Recyclable NHC Catalyst for the Development of a Generalized Approach to Continuous Buchwald-Hartwig Reaction and Workup

Article abstract of DOI:10.1021/acs.oprd.5b00349

A generalized approach to the optimization and implementation of Buchwald-Hartwig reactions in flow is reported, through the combination of three key factors: a highly active palladium catalyst, a universal approach for continuous workup and purification,

Full text of DOI:10.1021/acs.oprd.5b00349

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Full Paper
Recyclable NHC Catalyst for the Development of a Generalized
Approach to Continuous Buchwald-Hartwig Reaction and Work-Up
Anthony Chartoire, Carmen Claver, Martin Corpet, Jamin L Krinsky, Julie Mayen, David James
Nelson, Steven P Nolan, Itziar Peñafiel, Robert Woodward, and Rebecca Elizabeth Meadows
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.5b00349 • Publication Date (Web): 28 Dec 2015
Downloaded from http://pubs.acs.org on January 5, 2016
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Recyclable NHC Catalyst for the Development of a
Generalized Approach to Continuous Buchwaldꢀ
Hartwig Reaction and WorkꢀUp
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Anthony Chartoire,‡ Carmen Claver, ₤ Martin Corpet, ‡ Jamin Krinsky, ₤ Julie Mayen, ‡ David
Nelson, ‡$ Steven P. Nolan, ‡ Itziar Peñafiel, ₤ Robert Woodward,† Rebecca E. Meadows,†*
† Pharmaceutical Development, AstraZeneca, Silk Road Business Park, Macclesfield, SK10
2NA, United Kingdom
‡
EaStCHEM School of Chemistry, University of St Andrews, North Haugh, St Andrews, Fife,
KY16 9ST
₤
Department of Physical and Inorganic Chemistry, Universitat Rovira i Virgili,
C/ Marcelli Domingo s/n, Campus Sescelades, 43007, Tarragona, Spain
$
Current address: WestCHEM Department of Chemistry, Thomas Graham Building, 295
Cathedral Street, Glasgow, G1 1XL, UK
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TABLE OF CONTENTS GRAPHIC
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ABSTRACT
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A generalized approach to the optimization and implementation of BuchwaldꢀHartwig reactions
in flow is reported, through the combination of three key factors: a highly active palladium
catalyst; a universal approach for continuous workꢀup and purification, and a methodology for
catalyst recycling and reuse. The palladium Nꢀheterocyclic carbene (NHC) preꢀcatalyst
[Pd(IPr*)(cin)Cl] 4 (IPr* = 1,3ꢀbis(2,6ꢀbis(diphenylmethyl)ꢀ4ꢀmethylphenyl)imidazolꢀ2ꢀylidene;
cin = η3ꢀcinnamyl) is an excellent choice for continuous BuchwaldꢀHartwig reactions, due to its
inherent high activity and stability. In preparation for running this reaction in flow (published
concurrently), a detailed study has been carried out into its water stability, ultimately allowing
the recycling of the catalyst in the organic phase up to 3 times in batch mode. A “rightꢀfirstꢀ
time” workꢀup methodology has also been developed, resulting in a universal protocol that
allows the selective extraction of the BuchwaldꢀHartwig product into the aqueous stream as a
salt, while retaining the aryl bromide starting material in the organic stream with the catalyst,
thus negating the requirement for further purification. It is therefore envisaged that this approach
will particularly amenable to exploitation in the Pharmaceutical industry. An optimized, scalable
synthesis of [Pd(IPr*)(cin)Cl] is also reported on multiꢀhundred gram scale.
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KEYWORDS. BuchwaldꢀHartwig amination, NHC catalyst, palladium catalysis, catalyst
recycle, continuous processing, flow chemistry, designed workꢀup.
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Introduction
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CꢀN bond forming reactions are ubiquitous throughout industry and academia in the synthesis of
naturallyꢀoccurring and pharmaceutically relevant targets, and the BuchwaldꢀHartwig reaction
remains a fundamental methodology for their synthesis.1 However, there remain a number of
key challenges for putting these reactions into flow, not least the solid salt formation that is
unavoidable due to the nature of the inorganic or alkali metal alkoxide bases that are most
effective for this transformation. Not only is the resultant heterogeneous reaction mixture
regarded as highly undesirable when dealing with flow reactors due to the potential risk of
blocking, it also precludes the use of a solidꢀsupported catalyst for the continuous reaction, a
strategy typically adopted for running catalytic reactions in flow.2 The use of soluble organic
bases to avoid these issues has been assessed on a number of occasions,3,4 however, a recent
study stemming from this work has revealed them to be an unviable option in all but the minority
of cases.5 Other strategies to avoid this issue have included use of biphasic systems to solublise
the inorganic base, particularly in combination with packedꢀbed reactors to combat the mixing
issues inherent in running such systems in continuous flow mode.6
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ARꢀA2 (3) is a candidate drug (CD) that was previously under development at AstraZeneca for
the treatment of CNS (central nervous system) disorders, reaching Phase II clinical trials.7,8 One
of the key bondꢀforming reactions in its synthesis is the BuchwaldꢀHartwig reaction between
compound 1 and Nꢀmethylpiperazine to give key intermediate 2. The existing process chemistry
conditions have been published previously, however, we were interested in developing a
continuous process for the manufacture and isolation of intermediate 2 as a viable manufacturing
alternative to the current route.
