screening can be presented in a number of ways. In this case they are shown as: (a) Table III, where the initial raw data is given and the
difference in concentration between the original solution and the solution following scavenger treatment is shown. Conversion of this to the actual concentration in the API stream is given in the final column; and
(b) Figure 1, where the scavenger performance is shown from left to right in terms of optimal performance.
In this example the solid API, with 98 µg g–1 Pd present as an impurity, was diluted with 15 volumes of process solvent prior to analysis. The analytical results on the solution were therefore multiplied, based on this dilution factor, and taking into consideration the density of the solvent to give: (a) the initial Pd levels present in the API; and (b) the Pd levels present after scavenger treatment. At this stage of the screening, the final Pd levels
following scavenger treatment were all above the target required by the process, necessitating further optimisation. For most screening, the best three performing scavengers from the initial screening are taken through to the optimisation stage.
Table III Initial Screening Results with Respect to Palladium Concentrationa
Scavenger type Scavenger added, w/v% Pd in the process solvent,mg l–1 Pd in API, calculated, µg g–1
Initial sample 0 6.5 74
Smopex®-234 0.5 5.5 62
QuadraPure® DMA 0.5 5.0 57
Smopex®-105 0.5 4.8 54
QuadraPure® TU 0.5 3.8 43
QuadraSil® AP 0.5 3.5 40
QuadraSil® MP 0.5 2.5 28 aTrials were conducted at 10 ml scale
Fig. 1. Pd concentration pre- and post-scavenger screening: initial screen
Screening Optimisation
Based on the results from the initial screening, three scavengers were taken through to the optimisation stage: QuadraPure® TU (thiourea functionalised polymer resin), QuadraSil® MP (mercapto propyl functionalised silica) and QuadraSil® AP (amino propyl functionalised silica). During this phase, testing focused on modifying the amount of scavenger used,
2
1
0
Fig. 2. Effect of amount of scavenger on Pd removal. Specification was met by QuadraSil® MP at 2 w/v% loading
7 Initial sample6
5
Pd,
mg
l–1
4
3
22ºC 40ºC
the effects of temperature increase on the scavenging performance and possible use of a multi-scavenger system. Time taken for recovery was determined during the later kinetic trials.
Optimisation: Experimental
Based on the Pd removal rates from the first screen, the amount of scavenger used was modified accordingly. As a 0.5 w/v% addition (with respect to volume of process solution) did not yield complete metal removal, the amount of scavenger added was increased to 1 w/v% and 2 w/v% (Figure 2).
Typically the higher temperature would be: (a) 60ºC
2
1
0
Fig. 3. Effect of temperature increase with 1 w/v% scavenger
7 Initial sample
6 QS-MP 5
Pd,
mg
l–1
4
3
22ºC 40ºC
(b) 10ºC below the boiling point of the solvent, or (c) dictated by the process conditions or API stability.
In this case, the agreed higher temperature was 40ºC and QuadraSil® MP was screened at 1 w/v% and 2 w/v% to determine the effect due to temperature (Figures 3 and 4).
From these results, the optimal conditions were found to be 2 w/v% of QuadraSil® MP for 2 h at room temperature to give 0.5 mg l–1 in the solution, which equated to 5.65 µg g–1 in the API. This was below the required upper limit of 10 µg g–1. No performance improvements were seen by increasing the temperature
2
1
0
Fig. 4. Effect of temperature increase with 2 w/v% scavenger
and, from a processing point of view, room temperature was preferable. It was also deemed unnecessary to test a mixture of scavengers as the targeted Pd removal was achieved with a single scavenger.
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At this stage in the screening programme, the scavenger and the conditions under which that scavenger will be best utilised have been determined using a fixed time under batch conditions. The decision for the process chemist now is whether the process will be transferred to the pilot plant in batch or in a cartridge system. To support this decision, a batch isotherm will be run followed by a kinetic trial for cartridge systems. This data is then utilised in a first principles modelling system and the actual and theoretical data compared before the system is defined.
Batch Isotherms and Kinetic Studies
During this phase of the screening, we are looking at: (a) the theoretical maximum metal loadings which can
be achieved for the target scavenging process. Data from this stage will help to determine the weight or volume of scavenger required in the larger scale process
(b) the breakthrough point (where the metal is no longer being removed by the scavenger) to determine at what point the chemist or engineer stops the process
(c) the kinetics of the adsorption process, considering the various mass transfer resistances which control the Pd from the liquid phase to the solid phase. This will indicate what contact time is required to ensure the metal content is reduced to the required levels.
For this project, a kinetic trial in batch was considered for the three best per forming scavengers, shown as raw data in Figure 5. Due to the more challenging nature of the solution, kinetics were slower than is often seen, with target recovery in 4 h. This was within process requirements. Note that kinetics for
Pd removal are typically fast with up to 99% recovery often being seen within 10 min. Factors that can affect the metal uptake are: (a) nature of the Pd catalyst (in terms of accessibility of
the Pd species) (b) presence of other reagents that can compete with
the metal uptake, and (c) reactions within the API itself.
A batch isotherm trial was carried out to determine the maximum loading capacity of the material as well as investigating how changing initial concentrations of the feed solution may affect this capacity (Figure 6).
Prior to designing a full-scale cartridge system, a column trial is carried out in which feed solution is flowed through a fixed bed of the ion exchange material and the outlet concentration from the column is measured over time. An outlet concentration of 0 mg l–1 indicates that all of the Pd has been recovered from the feed solution. An outlet concentration above 0 mg l–1 indicates that the material has almost reached its maximum loading capacity and that the feed flow should be stopped. The time before the outlet concentration rises above 0 mg l–1 can be increased by increasing the column size (Figure 7).
First Principles Modelling
The results obtained from laboratory isotherm and column trials are used to estimate several equilibrium and kinetic parameters which describe the adsorption
1.2
Equ
ilibr
ium
load
ing,
wt% 1.0
0.8
0.6
0.4
Experimental results
5 QS-MP QS-AP QP-TU
0.2
Pd,
mg
l–1 4 03
0 5 10 15 2 Equilibrium concentration, mg l–1
1 Fig. 6. Results of isotherm trial where varying masses of QuadraSil® MP material were added to 20 ml solutions of
Initial 30 120 240 30 120 240 30 120 240 customer solution with initial Pd concentration of 14 mg l–1
sample Sample intervals, min
0
and mixed until equilibrium was reached. Equilibrium concentration was measured by ICP-MS and the equilibrium
Fig. 5. Batch kinetic trial raw data: Pd removal profile with respect to time
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Experimental results
∂C ∂C ∂2C rb ∂q = – uv + Dax – (ii)
2∂t ∂z ∂z e ∂t
Out
let c
once
ntra
tion,
mg
l–1
4
3
2
1
0 0 2 4 6 8 10 12
Time, h Fig. 7. Results of the column trial where a feed solution
Equation (ii) is fitted to the results shown in Figure 7 to determine the kinetics parameters of adsorption (contained within the ∂q/∂t parameter in the equation which represents the rate of adsorption). The results of this fitting are shown in Figure 9. Again a very high R2
value of 0.99 was obtained. Once these model parameters have been estimated,
Equations (i) and (ii) can be used to determine the performance of the QuadraSil® MP material as a function of time, feed flow rate, concentration and the size or scale of the column through which the feed is having an initial concentration of 5.5 mg l–1 Pd was flowed
through a column of QuadraSil® MP at a flow rate of flowed, effectively allowing scale-up and optimisation 17.0 ml h–1 equivalent to three bed volumes per hour, where one bed volume is equal to the volume occupied by the Quadrasil® MP in the column). The outlet Pd concentration of samples collected from the column outlet were analysed by ICP-MS (10)
of Pd from solution. The parameters are part of the models described in Equations (i) and (ii) (13, 14) and by fitting these models to the experimental data the values of these parameters are estimated.
qtKCe qe = (i)
1 + KCe
Equation (i) is fitted to the results shown in Figure 6 to determine K and qt, the material equilibrium constant and maximum capacity respectively. The results of this fitting are shown in Figure 8. An R2 value of 0.99 was obtained indicating the fitting is very good.
of the process design to ensure full Pd recovery, as further discussed in the next section.
Scale-Up
The ultimate aim of scale-up is to take the understanding obtained from the small-scale scavenger performance and propose a system that can achieve 100% scavenger utilisation at the end of the system life, i.e. the entire scavenger mass should be loaded to its maximum capacity at the point of scavenger change out. In reality this is an impossible task as, for example, in a column system axial diffusion, radial velocity gradients, near-wall effects and slow kinetics inevitably lead to broadening of the mass transfer zone and non-ideal behaviour (15, 16). However, a robust engineered solution should aim to get as close to full utilisation of the scavenger as is possible for a given set of conditions as this helps to minimise the installed
6
Equ
ilibr
ium
load
ing,
wt% 1.0
0.8
0.6
0.4
Experimental results Predicted results
R2 = 0.99
Out
let c
once
ntra
tion,
mg
l–1 Experimental results Predicted results
R2 = 0.99
0 2 6 104 8 Time, h
Fig. 9. The experimental results from Fig. 7 are shown again, as well as the predicted results from Equation (ii)
5
4
3
2
1
00 0 5 10 15
Equilibrium concentration, mg l–1
Fig. 8. The experimental results from Fig. 6 are shown, as well as the predicted results from Equation (i)
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scavenger volume and, ultimately, the process cost. For a batch system, the challenge is even greater, which drives Johnson Matthey to recommend a cartridge system wherever possible. Scavenger systems using cartridges also offer the added benefit of containment when a potent API is being manufactured.
