Removal of palladium from cross-coupling reactions using isocyanide reagents

Article abstract of DOI:10.1002/adsc.201400754

Isocyanide reagents removed residual palladium from palladium-catalyzed cross-couplings, to sub-ppm levels. The results were similar using either Pd(II) or Pd(0) precatalysts. Using the 3-isocyanopropylated silica gel reagent 1, no chromatography or other

Full text of DOI:10.1002/adsc.201400754

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DOI: 10.1002/adsc.201400754
Removal of Palladium from Cross-Coupling Reactions Using
Isocyanide Reagents
Jonathan M. French,a Justin R. Griffiths,a and Steven T. Divera,*
a
Department of Chemistry, University at Buffalo, The State University of New York, Amherst, NY 14260, USA
E-mail: diver@buffalo.edu
Received: July 30, 2014; Revised: November 3, 2014; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201400754.
Abstract: Isocyanide reagents removed residual pal-
ladium from palladium-catalyzed cross-couplings, to
sub-ppm levels. The results were similar using
either Pd(II) or Pd(0) precatalysts. Using the 3-iso-
cyanopropylated silica gel reagent 1, no chromatog-
raphy or other treatments were required. The solu-
ble isocyanide potassium isocyanoacetate
Scheme 1. Isocyanide-containing reagents used as palladium
scavengers.
(KO2CCH2NC) was also found to be highly effec-
tive when combined with silica gel chromatography.
triazine was one of the first reagents identified that
could remove palladium species,[4] and when placed
on a polystyrene support, was able to remove palladi-
um from a reaction work-up.[5] Crudden et al. demon-
strated that both thiol- and amine-containing silica
and mesoporous silica supports effectively removed
palladium(II) from solution.[6] Accordingly, thiol-
grafted silica gel has been used by industrial groups
Keywords: isocyanides; palladium removal; palla-
diumd scavengers; potassium isocyanoacetate
(KO2CCH2NC); Suzuki reaction
Owing to its versatility in cross-coupling reactions, for the removal of palladium.[7] One of the shortcom-
palladium (Pd) has found broad application in organic ings of existing reagents is the ability to bind strongly
synthesis.[1] Despite the venerated status of Pd in or- to multiple oxidation states of the metal. Regardless
ganic synthesis, a problem associated with Pd-mediat- of the initial catalyst used, both Pd(II) and Pd(0) oxi-
ed cross-coupling is practical in nature: the palladium dation states are present at the end of the cross-cou-
catalyst and decomposed Pd by-products can be diffi- pling reaction. Thiol-based systems work best for pal-
cult to remove from the desired product. This is espe- ladium(II) and phosphine ligands tend to work best
cially a concern in the synthesis of bioactive com- for palladium(0).[8] As a result, no single scavenger
pounds where trace transition metal is undesired. In has emerged that can efficiently remove all of the dif-
the pharmaceutical industry, there is a regulatory ferent metal species present, and this shortcoming
standard requiring less than 5–10 ppm of residual pal- continues to drive the development of new metal
ladium in any active pharmaceutical ingredient scavengers.[9]
(API).[2] As a result, screening assays are often used
Isocyanides present unique ligand properties due to
to help identify the best available scavenger or purifi- their sigma donor strength and their weak pi acidity.
cation may be done after the cross-coupling step.[3] In The polar isocyanide 2 was previously shown to
this report, isocyanides 1 and 2 were found to remove quench and remove ruthenium from metathesis reac-
Pd efficiently in several different cross-coupling reac- tions in solution[10] and more recently, isocyanide 1,
tions, for both Pd(0) and Pd(II) oxidation states supported on silica gel[11] effectively removes a wide
(Scheme 1).
variety of Grubbs’ ruthenium carbenes from metathe-
New scavengers are needed that function effective- sis reactions to less than 10 ppm Ru. Because isocya-
ly for the wide range of Pd catalysts existing in either nide is a good ligand for other late transition
the Pd(0) or Pd(II) oxidation states. Existing scaveng- metals,[12] and because of Pdꢀs importance in cross-
er materials include solid-supported amines and coupling reactions, we investigated Pd removal using
À
thiols, but not isocyanides. For instance, trimercapto- isocyanide reagents, where a unique isocyanide Pd
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Jonathan M. French et al.
Table 1. Removal of palladium from a Suzuki reaction.
[a]
Equivalents of isocyanide are based on catalyst loading:
e.g., 8 equiv. 1 amount to 24 mol% 1.
Maximum theoretical concentration of Pd in 3 before
treatment: 16,000 ppm.