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Scheme 1. Palladiumꢀcatalysed amination of 1 to give 2, a key intermediate in the synthesis of
ARꢀA2 (3).
Our vision for developing this reaction into a continuous system takes a different approach to the
perceived issues highlighted above: develop a reactor capable of dealing with the solid salt
formation inherent in the reaction; incorporate a recycle of a suitably stable catalyst in situ, and
thereby create a generic reaction system, incorporating a continuous workꢀup that allows for the
reuse of the catalyst and ultimately has the potential to be applicable beyond this immediate
project. The intended reaction system is described in Figure 1. Employing our bespoke flow
reactor (described in detail elsewhere)9 for conducting the reaction, followed by a postꢀreaction
acidic aqueous quench in a mixerꢀsettler gives us two output streams: the aqueous containing the
product salt, along with any dissolved inorganics, and the organic stream containing the residual
palladium catalyst, with the intention that this could then be recycled and reused following a
defined treatment protocol.
Figure 1. Schematic for the BuchwaldꢀHartwig reaction and workꢀup in flow, including catalyst
recycle.
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To achieve this vision, it was necessary to have a highly active catalyst that was stable enough to
withstand the aqueous acidic workꢀup that would be developed for the process. Since the advent
of their widespread use at the end of the 20th century, Nꢀheterocyclic carbene (NHC) ligands
have become an important and useful classes of ancillary ligands for organometallic catalysis. In
particular, palladium NHC precatalysts (Figure 2) have proven to be highly active for various
reactions,10 not least BuchwaldꢀHartwig coupling,11 where immobilized forms of these ligands
have also been employed.12 While several strategies exist for the formation of stable and
efficient precatalysts, the [Pd(NHC)(cin)Cl] (cin = η3ꢀcinnamyl) family13 has proven to be
particularly reliable in terms of activity and stability. Among these, [Pd(IPr*)(cin)Cl] (IPr* =
1,3ꢀbis(2,6ꢀbis(diphenylmethyl)ꢀ4ꢀmethylphenyl)imidazolꢀ2ꢀylidene) 4,14 incorporating one of
the bulkiest NHC ligands reported to date, has been demonstrated to be amongst the most active
precatalysts for the BuchwaldꢀHartwig amination reaction, allowing the formation of aromatic
amines from challenging substrates under mild conditions and with low catalyst loadings.15 For
this reason, along with the inherent stability offered by the bulky aryl groups, this became the
catalyst of choice for our study.
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Figure 2. NHC’s for cross coupling: [Pd(IPr)(cin)Cl] and [Pd(IPr*)(cin)Cl] 4.
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Discussion
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The development of our flow methodology for this transformation required the investigation of a
number of key aspects of the process as a whole. In particular, detailed investigations were
carried out into the workꢀup and isolation stages of the process and as a consequence of this, a
study into the stability of the NHC catalyst and its ability to undergo successful recycling was
also deemed necessary. This manuscript is primarily concerned with the development of the
separate aspects of the process and studies into the stability and recyclability of the NHC catalyst
prior to running the scaledꢀup manufacture of the flow process.
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Large Scale Manufacture of Pre-Catalyst:
As the above catalyst was not commercially available, it became necessary to develop a larger
scale synthesis of the [Pd(IPr*)(cin)Cl] precatalyst 4 in order to meet the demands of a multiꢀkilo
scale synthesis of 2. The synthesis of the IPr* ligand was first reported by Marko et al. in 201016
and although this protocol was adequate to prepare the ligand on a laboratory scale (<10 g), it
proved less efficient when scaling up the reaction process. It was therefore decided to optimize
the synthesis to enable a more practical and scalable route.