Optimisation can be achieved by manipulating variables such as the liquid linear velocity, the column diameter and the aspect ratio of the scavenger bed (17), while being mindful of customer requirements that could place limits on the proposed design. Such requirements might include the need for the system to be either a once-through or a recycle system; the processing time requirements; the need for a reusable or disposable system depending on the potency of the API; and the operability of the system. At this point the scavenger system will be well-defined, leaving only the mechanical design and the selection of the final conditions and materials of construction to satisfy the needs of the process, the relevant regulations and ultimately the characterisation of a safe and robust system. At this final stage, all of the data from the screening
programme is collated and used in the design of the final system used during piloting. Examples of a scalable system, the sealed flow cartridge system, are shown in Figure 10.
Conclusion
The use of a screening programme has been demonstrated and the steps required outlined in this article along with the results obtained, in order to design a robust plant-scale recovery process. Whether the process will be run in batch or a cartridge system, the method is essential in ensuring that optimal use of the scavenger is achieved while attaining Pd removal targets. For challenging processes, such as the one highlighted here where the nature of the process solution is complex and the initial metal levels are low (in the diluted form), the screening process becomes even more valuable.
Johnson Matthey provides screening and scale-up services to the pharmaceutical industry and has become expert through its application of knowledge in this area. To date, numerous plant-scale scavenging projects are running globally.
Acknowledgements
The authors would like to thank Steve Colley, Les Hutton, Jade Osei-Tutu and Carin Seechurn (Johnson Matthey Plc, UK) and Andrew Teasdale, Principal Scientist at AstraZeneca, UK, also Chair of the AstraZeneca impurities advisory board.
References 1. “ICH Harmonised Guideline, Guideline for Elemental
Impurities, Q3D”, Current Step 4 Version, International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, 16th December, 2014: http://www. ich.org/fileadmin/Public_Web_Site/ICH_Products/ Guidelines/Quality/Q3D/Q3D_Step_4.pdf (Accessed on 26th August 2016)
2. C. C. C. Johansson Seechurn, M. O. Kitching, T. J. Colacot and V. Snieckus, Angew. Chem. Int. Ed., 2012, 51, (21), 5062
3. J. Magano, ‘Large-Scale Applications of Transition Metal Removal Techniques in the Manufacture of Pharmaceuticals’, in “Transition Metal-Catalyzed Couplings in Process Chemistry: Case Studies from the Pharmaceutical Industry”, eds. J. Magano, J. R. Dunetz, Wiley-VCH Verlag, Weinheim, Germany, 2013, p. 313
4. E. J. Flahive, B. L. Ewanicki, N. W. Sach, S. A. O’Neill-Slawecki, N. S. Stankovic, S. Yu, S. M. Guinness and J. Dunn, Org. Process Res. Dev., 2008, 12, (4), 637
Fig. 10. Sealed flow cartridge systems for use at different scales: (a) large-scale laboratory use; (b) plant-scale system
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5. S. Phillips and P. Kauppinen, Platinum Metals Rev., 2010, 54, (1), 69
6. G. Reginato, P. Sadler and R. D. Wilkes, Org. Process Res. Dev., 2011, 15, (6), 1396
7. J. Frankham and P. Kauppinen, Platinum Metals Rev., 2010, 54, (3), 200
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9. M. J. Girgis, L. E. Kuczynski, S. M. Berberena, C. A. Boyd, P. L. Kubinski, M. L. Scherholz, D. E. Drinkwater, X. Shen, S. Babiak and B. G. Lefebvre, Org. Process Res. Dev., 2008, 12, (6), 1209
10. C. E. Garrett and K. Prasad, Adv. Synth. Catal., 2004, 346, (8), 889
11. J.-P. Huang, X.-X. Chen, S.-X. Gu, L. Zhao, W.-X. Chen and F.-E. Chen, Org. Process Res. Dev., 2010, 14, (4), 939
12. G. Lecornet, ‘Analysis of Elemental Impurities in Drug Products using the Thermo Scientific iCAP 7600 ICP-OES Duo’, Application Note 43149, Thermo Fisher Scientific Inc, Massachusetts, USA, 2016
13. C. E. Borba, G. H. F. Santos and E. A. Silva, Chem. Eng. J., 2012, 189–190, 49
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15. J. B. Butt, “Reaction Kinetics and Reactor Design”, Second Edition, Marcel Dekker Inc, New York, USA, 2000, pp. 332–333
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The Authors
Stephanie Phillips is the Market Specialist for Johnson Matthey’s Advanced Ion Exchange (AIX) business at Royston, UK. Stephanie has worked in Sales and Marketing since 2001 and has been involved with the development and marketing of the Smopex® range of products since that time. Stephanie has a BSc in Chemistry and an MSc in Analytical Chemistry.
Duncan Holdsworth is a Senior Process Engineer in the Johnson Matthey AIX business and is based in Royston, UK. Duncan has worked as a Process Engineer within the various Johnson Matthey business divisions since 2010. He most recently joined AIX where he manages the scale up, design, fabrication and commissioning of the various process units operating in both the pharmaceutical and industrial chemicals markets. Duncan gained his MEng in Chemical Engineering from the University of Sheffield, UK.
Pasi Kauppinen gained his PhD in University of Oulu, Finland, and works currently as a Principal Scientist in AIX at the Johnson Matthey plant in Turku, Finland. In this role he is focused on developing AIX processes and products globally
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Carl Mac Namara is a Process Engineer within the Johnson Matthey Water Technologies group, Chilton, UK. He obtained his MEng in Chemical Engineering from Cork Institute of Technology, Ireland, and an Engineering Doctorate from the University of Birmingham, UK. His doctorate and post-doctoral projects were based in Procter & Gamble’s Newcastle Innovation Centre, UK, where he carried out fundamental research on textile cleaning processes. His current role is focused on modelling and developing new water treatment technologies all the way from R&D through to commercial stages.
The Use of Metal Scavengers for Recoveryof Palladium Catalyst from SolutionIntroduction Cross-coupling reactions are among the most impor-
tant chemical processes in the fine chemical and phar-
maceutical industries. Widely used procedures such
as the Heck, Suzuki and Sonogashira cross-coupling
reactions and Buckwald-Hartwig aminations most
commonly employ a palladium-based catalyst (1).
Initially these reactions used simple Pd catalysts such
as palladium chloride and palladium acetate,often in
conjunction with a ligand.However, the need to carry
out more challenging coupling reactions (for exam-
ple those using less reactive aryl halides or pseudo-
halides, including aryl chlorides) has resulted in the
development of more advanced Pd catalysts (1, 2).
Product Clean-UpOnce the reaction is complete, the catalyst must be
separated from the product to avoid contamination
by Pd as well as the loss of precious metal into the
product or waste stream. Heterogeneous catalysts
may be separated quite easily from the product solu-
tion and sent for refining to recover the metal, but
homogeneous catalysts are more problematic. One
way to achieve separation is by recrystallisation of the
product; however this can result in the loss of up to
1% of the product yield.
Therefore an alternative method for removing the
residual Pd is required. Scavengers such as Smopex®
can be used to recover platinum group metals
(pgms) including Pd down to parts per billion
(ppb) levels. Smopex® is a fibrous material with a
polypropylene or viscose backbone grafted with
functional groups that can selectively remove the
pgms from solution (Figure 1).The fibres can carry a
metal loading of up to 10 wt%, and the loaded fibres
can then be collected and sent for traditional refining
to recover the precious metal (3).
Smopex® Metal ScavengersThe choice of scavenger for a particular process
depends on several factors. These include the oxida-
tion state of the Pd catalyst, the nature of the solvent
system (aqueous or organic), the presence of byprod-
ucts or unreacted reagents in solution and whether
the scavenger will be applied in a batch process or
continuous flow system. Some examples of Smopex®
fibres that can be applied under different conditions
are shown in Figure 2.
Process ScreeningPrior to using a scavenger in a particular process, it is
common practice to screen a selection of scavengers
to determine the most selective individual or combi-
nation of scavengers. Properties including the type of
scavenger used (based on metal species), amount of
scavenger used (based on concentration),and effects
of solvent and permitted temperature will be investi-
gated and optimised, as well as the kinetics and flow
system requirements. Data is also available on the
scavengers which are known to perform best for spe-
cific reactions (4),and this can be used to make a rec-
ommendation on the scavenger that is likely to offer
the best recovery in each case.
Two examples to illustrate the screening process
follow.
FINAL ANALYSIS
Fig. 1. (a) Smopex®, a fibrous material with a polypropyleneor viscose backbone; (b) Schematic representation of thefunctional groups (red) located on the surface of theSmopex® fibres (3)
(a)
(b)
Case Study 1: Suzuki ReactionThe process stream from a Suzuki coupling reaction
using the catalyst trans-dichlorobis(triphenylphos-
phine)palladium(II) (PdCl2(PPh3)2) in toluene was
analysed and found to contain 100 parts per million
(ppm) of Pd as well as triphenylphosphine and inor-
ganic salts. For Pd present following a reaction using
PdCl2(PPh3)2, thiol-based scavengers are known to be
the most suitable as they are able to break down any
Pd complexes in the solution and bind strongly to the
metal.An excess of Smopex® was applied for the ini-
tial screening process at a rate of 1 wt% Smopex® for
100 ppm Pd.