[b]
Figure 1. Removal of Pd(0) and Pd(II) from a toluene solu-
tion. Conditions: 0.01M Pd(OAc)2 or Pd(PPh3)4 in toluene,
treated with 1 (n equiv.) at room temperature, under stir-
ring.
a significant fraction of Pd from the non-polar prod-
bond might offer the needed flexibility to bind Pd(0) uct 3. In all of these reactions, ppm Pd reported is the
and Pd(II) with similar effectiveness. amount of Pd detected in the crude, evaporated or-
First, the isocyanide silica gel 1 was evaluated for ganic product (after removal of reaction solvent).
the removal of Pd(II) using a solution of Pd(OAc)2 in After only 4 h, 8 equiv. (24 mol%) removed
1
toluene at an initial concentration of 1227 ppm Pd 99.999% Pd after simple filtration (fritted filter
(Figure 1). To the solution was added either 4 or funnel) to remove the silica gel (entry 2); 16 equiv.
8 equiv. 1. After a time interval, the silica gel was al- (48 mol%) silica gel
1
proved more effective
lowed to settle, and an aliquot was removed and ana- (entry 3). After 4 h, 8 equiv. silica gel 1, removed by
lyzed for Pd using a digestion protocol followed by column chromatography through silica gel, resulted in
analysis using inductively-coupled plasma mass spec- the removal of 99.999% Pd (entry 4). In entries 2–5,
trometry (ICP-MS).[13] With 4 equiv. 1, a 24 h period there was no pretreatment with celite, which bodes
is required to reach less than 1 ppm (99.935% Pd re- well for silica gel-based recovery of expensive plati-
moved). For a reaction that used 5 mol% Pd catalyst, num group metals. Purification through silica gel is
this amounts to 20 mol% silica gel 1 needed. With acceptable for small-scale reactions, but stirring over
8 equiv. 1, there is faster capture of Pd; after only 1 h, silica 1 followed by filtration would be preferred in
there was 5 ppm Pd and after 4 h, 1 ppm Pd was large-scale reactions.
reached (99.886% Pd removed). Most likely the use
The homogeneous isocyanide KO2CCH2NC was
of fewer equivalents 1 requires recruitment of isocya- also highly effective for the removal of residual palla-
nides that may be less available on the surface of the dium from the Suzuki reaction, when combined with
material.
silica gel chromatography (Table 1, entry 5). Previous-
Next, isocyanide 1 was evaluated for the removal of ly, our laboratory had shown that the isocyanide 2
Pd(0) from a stock solution of Pd(PPh3)4 in toluene. was effective for the removal of ruthenium metal
Isocyanide 1 reduced Pd levels more quickly for from metathesis reactions.[10] To the best of our
Pd(0) and there was a less dramatic difference be- knowledge, this commercially available isocyanide has
tween 4 or 8 equiv. 1. Only 4 equiv. 1 results in not been previously shown to remove Pd from
99.031% removal of Pd after 1 h (12 ppm). A longer a cross-coupling reaction.
treatment period (> 4 h) brought Pd levels below
Removal of Pd from the polar products of Suzuki
2 ppm. Use of 8 equiv. 1 is somewhat more effective cross-coupling is more difficult, but possible with iso-
at the shorter time periods, but both 4 and 8 equiv. cyanides. Cross-coupling of 3-bromopyridine with
treatments could reach >99.764% Pd removal after phenylboronic acid was performed with two different
a 24 h period.
Pd precatalysts (Table 2). The resulting biaryl 4 is ca-
Since screening showed promising results, the isocy- pable of coordination to Pd, so passive treatment
anide scavengers were evaluated in a standard Suzuki methods such as celite were expected to be ineffec-
coupling (Table 1). After the cross-coupling was com- tive. Celite alone was found to be a poor scavenger
plete, several different treatment conditions were in- with either Pd source (Table 2). Silica gel purification
vestigated. To establish a benchmark, the crude reac- gave substantial improvements for Pd(0), but less im-
tion was passed through celite (Table 1, entry 1). With provement was seen with Pd(II). The silica 1 was
a Pd concentration as high as 16000 ppm Pd in the used to treat the crude reaction, followed by simple
product, the celite treatment was found to remove filtration without chromatography, and gave similar
2
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Removal of Palladium from Cross-Coupling Reactions
Table 2. Removal of palladium from a polar product of
Suzuki coupling using Pd(0) and Pd(II) precatalysts.
Table 3. Removal of palladium from a Buchwald–Hartwig
reaction.
[a]
Equivalents of isocyanide are based on catalyst loading:
e.g., 8 equiv. 1 amount to 40 mol% 1.
Maximum theoretical concentration of Pd in 6 before
[a]
[b]
Equivalents of isocyanide are based on catalyst loading:
e.g., 8 equiv. 1 amount to 24 mol% 1.