Synthesis of aniline 5 involves the condensation of neat paraꢀtoluidine with two equivalents of
diphenylmethanol at 160 °C in the presence of zinc chloride and concentrated hydrochloric acid
(Scheme 2).16 Marko reported that this protocol yielded aniline 5 in 75 % yield on a 13.4 g
scale.16 In our case, using similar reaction conditions on a larger scale globally resulted in a
slightly improved yield. Indeed, nine successive batches of aniline 5 (~250 g per batch) were
prepared to give almost 2 kg of the aniline in excellent average yield (81 %). It is important to
state that Marko performed this reaction in a sealed tube, however, for safety and practical
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reasons due to the scale we were operating at, the reaction was run in an open system using a
Dean Stark apparatus to trap and eliminate the water formed during the reaction.
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Scheme 2. Preparation of IPr*∙HCl on a large scale.
Next, formation of diimine 6 was carried out by reaction of two equivalents of 5 with glyoxal in
the presence of MgSO4 at ambient temperature in dichloromethane for 4 days. The reaction was
initially reported on an 8.1 g scale using a 2:1 ratio of aniline 5 to glyoxal, to give 6 in a yield of
90 %.16 However, when similar reaction conditions were employed by us on a larger scale, this
ratio only resulted in partial conversion (~50 %) of the starting aniline after 4 days reaction time.
It was found that adding an additional 0.5 equivalents of glyoxal, along with MgSO4 after 3 days
of reaction time was beneficial to the course of the reaction, giving a considerable increase in
yield for the preparation of diimine 6 on scale. In this way, 1.7 kg of the diimine was prepared
over 4 batches in an average yield of 85 %.
Next, formation of the IPr*∙HCl salt 7 by ring closure of the diimine using paraformaldehyde in
the presence of ZnCl2 and HCl (4 M in 1,4ꢀdioxane) was carried out (Scheme 2). Marko
reported this step to yield IPr*∙HCl in 60 % yield on a 3.4 g scale, using chloroform as the
reaction solvent.16 Unfortunately these reaction conditions gave a yield of 45ꢀ50 % when carried
out on the larger scale required. Having such a low yielding step late on in the synthesis of the
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precatalyst was clearly undesirable, therefore after investigating a range of alternative solvents,
tetrahydrofuran (THF) was subsequently found to be an excellent alternative to chloroform in
this case, as well as being a more processꢀfriendly solvent on a larger scale. These conditions
allowed the preparation of 0.67 kg of the ligand salt across 4 batches in an average yield of 63 %
(Scheme 2). Tout modified route now represents an efficient and scalable synthesis of ligand salt
7 without the need for chromatography or any additional purification steps.
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Scheme 3. Formation of [Pd(IPr*)(cin)Cl] (4).
Finally, the formation of the [Pd(IPr*)(cin)Cl] complex 4 by reaction of IPr*∙HCl and
[Pd(cin)Cl]2 in the presence of potassium tertꢀbutoxide in THF was investigated.14 The
preparation of the complex was reported in an excellent yield (95 %) on a 2 g scale, however, the
use of high dilution in this step (0.025 M) made it unsuitable for scaleꢀup. Ultimately, it was
found that the synthesis of complex 4 could be carried out successfully at a concentration 0.1 M
without significantly affecting the yield, giving 370 g of [Pd(IPr*)(cin)Cl] complex 4 over 4
batches in an excellent overall yield (92 %) and excellent purity, as indicated by elemental
analysis.
Choice of Reaction Solvent and Base:
Previous reports on the use of [Pd(IPr*)(cin)Cl] 4 in BuchwaldꢀHartwig reactions have
highlighted the combination of potassium tertꢀamylate and dimethoxyethane (DME) as the
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superior base and solvent for this reaction at ambient temperature, however, when moving to
lower catalyst loadings and higher temperatures, toluene was found to be more effective.15
When selecting a base and solvent for our flow process, factors other than high conversions
needed to be taken into consideration; although the organic soluble base potassium tertꢀamylate
was amenable to our flow setꢀup, the waterꢀsoluble solvent DME would not be a viable option
for the continuous workꢀup, as well as being undesirable from a SHE (Safety, Health and
Environmental) perspective. Both toluene and 2ꢀmethyltetrahydrofuran (2ꢀMeTHF) were
investigated as possible alternatives but ultimately, despite slightly higher catalyst activities
being obtained using 2ꢀmethyltetrahydrofuran, it was the superior water immiscibility of the
toluene that made it the preferred choice for our process.
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Work-up and Isolation Stages:
A key part of the reaction system shown in Figure 1 was the construction of a mild and efficient
workꢀup that could be easily translated to a flow reactor, allowing the selective extraction of the
product as its salt, whilst being mild enough for the catalyst to survive and be effectively
recycled. Quantitative analysis of the extraction of the two species 1 and 2 at varying pH was
therefore carried out in a system closely resembling the genuine reaction workꢀup: equal
volumes of toluene and water in the presence of KBr and tertꢀamyl alcohol at 30 °C, titrated with
5 M acetic acid. This revealed that although the two species are predicted to have very similar
pKas,17 their extraction profiles are remarkably different (Figure 3).
