N, C-Disubstituted Biarylpalladacycles as Precatalysts for ppm Pd-Catalyzed Cross Couplings in Water under Mild Conditions

Article abstract of DOI:10.1021/acscatal.9b04204

Various monosubstitution and disubstitution patterns on the parent biarylamine skeleton characteristic of palladacycles, as well as the counterion effect, have been studied while looking for ways to increase the effectiveness of the catalyst formed under micellar catalysis conditions in water, with the goal of reducing the amount of Pd needed for coupling reactions. Several substituted palladacycles containing readily accessible ligands were chosen for evaluation. The results indicate that (1) preactivation of Pd(II) salts as precursors for Suzuki-Miyaura (SM) couplings via treatment with a reducing agent is not required; (2) reactions could be performed with approximately half the loading of Pd, relative to that previously required based on a combination of a Pd(II) salt and ligand; and (3) the most effective palladacycle precatalyst has been identified as that containing an isopropyl group on both an aryl ring and on nitrogen, together with the ligand EvanPhos and triflate as the counterion (P13). This precatalyst is also effective in other C-C bond-forming reactions, such as Heck and Sonogashira couplings. No organic solvents were needed for these processes, while the aqueous reaction medium could be recycled several times. A one-pot, four-step sequence involving Suzuki-Miyaura, reduction, alkylation, and acylation reactions highlights the potential for this precatalyst to maximize synthetic gain while minimizing costs and waste generation.

Full text of DOI:10.1021/acscatal.9b04204

Letter
pubs.acs.org/acscatalysis
Cite This: ACS Catal. 2019, 9, 11647−11657
N,C‑Disubstituted Biarylpalladacycles as Precatalysts for ppm Pd-
Catalyzed Cross Couplings in Water under Mild Conditions
Ruchita R. Thakore,†,∇ Balaram S. Takale,*,†,∇ Fabrice Gallou,‡ John Reilly,§
and Bruce H. Lipshutz*,†
†Department of Chemistry and Biochemistry, University of California, Santa Barbara, California 93106, United States
‡Novartis Pharma AG, CH-4057 Basel, Switzerland
§Novartis Institutes for BioMedical Research (NIBR), Cambridge, Massachusetts 02139 United States
S
* Supporting Information
ABSTRACT: Various monosubstitution and disubstitution patterns on
the parent biarylamine skeleton characteristic of palladacycles, as well as
the counterion effect, have been studied while looking for ways to
increase the effectiveness of the catalyst formed under micellar catalysis
conditions in water, with the goal of reducing the amount of Pd needed
for coupling reactions. Several substituted palladacycles containing
readily accessible ligands were chosen for evaluation. The results
indicate that (1) preactivation of Pd(II) salts as precursors for Suzuki−
Miyaura (SM) couplings via treatment with a reducing agent is not
required; (2) reactions could be performed with approximately half the
loading of Pd, relative to that previously required based on a
combination of a Pd(II) salt and ligand; and (3) the most effective
palladacycle precatalyst has been identified as that containing an
isopropyl group on both an aryl ring and on nitrogen, together with the ligand EvanPhos and triflate as the counterion (P13).
This precatalyst is also effective in other C−C bond-forming reactions, such as Heck and Sonogashira couplings. No organic
solvents were needed for these processes, while the aqueous reaction medium could be recycled several times. A one-pot, four-
step sequence involving Suzuki−Miyaura, reduction, alkylation, and acylation reactions highlights the potential for this
precatalyst to maximize synthetic gain while minimizing costs and waste generation.
KEYWORDS: palladacycles, ppm palladium, green chemistry, Suzuki−Miyaura couplings, Heck couplings, Sonogashira couplings,
E factors
Pd2(dba)3),2 palladacycles allow in situ generation of active
alladacycles as precatalysts for a variety of Pd-catalyzed
Preactions provide several advantages over traditional
Pd via a base-initiated, facile loss of HX and reductive
approaches to active forms of Pd(0).1 Thus, rather than
elimination, leading to a monoligated, 12-electron Pd(0)
complex.1 These precatalysts are attractive in that they have a
either mixing a source of Pd(II) (e.g., PdCl2) and ligand, or
tendency to be stable toward air, moisture, and temperature,3
using a source of preformed and ligated Pd(0) (e.g.,
avoiding the potential vagaries associated with the source of
Pd (e.g., Pd(OAc)2),4 as well as the nature of the salts within
the reaction mix that can vary according to the mode of
Pd(II) reduction. Handling of sensitive individual phosphines
(e.g., pyrophoric t-Bu3P)5 is also averted. Moreover,
preformed precatalysts may also show increased activity in
comparison to alternative approaches to in-situ-prepared
catalysts.6
Although tremendous advances in Pd catalysis have been
made utilizing palladacycles of various “generations”, where
both the nature of the ring itself and associated counterion
are highly influential,1 these have all been developed within
Received: September 30, 2019
Revised: November 6, 2019
Published: November 11, 2019
Figure 1. Evolution of palladacycle precatalysts.
