Continuous flow Negishi cross-couplings employing silica-supported: Pd-PEPPSI - IPr precatalyst

Article abstract of DOI:10.1039/c6cy00331a

The synthesis of a triethoxysilyl functionalised Pd-PEPPSI-IPr complex prepared via azide-alkyne cycloaddition is described. The complex was immobilised onto silica gel and applied as a heterogeneous catalyst in the Negishi reaction. The catalyst was active in both batch and continuous flow operation and was particularly effective for the coupling of heteroaryl chlorides. Long-term continuous flow experiments demonstrated good catalyst activity over fifteen hours.

Full text of DOI:10.1039/c6cy00331a

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Bogdan, A. L. Aguirre, T. Iwai, S. W. Djuric and M. G. Organ, Catal. Sci. Technol., 2016, DOI:
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Continuous flow Negishi cross-couplings employing silica-
supported Pd-PEPPSI-IPr Precatalyst
Gregory A. Price,a Andrew R. Bogdan,b Ana L. Aguirre,b Toshiyuki Iwai,a Stevan W. Djuricb and
Michael G. Organ*a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
The synthesis of a triethoxysilyl functionalised Pd-PEPPSI-IPr complex prepared via azide-alkyne cycloaddition is described.
The complex was immobilised onto silica gel and applied as a heterogeneous catalyst in the Negishi reaction. The catalyst
was active in both batch and continuous flow operation and was particularly effective for the coupling of heteroaryl
chlorides. Long-term continuous flow experiments demonstrated good catalyst activity over fifteen hours.
www.rsc.org/
activity.10 Of the various catalytic systems described in the
literature, the Pd-PEPPSI (pyridine-enhanced precatalyst
preparation, stabilisation and initiation) family of precatalysts
Introduction
Continuous flow organic synthesis has undergone rapid
development in recent years owing to the considerable
benefits afforded over conventional batch reaction processes.
Flow reactors enable greater control of reaction variables,
enhanced reaction efficiency,1 and improved safety profiles for
processes that have risk associated with them.2 Additionally,
the ability to number up and adjust scale without altering the
reaction conditions is a distinct advantage inherent to flow
chemistry.3
has emerged as a highly active and ‘user-friendly’ catalyst
system for numerous coupling reactions.11 Currently, Pd-
PEPPSI pre-catalysts are used as homogeneous catalysts,
however several immobilisation strategies have recently been
applied to NHC-Palladium complexes including Pd-PEPPSI
derivatives. In general, covalent tethering techniques have
been explored due to the formation of stable linkages
between the support and catalyst.12 A facile approach to
immobilisation involves substitution of one of the N-aryl arms
of the NHC ligand with an alkyl chain containing a tethering
group (Figure 1).13 However, by removing some of the steric
bulk around the palladium centre the stability and catalytic
activity of the complex is diminished.14 Hashmi and co-workers
have described the use of a gold-carbene complex connected
Palladium catalysed cross-coupling reactions are widely
employed and extremely versatile reactions for the
construction of carbon-carbon and carbon-heteroatom bonds.4
Given the importance of these reactions for the production of
compounds in the pharmaceutical and fine chemical industries
many attempts have been made to carry out these
transformations in a continuous flow setup.5 Of the possible
ways to achieve this goal the use of heterogeneous catalysts in
the form of supported metal particles6 and films5d, 7 has been
investigated, further, packed bed reactors have received
significant attention.8 Combining these two branches of
chemistry would enable recovery and re-use of the palladium
catalyst and also simplify purification of the final product by
reducing the level of metal present in the eluent stream due to
metal/ligand particulates. Under batch conditions, N-
heterocyclic carbene (NHC) ligands are now well-established
alternatives to the phosphine ligands traditionally employed in
palladium catalysed coupling reactions.9 This is due to the
favourable electronic and steric parameters of NHC ligands
that give rise to Pd-NHC complexes with high catalytic
to
a silsesquioxane cage as a mimic of the surface
attachment.15 Very active catalysts could be obtained in this
way, although they remained soluble in the reaction medium.
Immobilisation via functionalisation of the N-heterocyclic
backbone has also been utilised to prepare heterogeneous
NHC-metal catalysts with a range of metals (Figure 1),16
although examples featuring Pd-NHC complexes are rare.17
N
N
O
R
3
3
L Pd L
L
N
N
N
N
R
R
Mes
Mes
CuL
R = Mes, Ad
RuLn
R = Me, Mes, C10H21
(CH2)3Si(OEt)3
,
Figure 1: Immobilisation strategies for solid supported NHC-metal
complexes.