In this case toluene was used as the process sol-
vent, therefore hydrophobic fibres were recommend-
ed. A process temperature of 80ºC was used in the
coupling step, but the preferred stage for Pd recovery
was after the washing step, at a slightly lower temper-
ature of 60ºC. Screening was carried out using
Smopex®-111 and Smopex®-234, both thiol-based
scavengers (see Figure 2). In both cases, 1 wt% of
Smopex® was stirred at 60ºC for 1 hour, the liquor was
then filtered off and the filtrate was found to contain
<2 ppm Pd when Smopex®-111 was used,and <5 ppm
with Smopex®-234. After further optimisation it was
determined that the amount of Smopex® could be
reduced by half if 3 hours’ contact time was applied.
Case Study 2: Multiple Palladium SpeciesA process stream from a tetrakis(triphenylphos-
phine)palladium(0) (Pd(PPh3)4)-catalysed coupling
reaction with tetrahydrofuran as the solvent was
analysed and found to contain 30 ppm of Pd. In this
case,the Pd was present as both Pd(II) and Pd(0) and
therefore two different scavengers were tested.
Scavenging conditions of 60ºC for 1 hour were again
applied, and a first pass with Smopex®-105 (an anion
exchanger) gave 85% Pd recovery. A further treatment
with Smopex®-101 (a cation exchanger) recovered
the additional 15%, giving an overall recovery of
100%. In some similar cases a thiol fibre such as
Smopex®-111 can give total recovery on its own, but
where this is not achievable, a mixture offers another
way to achieve full recovery of the Pd.
In ConclusionThe widespread use of Pd catalysts for coupling reac-
tions continues to precipitate a requirement for Pd
scavenging of the product solution. Metal scavengers
such as Smopex® fibres can be used with a wide vari-
ety of processes to recover Pd, other pgms or base
metals down to ppb levels, and offer a viable alterna-
tive to traditional procedures such as product recrys-
tallisation.
STEPHANIE PHILLIPS and PASI KAUPPINEN
References1 C. Barnard, Platinum Metals Rev., 2008, 52, (1), 38
2 T. J. Colacot, Platinum Metals Rev., 2009, 53, (4), 183
3 Smopex® Metal Scavengers, A powerful and effectiveway to recover metal from solution:http://www.smopex.com/ (Accessed on 30th October2009)
4 Smopex® Metal Scavengers, ‘Fibre Selection Guide’:http://www.smopex.com/userfiles/file/Smopex%20selection%20guide2.pdf (Accessed on 1st December 2009)
The Authors
Stephanie Phillips is the Product Specialist for Smopex® working forJohnson Matthey’s Chemical Products and Refining Technologies atRoyston, UK. Stephanie has worked in Sales and Marketing since2001 and has been involved with the development and marketingof the Smopex® range of products since that time. Stephanie has aBSc in Chemistry and an MSc in Analytical Chemistry.
Dr Pasi Kauppinen works as Smopex® Development Manager at theJohnson Matthey plant in Turku, Finland. He has expertise in therecovery of platinum group metals and catalysts from solution, polymer absorbents, catalysis and the Smopex® product range.
Fig. 2. Examples of Smopex® functional groups graftedonto polypropylene fibres (3)
Platinum Metals Rev., 2008, 52, (2), 64–70 64
Microwave heating has developed as an impor-tant tool for research chemists, enabling reactionsto be carried out and optimised more quickly thanusing traditional heating methods (1–3). Directirradiation of the reaction mixture produces amore uniform and homogeneous heating profilethan does, for example, an oil bath. In most casesthe observed increase in rate can be explained bythe extremely efficient energy transfer and homo-geneous heating effect. This can lead tosuperheating of the reaction mixture (4): indeed,even microwave heating of an open vessel canachieve temperatures several degrees higher thanthe boiling point of the solvent (5).
In certain cases the presence of elements thatstrongly absorb microwave energy and release itefficiently as heat can cause localised ‘hotspots’tens of degrees higher than the bulk temperature,generating significant rate enhancements (6–8).This effect can be exploited to heat materials oflow microwave absorbance by the use of ‘passiveheating elements’ (9). Non-polar and poorlyabsorbing solvents can also be superheated byadding small amounts of a strongly absorbingcosolvent such as an ionic liquid (10–13). Theapplication of this selective heating can be particu-larly striking when the element is a heterogeneous
catalyst (14–16). A localised increase in tempera-ture at a catalyst surface over the bulk temperature,or a selective absorption of microwave energy bycatalytic species or organometallic intermediateson a reaction pathway, can lead to increased selec-tivity for the catalytic process while unwanted(thermally driven) side reactions are minimised bya relatively low bulk temperature (17). A synergis-tic advantage between microwave heating andplatinum group metal catalysis can therefore bedemonstrated (18).
The use of commercially available focused(monomode) microwave units (19–21) enhancesthe safety and reproducibility of reactions. Thestandard integration of monomode units intomany laboratory environments has expanded thearmoury of techniques available to chemists, allow-ing ready access to previously difficult-to-achievechemistries. These include high-temperature reac-tions such as Ullmann couplings (22); someheterocycle preparations previously requiringmetal baths (23, 24); the use of near-critical wateras solvent (25–29); and shortening the reactiontime on slow processes such as cycloadditions (30)to practically useful timescales, including replacingthe need for autoclaves (31); and automated pep-tide synthesis (32, 33).
Safer, Faster and Cleaner Reactions UsingEncapsulated Metal Catalysts andMicrowave HeatingPERFORMANCE ENHANCEMENT OF PALLADIUM, PLATINUM AND OSMIUM CATALYSTS
By M. R. Pitts*Reaxa Ltd., Hexagon Tower, Blackley, Manchester M9 8ZS, U.K.; E-mail: [email protected]
The combination of focused microwave heating and encapsulated metal promoters (EnCatTM)offers a safer, cleaner and more cost-effective solution to a wide range of catalyst-mediatedreactions, some of which are not widely accessible to the bench chemist due to high hazardratings. These include the palladium-catalysed Sonogashira cross-coupling, palladium-catalysed transfer hydrogenation, platinum-mediated hydrogenation and osmium tetroxide-catalysed dihydroxylation.
For the reasons discussed, metal-catalysedreactions work particularly well under microwave irra-diation; however safety and isolation issues still arisefrom their use. Elemental metal can deposit fromreaction mixtures onto the side of the glass tube,causing localised superheating of the glass and explo-sive rupture of the vessel (34). This can occur withboth homogeneous and heterogeneous catalysts. Itcan also be difficult to remove metal species selective-ly from the product on completion of the reaction.
The EnCatTM range of encapsulated metal cata-lysts were designed to address these issues ofpurification and reuse. Unlike other immobilisedhomogeneous catalysts such as FibreCatTM, wherephosphine ligands are attached to polyethylene fibres(35), the homogenous catalyst in EnCat is containedwithin a resin microcapsule. The use of such support-ed or ‘heterogenised’ catalysts industrially is beingdriven by regulatory pressures towards lower residuallevels of metal catalysts within active pharmaceuticalintermediates (APIs) (36, 37).
EnCats are prepared by an interfacial micropoly-merisation of an organic solution containing thehomogeneous metal catalyst, monomers (function-alised isocyanates) and additives, dispersed as asuspension in an aqueous phase. Reactive groupsgenerated at the interface combine to form polymerwalls and, as the surrounding matrix forms, the cata-lyst is entrapped to give spherical microcapsules (38).The individual catalytic species gain additional stabil-isation through interaction with the amidefunctionality of the polyurea matrix, resulting in verylow levels of metal leaching. Consequently the cata-lyst can be recovered efficiently by simple filtrationand reused.
Examples of catalysts already encapsulated thisway include palladium(II) acetate (39, 40) with andwithout various phosphine ligands (41), palladium(0)nanoparticles (42), platinum(0) (43) and osmiumtetroxide (44). Here we describe how EnCats providea homogeneous catalyst in a more effective form foruse with microwave heating.
EnCats in Microwave HeatedReactions
EnCats have been shown to be highly compatiblewith microwave heating (45, 46). Following the excel-
lent work by Ley and coworkers in demonstratingmicrowave-enhanced palladium EnCat-catalysedSuzuki couplings in both batch and flow modes (47),we were keen to understand the role of EnCat inheating bulk solution. Ley found that cooling reac-tions while providing a fixed microwave powerequivalent to that required for good conversion in thenon-cooled method resulted in cleaner products atsimilar or better conversions. The lower bulk temper-ature in the case of cooling may explain the reductionin side reactions, with the temperature ‘inside’ theEnCat beads potentially much higher. It is knownthat Pd/C preferentially absorbs microwave energywhen suspended in a virtually microwave-transparentsolvent, and ‘passively’ heats the surroundings (48).To investigate whether EnCat acts in the same way, a5 cm3 sample of anhydrous toluene, with variousadditives, was irradiated at a constant power of 200W for 5 minutes and the temperature recorded(Figure 1). Adding 250 mg of Pd EnCat had a negli-gible effect on the heating profile, as did the additionof ‘blank’ EnCat beads containing no metal. Additionof an equivalent amount of homogeneous palladiumacetate (27 mg) also had no effect on the heatingbehaviour, whereas 50 mg of palladium (5%) on car-bon caused a significantly increased rate of heating.