Maximum theoretical concentration of Pd in 4 before
treatment: 25,300 ppm.
[b]
treatment: 20,100 ppm.
results with either Pd source (4 h, room temperature).
Use of polar 2 combined with silica gel purification
gave excellent results. Celite and unmodified silica gel
did not effectively remove Pd, leaving yellow samples
after treatment. The product of this Suzuki coupling
is difficult to purify due to the presence of the pyri-
dine. Each of the isocyanide treatments was per-
formed without any prior celite purification.
Palladium can also be removed effectively from
a Heck reaction, with similar results as those observed
in Table 1 and Table 2. The data can be found in the
Supporting Information.
Scheme 2. Removal of Pd from a polar, chelating diamine.
Palladium removal with isocyanide scavengers is that might be encountered in the synthesis of pharma-
also effective for the widely-used Buchwald–Hartwig ceuticals and drug candidates. Furthermore, the 1,2-
amination. The unique Pd ligand system employed, benzenediamine 7 is capable of bidentate coordina-
the elevated reaction temperatures and the potential tion to Pd, which should make Pd removal more diffi-
of the substituted aniline product to bind and retain cult. Crude diamine 7 was isolated and found to be
Pd were expected to pose a challenge for the Pd re- contaminated with 221 ppm Pd. On treatment with 1,
moval step. Simple filtration through celite was inef- a ten-fold reduction of Pd was found, leaving
fective, leaving high levels of residual Pd (Table 3, 20.8 ppm Pd in the sample (Scheme 2). A known thiol
entry 1). In contrast, isocyanide silica 1 reduced Pd scavenger resulted in a comparable reduction, to
levels to less than 3 ppm Pd using a 4 h treatment 26.1 ppm Pd. It is particularly difficult to remove Pd
time and simple filtration (entries 2 and 3). Use of from polar, chelating diamines. In additional experi-
silica gel 1 combined with column chromatography re- ments, diamine 7 was recovered in high yield after ex-
moves 99.998% Pd and reduces Pd levels to below posure to Pd(II) and either the silica gel reagent
1 ppm (entry 4). Use of the homogeneous isocyanide, 1 (96%) or soluble isocyanide 2 (99%). No evidence
when followed by silica gel chromatography, regis- of cross-coupling to the isocyanide was found.[15] This
tered 0.5 ppm Pd, for 99.998% removal (entry 5).
Last, an even more challenging case was examined between isocyanide reagents and amine functionality.
for Pd removal using isocyanide scavengers. A double Isocyanide complexes of Pd(II) and Pd(0) are docu-
demonstrates excellent functional group compatibility
Buchwald–Hartwig amination was conducted, which mented in the literature.[16] For example, Angelici
requires high Pd catalyst loading and high reaction et al. prepared cis-Cl2Pd(CNR)2 in a displacement re-
temperatures. The double Buchwald–Hartwig reaction action starting from Cl2Pd(NCCH3)2.[16a] Ito and co-
of amines onto a 1,2-dibromoarene provides a key workers used a Pd(OAc)2-t-octyl isocyanide catalyst
step to build benzimidazoles[14a] and benzimidazolium system, thought to form a Pd(0) isocyanide complex
ring systems.[14b] As an intermediate used in heterocy- in situ, to achieve intramolecular bissilylation of alky-
cle synthesis, the diamine 7 is typical of intermediates nes.[16b] In a Pd(II) complex, an isocyanide is capable
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Jonathan M. French et al.
of displacing a Ph3P ligand.[16c] tert-Butyl isocyanide
can displace both phosphines from Pt[P(t-Bu)3]2 to
form the trinuclear species {Pt3[m-(t-BuNC)]3(t-
BuNC)3}.[16d] Figueroa et al. successfully prepared
monomeric (ArNC)2Pd(0) employing aryl isocyanides
with very bulky aromatic groups.[16e] For the most
part, preparations of Pd(0) isocyanide complexes
result in polynuclear species.[16f,g]
The Pd complex Cl2Pd(PPh3)2 was removed from
solution by silica gel 1.
A THF solution of
Cl2Pd(PPh3)2 was treated with 16 equiv. of silica gel 1.
The yellow solution became clear and colorless when
the silica gel was allowed to settle after a few minutes.
After 30 min, the silica gel was isolated by filtration
and the eluent was found to contain Ph3P, indicating
that a ligand displacement reaction had taken place.