Another option that has been investigated is to functionalise
the para-position of one or both of the N-aryl rings of the NHC
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ligand with
a tethering group. This method enables
preparation of symmetrical and unsymmetrical NHC ligands
(about the C2 axis), and has the benefit of retaining the
requisite steric bulk around the metal centre. To this end,
Claver and co-workers have recently reported the
immobilisation of a range of palladium-acetylacetonate- NHC
complexes through para-functionalisation.18 Installation of a
triethoxysilyl tether was accomplished through a thiol-ene
reaction and the complexes exhibited good activity and
recyclability in Suzuki-Miyaura reactions under batch and
continuous flow conditions. In an alternative approach,
Kirschning and co-workers,19 reported a PEPPSI-IPr catalyst
that was immobilised on a polyvinylpyridine support through
the ligand trans to the NHC. Although a number of studies
have addressed the use of heterogeneous palladium catalysts
for Suzuki-Miyaura cross-couplings under flow conditions, until Scheme 1: Preparation of TMS-alkyne functionalised aniline (3)
recently there was a lack of literature precedent concerning
adduct
4 afforded an intermediate hydroxylated imidazolium
Negishi cross-couplings carried out as continuous flow
processes. One of the challenges often encountered when
performing Suzuki-Miyaura reactions in flow is the
precipitation of insoluble salts during the course of the run. In
contrast, Negishi couplings generally result in homogeneous
mixtures providing an appropriate solvent system is selected
for the reaction. Moreover, the Negishi reaction provides a
facile means to install new sp3-carbon centres in organic
salt that subsequently underwent dehydration to yield
imidazolium salt
5. With
5
in hand we next explored routes to
(Scheme 2). We opted for a mild
palladium NHC complex
9
approach whereby intermediate copper complex (7) was
‘clicked’ to an azide adorned with a triethoxysilyl group, before
undergoing transmetallation with a Pd source. This protocol is
appealing as the use of a strong base in the synthesis of metal
complexes is avoided,29 and crucially the copper-NHC
intermediate can also be functionalised and immobilised on a
silica support for use in continuous flow reactions. Initially, we
11b,
molecules through sp2-sp3 and sp3-sp3 cross-couplings.9f-i,
11h, 11q, 11r, 11w, 11z, 11aa, 11ad, 11aj, 20 This is of increasing relevance to
the pharmaceutical industry, where there is a renewed
interest in targeting structurally complex drug candidates that
contain more sp3 centres.21 In this regard, Alcazar et al.22 and
McQuade and co-workers23 have described the use of a silica-
supported diphenylphosphine based Pd(II) catalyst, SiliaCat
DPP-Pd, for flow Negishi reactions.24 Good to excellent
conversions were reported for a range of couplings between
alkyl zinc species and aryl iodides, bromides and activated
chlorides at 60 oC. The catalyst was found to be stable for a 4 -
13 h period.
examined the direct preparation of Cu-NHC complex (
7) from
perchlorate salt 5 using the method reported by Zhu and co-
workers.30 Under these conditions, the desired metallation
was found to take place concomitant with deprotection of the
TMS-alkyne to give
7 in moderate yield. The reaction suffered
from poor reproducibility between batches and drastically
reduced yields upon scale-up resulting from undesired Glaser-
Hay coupling31 between two terminal alkyne units. Owing to
the improved versatility of imidazolium salts having halide
counter-ions we examined exchange of perchlorate for
chloride using an anion exchange resin. Gratifyingly, filtration
Given our group’s longstanding interest in the Negishi
reaction11b, 11h, 11q, 11r, 11w, 11x, 11z, 11aa, 11ad, 11aj, 20a we sought to
immobilise a Pd-NHC complex on a silica support for use in
continuous flow couplings. Herein, we report the synthesis and
subsequent immobilisation of a triethoxysilyl functionalised
Pd-PEPPSI-IPr complex prepared via azide-alkyne cycloaddition
chemistry.25 The efficacy of the solid supported pre-catalyst in
Negishi cross-coupling reactions under both batch and flow
conditions is also described.
of
conversion to imidazolium salt 6 32
copper(I) oxide33 yielded Cu-NHC
along with trace amounts
5
through DOWEX® ion-exchange resin resulted in clean
.
Treatment of with
6
7
of the TMS-protected alkyne analogue. The alkyne could be
completely deprotected in a second step by reacting the crude
Cu-NHC mixture with tetrabutylammonium fluoride in THF
resulting in a 65% yield of
that no Glaser-Hay by-products were observed when the Cu2O
protocol was used to prepare , and no evidence of halide
7 over two steps. It should be noted
7
scrambling at the copper centre could be detected by 19F{1H}
NMR spectroscopy. Inspired by the report of Gautier et al.34
that Cu-NHC complexes can act as both catalyst and substrate
Results and Discussion
The synthesis of PEPPSI complex
9
began with preparation of
using
TMS-protected alkyne functionalised imidazolium salt
5
for azide-alkyne cycloadditions, we found that
7
underwent
in
to a
modifications to the method described by Furstner and co-
workers for the preparation of unsymmetrical imidazolium
reaction with 3-azidopropyltriethoxysilane to give
excellent yield. We next investigated transmetallation of
8
8
salts.26 4-Iodo-2,6-diisopropylaniline (
2
) prepared from
iodination,27 underwent Sonogashira coupling with
trimethylsilylacetylene28 furnishing alkyne
in 71% yield over
with Furstner’s oxazolinium
1 by
Pd(II) centre and soon realised that the triazole on the NHC
backbone interfered with ligand transfer. After careful
selection of the solvent and reaction conditions,
3
2 steps (Scheme 1). Reaction of
3
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palladium content of 2.17 wt%, and nitrogen content of 2.15
wt%, both of which are in excellent agreement with the results
obtained by ICP analysis.