These results suggest Pd EnCat does not causesuperheating of the bulk solution, and behaves morelike homogeneous palladium acetate than palladiumon carbon.
Palladium(II) for Cross-CouplingReactions
Considerable effort has been focused on the useof Pd EnCat to facilitate cross-coupling reactions(41). The extremely low leaching of metal species andease of handling of EnCat beads greatly simplifypurification of these reactions. Many examples havebeen published regarding the use of EnCats withmicrowave heating for the acceleration of specificreactions (49–52). An important advantage, often notconsidered, is improved safety when using EnCats ina microwave reactor. Deposition of a film of elemen-tal metal on the glass walls of microwave tubes byprecipitation from solution is a common problemwith conventional metal catalysts. This has beenshown not to occur with Pd EnCat (53). Where a
Platinum Metals Rev., 2008, 52, (2) 65
film is deposited, it absorbs microwave energystrongly, and hotspots can form, resulting in vesselfailure. With modern microwave reactor designssuch ruptures are well contained; however therelease of vapours and subsequent decontamina-tion pose serious issues. These can lead torestrictions on the use of particularly hazardousreagents.
By way of example, a useful palladium-mediatedmicrowave process is the carbonylation of arylhalides with solid sources of carbon monoxide(54). Molybdenum hexacarbonyl has been shownto be an effective carbon monoxide releasing agent(55, 56), however it is a very toxic substance withrelatively high volatility (57). The risk of vessel rup-ture in such procedures can be greatly reduced bysubstituting Pd EnCat for the traditional palladiumcatalyst. The reaction proceeds with quantitativeconversion as shown in Scheme I.
EnCats have been applied in flow chemistrywith the beads packed in simple columns and
reagents passed over them. The initial work inthis area is extremely promising for the process-intensification of homogeneous catalytic reactions(47, 58–60).
A low degree of leaching of the catalytic speciesis vital in a continuous process, in order to avoidrapid deactivation and resulting contamination ofthe product flow stream. Certain substrates areknown to induce leaching of palladium fromEnCat resins, with aryl iodides and alkynes show-ing a high propensity. Indeed, running themicrowave-assisted Sonogashira reaction inScheme II with Pd EnCat 30 resulted in productwith a palladium content of 83 ppm. The triph-enylphosphine-entrapped Pd EnCat (polyTPP30)resin demonstrates an extremely high retention ofboth the palladium and phosphorus ligand, and hasbeen used to great effect in the same reaction(Scheme II). Using Pd EnCat polyTPP30 as thecatalyst, the residual palladium concentration in theproduct was only 14 ppm.
Fig. 1 Rate of heating of toluene containing various dopants under microwave irradiation
Pd EnCat 30Mo(CO)6
DBU, THFMicrowave
120ºC30 min
Me
I
Ph+ H2N
Yield 98%
PhN
H
NH
Me
O
DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene
Scheme I
Platinum Metals Rev., 2008, 52, (2) 67
Palladium(0) for HydrogenationReactions
The nanoparticulate palladium(0) EnCatcatalyst has been demonstrated as a highlychemoselective hydrogenation and transferhydrogenation catalyst (61, 62). In additionto the improved selectivity shown by PdEnCat NP30, a superior safety profile andease of handling make it a powerful alterna-tive to palladium on charcoal.
Transfer hydrogenation with Pd EnCatNP30 is easily performed in the microwave,allowing reactions in minutes rather thanhours. A recent paper by Quai and coworkersdemonstrated the efficiency of microwave-assisted transfer hydrogenation for O-benzyldeprotection (Scheme III) (63). The use ofEnCat was recommended to improve thesafety of the process and reduce palladiumcontamination of the products.
Scheme IV shows a representative exam-ple of an aromatic nitro reduction. Thesereactions are conventionally carried out atambient temperature overnight (64). How-ever, the microwave transfer hydrogenationprocedure gave a quantitative conversion tothe final product in only 5 minutes.
Platinum(0) for Hydrogenation andReduction Reactions
To complement the palladium(0) EnCatrange, a platinum(0) EnCat has recently beendeveloped, offering the same benefits over itscarbon-supported equivalents as the palladiumversion: improved safety profile, ease of handlingand low metal leaching. Pt(0) EnCat 40 performssimilarly to Pt/C in hydrogenation reactions, andis particularly useful in selective reductions in thepresence of aryl chlorides. The reaction shown inScheme V gave 3-chloroaniline with > 98%selectivity at room temperature under an atmos-phere of hydrogen after one hour (65).Microwave-assisted hydrogenations have recent-ly been investigated (66), and equipment to runthem in the laboratory is becoming commerciallyavailable (67, 68). With microwave reactorsdesigned to meter pressures up to 15 bar and runat them, such technology offers the benchchemist simple, safe access to hydrogenation.
The microwave-assisted hydrogenation of 3-chloronitrobenzene shown in Scheme V was runusing a standard microwave vial. A hydrogenatmosphere (at slight positive pressure) wasintroduced via a needle and manifold cycledbetween vacuum and hydrogen from a lecture
Pd EnCat 30or polyTPP30
CuI, Et3N, THFMicrowave
140ºC20 min Yield 99%
Ph
Me
O
Ph
Me
O
I
+ Scheme II
Pd(0) EnCat NP30HCOONH4, DMF
Microwave (cooled)80ºC
10 minOPh
R
R = NH2, NHMe, COOH, CN, COR, heterocycle, etc.
HO
R
Scheme III
Yield > 99%
Pd(0) EnCat NP30HCOONH4, EtOH
Microwave80ºC5 min
HO HO
NH2NO2
Scheme IV
Platinum Metals Rev., 2008, 52, (2) 68
bottle. Following irradiation at a constant power(30 W) for 13 minutes all the starting materialwas consumed, giving 3-chloroaniline in 85%yield. With equipment designed to charge gas to agiven pressure and monitor the pressure drop, it isto be expected that this reaction could be opti-mised to higher selectivities.
The osmium tetroxide-catalysed dihydroxyla-tion reaction is Nobel Prize-winning chemistry(69); however the routine use of osmium in thelaboratory is avoided where possible due to its tox-icity, the likelihood of contact due to its volatilityand its propensity to cause burns (70). Os EnCat40 is an encapsulated osmium tetroxide that issafer to handle because no osmium tetroxidevapour can escape the polymer matrix (44). TheEnCat acts as a reservoir of osmium tetroxide,releasing catalytic amounts under oxidation reac-tion conditions, but retaining sufficient activity forrecycling (71). Following the reaction only verylow levels of residual osmium are detectable in thereaction media. Os EnCat 40 has been successful-ly applied to asymmetric dihydroxylation reactions(72). To demonstrate the application of Os EnCat40 under microwave conditions, the simple dihy-droxylation in Scheme VI was carried out at 80ºCand was complete in 20 minutes. The correspond-ing reaction at ambient temperature, when allowedto proceed overnight, gave the product in 86%yield (73). With the reaction performed in a sealedmicrowave tube, the contents could be removed
via syringe with a fine filter fitting, minimising con-tact and potential hazards, and allowing routine,safe use of such chemistry.
ConclusionsMicrowave heating has expanded the arsenal of
synthetic methods available to the bench chemist.The use of encapsulated platinum group metal cat-alysts coupled with the inherently safe design ofmodern microwave apparatus enables safe accessto an even greater range of useful transformations.Such a synergistic combination of technologiesenables reactions to be performed that furnishclean products with very low levels of residualmetal, thus simplifying the preparation of complexmolecules.
Pt(0) EnCat 40H2, EtOH
Microwave 30 W13 min
Yield 85%
Cl NO2 Cl NH2
Scheme V
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Ph
Os EnCatNMO
H2O/acetone
Microwave80ºC
20 min
Ph
OH
Ph
OH
PhScheme VI
Yield 91%NMO = N-methylmorpholine N-oxide
Platinum Metals Rev., 2008, 52, (2) 69
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The AuthorMike Pitts obtained his first degree at LoughboroughUniversity, U.K., in 1997. Zeneca sponsored a project ondioxirane chemistry in his final year, following a successfulindustrial placement year as part of the degree. He then movedto the University of Exeter, U.K., to obtain a Ph.D. withProfessor Chris Moody on ‘Selective Reductions with IndiumMetal’. A postdoctoral stay with Professor Johann Mulzer at theUniversity of Vienna, Austria, followed, where he completed aformal total synthesis of laulimalide as part of a European
Network focused on antitumour natural products. Mike returned to the U.K. in 2002to work for StylaCats Ltd., a start-up company from the University of Liverpool,where he initiated and developed a microwave research platform. In September 2005he moved to Reaxa Ltd. in Manchester, a technology spin-out from Avecia, to developmicrowave processes with their proprietary catalysts. In August 2007 he took up hiscurrent position managing Sustainable Technologies at the Chemistry InnovationKnowledge Transfer Network.