A reflectance IR spectrum of the product formed
between silica gel 1 and Cl2Pd(PPh3)2 revealed a new
isocyanide absorption consistent with a Pd(II)-bound
isocyanide (Figure 2). This commonly used precatalyst
was chosen because several X2Pd(CNR)2 organome-
tallic complexes are known in the literature,[16] allow-
ing for spectroscopic comparisons to be made. In Fig-
ure 2a, the reflectance IR spectrum of silica gel
1 shows a strong absorption at 2147 cmÀ1, which is in-
dicative of an isocyanide. The reflectance IR spectrum
of the silica gel isolated after scavenging PdCl2(PPh3)2
is shown in Figure 2b. In addition to the isocyanide
Figure 2. Reflectance IR spectra of silica gel 1 (top), and
silica gel 1-Cl2Pd(PPh3)2 (bottom).
peak at 2147 cmÀ1, a new absorbance appeared at Experimental Section
2231 cmÀ1. This new peak is shifted 84 cmÀ1 as com-
pared to the free isocyanide, consistent with Angeli- Representative Procedure: Preparation of Aniline 6
ciꢀs observed difference between peak frequencies in
To an oven-dried 50-mL Schlenk tube were added 1.0 mmol
the free isocyanide and in isocyanide bound to both
of the aryl bromide, 1.2 mmol (1.2 equiv.) of morpholine,
Pd(II) and Pt(II) complexes.[16a] The broadness of the
and 1.2 mmol (1.2 equiv.) of sodium tert-butoxide. 5 mL of
new peak may be due to a single species or due to
multiple species with different coordination num-
bers.[17] It is also possible that there is a monodentate
species, unknown in the literature, or that a bidentate
trans-isomer, trans-Cl2Pd(1)2 is present. To the best of
our knowledge, trans-Cl2Pd(RNC)2 species do not
appear to be known, but the congener trans-Br2Pd(t-
BuNC)2 is and has an absorbance at 2224 cmÀ1, simi-
lar to the observed stretching frequency.[16g] The new
peak is consistent with at least one Pd-(RNC) bond.
Further studies are ongoing.
In conclusion, isocyanide reagents offer effective
means for the removal of residual palladium from
cross-coupling reactions. Isocyanides have not been
used previously to remove Pd from cross-coupling re-
actions. Isocyanide reagents, due to their unique
ligand properties, are able to effectively remove Pd(0)
and Pd(II) with similar effectiveness. In general, the
isocyanide scavenging reagents were able to reach 1–
10 ppm levels of residual Pd, often without the need
of a chromatography step. Reflectance IR of the Pd
treated silica gel show a new peak consistent with
a Pd-isocyanide bond.
freshly distilled toluene were then added to the Schlenk
tube followed by the addition of 0.025 mmol (5 mol%) of
Pd2(dba)3 and 0.075 mmol (7.5 mol%) of (+/-)-BINAP. The
reaction vessel was then placed directly in a preheated oil
bath at 908C for 18 h and subsequently treated with 8 equiv.
(relative to Pd catalyst used) of silica gel 1. The reaction
was left to stir for 4 h at the same temperature. The reaction
mixture was then cooled, filtered through a medium porosi-
ty filter frit and washed with 5 mL of CH2Cl2 and the filtrate
was concentrated under vacuum (rotary evaporator). The
recovered material was weighed and the desired product
was then digested for 12 h at room temperature in 2 mL of
concentrated nitric acid yielding 1.52 ppm Pd based on the
sample weight. The product 6 could be isolated for charac-
terization purposes, providing spectral data in good agree-
ment with previously published data.
Further experimental details, including ICP analytical
methods, can be found in the Supporting Information.
Acknowledgements
The authors thank the NSF (CHE-0848560 and CHE-
1012839), and the SUNY Technology Accelerator Fund for
4
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financial support of this work. The authors thank Dr. Alice
Bergmann (Director, UB Mass Spectrometry Center) for as-
sistance with the ICP-MS measurements and Caley A. Ri-
chardson (Prof. Brightꢀs group, UB Chemistry) for making
the IR measurements.
[8] E. J. Flahive, B. L. Ewanicki, N. W. Sach, S. A. OꢀNeill-
Slawecki, N. S. Stankovic, S. Yu, S. M. Guinness, J.
Dunn, Org. Process Res. Dev. 2008, 12, 637–645.
[9] Imidazolium salt scavengers remove both Pd(0) and
Pd(II) from aqueous solutions, to ppm levels, see: R.
Buscemi, F. Giacalone, S. Orecchio, M. Gruttadauria,
ChemPlusChem 2014, 79, 421–426.
[10] B. Galan, K. Kalbarczyk, S. Szczepankiewicz, J. B. Keis-
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6 Removal of Palladium from Cross-Coupling Reactions
Using Isocyanide Reagents
Adv. Synth. Catal. 2015, 357, 1 – 6
Jonathan M. French, Justin R. Griffiths, Steven T. Diver*
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