Scheme 2: Preparation of triethyoxysilyl-functionalised Pd-PEPPSI complex
9.
35
transmetallation to PdCl2(3-ClPy)2 proceeded in toluene at
110 oC to give triethyoxysilyl functionalised palladium complex
Evaluation of Catalytic activity
9
in moderate yield. Immobilisation onto the surface was
In order to evaluate the catalytic activity of 10 a series of
Negishi coupling reactions were carried out under batch
conditions. Initially, we chose to study the coupling of 2-
carried out by reaction of 9 with high purity silica gel (Davisil™
grade 646) in toluene (Scheme 3). The supported catalyst was
then subjected to continuous Soxhlet extraction with EtOAc for
24 hours, after which the silica support was passivated with
hexamethyldisilazane. Characterisation of 10 by ICP elemental
chloro-4-methylquinoline
(11
)
with
(6-ethoxy-6-
oxohexyl)zinc(II) bromide (12) using conditions developed
previously in our group.11aj We were pleased to find that 10
displayed excellent activity for the coupling at room
temperature (Table 1, entry 1) although the reaction took 16 h
to complete, compared to 2 h for the homogeneous PEPPSI
complexes (Table 1, entries 2 and 3). However, by increasing
the concentration with respect to aryl halide from 0.1 M (entry
1) to ~0.5 M (entry 4), full conversion with 10 was achieved in
2 h. In light of this high activity we next set about confirming
that the observed efficacy in these reactions was not the result
of something other than Pd-NHC complex 10, thus a number of
control experiments were carried out (Table 1, entries 5-8 and
analysis gave
a palladium content of 2.28 wt%, which
corresponds to an effective catalyst loading of 0.21 mmol/g.
The nitrogen content of 10, together with the Pd/N ratio give
further information about the composition of the solid
supported catalyst. The nitrogen loading was found to be 2.09
wt% giving a Pd/N atom ratio of 1:6.9, which is in close
agreement with the calculated ratio of 1:6. We used SEM/EDX
elemental analysis to view the silica particles after
immobilisation and to verify the elemental compositions
obtained by ICP analysis. EDX elemental analysis indicated a
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activity observed for 10 is derived from the Pd-NHC complex.
Next, the recyclability of 10 in this reaction was studied over
five cycles (Table 2).
Table 2: Recycling of 10 under batch conditions.
Cycle
1
2
3
4
5
Time (h)
Conversion (%)a
16
16
24
24
24
72
30
83
>99
98
>99
>99
Conditions: 2-chloro-4-methylquinoline (11, 0.5 mmol, ~0.1 M), THF (2.5 mL), LiBr
(139 mg, 1.6 mol, 3.2 equiv.), RZnBr (12, 1.25 mL, 0.65 M in DMI, 0.8 mmol), 10
a
(60 mg, 2.5 mol%). Conversion determined by 1H NMR spectroscopy of the
crude reaction mixtures.
The coupling was performed under the same conditions as
those described for the preliminary screening (see Table 1),
except a 2.5 mol% loading of supported catalyst was used.
After each cycle, 10 was collected by filtration, washed with
dichloromethane and Et2O and then dried under vacuum.
Conversion of starting material to product was determined by
1H NMR spectroscopy. It was found that this recycled complex
maintained high activity over five successive reactions,
although the observed reaction rate slowed after the second
cycle. In these cases, extending the reaction time from 16 h to
24 h was sufficient to restore quantitative conversion to
coupled product. The oxidation state of palladium during the
recycling process is currently unknown however it is possible
that the silica support stabilises the Pd centre, perhaps
through formation of an oxo-palladium species.
Scheme 3: Immobilisation of Pd-PEPPSI complex (9) onto silica gel.
ESI†). In all cases involving PdCl2 only trace amounts of coupled
product were observed, concurrent with the formation of
palladium black. Furthermore, the use of 1-benzyl-4-(p-tolyl)-
1H-1,2,3-triazole in combination with PdCl2(MeCN)2 (Table 1,
entry 7) did not result in conversion to coupled product.
Equally, a Pd(OAc)2/nBu4NBr combination that is known to
generate Pd-nanoparticles20c displayed no catalytic activity.
Collectively, these control experiments confirm the catalytic
Substrate scope under batch and continuous flow conditions
Table 1: Initial screening of Pd complexes under batch conditions.