58 C. K. Y. Lee, A. B. Holmes, S. V. Ley, I. F.McConvey, B. Al-Duri, G. A. Leeke, R. C. D. Santosand J. P. K. Seville, Chem. Commun., 2005, 2175
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64 Results from Reaxa laboratories are available in‘Pd(0) EnCatTM NP30 Hydrogenation & TransferHydrogenation User Guide’, Reaxa Ltd., April 2006:http://www.reaxa.com/images/stories/reaxa_pd0_encat_30np_user_guide_2006.pdf
65 Results from Reaxa laboratories are available in
‘Pt(0) EnCatTM 40 User Guide’, Reaxa Ltd., March2007:http://www.reaxa.com/images/stories/Reaxa%20Pt(0)%20EnCatT%20User%20Guide_mar_07.pdf
66 G. S. Vanier, Synlett, 2007, 13167 C. M. Kormos and N. E. Leadbeater, Synlett, 2006,
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71 D. C. Whitehead, B. R. Travis and B. Borhan,Tetrahedron Lett., 2006, 47, (22), 3797
72 A.-L. Lee and S. V. Ley, Org. Biomol. Chem., 2003, 1,3957
73 Results from Reaxa laboratories are available in‘User Guide – Catalytic Oxidations with OsEnCatTM Microencapsulated Osmium TetroxideCatalysts’, Reaxa Ltd.:http://www.reaxa.com/images/stories/reaxaosencatuserguide.pdf
AcknowledgementsFinancial support provided by the National Institutes
of Health (GM 86485) is warmly acknowledged. We are
indebted to Johnson Matthey for generously providing
the catalysts and ligands that were successfully applied
to the cross-coupling chemistry discussed herein.
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The AuthorsBruce Lipshutz began his career at University of California (UC) Santa Barbara, USA, in 1979, where today he is Professor of Chemistry. His programme has recently shifted towards green chemistry, with the specifi c goal of getting organic solvents out of organic reactions. For this, ‘designer’ surfactants have been introduced that allow for transition metal-catalysed cross-couplings to be carried out in water at room temperature.
Ben Taft received his BS in Chemistry at California State University, Chico, in 2004. He took a PhD from UC Santa Barbara in 2008 with Bruce H. Lipshutz. He then moved to Stanford as an NIH postdoctoral fellow under Barry Trost. He began at Novartis, in Emeryville, in 2011, where he works in the oncology discovery group.
Alexander Abela carried out his graduate work in the Lipshutz group at UC Santa Barbara, focusing on transition metal-catalysed Suzuki-Miyaura cross-coupling reactions in water and C–H activation chemistry. Following completion of his PhD, he joined the Guerrero group at UC San Diego in 2012 to continue his studies as a postdoctoral scholar.
Subir Ghorai took his PhD in 2005 from the Indian Institute of Chemical Biology. After a year of research at UC Riverside, he joined the Lipshutz group at UC Santa Barbara. Currently, he is in the Catalysis and Organometallics group at Sigma-Aldrich in Wisconsin, USA. His research interests are focused on catalysis, organometallics, and green chemistry.
Arkady Krasovskiy holds a PhD in organic chemistry from M. V. Lomonosov Moscow State University, Russia. He has extensive training in synthetic/organometallic chemistry gained during his postdoctoral time in the Knochel (2003–2006), Nicolaou (2006–2008), and Lipshutz (2008–2011) laboratories. Currently he is working in Core Research & Development at the Dow Chemical Company in Midland, MI, USA.
Christophe Duplais took his PhD in 2008 from the University Cergy-Pontoise in France, under the guidance of Gerard Cahiez. He then did a postdoctoral stay in the labs of Bruce Lipshutz at UC Santa Barbara, before accepting a position in 2011 with the CNRS, located in French Guyana.
By Thomas J. Colacot
Johnson Matthey, Catalysis and Chiral Technologies,2001 Nolte Drive, West Deptford, New Jersey 08066,USA;
Fig. 1. From left: Professor Kohei Tamao (a significant contributor in Kumada coupling),Professor Gregory C. Fu (a significant contributor in promoting the bulky electron-richtert-butyl phosphine for challenging cross-coupling), Professor Akira Suzuki (2010 NobelPrize in Chemistry Laureate), Dr Thomas J. Colacot (author of this article) and ProfessorTamejiro Hiyama (who first reported Hiyama coupling) in front of a photograph ofProfessor Victor Grignard (who initiated the new method of carbon–carbon coupling) inthe library of the University of Lyon, France
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The AuthorDr Thomas J. Colacot, FRSC, is aResearch and Development Managerin Homogeneous Catalysis (Global) ofJohnson Matthey’s Catalysis andChiral Technologies business unit.Since 2003 his responsibilities includedeveloping and managing a new cat-alyst development programme, cat-alytic organic chemistry processes,scale up, customer presentations andtechnology transfers of processesglobally. He is a member of PlatinumMetals Review’s Editorial Board,among other responsibilities. He hasco-authored about 100 publicationsand holds several patents.
described reactions in previous chapters the editor
considered the exceptional results possible when
employing these techniques worthy of separate
chapters. In the chapters on microwave synthesis and
catalyst recycling the ‘green’ aspects of the subject
are highlighted. In the case of microwave synthesis,
reduced reaction times, minimised side products
and improved yields are cited as reasons for its
consideration.
As in other chapters the authors, Ke-Hu Wang and
Jun-Xian Wang (Northwest Normal University, China),
discuss a range of microwave assisted coupling
reactions, most of which were reported within the
previous decade. In most cases the short reaction
times (with some reactions completing in a matter
of minutes) are emphasised as a unique feature of
microwave assisted synthesis, often coupled with
excellent yields.
In the chapter on catalyst recycling Árpád Molnár
places the focus on some of the shortcomings in
reported recyclable catalysts. In the lengthy introduction,
some common misconceptions with regards to what
is a stable, recyclable catalyst are addressed. Where at
times, effi cacy is maintained while catalytic metal is
being lost, the true recyclable nature of the catalyst is
brought into question. This topic is covered in detail
along with some techniques that can be utilised
to monitor low levels of Pd loss. Nanoparticle,
complex-based and polymer immobilised catalysts
are covered along with a number of other reusable
catalyst types. Here, numerous impressive examples of
robust catalysts are discussed, with some performing
twenty runs of a Heck coupling reaction without loss of
performance (9). The design of reactions is also brought
into question here. Low numbers of repeat runs using
O
O
OTBS
O
O
OTBS
(HO)2B+Br
MeO
O
MeO
O
95%
Pd(OAc)2 (20 mol%)
K2CO3, TBABH2O, 70ºC, 30 min
Fig. 3. A ligand free coupling of tropolone with an aryl trihydroxyborate catalysed by Pd(OAc)2 and tetrabutylammonium bromide using water as reaction solvent (8) (Image courtesy of Wiley and Sons, Copyright 2013)
other chapters in this book are also used in industry
including microwave assisted synthesis, continuous
fl ow coupling reactions and reusable catalysts. This
chapter exhibits a number of excellent examples
of improvements to reaction rates and conditions
achieved by incorporating Pd catalysed coupling
reactions. Despite the complexity of a number of
these compounds, equivalent or improved yields and
stereocontrol was achieved by using these coupling
reactions, often with an economic benefi t due to fewer
side products, the use of lower quantities of reagents
and a reduced need for purifi cation steps.
SummaryThis book is an excellent, modern summary of the
state of Pd-catalysed coupling reactions. The focus
on highly effi cient reactions and recyclability of the
catalysts is in tune with the ethos being adopted by
many in the chemical industry. Atom effi ciency and
the application of cleaner, less wasteful chemistry is
now very achievable. This book would be an excellent
starting place for an organic chemist who is interested
in reducing costs and increasing effi ciencies of
existing reaction processes or one who is designing
new synthetic routes.
References 1 R. F. Heck and J. P. Nolley, J. Org. Chem., 1972, 37,
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The ReviewerRobert Hanley obtained a BSc in pharmaceutical science from Cork Institute of Technology, Ireland, and a Master’s degree in green chemistry from Imperial College London, UK. He previously worked for Johnson Matthey Pharmaceutical Materials, Ireland, in the area of prostaglandin synthesis. Currently he is working as a development chemist for Johnson Matthey within the Emission Control Technologies division, his main area of research being diesel oxidation catalysts.
“Palladium-Catalyzed Coupling Reactions: Practical Aspects and Future Developments”
The Directed ortho Metallation–Cross-Coupling Fusion: Development and Application in SynthesisPlatinum group metals catalytic synthetic strategy for pharmaceutical, agrochemical and other industrial products
15a 92% yield from 13 15b 55% yield from 13 15c 56% yield from 13 15d 73% yield from 13 15e 75% yield from 13 using PhB(OH)2 using 2-MeOC6H4B(OH)2 using 3-thienylboronic acid using 3-bromothiophene using 3-bromopyridine
PG = TIPS or Boc; Ar1 = Ph, o-Tol, pyridin-3-yl; X = Br or IE = I, Br, BPin (after pinacolation); Ar2 = 8 examples including Ph, 2-MeOC6H4, pyridin-3-ylR1 = H, MeAr3 = CHCH(4-MeC6H4), Ph, 2-MeOC6H4, 3-MeOC6H4, 4-MeOC6H4, 4-FC6H4, 4-ClC6H4, 4-BrC6H4, furan-3-yl, thiophen-3-yl, pyridin-3-yl, naphthalen-1-yl, isoquinolin-4-yl
Scheme II. Indole functionalisation utilising the DoM and cross-coupling protocol
protocol lends itself to a one-pot procedure whereby
the deprotonation, transmetallation (if necessary)
to a zincate and transition metal-catalysed cross-
coupling occur sequentially in the same reaction
vessel. Among the cases illustrated in Schemes IX–XI (24–26), of note is the use of the oxazole DMG which
by hydrolysis provides the desired carboxylic acid
in the target molecule 43 (Scheme IX). This is a
further demonstration of the use of tetrazole as a DMG
in the synthesis of the ‘sartan’ pharmaceutical 46
(Scheme X) and the use of catalytic zinc chloride and
of the pyridine N-oxide as a DMG in the preparation of
azabiaryl 49 (Scheme XI).