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Figure 3. Extraction profiles of 1 and 2 at varying pH (Conditions: 1 mmol 1, 1 mmol 2, 1
mmol KBr, 1 mmol tꢀAmOH, 10 mL PhMe, 10 mL water, titrant: 5 M acetic acid, 30 °C.
Analysed by 1H NMR against internal standard (1,3,5ꢀtrimethoxybenzene)).
Figure 3 reveals that a pH window exists around pH 5ꢀ5.5 where the product 2 can be selectively
extracted, leaving behind any unreacted aryl bromide 1 in the organic phase. The aryl bromide 1
does not begin to be extracted into the aqueous phase until pH<5. This had two consequences
for our flow process: firstly, it meant that our workꢀup and isolation stage would also be
amenable to running in flow by means of a pHꢀcontrolled mixerꢀsettler, giving efficient and
clean extraction of the product into the aqueous phase; and secondly, in order to successfully
recycle our chosen NHC catalyst it would need to withstand a mild (pH ~5.5) aqueous acidic
wash prior to being reused. It is envisaged that the opportunity of an “extraction window” is
likely to be applicable to the vast majority of BuchwaldꢀHartwig reactions and as such this
“rightꢀfirstꢀtime” approach to workꢀups can be employed universally for the optimization of
extractions and purifications in this class of reaction under flow conditions.18
Catalyst Stability:
In order to effect a successful recycle of the catalyst, it was necessary to have a quantitative
understanding of its sensitivity to water. With this aim five batches of toluene containing
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different amounts of water were prepared and the reactivity of the catalytic system in each batch
was studied, ranging from “stillꢀdried” (Batch A) to water saturated (Batch E). The system was
shown to be particularly sensitive to the presence of water, as observed in Figure 4; a dramatic
decrease in conversion occurs from 98 % in 1 hour when “dry” toluene was employed, to 42 %
when the waterꢀsaturated toluene was used without any drying treatment. It is, however,
remarkable that in no case was the precipitation of palladium black observed.
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Batch Water content
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Figure 4. Impact of varying levels of water on conversion at 1 hour reaction time (analysed by
GC relative to an internal standard, undecane).
Exploring the possibility that the drop in conversion could potentially be due to quenching of the
base by the additional water present, additional equivalents of the potassium tertꢀbutoxide base
were added to the reactions using waterꢀspiked toluene to determine if the same levels of activity
could be obtained with less dry toluene. The results in Figure 5 demonstrate that at the higher
water levels (80 ppm), it was not possible to increase the conversion of the amination reaction,
even by adding an extra 2 equivalents of base, however, at lower water levels (45 and 55 ppm)
the conversion was successfully increased by employing 1.5ꢀ2 equivalents of base (94ꢀ99 %
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conversion). Increasing the base levels further to 3 equivalents was observed to have a
deleterious effect on the reaction, suggesting a shift in equilibrium between the active catalytic
species and other less active offꢀcycle palladium species. Further investigations into the catalytic
cycle are required to fully define this.
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Batch B (44 ppm water)
Batch C (55 ppm water)
Batch D (80 ppm water)
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Eq. of base
Figure 5. Impact of additional base on conversion at varying water levels at 1 hour reaction time
(analysed by GC relative to an internal standard, undecane).
This informed us that at lower water levels, the “drying” effect of excess potassium tertꢀamylate
can counteract the inhibitory effect of the water in the reaction, suggesting that the catalyst itself
is robust to water levels ≤55 ppm.
Recycling Studies:
Due to the observed water sensitivity of the reaction system, as highlighted in Figure 4, various
methods of controlling the water levels in the recycled catalyst stream were assessed. The usual
solid drying agents (MgSO4, SiO2 etc.) were rejected due to the necessity for an additional
filtration step, which would be impractical for a flow process. A brief study was therefore
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conducted into alternative liquid organic reagents that could potentially react with the water
present in the organic phase, but not have a detrimental effect on the catalyst. However, all
reagents assessed (including trimethylchlorosilane, acetyl chloride and acetic anhydride) were
found to be inefficient in effecting the recycling of the palladium species, giving < 60 %
conversion on recycling of the catalystꢀcontaining organic phase.