The use of 10 in packed bed reactors for continuous flow
Negishi couplings was then evaluated. In light of our batch
experience, we again chose the coupling of 2-chloro-4-
Entrya
[Pd] (mol %)
Time (h)
Yieldd (%)
O
methylquinoline
(
11)
with (6-ethoxy-6-oxohexyl)zinc(II)
BrZn
OEt
bromide (12) as the model reaction. The flow reactor was
comprised of a FEP (fluorinated ethylene propylene) tube
(0.159 cm ID x 8 cm) packed with 70 mg of 10. Connected to
the reactor outlet was a length of FEP tubing (0.025 cm ID x 20
cm) that fed directly into a quench solution of saturated
NaHCO3/H2O. Flow screening was conducted using the same
reagent stoichiometry and solvent system as for the batch
reactions detailed in Table 1. A stock solution of aryl halide,
organozinc and LiBr in THF/DMI (2:1) was passed through the
5
12
[Pd], LiBr
O
THF/DMI,
rt
N
OEt
N
Cl
5
11
13
1
2
10 (2.0)
9 (1.0)
16
2
80
90
3
4b
Pd-PEPPSI-IPr (1.0)
10 (2.0)
2
81
2
85
catalyst bed at room temperature at a flow rate of 20 μL/min
5
PdCl2 (5.0)
24
24
trace
trace
giving a residence time (tR) of ~9 min. Using these conditions
coupled product 13 could be obtained in high yield on a 2.4
mmol scale (Scheme 4). Substrate scope was then examined
and various functional groups were well tolerated including
6
PdCl2(MeCN)2 (5.0)
PdCl2(MeCN)2 (5.0) + triazolec
7
8
24
24
trace
trace
(5.0)
Pd(OAc) (5.0) + nBu4NBr (100)
nitriles, esters, ketones and alkenes (Scheme 4, 13
Further, N-heteroaryl chlorides could be coupled uneventfully
in excellent yield (13 17 20). Typically, cross-couplings
, 14, 16-19).
a Conditions: 2-chloro-4-methylquinoline (11, 0.5 mmol, ~0.1 M), LiBr (3.2 equiv.),
b
RZnBr (1.8 equiv., 0.6 M in DMI), THF. Conditions: 2-chloro-4-methylquinoline
c
(11, 0.5 mmol, ~0.5 M), LiBr (3.2 equiv.), RZnBr (1.8 equiv., 0.6 M in DMI), THF.
,
,
d
triazole ligand = 1-benzyl-4-(p-tolyl)-1H-1,2,3-triazole. isolated yield following
involving 2-chloropyridyl-like species can be difficult to affect
with commercially available immobilised catalysts.22 Even
deactivated substrates such as 2-chloro-6-methoxypyridine
purification on SiO2
(
18) underwent reaction in high yield upon reduction of the
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10,
10,
LiBr
LiBr
R1
X
R2 ZnBr
R1 R2
R1 Cl
R2 ZnBr
R1 R2
THF/DMI
THF/DMI
O
OEt
O
O
NC
N
OEt
N
OEt
N
13, X = Cl, 88%
14, X = Br, 74%
21, 95%
22, 95%
(10% homo coupled)
EtO
O
O
CN
O
N
N
3
N
O
N
Boc
22, 25%
23, 42%
15, X = Br, 23%
16, X = Br, 63%
O
N
MeO
N
O
N
CN
CN
O
N
OEt
O
17, X = Cl, 61%
18, X = Cl, 80%, 15 ꢀl/min
24, 85%
25, 95%
O
3
O
N
O
N
N
F
26, 72%
27, 91%
19, X = Cl, 43%
20, X = Br, 64%
Scheme 5: Substrate scope with 10 using commercially available organozinc
reagents, displaying isolated yields. Conditions: 10 (350 mg, 0.21 mmol/g,
0.0735 mmol), aryl chloride (1.12 mmol, 1.0 equiv.), DMI (3.0 mL), RZnBr
(0.5 M in THF, 4.5 mL, 2.25 mmol, 2.0 equiv.), rt, 50 μL/min, tR = ~10 min.
Scheme 4: Substrate scope with 10 in continuous flow couplings displaying
isolated yields. General Conditions for couplings in flow: aryl halide (~0.1 M),
THF, organozinc in DMI (1.8 equiv.), LiBr (3.2 equiv.), 10 (70 mg, 0.21
mmol/g, 0.015 mmol), rt, 20 μL/min residence time ~ 35 mins.