Recently, a one-pot DoM–Negishi cross-
coupling strategy that can utilise esters as DMGs
N
NMeO F
34
N
NMeO F
33N
HNO F
39N
NMeO F
N
NMeO F
37
I HO
Li+ –ZnEt2
38
1. SOCl2(nBu)2NCHO
toluene
2. MeOHno yield given
1. (iPr)2NZnEt2Li (1.1 equiv.)2. I2 (3.9 equiv.)
THF, –10ºC to RT, 85% yield74% yield from 39
HOBr (2.2 equiv.)
LDA (2.2 equiv., addn. at –30ºC)Tri(2-furyl)phosphine (8 mol%)Pd2(dba)3•CHCl3 (2 mol%)
THF, 45ºC, 60 min, 68% yield from 39
(iPr)2NZnEt2Li(1.1 equiv.)
THF, –10ºC to RT
Allyl alcohol (15 equiv.)Pd(OAc)2 (2.5 mol%)
dppf (5.5 mol%)NH4OAc (2 equiv.)
ethylene glycol130ºC, 7–8 h, 77% yield
57% yield from 39
Scheme VIII. Sequential and ‘one-pot’ DoM–Heck coupling synthesis of naphthyridine 37 (Note: The authors provide the yields for the optimisation, but also for a process whereby all of the batch is taken through the whole process with only minimal purifi cation. Hence overall yields comparing the two processes are given even though no yield is given for the conversion of 39 to 33)
N
O
Me
Me40
O
N
N
Me
Me
NnPr
N
OH
N
N
Me
Me
NnPr
N
Br
N
O
Me
Me
N
N
Me
Me
NnPr
N
42
41
43
nBuLi (1.2 equiv.)ZnCl2 (1.8 equiv.)0ºC, THF, 120 min
then Pd(PPh3)4 (1 mol%)41 (1 equiv.)
55ºC, 24 h, 55% yield
HCl, refl ux
30 min, 85% yield
Scheme IX. One-pot DoM–Negishi cross-coupling strategy for the synthesis of telmisartan 43 angiotensin II receptor antagonist (24)
of considerable scope for the synthesis of biaryls and
heterobiaryls were demonstrated by C–H activation at C-2
(DoM) and at C-3 (Ir-catalysed boronation) of 58 which
offer new routes for the regioselective construction of
substituted biaryls 60 and 59 respectively.
1.4 The Use Of DoM–Cross-Coupling Strategies in Total SynthesisWe have also employed the DoM–cross-coupling
strategy as part of syntheses of targeted drugs and
natural product intermediates. In 2004, we reported
a synthesis of the tetracyclic A/B/C/D ring core 66 of
the antitumour agent camptothecin (Scheme XVII) (39).
This route is highlighted by an anionic ortho-Fries
rearrangement of O-carbamate 61 to give the
quinolone 62, a Negishi cross-coupling of trifl ate 63
to give biaryl 65, and a modifi ed Rosenmund–von
Braun reaction to provide the tetracyclic core 66 of
the antitumour alkaloid camptothecin in seven steps
with an overall 11% yield.
Most recently, we have completed a total synthesis
of schumanniophytine 72 (Scheme XVIII) (40), a
natural product which had been prepared only once
previously (41). Starting with DoM chemistry to obtain
the cross-coupling partners 68 from 67, our route
takes advantage of a combined DoM–cross-coupling
strategy using Stille or Suzuki-Miyaura reactions to
synthesise biaryl 69, and also incorporates a key ortho-
silicon-induced O-carbamate remote anionic Fries
rearrangement of carbamates 70 to provide amides 71.
ArHetAr
DMG
H
R
60
DMGR
DMGR
H HH
ArHetAr
5859
1. DoM
2. Suzuki-Miyaura
C2–H activation
1. Ir/B2Pin2
2. Suzuki-Miyaura
C3–H activation
DMG = CONEt2, OCONEt2, OMOM, SO2NEt2
Scheme XVI. Complementary ortho and meta boronation/Suzuki–Miyaura cross-coupling reactions of DMG bearing aromatics (38)
N OCONEt2
61 62 63
NH
CONEt2
O N
CONEt2
OTf
1. LDA (1.3 equiv.)THF, –78ºC, 1 h
2. MeOH61% yield
Tf2O (1 equiv.)NEt3 (1.8 equiv.)
CH2Cl2, 0ºC, 1 h70% yield
NBr OMe
N
CONEt2
N OMe
64 65
Steps
NN
O
66
1. tBuLi (2.0 equiv.)THF, –78ºC, 15 min
2. Anhyd. ZnBr2 (1.1 equiv.)–78ºC, 1 h
3. 63/Pd(PPh3)4 (3 mol%) THF/refl ux, 60 h
57% yield
Scheme XVII. Key reactions in the synthesis of the tetracyclic core 66 of camptothecin: anionic ortho-Fries rearrangement 61–62 and Negishi cross-coupling 64–65 (39)
Scheme XIX. Synthesis of ancistrocladinium B 76 as atropo-diasteromers (P/M) 46/54 and ancistrocladinium C 77 as atropo-diasteromers (P/M) 3/2 using a DoM–C–N cross-coupling strategy (42)
Scheme XXVIII. Large scale synthesis of phenanthrene-9,10-diones 113 using a combined DoM–cross-coupling–DreM strategy. 109 was used at a scale of 245.7 g, 111 was produced at a scale of 311.5 g and 112 at 200 g (68)
O O
CONEt2
MeBr
OH
MeMe
O
Li+ –B(OiPr)3CONEt2CONEt2
1. B(OiPr)3 (2 equiv.)THF, –25ºC
2. LDA (2 equiv.)<–20ºC, 2 h 3. H2O, 20ºC
quantitative conversion
(0.7 equiv.)
PdCl2•dppf (2.5 mol%)H2O, refl ux, 12 h
88–98% yield
114115
116
117
MeOH
MeMe
O
OH
OH
MeMe
118O
OH
MeMe
119
NC
NC
FN
NH
Et2NLi (3.5 equiv.)THF (<0.24 M)
0ºC to –5ºC, 14 h63% yield
Scheme XXIX. Large scale synthesis of mPGE synthase I inhibitor 119 using the combined DoM–cross-coupling–DreM strategy. 114 was used at a scale of 3.75 kg, 117 was produced at a scale of 7.69 kg (69)
Ar = C6H5, 2,3-di-MeC6H3, 3,5-di-ClC6H3, 2-Et2NC(O)C6H4, naphthalen-2-yl, thiophen-3-yla Some of the products were taken to the next steps without purifi cation
–
–
Scheme XXX. Double use of the N-cumylsulfonamide DMG in the synthesis of substituted saccharins 124
6. Diversifi cation of the DoM–Cross-Coupling Strategy While DoM reactions constitute one
functional group per DMG for synthetic
considerations, signifi cant advantage is
gained in diversifi cation, with or without
protection requirements, to the creation of
2,6-disubstituted DMG-bearing aromatics.
Perhaps insuffi ciently appreciated and
adapted as yet, such a sequence is shown in
Scheme XXX.
Another conceptual element, a double DoM
process (Scheme XXXI), may also be the tip
of the iceberg in synthesis.
7. The DMG as a Pseudohalide in Cross-Coupling Reactions Adaption of methodology which uses the
DMG aromatic as a pseudohalide coupling
partner, already demonstrated in our Corriu-
Kumada reaction of aryl O-carbamates
in the early 1990s, has taken on new
possibilities in O-carbamate, O-sulfamate
and sulfonamide Corriu-Kumada and
Suzuki-Miyaura reactions (Scheme XXXII)
in our laboratories as well as others. The
potential of this chemistry, including the
excision of the DMG by transition metal-
catalysed -hydride elimination processes,
is only now surfacing in the literature.
We hope the aims of this review have been met and
will be valuable to synthetic chemists. The prognostic
views expressed throughout this fi nal section are, as
many times experienced by all, dangerous to place, as
we do, into the literature.
AcknowledgementsThis review is dedicated to Alfred Bader, benefactor
of Snieckus Innovations, for giving us the opportunity
to impel our basic knowledge of chemistry to reach
practical ends.
Victor Snieckus thanks the Natural Sciences and
Engineering Research Council of Canada (NSERC)
for support by the Discovery Grant program. Suneel
Singh is grateful to NSERC for an industrial post
doctoral fellowship award.