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The difficulty encountered in efficiently removing the water from the organic phase while
retaining activity led to an alternative approach being attempted. In the standard reaction
conditions where the aryl halide is the limiting reagent, the palladium catalyst should be present
as an [IPr*ꢀPd(0)] species once all of the starting material is consumed. By switching to
conditions where either the amine or the base are the limiting reagents, in a theory more stable
Pd(II) species (8 or 9) could be obtained, which would potentially be better able to withstand the
acidic quench (Scheme 4).
Scheme 4. Theoretical Pd(II) complexes resulting from running BuchwaldꢀHartwig reaction
under baseꢀ or amineꢀstarved conditions.
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Thus, the reaction was conducted under both amineꢀstarved and baseꢀstarved conditions on an
initial run and then the organic phase subjected to the standard reaction conditions on a recycled
run (Table 1). This protocol showed better conversion on recycle, especially when baseꢀstarved
conditions were employed (entry 2), indicating that the Pd(II) species present at the end of the
reaction was indeed more stable to the aqueous acidic workꢀup, although it must be noted that
this was at the expense of sacrificing conversion (relative to the more expensive coupling
partner, the aryl bromide 1) on the first reaction run. It is interesting to note, that combining the
reagentꢀstarved protocols with azeodrying of the organic phase proved counterꢀproductive
(entries 3 and 4).
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Table 1. Catalyst recycling after amine and base starved reactions.
Conversion (%)a
Entry
Base (equiv.)
Amine (equiv.)
1st run
86
2nd run
1
2
3b
1.1
0.95
1.1
0.9
1.1
0.9
1.1
75
96
89
87
71
63
4b
0.95
94
a)
Conversion measured by GC against an internal standard (undecane)
.
Conversion refers to
conversion of aryl bromide 1 in all cases.
b)
Azeotropic drying of the organic phase after phase separation
Finally, conditions combining the protocols described above with the use of an excess of base in
the second run were employed, as this protocol had already been observed to enhance conversion
in the presence of low levels of water (Figure 5). Running the initial reaction under the standard
conditions (1 equivalent of 1, 1.1 equivalents of potassium tertꢀamylate, 1.1 equivalents of Nꢀ
methylpiperazine), and the subsequent recycled runs with 1.5 equivalents of base allowed
efficient recycling of the catalyst, with full conversion being observed on the second run, and a
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satisfactory 77 % conversion on the third run (Table 2, entry 1), a conversion level that is easily
tolerated by the designed extractive workꢀup (Figure 3). Combining this approach with the other
methods described was not as efficient (entries 2ꢀ4), and therefore an additional recycle was not
attempted.
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Table 2. Efficient recycling of catalyst 4 employing additional KOtAm on recycled runs.
Conversion (%)a
Entry
Conditions
Standard
1st run
>99
94
2nd run
98
3rd run
77
1
2
3
Baseꢀstarved
86
n/a
Amineꢀstarved
85
80
n/a
4
Standard, with Azeoꢀdrying
>99
68
n/a
a)
Conversion measured by GC against an internal standard (undecane). Conversion refers to
conversion of aryl bromide 1 in all cases.
The methodology demonstrated here in batch mode, can now be applied to the continuous
BuchwaldꢀHartwig reaction of 1 with effective catalyst recycle.
Conclusions
We have now reported for the first time a scalable and efficient synthesis of the palladium NHC
preꢀcatalyst [Pd(IPr*)(cin)Cl] 4, carried out on multiꢀhundred gram scale. Through inꢀdepth
studies of its sensitivity to acid, water and other reagents we have also established a protocol to
reuse and recycle the catalyst up to 3 times in the BuchwaldꢀHartwig reaction of a key
pharmaceutical intermediate in batch. Through a quantitative study of the workꢀup conditions,
we have also established a precise and universal workꢀup protocol for BuchwaldꢀHartwig
reactions. This “rightꢀfirstꢀtime” approach to extractions allows selective separation of the
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BuchwaldꢀHartwig product from the catalyst and other species present, despite their apparent
similar pKas, negating the requirement for further purification, and is therefore particularly
amenable to exploitation in pharmaceutical processes. This work forms the foundation of a
multiꢀkilo process for the BuchwaldꢀHartwig reaction run in a continuous flow reactor with
continuous workꢀup, which is reported in tandem.9 It is envisaged that this combination of a
highly active catalyst, a generalized approach to continuous workꢀup and purification and an
efficient methodology for catalyst recycling could form the basis for a universal approach for the
implementation of BuchwaldꢀHartwig reactions in flow beyond the immediate case study.