Long-term activity of catalyst and heterogeneity tests
flow rate to 15
μL/min (tR = ~12 min). Unfortunately, the
coupling of an N-Boc-protected indole led to low product
recovery under these flow conditions (15). It should be noted
that during the course of these studies we found that coupling
of 4-bromobenzonitrile with (6-ethoxy-6-oxohexyl)zinc(II)
bromide (to generate 14) could be effected with simple
palladium halide salts, perhaps through a metal promoted SnAr
reaction. With these results in hand, we conducted further
screening of 10 in continuous flow Negishi couplings using
commercially available organozinc reagents. Supported
precatalyst 10 (350 mg) was packed into an Omnifit column
(0.3 cm x 10 cm) possessing a larger void volume than the
The long-term activity of 10 was assessed using the model
reaction leading to 13 (see Figure 2). Fresh reagents were
pumped into the reactor and the conversion to product
monitored over a prolonged period of time. Using a flow rate
of 20 μL/min (tR = ~9 min) we observed a gradual decrease in
conversion over a period of 15 hours. Intrigued by this slow
loss in activity, a series of heterogeneity tests were performed
on the supported catalyst. First, we carried out a filtration
test36 whereby coupling is initiated, the catalyst is removed by
filtration, and then the filtrate is subsequently monitored for
further catalytic activity. Any continued conversion within the
filtrate indicates leaching of a soluble palladium catalyst into
solution. In the first experiment a ca. 20% increase in
conversion was observed over 24 h in the filtrate following
removal of 10. We wondered whether the observed activity in
the filtrate might be due, at least in part, to washing off non-
previously used system (i.e., 500
solution of aryl halide and organozinc reagent in THF/DMI (3:2)
(0.15 M) was pumped through the reactor at 50 L/min (tR
μL vs. 171 μL). A stock
μ
=
~10 min) at rt. The products were purified by reverse phase
HPLC and isolated as TFA salts. Single columns could be used
to generate small libraries of compounds by simply washing
the column after each run with a small volume of solvent and
changing the organozinc being used (Scheme 5). 2-Chloro-4-
methylquinoline and 2-chloro-7-methoxy-4-methylquinoline
could be coupled with a variety of organozinc reagents in good
to excellent yield. Again, various functionalities were well
tolerated in the reaction.
covalently bound
9, rather than leaching from 10 per se.
Therefore, THF (3 mL) was flowed through a packed bed of 10
into a vial containing aryl halide, organozinc reagent, and LiBr
in DMI. After 36 h at room temperature, conversion in the vial
reached 52
% signifying that some unbound palladium
complex had been liberated from the support. To address this
issue, 10 was subjected to Soxhlet extraction with THF at
reflux. Subsequently, THF was pumped through a bed of the
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content after 4.5, 7.5, 10.5 and 13.5 h of continuous operation.
It was found that palladium leaching reaches ~40 % of total
palladium content after 13.5 h corresponding to ~0.62 mg of
Pd in the reaction stream (Figure 3). We observed a high initial
leaching of Pd in the first hours of the experiment (82 ppm,
28%, 0.44 mg, in 4.5 h), followed by a lower level of constant
leaching over a further 10 h. To confirm the leaching was not
due to degradation of the silica support the stream was
analysed for the presence of silicon. Low levels of silicon (< 8
ppm) were detected in all samples illustrating that the support
remains intact during the reaction. The leached palladium
species displayed poor catalytic activity as detailed above, thus
it is reasonable to assume that the initial level of leaching
observed is due to decomposition of the catalyst that releases
Pd into the flow stream. The level of palladium leaching
detected may be greatly influenced by the reaction conditions.
For example, the N-heterocycles in this study may facilitate
greater leaching from the support due to coordination of the
nitrogen to the Pd centre, thus ‘stripping’ it off the support.
Additionally, the use of excess organozinc reagent (1.8 equiv.)
100
95
90
85
80
75
70
65
0
2
4
6
8
Time (h)
10 12 14
Figure 2: Long-term Negishi coupling at 20 μL/min residence time ~ 9 mins.
Conditions: 2-chloro-4-methylquinoline (11, 2.4 mmol, ~0.1 M), THF,
organozinc in DMI (1.8 equiv.), LiBr (3.2 equiv.), 10 (70 mg, 0.21 mmol/g,
0.015 mmol), 20 μL/min residence time ~ 9 mins. Product ratio determined
by 1H NMR spectroscopy.
newly extracted material into a vial containing the reagents. In
this case no catalytic activity could be detected after 36 h
demonstrating that the additional extraction of 10 with THF
had removed the unbound complex. Moreover, the THF-
extracted material had essentially the same catalytic activity in
flow couplings as the non-extracted catalyst. After repeating
the filtration test with freshly extracted 10 we observed a ca.