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Victor Snieckus was born in Kaunas, Lithuania and spent his childhood in Germany during World War II. His training was at the University of Alberta, Canada, (BSc Honors), strongly infl uenced by the iconoclastic teacher, Rube Sandin; the University of California, Berkeley, USA, (MSc), where he gained an appreciation of physical organic principles under D. S. Noyce; the University of Oregon, USA, (PhD), discovering his passion for organic synthesis under the excellent mentor, Virgil Boekelheide; and at the National Research Council, Ottawa, Canada, where he completed a postdoctoral tenure with the ardent Ted Edwards. His appointments have been at the University of Waterloo, USA, (Assistant Professor, 1966); Monsanto (NRC Industrial Research Chair, 1992–1998); and Queen’s University, Canada, (Inaugural Bader Chair in Organic Chemistry, 1998–2009). Some of his awards include A. C. Cope Scholar (2001, one of 4 Canadians); Order of the Grand Duke Gediminas (2002, from the President of Lithuania); Arfedson-Schlenk (2003, Geselschaft Deutscher Chemiker); Bernard Belleau (2005, Canadian Society for Chemistry); Givaudan-Karrer Medal (2008, University of Zurich, Switzerland); Honoris causa (2009, Technical University Tallinn, Estonia); and Global Lithuanian Leader in the Sciences (2012). In research, the Snieckus group has contributed to the development and application of the directed ortho metallation reaction
(DoM) and used it as a conceptual platform for the discovery of new effi cient methods for the regioselective synthesis of polysubstituted aromatics and heteroaromatics. The directed remote metallation (DreM) reaction and DoM–linked transition metal catalysed cross-coupling reactions (especially Suzuki-Miyaura) were fi rst uncovered in his laboratories. These have found broad application in the agrochemical and pharmaceutical industries, e.g. the fungicide silthiofam (Monsanto), the anti-AIDS medication efavirenz and the anti-infl ammatory losartan (Bristol-Myers Squibb). He continues fundamental research as Bader Chair Emeritus as well as Director of Snieckus Innovations, an academic unit that undertakes synthesis of small molecules for the pharmaceutical and agrochemical industries.
Johnathan Board received his MChem from the University of Sussex, UK, and subsequently undertook his PhD with Professor Philip J. Parsons, also at the University of Sussex, working towards the synthesis of the backbone of lactonamycin. He joined the Snieckus group at Queen’s University Kingston, Ontario, Canada in 2007 as a postdoctoral fellow and worked on projects with industrial partners. In 2010 he helped set up Snieckus Innovations in which organisation he is currently a laboratory and research manager.
Jennifer Cosman received her BScH in Chemistry at Queen’s University Kingston in 2010. She joined Snieckus Innovations in early 2011, working on the custom synthesis of small molecules. In 2013 she began her MSc degree under the co-supervision of Professors P. Andrew Evans and Victor Snieckus, and is currently at Queen’s University completing this programme.
Suneel Pratap Singh was born in India, where he obtained his PhD degree (Organic Chemistry) in 2008 from the Indian Institute of Technology, New Delhi, under the supervision of Professor H. M. Chawla. After postdoctoral training on synthetic aspects of organosulfur chemistry with Professor Adrian Schwan at University of Guelph, Guelph, Ontario, Canada, he joined Snieckus Innovations in 2011. His research interests include directed ortho metallation and development of new synthetic methodologies for heterocycles.
Toni Rantanen received his PhD from RWTH Aachen University, Germany, where he studied under the supervision of Professor Carsten Bolm on the topics of organocatalysis, microwave chemistry and ball milling. In 2007 he joined the Snieckus group fi rst as an industrial postdoctoral fellow followed by academic research on the synthesis and functionalisation of heterocycles. In 2010, he helped to inaugurate Snieckus Innovations at which he is currently utilising his formidable experience as a laboratory and research manager.
butylphosphine)dipalladium(I), [Pd(μ-Br)( tBu3P)]2,was synthesised and fully characterised by Mingos(1, 2). However, its potential as a unique C–C andC–N coupling catalyst (3) was first explored byHartwig (6). It has emerged as one of the bestthird-generation coupling catalysts for cross-cou-pling reactions, including C–heteroatom couplingand α-arylations. In this review, the physical andchemical characteristics of the Pd(I) dimer as a cat-alyst material are discussed from a practicalviewpoint, and up to date information on its appli-cations in coupling catalysis is provided.
Characteristics and HandlingThe Pd(I) dimer is a dark greenish-blue
crystalline material, which gives a single peak in the31P NMR spectrum at (δ) 87.0 ppm. The 1H NMRspectrum gives a peak at (δ) 1.33 ppm (singlet; onexpansion it appears as a distorted triplet) in deuter-ated benzene (1, 2). The compound decomposes in
chlorinated solvents, especially in deuterated chlo-roform. The X-ray crystal structure is reported inthe literature as a dimer with Pd–Pd bonding, stabilised by bromine atoms via bridge formation(1, 2). It can be handled in air as a solid for a shortperiod of time, allowing the user to place it into areactor in the absence of a solvent, degas and thencarry out catalysis under inert conditions. However,this compound is highly sensitive to air and mois-ture in the solution phase. It can also decompose inthe solid phase if not stored under strictly inert conditions. The solid state decomposition patternover time was monitored in our laboratory at 0, 48and 112 hours (Figure 1) (4). Its sensitivity towardsoxygen is well understood, and is based on the formation of an oxygen-inserted product with theelimination of hydrogen (Scheme I) (5). Figure 2shows the oxygen sensitivity of the Pd(I) dimer ona proton-decoupled 31P NMR spectrum recordedusing a solvent which was not degassed. The peakat 107 ppm indicates the presence of the oxygen-inserted decomposition product.
183Platinum Metals Rev., 2009, 53, (4), 183–188
A Highly Active Palladium(I) Dimer forPharmaceutical Applications[Pd(μ-Br)(tBu3P)]2 AS A PRACTICAL CROSS-COUPLING CATALYST
By Thomas J. ColacotJohnson Matthey, Catalysis and Chiral Technologies, West Deptford, New Jersey 08066, U.S.A.; E-mail: [email protected]
The Pd(I) dimer [Pd(μ-Br)( tBu3P)]2 is one of the best third-generation cross-coupling catalystsfor carbon–carbon and carbon–heteroatom coupling reactions. Information on itscharacterisation and handling are presented, including its decomposition mechanism in thepresence of oxygen. The catalytic activity of [Pd(μ-Br)( tBu3P)]2 is higher than either( tBu3P)Pd(0) or the in situ generated catalyst system based on Pd2(dba)3 with tBu3P. Examplesof suitable reactions for which the Pd(I) dimer offers superior performance are given.
DOI: 10.1595/147106709X472147
0 h 48 h 112 h
Fig. 1 The solid stateoxygen sensitivity of purePd(I) dimer, [Pd(μ-Br)( tBu3P)]2, withtime (4)
Applications in Coupling CatalysisThe high catalytic activity of the Pd(I) dimer
[Pd(μ-Br)(tBu3P)]2 is due to its ease of activation,presumably to a highly active, coordinatively unsat-urated and kinetically favoured ‘12-electron’catalyst species, (tBu3P)Pd(0) (Scheme II). Thisrenders the Pd(I) dimer more active than either theknown ‘14-electron Pd(0)’ catalyst, (tBu3P)2Pd(0),or the Pd(0) catalyst generated in situ by mixingPd2(dba)3 with two molar equivalents of tBu3P. Theapplications of the Pd(I) dimer in organic synthesisare described below.
Carbon–Heteroatom CouplingHartwig identified the potential of the Pd(I)
dimer as a highly active catalyst for C–N coupling
using aryl chlorides as substrates with variousamines at room temperature. A few examples areshown in Scheme III (6). Typically, aryl chloridecoupling requires higher temperatures and longerreaction times when using the in situ generatedPd(0) catalyst, or even the (tBu3P)2Pd(0) complex(7). Around the same time, Prashad and cowork-ers at Novartis reported an amination reactionusing [Pd(μ-Br)(tBu3P)]2 with challenging sub-strates such as hindered anilines (8). Scheme IVshows the coupling of N-cyclohexylaniline withbromobenzene, comparing the performance ofthe Pd(I) dimer with those of in situ generated cat-alysts derived from Pd(OAc)2 with tBu3P, BINAP,Xantphos or DPEphos. The performance of[Pd(μ-Br)(tBu3P)]2 is superior in each case.
Platinum Metals Rev., 2009, 53, (4) 184
180 140160 120 100 80 60 40 20 0 ppm
Fig. 2 The oxygensensitivity of Pd(I)dimer, [Pd(μ-Br)( tBu3P)]2, as observed in the 31P NMR (ppm)spectrum recordedusing non-degassedC6D6
P P B r
P d B r
P d O 2
-2 H
O P d
O P d
C H 2
C H 2
P
B r P
B r
3 1 P N M R : 8 7 P P M 3 1 P N M R : 1 0 7 P P M P d ( I ) d i m e r
31P NMR: 107 ppm
–2H
P P
Br
Pd
Br
Pd P Pd
Highly active 12-electron species
Scheme I Theoxygen sensitivityof Pd(I) dimer,[Pd(μ-Br)( tBu3P)]2,with the formationof an inactive Pd-Ospecies (5)
Scheme II The activationof Pd(I) dimer to a 12-electron catalystspecies during couplingcatalysis
Pd(I) dimer
31P NMR: 87 ppm
Hartwig’s group subsequently conducted adetailed study to understand the activity and scopeof [Pd(μ-Br)(tBu3P)]2 in the amination of five-membered heterocyclic halides. Variouscombinations of Pd precursors with tBu3P werestudied for a model system, the reaction of N-methylaniline with 3-bromothiophene. Thefastest reaction occurred with the Pd(I) dimer (9).