© XXXX American Chemical Society
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Scheme 1. Impact of Counterion and Alkyl Substitution on Reactivity of Palladacycles P6−P13
Scheme 2. Synthesis of Newly Designed Palladacycles
the domain of traditional organic synthesis using principles
that apply to chemistry in organic solvents.7−9 However, the
“rules” by which such reagents operate can be very different
when used in water,10 where homogeneous catalysis is usually
happening inside nanoreactors.11 With an organic solvent as
the reaction medium, there is no hydrophobic effect, no
exchange phenomena, and little opportunity to effect
sequential processes within the same reaction vessel. To
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offers no advantage over the N-nonalkylated, P10. Taken
together, this series may reflect a degree of reaction inhibition
due to generation of the byproduct carbazole, since such
amines can function as potential (undesirable) alternative
ligands for Pd. Under more highly concentrated micellar
conditions, this newly generated ligand could compete with
EvanPhos, thereby reducing the overall effective amount of
active catalyst; at the ppm level, this could have a dramatic
impact (vide infra). Also note that the use of arylboronic acid
2, although used in slight excess (1.25 equiv), led to virtually
none of the corresponding homocoupled product, which is a
potentially problematic polychlorinated biphenyl (PCB).16
Following identification of both the preferred counterion
and palladacycle substitution pattern, additional palladacycles
were prepared with each containing a related biaryl ligand
other than EvanPhos,14 utilizing the sequence outlined in
Scheme 2.
Scheme 3. Comparisons of Palladacycles Used for Suzuki−
Miyaura Couplings
For eventual comparison purposes, mesylate versions P6,
P14, P16, P18, P20 were also generated, utilizing the general
procedure outlined in the Supporting Information (SI).
Model SM reactions were performed using 0.15 mol % (1500
ppm) of each palladacycle at the slightly higher than normal
temperature of 55 °C (Scheme 3).17 Essentially no reaction
was observed when mesylate-based palladacycle P6 contain-
ing EvanPhos was used for this coupling. By contrast, all
three modifications combined into P13: i.e., (1) replacing
mesylate with triflate; (2) insertion of the isopropyl group
onto nitrogen; and (3) placement of an isopropyl residue on
the biaryl backbone in this particular location, imparting the
greatest reactivity among all new palladacycles examined.18,19
Other ligands in both the mesylate and triflate series of
palladacycles (P14, P16, P18, P20 and P15, P17, P19, P21,
respectively) were also prepared. The triflate-containing
palladacycles, in all cases, were found to be superior, in
terms of activity. Surprisingly, a triphenyl-phosphine-contain-
ing palladacycle P21 (L = Ph3P) was also quite effective at
this ppm level of catalyst in water. However, when tested for
generality, especially with more challenging coupling partners,
this palladacycle was not competitive (see compounds 26, 28,
33, and 39 in Table 1 and compounds 49 and 54 in Table
2).
maximize the “like dissolves like” influence of the inner cores
of these nanomicellar arrays, we recently introduced the
highly hindered, and highly lipophilic palladacycle precatalyst
based on the ligand HandaPhos,12 effecting a variety of
valuable reactions in water under very mild conditions. Levels
of this precatalyst at 300 ppm or even lower sufficed to
catalyze Suzuki−Miyaura couplings.13 Although this newly
found, biaryl-disubstituted palladacycle serves as a micellar-
matched, readily available precatalyst, preparation of
HandaPhos involves a lengthy synthetic route.12 Hence, we
have continued our search for alternative palladacycles
composed of, in particular, commercially available ligands
that might lead to similar reactivity. In this report, we
disclose our discovery of an unprecedented, N,C-disubstituted
palladacycle of general structure P5 (X = Cl, OMs, OTf, etc.)
that, indeed (Figure 1), allows for ppm-level Pd catalysis in
these cases between 1500 ppm and 3000 ppm (0.15−0.30
mol %) of Suzuki−Miyaura, Heck, and Sonogashira couplings
in water.