10% increase in conversion in the filtrate over 36 h (compared
to 100% conversion without filtration of 10 in 16 h and 100%
could facilitate catalyst decomposition. In
a
control
experiment, an organozinc solution was passed through a
packed bed of 10 into a vial containing aryl chloride in THF. In
this case the catalyst immediately darkened and significant
quantities of palladium black were found in the reaction
stream. No cross-coupling product was detected in the vial
over a period of 48 h demonstrating a change in catalyst
structure to something that is inactive. A further batch
reaction was carried out with the recovered supported catalyst
conversion in 2 h for 9). In addition to these studies, reaction
streams from continuous flow couplings were left overnight
without the addition of a quench solution and analysis
revealed only a small (ca. 2%) increase in conversion. These
results, combined with the short reaction time observed for
(
10) from the organozinc wash. The material was found to
have a significantly diminished catalytic activity (~30%
conversion in 26 h), thus signalling that partial decomposition
of the active catalyst occurred in the presence of excess
organozinc reagent. Therefore, reducing the number of
equivalents of organozinc reagent used in these couplings may
improve the lifetime of the catalyst under continuous flow
conditions.
homogeneous Pd-NHC complex
(9) suggest that after
extraction with THF only a small amount of active palladium
catalyst leaches from the support during the reaction cycle.
Finally, the level of palladium leaching was determined by ICP-
AES analysis for the continuous flow synthesis of 13
.
Supported precatalyst 10 (70 mg total, 1.6 mg of Pd) was used
in the experiment and samples were analysed for metal
Conclusions
100
95
90
85
80
75
70
65
60
55
50
Reliable methods have been developed for the preparation
and immobilisation onto silica of triethoxysilyl functionalised
Pd-PEPPSI-IPr complex
9 onto silica gel. The resultant
supported catalyst (10) was found to be active in Negishi cross-
coupling reactions under batch and continuous flow conditions
at room temperature. In batch the catalyst could be recycled
at least five times with minimal loss in activity. Conversely, 10
could also be used in packed-bed reactors, giving moderate to
excellent yields of coupled product with various functionalised
alkylzinc reagents and aryl halides. In particular, N-heteroaryl
chlorides proved to be excellent coupling partners. Precatalyst
10 displayed good activity after fifteen hours of continuous
flow operation, although a slow decrease in conversion was
observed over the course of the experiment. Leaching
experiments and heterogeneity tests indicated loss of
palladium from the support during cross coupling, however
the leached material displayed low levels of catalytic activity.
0
5
10
15
Time (h)
Figure 3: Percentage palladium remaining on support during flow reaction.
Conditions: 2-chloro-4-methylquinoline (2.4 mmol, ~0.1 M), organozinc in
DMI (1.8 equiv.), LiBr (3.2 equiv.), 10 (70 mg, 0.21 mmol/g, 0.015 mmol), 20
μL/min residence time ~ 9 mins.
6 | J. Name., 2012, 00, 1-3
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filtration and washed thoroughly with H2O (2 L) and acetone (2
L) before being dried in vacuo at 80 oC.38
Experimental Section
Synthesis of IPr-triazole-CuCl (8)
In air, a vial was charged with SiO2 (14.2 g),
9 (4.7 g, 4.9 mmol)
Under argon,
a
vial was charged with 1-(2,6-
mmol) and toluene the resultant suspension was rotated in a
o
rotisserie oven for 24 h at 100 C. After cooling to rt the silica
diisopropylphenyl)-3-(2,6-diisopropylphenyl-4-
ethynylphenyl)imidazol-2-ylidene]copper(I) chloride (4.6 g, 9.0
mmol) and sealed with a septum. MeCN (100 mL) and (3-
azidopropyl)triethoxysilane37 (3.3 g, 13.3 mmol) were added
and the mixture stirred for 16 h at 35 oC. After cooling to rt the
solvent was removed in vacuo and the residue filtered through
a plug of SiO2 using CH2Cl2/EtOAc (1:1) as eluent. The filtrate
was concentrated to ~5 mL and pentane added to induce
was collected by filtration, washed with CH2Cl2 (100 mL) and
subjected to Soxhlet extraction using EtOAc for 24 h. The silica
was collected by filtration, washed with EtOAc (50 mL) and
CH2Cl2 (100 mL) and then dried in vacuo. The supported
complex was suspended in a mixture of toluene (20 mL) and
hexamethyldisilazane (20 mL) and rotated for 24 h at rt. The
supernatant liquid was decanted and the silica washed with
CH2Cl2 (2 x 50 mL), EtOAc (2 x 50 mL) and EtOAc/MeOH (2:1)
before being dried in vacuo (17.3 g of silica obtained after
drying). Analysis found: C 12.11; H 1.90; N 2.09; Pd 2.28; Cl
2.00; Si 37.4.
precipitation of
8 as an off-white solid that was collected by
1
filtration (5.9 g, 86 %). H NMR (400 MHz, (CDCl3): δ 7.89 (s,
1H), 7.73 (s, 2H), 7.50 (t, J = 7.6 Hz, 1H), 7.30 (d, J = 8.1 Hz, 2H),
7.15 (s, 2H), 4.46 (t, J = 7.1 Hz, 2H), 3.84 (q, J = 7.1 Hz, 6H), 2.52
- 2.65 (m, 4H), 2.12 (t, J = 8.1 Hz, 2H), 1.35 (d, J = 6.1 Hz, 6H),
1.31 (d, J = 7.1 Hz, 6H), 1.28 (d, J = 7.1 Hz, 6H), 1.21 - 1.26 (m,
15H), 0.68 (t, J = 8.1 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ
179.9, 146.4, 145.8, 145.1, 134.0, 133.6, 132.5, 130.1, 123.7,
123.0, 123.0, 121.1, 120.3, 58.1, 52.1, 28.4, 28.3, 24.4, 24.3,
23.8, 23.4, 23.4, 17.9, 7.0. HRMS calculated for
C38H58ClCuN5O3Si [M++H]+: 758.3288, found: 758.3295.