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Experimental
[Pd(cinnamyl)(Cl)]2 was generously supplied by Johnson Matthey and (R)ꢀ8ꢀbromoꢀ5ꢀmethylꢀ
1,2,3,4ꢀtetrahydronaphthalenꢀ2ꢀyl)ꢀ(S)ꢀ1ꢀ(phenylethyl)amine hydrochloride was donated by
AstraZeneca plc.7,8 All other reagents were used as received from suppliers unless otherwise
stated. NMR data were acquired on Bruker 300, 400 or 500 MHz spectrometers at 303 K (unless
stated otherwise) in the specified deuterated solvent. All chemical shifts are given in ppm and
13
coupling constants in Hz. Signals on the C{1H} spectra are singlets unless otherwise stated.
1
Spectra were referenced to residual protonated solvent signals (for H) or solvent signals (for
1
13
1
13
13C{1H}): (CD2Cl2 H δ 5.32 ppm, C δ 53.84 ppm; CDCl3 H δ 7.26 ppm, C δ 77.16 ppm).
GCꢀMS analyses were carried out on an Agilent 7890A with a MS 5975C detector using a HPꢀ5
column (30 m, 0.25 mm, 0.25 ꢁm). Elemental analyses were performed by Stephen Boyer at
London Metropolitan University, 166ꢀ220 Holloway Road, London, N7 8DB.
2,6-Bis(diphenylmethyl)-4-methylaniline (5). In a 3 L roundꢀbottomed flask equipped with a
stirrer bar and fitted with DeanꢀStark apparatus, pꢀtoluidine (72.8 g, 679 mmol, 1 equiv.) and
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diphenylmethanol (250 g, 1.36 mol, 2 equiv.) were melted together at 100 °C. Once fully
melted, an addition funnel containing a solution of ZnCl2 (46.2 g, 339 mmol, 0.5 equiv.) in
concentrated HCl (37%, 57.4 mL, 1.89 mol, 2.8 equiv.) was fitted on the flask, and the ZnCl2
solution added to the hot melt, keeping the flask open. The reaction media was then heated to
160 °C, and stirred until the mixture became solid (ca. 3 hours). The reaction media was then
allowed to cool to room temperature, dissolved in dichloromethane (2 L), and washed with
saturated aqueous NH4Cl (1 L) and brine (1 L). After drying over anhydrous K2CO3, silica (170
g) was added to the solution and the mixture was filtered. After evaporation, the resulting solid
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was washed with EtOAc (1 L) and dried. Yield : 260 g, 87%. H NMR (CDCl3, 400 MHz): δ
(ppm) 7.34ꢀ7.20 (m, 12H), 7.14ꢀ7.09 (m, 8H), 6.40 (s, 2H), 5.47 (s, 2H), 3.30 (s, 2H), 2.04 (s,
3H). 13C{1H} NMR (CDCl3, 100 MHz): δ (ppm) 142.9 (Cq), 139.8 (Cq), 129.7 (CH), 129.4
(Cq), 129.2 (CH), 128.6 (CH), 52.5 (CH), 21.3 (CH3). Spectroscopic data matched those reported
in the literature.16
N,N’-Bis(2,6-bis(diphenylmethyl)-4-methylphenyl)diazabutadiene (6). The aniline 5 (500 g,
1.14 mol, 2 equiv.) was dissolved in dichloromethane (2 L) in a 5 L glass reactor. Glyoxal (40 %
in H2O, 62.5 mL, 545 mmol, 0.97 equiv.), anhydrous MgSO4 (275 g, 2.28 mol, 2 equiv.) and
formic acid (5.00 mL, 132 mmol, 0.2 equiv.) were then added, and the reaction mixture was
stirred for 3 days, before additional glyoxal (40 % in H2O, 31.2 mL, 272 mmol, 0.48 equiv.) and
MgSO4 (138 g, 1.14 mol, 1 equiv.) were added. The mixture was stirred for 1 more day. The
crude mixture was poured on a frit, and the bright yellow MgSO4 cake was washed with
dichloromethane (ca. 20 L) until all colour had been removed. Solvent use could be minimised
by evaporating ca. 1.5 L of washings at a time on the rotary evaporator, and reusing this solvent
for subsequent washings of the filter cake. After evaporation of the solvents, the bright yellow
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solid was washed with hot EtOAc (250 mL), and dried under vacuum. Yield : 446 g, 87%. H
5
6
NMR (CDCl3, 400 MHz): δ (ppm) 7.24ꢀ7.13 (m, 26H), 7.00ꢀ6.95 (m, 16H), 6.65 (s, 4H), 5.22
7
8
9
13
(s, 4H), 2.11 (s, 6H). C{1H} (CDCl3, 100 MHz): δ (ppm) 164.0 (CH), 146.9 (Cq), 143.9 (Cq),
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133.7 (Cq), 132.0 (Cq), 129.6 (CH), 129.2 (CH), 128.4 (CH), 126.4 (CH), 51.1 (CH), 21.5 (CH3).