More recently, Eichman and Stambuli reporteda very interesting zinc-mediated Pd(I) dimer-catalysed C–S coupling, which should generatemuch interest in the area of C–S coupling(Scheme V) (10). For the reactions of alkyl thiolswith aryl bromides and iodides, potassium hydridewas the best base, as illustrated in Scheme V. Forthe Pd-catalysed cross-coupling reactions of aryl
bromides and benzenethiol using zinc chloride incatalytic amounts, with sodium tert-butoxide asthe base, most of the reactions were sluggish andgave low yields. However, the addition of stoi-chiometric amounts of lithium iodide increasedthe rate of the reaction significantly, which isspeculated to be due to the anionic effects pro-posed by Amatore and Jutand (11).
Carbon–Carbon Bond FormationHartwig’s group also studied the Suzuki cou-
pling of sterically hindered tri-substituted arylbromides. A Pd(I) dimer loading of 0.5 mol%, inthe presence of alkali metal hydroxide base, gavegood yields at room temperature within minutes(Scheme VI) (6).
Platinum Metals Rev., 2009, 53, (4) 185
0.5 mol% Pd(I) dimer
NaOtBu, RT
15 min–1 h
R = Bu, Ph
or R2NH = morpholine
R
Yield 88–99%
Cl R
R NH +
R
N
Scheme III Arylchloride coupling atroom temperature (6)
Pd catalysts
NaOtBu, Toluene, 110°C
Catalyst loading Yield
[Pd(μ-Br)(tBu3P)]2 0.25 mol% 93%
Pd(OAc)2 + tBu3P 0.5 mol% 86%
Pd(OAc)2 + BINAP 0.5 mol% 27%
Pd(OAc)2 + Xantphos 0.5 mol% 27%
Pd(OAc)2 + DPEphos 0.5 mol% none
Br
+
HN N
Scheme IV Pd(I) dimer-catalysed C–N coupling of N-cyclohexylaniline (8)
0.5–2.0 mol% Pd(I) dimer
THF
ZnCl2 (catalyst)
KH (1.1 equiv.)
X = Br, I
Ar-X + RSH Ar-S-R
Yield 46–99%
R = tBu,
nBu, PhCH2
Scheme V Zinc-mediatedPd(I) dimer-catalysed C–Scoupling (10)
Research work from Ryberg at Astra Zeneca(12) demonstrated a very practical, clean methodfor C–CN coupling using the Pd(I) dimer [Pd(μ-Br)(tBu3P)]2 to produce 3 kg to 7 kg ofproduct routinely (Scheme VII). During the initialin situ studies, Pd2(dba)3 in combination withcommercial ligands such as Q-Phos, tBu2P-biphenyl or Cy2P-biphenyl gave poor results,although with proper process tweaking improve-ments were made. The conventional ligands, suchas Ph3P and dppf, were not useful. However, theP(o-tol)3/Pd2(dba)3 system behaved somewhatwell with the formation of some byproducts. The
Pd loading was as high as 5 mol% (12).For the α-arylation (13) of fairly challenging
carbonyl compounds, Hartwig identified thePd(I) dimer [Pd(μ-Br)(tBu3P)]2 as one of the bestcatalysts, especially for amides and esters. Thework from Hartwig’s group provided generalconditions for α-arylations of esters and amides(14–16). The coupling reactions of aryl halideswith esters are summarised in Scheme VIII (17).For aryl bromides, lithium dicyclohexylamide(LiNCy2) was the best base, while sodium hexa-methyldisilazide (NaHMDS) was required for arylchloride substrates. Intermolecular α-arylation of
Platinum Metals Rev., 2009, 53, (4) 186
Yield 84–95%
0.5 mol% Pd(I) dimer
KOH, THF
15 min, RT
Ph
R1R2
R3
PhB(OH)2
X
R1R2
R3
+
Scheme VI Roomtemperature Suzukicoupling of stericallybulky aryl bromides (6)
Pd(I) dimer, Zn(CN)2
Zn, DMF
50ºC, 1–3 hN
HN
Br
OH
N
O
N
HN
NC
OH
N
O
Yield 71–88%R1, R2 = Me, H; R = Me,
tBu
X = Br, Cl; R3 = Me, MeO, F
(i) LiNCy2 (X = Br) or
NaHMDS (X = Cl)
Toluene, RT, 10 min
(ii) Pd(I) dimer
RT–100ºC, 4 hR2
R1
R3O
OR
+
X
R3
OR1
OR
R2
Scheme VIII α-Arylation of esters under milder conditions using the Pd(I) dimer catalyst (17)
Scheme VIIThe Pd(I)dimer-catalysedcyanationreaction, whichmay be carriedout on akilogram scale(12)
X = Br;
R1 = H, CN, CF3, OCH3 or CH3; R2, R3 = H or CH3
in situ generated zinc enolates of amides was alsoreported in excellent yield under Reformatskyconditions using the Pd(I) dimer, (Scheme IX)(18). The appropriate choice of base for the sub-strate is critical for this reaction.
The α-vinylation of carbonyl compounds hasbeen reported recently by Huang and coworkersat Amgen, catalysed by the Pd(I) dimer in con-junction with lithium hexamethyldisilazide(LiHMDS) base (Scheme X) (19). The same cat-alytic system can be extended to the α-vinylation
of ketones and esters. The combination ofPd2(dba)3 with Buchwald ligands such as X-Phosand S-Phos gave inferior results, as did in situcatalysis with ligands such as Xantphos, (S)-MOP,BINAP and IPr-HCl (carbene) in the presence ofPd2(dba)3. Amgen researchers also reported astereoselective α-arylation of 4-substituted cyclo-hexyl esters using the Pd(I) dimer at roomtemperature, with lithium diisopropylamide(LDA) as the base. Diastereomeric ratios, dr, ofup to 37:1 were achieved (Scheme XI) (20).
Scheme IX α-Arylation ofamides underReformatskyconditions (18);Zn* = activatedzinc species
Scheme X α-Vinylationreaction usingPd(I) dimercatalyst (19);OTf =trifluoromethanesulfonate; OTs = tosylate
ConclusionsThe Pd(I) dimer [Pd(μ-Br)(tBu3P)]2 stands out
as unique among the third generation catalysts forcross-coupling. It has a higher activity than othercatalysts, a fact which can be attributed to its abili-ty to form a 12-electron ‘ligand-Pd(0)’ speciesduring the activation step in the catalytic cycle. Itsapplication to a wide variety of C–C, C–N and C–S
cross-coupling reactions will enable higher yieldsand better product selectivities under relativelymild conditions.
AcknowledgementsFred Hancock and Gerard Compagnoni of
Johnson Matthey’s Catalysis and Chiral Technologiesare acknowledged for their support of this work.
Platinum Metals Rev., 2009, 53, (4) 188
The AuthorDr Thomas J. Colacot is a Research and DevelopmentManager in Homogeneous Catalysis (Global) ofJohnson Matthey’s Catalysis and Chiral Technologiesbusiness unit. Since 2003 his responsibilities includedeveloping and managing a new catalyst developmentprogramme, catalytic organic chemistry processes,scale up, customer presentations and technologytransfers of processes globally.
1 R. Vilar, D. M. P. Mingos and C. J. Cardin, J. Chem.Soc., Dalton Trans., 1996, (23), 4313
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Pd(I) dimer, LDA
Toluene, RT, 3–24 h
Yield 37–85%
Up to 37:1 dr
R1 R
1
CO2Et
R–X+
CO2Et
R
Scheme XI Roomtemperaturediasteroselectiveα-arylation of 4-substitutedcyclohexyl estersusing Pd(I) dimer(20)
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The Authors
Madeleine Livendahl was born in Stockholm, Sweden, in 1983. She obtained her Master of Science in Chemistry from Stockholm University. In 2009 she joined the research group of Professor Antonio M. Echavarren at the Institute of Chemical Research of Catalonia (ICIQ) in Tarragona, Spain, with a predoctoral ICIQ fellowship. Her research interests are the discovery of new transition metal-catalysed reactions.
Pablo Espinet, born in Borja (Zaragoza, Spain) is Professor of Inorganic Chemistry in the University of Valladolid, Spain. He is Director of the research institute CINQUIMA (Center for Innovation in Chemistry and Advanced Materials). His research covers the experimental study of reaction mechanisms of palladium-catalysed reactions and the synthesis of functional metal-containing molecules.
Antonio M. Echavarren, born in Bilbao (Basque Country, Spain) is Professor of Organic Chemistry and Group Leader in the Institute of Chemical Research of Catalonia (ICIQ) in Tarragona, Spain. His research interests centre on the development of new catalytic methods based on the organometallic chemistry of transition metals as well as the synthesis of natural products and polyarenes.
Johnson Matthey Technology Review is Johnson Matthey’s international journal of research exploring science and technology in industrial applications
www.technology.matthey.com
Editorial team
Manager Dan CarterEditor Sara ColesEditorial Assistant Ming ChungSenior Information Offi cer Elisabeth Riley