General procedure for the preparation of alkylzinc reagents39
In a glovebox, a flame-dried round bottom flask was charged
with zinc dust (3.9 g, 60 mmol, 1.5 equiv.). The flask was
removed from the glovebox and I2 (0.5 g, 2 mmol, 0.05 equiv.)
was added before it was purged with argon (3x). DMI (40 mL)
was added portion-wise and the resultant suspension stirred
at rt until the colour of I2 disappeared (ca. 5 min). The alkyl
bromide (7.1 mL, 40 mmol) was added and the mixture heated
to 80 oC for 16 h at which time it was cooled to rt. and allowed
to stand without stirring for 10 h. The concentration of the
organozinc solution was determined by iodometric titration of
the resulting supernatant using Knochel’s procedure.40
Synthesis of Pd-PEPPSI-IPr-triazole (9)
Under argon, a two-necked round bottom flask equipped with
a condenser was charged with IPr-triazole-CuCl (8, 1.3 g, 1.8
35
mmol) followed by Cl2Pd(3-ClPy)2 (0.85 g, 2.12 mmol, 1.2
equiv.) and toluene (100 mL) after which the suspension was
stirred at 110 oC for 48 h. After cooling to rt, Et2O (100 mL) was
added and the suspension filtered through a pad of Celite®
using Et2O as eluent. The solvent was removed under reduced
pressure and the residue extracted with boiling hexanes (100
mL). The solvent was removed to give a yellow solid. In order
to remove any remaining copper species the crude product
was dissolved in CH2Cl2/EtOAc (95:5) and passed through a
plug of SiO2. Removal of the solvent in vacuo afforded Pd-
General procedure for Negishi coupling reactions in batch
Under argon, a vial was charged with 10 (50 mg, 0.21 mmol/g
loading, 2 mol%) and LiBr (139 mg, 1.6 mmol). THF (2.5 mL)
was added followed by the organozinc reagent (1.25 mL,
0.65M in DMI, 0.8 mmol). After stirring for 2 min the aryl
halide (0.5 mmol) was added and the reaction vial rotated in a
rotisserie oven at 10 rpm under a static argon atmosphere for
16 h. Alternatively, if the aryl halide was a solid at rt, it was
introduced into the reaction vial prior to the addition of THF.
After this time, the reaction mixture was filtered in air and the
heterogeneous catalyst washed with CH2Cl2 (2 x 20 mL) and Et-
2O (2 x 20 mL), after which it was dried under vacuum. The
reaction mixture was diluted with Et2O (20 mL), and then
washed successively with sat. aq. NaHCO3 (25 mL), water (25
mL) and brine (25 mL). After drying over anhydrous MgSO4 the
solution was filtered and the solvent removed in vacuo. The
residue was then purified by flash chromatography on silica
gel.
PEPPSI-IPr-triazole (9) as a yellow solid (1.02 g, 61 %).
(Alternatively the complex could by purified by column
chromatography on SiO2 (5 to 15% EtOAc/CH2Cl2). 1H NMR
(600 MHz, CDCl3): δ 8.59 (d, J = 2.7 Hz, 1H), 8.49-8.54 (m, 1H),
7.87 (s, 1H), 7.80 (s, 2H), 7.54 (d, J = 8.1 Hz, 1H), 7.48-7.52 (m,
1H), 7.36 (d, J = 7.6 Hz, 2H), 7.16 (d, J = 2.2 Hz, 2H), 7.06 (dd, J
= 8.1, 5.4 Hz, 1H), 4.44 (t, J = 7.0 Hz, 2H), 3.83 (q, J = 7.0 Hz,
6H), 3.11-3.24 (m, 4H), 2.05-2.13 (m, 2H), 1.53 (d, J = 6.5 Hz,
6H), 1.48 (d, J = 6.5 Hz, 6H), 1.23 (t, J = 6.8 Hz, 9H), 1.16 (d, J =
7.0 Hz, 6H), 1.13 (d, J = 7.0 Hz, 6H), 0.60-0.71 (m, 2H). 13C{1H}
NMR (151MHz, CDCl3): δ 153.7, 150.4, 149.4, 147.5, 147.3,
146.7, 137.4, 135.0, 134.8, 132.5, 132.0, 130.4, 125.2, 125.1,
124.3, 124.1, 121.6, 120.2, 58.6, 52.5, 28.9, 28.7, 26.3, 26.2,
24.3, 23.2, 23.2, 18.3, 7.5. HRMS calculated for
C43H62Cl3N6O3PdSi [M+H]+: 949.2747, found: 949.2742.