Spectroscopic data matched those reported in the literature.16
1,3-Bis(2,6-dibenzhydryl-4-methylphenyl)-1H-imidazol-3-ium chloride (IPr*∙HCl) (7). The
diimine (6) (250 g, 277 mmol, 1 equiv.) was dissolved in THF (2.5 L) in a 5 L reactor. ZnCl2
(37.8 g, 277 mmol, 1 equiv.) and paraformaldehyde (9.15 g, 305 mmol, 1.1 equiv.) were added
sequentially and the mixture was heated to 70 °C. Finally, HCl (4 M solution in dioxane, 104
mL, 416 mmol, 1.5 equiv.) was carefully added dropwise via a dropping funnel, and the medium
stirred for 3 hours at 70 °C. After this time, the solvent was evaporated, and the crude residue
was dissolved in EtOAc (1 L), washed with water (1 L) and brine (1 L), and the solvent removed
by evaporation. The resulting offꢀwhite powder was dried overnight at 130 °C under vacuum.
1
Yield : 168 g, 64%. H NMR (CDCl3, 400 MHz): δ (ppm) 11.85 (br s, 1H), 7.30 (d, J = 7.5 Hz,
8H), 7.20ꢀ7.03 (m, 24H), 6.77 (d, J = 7.1 Hz, 8H), 6.71 (s, 4H), 5.52 (s, 4H), 5.39 (s, 2H), 2.06
13
(s, 6H). C{1H} (CDCl3, 100 MHz): δ (ppm) 143.0 (Cq), 142.4 (Cq), 141.0 (Cq), 140.6 (Cq),
131.1 (CH), 130.5 (CH), 129.4 (CH), 128.6 (CH), 126.8 (CH), 126.7 (CH), 51.3 (CH), 21.9
(CH3). Spectroscopic data matched those reported in the literature.16
[Pd(IPr*)(cin)Cl] (4). In a glovebox, the IPr*∙HCl salt 7 (98.0 g, 103 mmol, 1 equiv.) was
dissolved in THF (1.3 L) in a 2 L roundꢀbottomed flask equipped with a stirrer bar, and KOtBu
(12.7 g, 113 mmol, 1.1 equiv.) was added. The mixture was stirred for 4 hours, then
[Pd(cinnamyl)(Cl)]2 (24.3 g, 46.9 mmol, 0.91 equiv. Pd) was added, and the reaction mixture
stirred overnight at ambient temperature. The reaction flask was then taken out of the glovebox
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and the mixture was concentrated and filtered through Celite to remove the Pd black and KCl.
The crude product was then filtered through silica gel (elution with dichloromethane), and dried
over MgSO4. After evaporation of the solvents, the yellow powder was dried for several days
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under high vacuum at 80 °C. Yield : 104 g, 95%. H NMR (CDCl3, 400 MHz): 7.49 (d, J = 7.2
Hz, 2H), 7.40 (t, J = 7.4Hz, 2H), 7.36ꢀ7.17 (m, 21H), 7.10ꢀ7.06 (m, 12H), 6.86ꢀ6.83 (m, 8H),
6.80ꢀ6.77 (m, 4H), 6.10 (s, 2H), 5.71 (s, 2H), 5.32 (s, 2H), 5.04ꢀ4.96 (m, 1H), 4.63 (d, J = 13.1
Hz, 1H), 2.60 (d, J = 6.5 Hz, 1H), 2.23 (s,6H), 1.25 (d, J = 11.4 Hz, 1H). C{1H} (CDCl3, 100
13
MHz): δ (ppm) 182.6 (Cq), 144.6 (Cq), 143.8 (Cq), 141.4 (Cq), 140.6 (Cq), 138.5 (Cq), 137.8 (Cq),
135.9 (Cq), 130.6 (CH), 130.3 (CH), 129.3 (CH), 129.2 (CH), 128.7 (CH), 128.4 (CH), 128.3
(CH), 127.7 (CH), 127.2 (CH), 126.4 (CH), 126.4 (CH), 123.5 (CH), 109.0 (CH), 91.3 (CH),
51.6 (CH), 47.4 (CH2), 22.0 (CH3). Elemental analysis: Calculated for C78H65ClN2Pd: C, 79.92;
H, 5.59; N, 2.39. Found: C, 79.80; H, 5.73; N, 2.46. Spectroscopic data matched those reported
in the literature.14
General procedure for the Buchwald-Hartwig reaction of 1 with [Pd(IPr*)(cin)Cl] 4, and
reuse of the organic phase: The aryl bromide 1 (86.1 mg, 0.25 mmol, 1 equiv.),
[Pd(IPr*)(cin)Cl] (2.9 mg, 1 mol%) and toluene (0.84 mL) were added to a dried 4 mL vial
equipped with a stirrer bar and sealed with a screw cap fitted with a septum. To this mixture was
then added Nꢀmethylpiperazine (30 µL, 0.270 mmol, 1.1 equiv.), followed by KOtAm 160 µL,
0.275 mmol, 1.1 equiv., 1.7 M solution in toluene) via syringe. The reaction mixture was then
stirred (800 rpm) at 50 ºC for 1 h. After this time, a solution of AcOH (250 µL of a 5 M solution
+ 750 µL of distilled H2O) was added to the reaction mixture. After phase splitting, the organic
phase was transferred via syringe under inert atmosphere to a dried 4 mL vial containing a
second portion of aryl bromide 1 (86.1 mg, 0.25 mmol, 1 equiv.), Nꢀmethylpiperazine (30.0 µL,
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0.270 mmol, 1.1 equiv.) and KOtAm (160 µL, 0.275 mmol, 1.1 equiv., 1.7 M solution in
5
6
toluene). The reaction was then repeated as above.