Initially, for the model reaction between educts 1 and 2
giving biaryl product 3, the nature of the counterion
associated with palladacycles containing the EvanPhos
ligand14 was screened, including alkyl sulfonates and triflates
(Scheme 1). Based on literature precedent, because of the
steric bulk of this initially selected ligand, chloride as a
counteranion was omitted.9a Palladacycle P8, bearing a
triflate, showed significantly greater reactivity, compared to
analogous palladacycles associated with other anions (P6 and
P7). Increasing lipophilicity by positioning an alkyl group on
the palladacycle ring increased the yield significantly (P10).
Unexpectedly, incorporation of two isopropyl residues (based
on previously observed reactivity),13 one on each ring (P9),
led to a precipitous decrease in conversion. Placement of an
n-pentyl residue on nitrogen, as in P11, dramatically reduced
the extent of product biaryl 3 formation. Remarkably,
alkylation of the amine, albeit in this case with a branched
lipophilic isopropyl group, along with a single isopropyl
residue on the biaryl, afforded the new palladacycle P13 and
led to the highest level of conversion to product 3. Also, the
less bulky N-methyl analogue P12, for which the preparation
of the N-methyl biarylamine precursor is quite challenging
(while synthesis of the N-isopropyl derivative is facile),15
To clarify if the reaction is performed by Pd-colloids/
aggregates, cryo-TEM images were obtained before and after
catalyst activation. The images show no presence of such
colloids (Figure 2).
Many Pd catalysts can lose activity due to the presence of
heteroatom-based chelating groups within either or both
reaction partners. Couplings are all the more challenging
when catalyst loadings are reduced below the typical range of
1−5 mol % (i.e., to the ppm level). Hence, coupling partners
were selected for study that had a tendency to be more
difficult under these circumstances. Therefore, a variety of
Suzuki−Miyaura couplings were examined preliminarily, using
1500−3000 ppm of catalyst precursor P13 (Table 1).
Functional groups such as esters, nitriles, aldehydes, amides,
amines, nitro, and carbamate were tolerated under the
reaction conditions, and the desired products (9−24) were
typically isolated in high isolated yields. Various hetero-
aromatic halides, such as thiophene-based halides or boronic
acids, which otherwise can be difficult to achieve, also
coupled efficiently (25−29).8 Double SM couplings could
also be performed, affording an excellent yield of the desired
product (e.g., 21), which, in this case, is tantamount to 750
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a
Table 1. Suzuki−Miyaura Couplings Using Palladacycle P13
a
Conditions: aryl bromide (unless indicated otherwise; 0.50 mmol), aryl boronic acid or other boron sources (0.63 mmol), K3PO4·H2O (1.0
b
mmol), 500−5000 ppm P13; isolated yields. 10% THF used as a cosolvent.
ppm (0.075 mol %) Pd invested per bond. Other
heteroaromatic bromide coupling partners, the biaryl
products from which could potentially deactivate the catalyst
via complexation, especially at these low loadings, were
efficiently coupled in good-to-excellent yields (25−42).
Several sources of boron, such as boronic acids, Bpin, and
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a
Table 2. Suzuki−Miyaura Reactions Involving Alkenyl/Alkynyl Coupling Partners
a
Conditions: aryl halide (0.50 mmol), aryl boronic acid or other boron sources (0.63 mmol), K3PO4·H2O (1.0 mmol), 1500−3000 ppm P13;
b
Isolated yields. 10% THF used as a cosolvent.
MIDA derivatives (boronates of N-methyliminodiacetic
acid),20 appear to all be amenable coupling partners (17,
18, 26, 30, 32, and 40).
Alkenyl and alkynyl coupling partners also participated
upon exposure to 1500−3000 ppm precatalyst P13 to form
internal alkenes or alkynes (see Table 2, 43−47). Selective
protecting groups, such as N-Boc and TIPS silyl ethers, were
screened and found to be stable under these mild reaction
conditions (48−52). A few heteroaryl chlorides were also
tested and, in each case, the desired product was obtained in
good yields (53−55).
Applications to intermediates associated with biaryl-
containing targets in the pharmaceutical area were examined
next, in all cases using 1500−3000 ppm of precatalyst P13 in
Figure 2. Cryo-TEM images.
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a
Scheme 4. Applications of SM Couplings to Targeted Biaryls within Known Pharmaceuticals
a
Conditions unless noted otherwise: aryl bromide (0.50 mmol), arylboronic acid (0.63 mmol), K3PO4·H2O (1.0 mmol), 1500−3000 ppm P13;
b
isolated yields. 10% THF was used as a cosolvent.