General procedure for Negishi couplings in continuous flow
An FEP (fluorinated ethylene propylene) tube (0.159 cm ID x 8
cm) was packed with 70 mg of 10 and a small wad of cotton
placed at the ends of the reactor to hold the supported
catalyst in place. Connected to the reactor outlet was a length
of FEP tubing (0.025 cm ID x 20 cm) that fed directly into a
Synthesis of solid supported Pd-PEPPSI-IPr (10)
Silica gel (20 g) was first suspended in H2O (100 mL) and HCl
(conc., 20 mL) was added. The suspension was then heated to
90 oC for 5 h. After cooling to rt the silica gel was collected by
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J. Name., 2013, 00, 1-3 | 7
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ARTICLE
Journal Name
4.
5.
E.-I. Negishi, Handbook of Organopalladium Chemistry for
Organic Synthesis, Wiley-VCH, New York, 2002.
quench solution of saturated NaHCO3/H2O (1:1). The total
reactor volume was 171 μL. The tubing containing the catalyst
was washed with THF (3 mL) pumped through the reactor at
20 μL/min. Under argon, a round bottom flask was charged
with 2-chloro-4-methylquinoline (428 mg, 2.4 mmol) and LiBr
(670 mg, 7.7 mmol, 3.2 equiv.). THF (13.6 mL) was added
followed by (6-ethoxy-6-oxohexyl)zinc(II) bromide (6.8 mL,
0.66 M in DMI, 4.5 mmol, 1.8 equiv.) and the mixture stirred
until the solids had dissolved. Contents of the flask were
drawn into a 30 mL syringe and placed on a New-Era NE-1000
pump set to infuse at a rate of 20 μL/min. The reaction mixture
was passed through the packed bed catalyst at rt and
deposited in the stirred quench solution; after ca. 1 h had
passed allowing for steady state, 19 mL was subsequently
collected. The mixture was extracted with Et2O (3 x 50 mL), the
organic phase washed with brine (100 mL) and the organic
layer dried over anhydrous MgSO4. The suspension was
filtered and the solvent removed in vacuo. The residue was
then purified by flash chromatography on silica gel (0 to 20%
EtOAc in hexanes) to give 13 as a clear oil (560 mg, 88%). Rf =
0.34 (20% EtOAc/hexanes). 1H NMR (400 MHz, (CD3)2CO): δ
8.01 (d, J = 8.1 Hz, 1H), 7.96 (d, J = 8.1 Hz, 1H), 7.68 (t, J = 7.6
Hz, 1H), 7.52 (t, J = 7.6 Hz, 1H), 7.24 (s, 1H), 4.06 (q, J = 7.1 Hz,
2H), 2.89 (t, J = 7.6 Hz, 2H), 2.67 (s, 3H), 2.29 (t, J = 7.6 Hz, 2H),
1.83 (quint, J = 7.6 Hz, 2H), 1.66 (quint, J = 7.6 Hz, 2H), 1.42
(quint, J = 7.6 Hz, 2H), 1.18 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (101
MHz, (CD3)2CO): δ 173.7, 163.1, 149.0, 144.9, 130.5, 129.7,
127.8, 126.3, 124.8, 123.0, 60.5, 39.4, 34.7, 29.9, 29.7, 25.7,
18.7, 14.7. 1H NMR (400 MHz, CDCl3): δ 8.01 (d, J = 8.1 Hz, 1H),
7.92 (d, J = 8.1 Hz, 1H), 7.64 (t, J = 7.6 Hz, 1H), 7.47 (t, J = 7.6Hz,
1H), 7.11 (s, 1H), 4.09 (q, J = 7.1 Hz, 2H), 2.9 (t, J = 8.1 Hz, 2H),
2.64 (s, 3H), 2.28 (t, J = 7.1 Hz, 2H), 1.81 (quint, J = 7.8 Hz, 2H),
1.68 (quint, J = 7.6 Hz, 2H), 1.43 (quint, J = 7.6 Hz, 2H), 1.21 (t, J
= 7.1 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ 173.7, 162.3,
147.6, 144.1, 129.2, 128.9, 126.7, 125.3, 123.5, 121.9, 60.1,
38.9, 34.2, 29.5, 28.9, 24.8, 18.6, 14.1. HRMS (ESI) calculated
for C18H24NO2 [M+H]+: 286.1802, Found: 286.1793.
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8.
9.
Acknowledgements
MGO acknowledges the National Science and Engineering
Research Council (NSERC) of Canada). The authors thank C. W.
Schruder for SEM data collection.
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8 | J. Name., 2012, 00, 1-3
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