7
8
9
The conversion was quantified by GCꢀMS employing undecane as internal standard. The
chromatographic method was the following: 5 min at 45°C; 45ꢀ250 ºC, 10 °C/min; final hold
time of 10 min. Retention time of aryl bromide 1: 27.64 minutes, retention time of 2: 33.58
minutes.
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Supporting Information. Additional experimental detail on the procedures for the pH
titrations, waterꢀdoping experiments and recycling studies can be found in the supporting
information.
Acknowledgements
The authors wish to thank the EU’s 7th Framework Programme (Synflow) Grant Agreement n.
[NMP2ꢀSLꢀ2012ꢀ280827] for funding and Chris Barnard at Johnson Matthey for the generous
supply of the palladium dimer as well as useful and stimulating technical discussions.
AUTHOR INFORMATION
Corresponding Author
* Dr. Rebecca E. Meadows, Pharmaceutical Development, AstraZeneca, Silk Road Business
Park, Macclesfield, SK10 2NA, United Kingdom. Rebecca.meadows@astrazeneca.com
ABBREVIATIONS
NHC, CD, CNS, cin, IPr*, THF, SHE
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References
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1 For recent publications using BuchwaldꢀHartwig chemistry to synthesise natural products and
medicinal chemistry targets see: Trabanco, A. A.; Duvey, G.; María Cid, J.; Macdonald, G. J.;
Cluzeau, P.; Nhem, V.; Furnari, R.; Behaj, N.; Poulain, G.; Finn, T.; Poli, S.; Lavreysen, H.;
Raux, A.; Thollon, Y.; Poirier, N.; D’Addona, D.; Ignacio Andrés, J.; Lutjens, R.; Le Poul, E.;
Imogai, H.; Rocher, J.ꢀP. Med. Chem. Commun., 2011, 2, 132; Pandya, V.; Jain, M.;
Chakrabarti, G.; Soni, H.; Parmar, B.; Chaugule, B.; Patel, J.; Joshi, J.; Joshi, N.; Rath, A.;
Raviya, M.; Shaikh, M.; Sairam, K. V. V. M.; Patel, H.; Patel, P. Bioorg. Med. Chem. Lett.,
2011, 21, 5701; Kumar, V. P.; Gruner, K. K.; Kataeva, O.; Knölker, H.ꢀJ. Angew. Chem. Int. Ed.,
2013, 52, 11073; Nguyen, T.; Yang, T.; Go, M.ꢀL. Bioorg. Med. Chem. Lett., 2014, 24, 1830;
Krasavin, M. Letters in Org. Chem., 2013, 10, 235
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11 [a] Gao, K.; Yorimitsu, H.; Osuka, A. Eur. J. Org. Chem. 2015, 2678; [b] Sugahara, T.;
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Organic Process Research & Development
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15 Chartoire, A.; Frogneux, X.; Nolan, S.P. Adv. Synth. Cat. 2012, 354, 1897ꢀ1901
16 BerthonꢀGelloz, G.;Siegler, M.A.; Spek, A.L.; Tinant, B.; Reek, J.N.H.; Markó, I.E. Dalton
Trans. 2010, 39, 1444ꢀ1446
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17 Values predicted using ACD Labs 2012 Expert software
18 Further details on this methodlogy will be reported in due time: Ashworth, I. A.; Hose, D.;
Meadows, R. E. manuscript in preparation
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