Figure 3. Residual palladium in product biaryls prepared using 3000 ppm palladium precatalyst P13.
aqueous nanoreactors (Scheme 4). These medicinal agents
included (1) product 56, an intermediate en route to
valsartan (antihypertensive agent);21a (2) biaryl 57, leading to
the anticancer agent sonidegib;21b (3) highly derivatized
intermediate 58, which led to anacetrapib;21c (4) difluori-
nated biaryl 59 as an intermediate en route to a GABA α2/3-
agonist;21d and (5) biaryl 62, found in Abbott’s PARP
inhibitor.21e Each was isolated in 83%−93% yields. Biaryl
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Scheme 5. Comparisons of Palladacycles Used for Suzuki−Miyaura Couplings
moieties 60, 61, and 63, which are recently developed
anticancer leads,22 were also formed very efficiently. In these
three cases, along with most other examples in Scheme 4,
THF (10%) was used as a cosolvent.23
couplings in Scheme 5, both failed to provide full
conversion.19
Formation of a free NH-containing carbazole, which is
generated in situ during catalyst activation (Scheme 6, upper
equation), was avoided by preparing both the N-Me and N-
Ph derivatives of the biarylamine precursors.26 Such NH-
carbazole byproducts could potentially impact catalyst
reactivity, as well as complicate product purification.26
Colacot et al. have done an extensive mechanistic study
regarding the role of carbazoles as inhibitors of amination
reactions using π-allylpalladium-based precatalysts.27 Curi-
ously, no inhibition was observed when these precatalysts
were applied to SM couplings, although this system was
found to be superior to biarylamine-based palladacycles for
three types of reactions.28 Nonetheless, differences between
precatalysts and the extent of inhibition due to variations in
the nature of the byproducts formed from each might well be
manifested, or even accentuated, because of differences in
reaction media (i.e., organic solvents versus water). This led
us to further explore the effect of substitution on both the
biaryl backbone, as well as on the palladacycle nitrogen. From
One of the major advantages of micellar catalysis-enabled
ppm Pd-catalyzed couplings is the amount of residual FDA-
imposed limits for Pd on the order of 10 ppm are especially
challenging,24 and rarely met, when traditional loadings in the
1−5 mol % range of palladium catalyst are utilized. To
illustrate that the use of this technology at these ppm levels
of precatalyst either eliminates this concern or reduces the
anticipated level of impurity by at least an order of
magnitude, three biaryl products (20, 28, and 35) were
selected in which coordination of palladium is likely. As
expected, however,25 based on ICP-MS analysis, each showed
the presence of only trace amounts of residual palladium
(Figure 3).
In addition, other classes of palladacycles that are generally
efficient in organic solvents at high temperatures were found
to be inferior to P13. As shown by the two examples of SM
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Scheme 6. Catalyst Activation Step and Inhibitory Effect of External Additives (Carbazoles)
Scheme 7. One-Pot, Four-Step Reaction Sequence, All in Water without Isolation of Intermediates
the two examples (see Scheme 6), involving SM couplings of
7 with 2 giving 8, and 64 with 65 giving 42, it was found
that the NH-carbazole has a noticeable inhibitory effect on
the extent of conversion, while N-Me and N-isopropyl
carbazoles show a less significant impact. Nonetheless, the
N-isopropyl carbazole has the least impact on catalyst
reactivity. Moreover, the N-isopropyl-containing palladacycle,
P13, is far easier and higher yielding to prepare than the N-
methyl analogue (see pages S4 and S5 in the SI).15
Given that these aqueous nanomicellar conditions can be
broadly applied to many synthetic problems,29 sequential
reactions that avoid workup and purification of intermediates
can lead to enhanced savings in time, and minimize waste
creation and costs associated with processing organic solvents
and associated water waste streams. A representative four-
step, one-pot series of reactions illustrative of the potential
involving (1) a Suzuki−Miyaura coupling, (2) a nitro group
reduction, (3) an N-alkylation, and finally, (4) an acylation, is
documented in Scheme 7. Initially, Suzuki−Miyaura coupling
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Suzuki−Miyaura coupling. After each of four subsequent
couplings, and with each involving a different set of coupling
partners, the products could be easily isolated and further
purified; e.g., via filtration through a silica plug (see Figure 4
and the SI). As shown, for oils formed from couplings I and
V, these could be decanted away from the aqueous medium
and then purified accordingly. In cases II, III, and IV, the
products are solids, leading to straightforward filtration as
means of facile isolation. In no case was any organic solvent
used for reaction workup, thereby reducing the E factor,31
based on this reaction variable, to zero. Even with inclusion
of the water, the E factor remains remarkably low (1.7).32
In addition to the efficiency of ppm levels of precatalyst
P13 in Suzuki−Miyaura cross-couplings, other important Pd-
catalyzed C−C bond-forming reactions, such as Heck and
Sonogashira couplings (Scheme 8), were investigated, using
this same technology. Heck reactions at the ppm level of Pd
in water are rare; nevertheless, this could be accomplished at
the 3000 ppm level (0.30 mol %) of P13, albeit only when
aryl iodides are the reaction partners. The four examples of
Heck couplings, along with the one case involving a
Sonogashira coupling, suggest that this same precatalyst
can, indeed, be used rather broadly for Pd-mediated catalysis.
In summary, a new N,C-disubstituted palladacycle (P13)
has been developed for use under aqueous micellar catalysis
conditions, substituted with isopropyl groups at both nitrogen
and one of the biaryl rings. These residues lead to a lowering
of Pd loadings required for catalysis, in this case, those
associated with Suzuki−Miyaura couplings. The new
precatalyst contains the readily fashioned (i.e., prepared in
two steps), commercially available ligand EvanPhos (Sigma−
Aldrich Catalog No. 902292). The aqueous reaction mixtures
can be recycled without a loss of activity; hence, the
associated E factor, as a measure of waste generation, is
essentially zero. Tandem reactions effected in a single
reaction vessel showcase the myriad opportunities to create
complex structures resulting from sequential processes
occurring without an isolation of intermediate products.
Further advances in green chemistry that assist with the
“switch”10a of organic synthesis from a petroleum-based
sustainable discipline to a water-based sustainable discipline
will be forthcoming in due course.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acscatal.9b04204.
■
S
Synthetic procedures and characterization of newly
synthesized compounds (PDF)
Figure 4. E factor determination and recycling of the aqueous
reaction medium.
AUTHOR INFORMATION
Corresponding Authors
*E-mail: lipshutz@chem.ucsb.edu (B. H. Lipshutz).
*E-mail: balaram_takale@ucsb.edu (B. S. Takale).
ORCID
■
between educts 66 and 67 leads to product 32, investing only
2500 ppm of precatalyst P13. The nitro group in 32 was then
reduced using carbonyl iron powder (CIP)30 to form aniline
derivative 68. Benzyl bromide was then added to afford the
resulting monoalkylated aniline intermediate 69, which then
underwent acylation with the ostensibly water-sensitive acid
chloride 3-trifluoro-methylbenzoyl chloride to give final
product 70 in an impressive 83% overall yield (Scheme 7).
Recycling of these aqueous reaction mixtures containing
the surfactant was readily accomplished, following an initial
Balaram S. Takale: 0000-0001-8279-944X
Bruce H. Lipshutz: 0000-0001-9116-7049
Author Contributions
∇These authors contributed equally.
Notes
The authors declare no competing financial interest.
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a
Scheme 8. Applications of Precatalyst P13 to Heck and Sonogashira Couplings
a
Conditions: aryl iodide (0.50 mmol), enoate or alkyne (0.75 mmol), Et3N (1.0 mmol), 3000 ppm P13; isolated yields. 10% THF was used as a
cosolvent.
precursors for the phosphine-free Heck reactions. J. Organomet.
ACKNOWLEDGMENTS
■
Chem. 2001, 622, 89−96.
Financial support provided by PHT International (postdoc-
(7) Schnyder, A.; Indolese, A. F.; Studer, M.; Blaser, H. U. A New
toral fellowship to B.S.T.), Novartis, and the NSF (No. CHE-
1856406) is warmly acknowledged with thanks.
Generation of Air Stable, Highly Active Pd Complexes for C−C and
C−N Coupling Reactions with Aryl Chlorides. Angew. Chem., Int.
Ed. 2002, 41, 3668−3671.
(8) Kinzel, T.; Zhang, Y.; Buchwald, S. L. A New Palladium
Precatalyst Allows for the Fast Suzuki-Miyaura Coupling Reactions
of Unstable Polyfluorophenyl and 2-Heteroaryl Boronic Acids. J. Am.
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ACS Catalysis
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̈
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(32) We did look into reducing the amount of Pd originally, but
the results varied from substrate to substrate. Hence, we had to pick
a level of precatalyst that would work for almost all cases. Also, we
added fresh precatalyst with each recycle, since handling such small
amounts invariably led to losses, although as the scale goes up, this
would probably not be an issue.
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DOI: 10.1021/acscatal.9b04204
ACS Catal. 2019, 9, 11647−11657