HandaPhos: A General Ligand Enabling Sustainable ppm Levels of Palladium-Catalyzed Cross-Couplings in Water at Room Temperature

Article abstract of DOI:10.1002/anie.201510570

The new monophosphine ligand HandaPhos has been identified such that when complexed in a 1:1 ratio with Pd(OAc)₂, enables Pd-catalyzed cross-couplings to be run using ≤1000 ppm of this pre-catalyst. Applications to Suzuki-Miyaura reactions involving highly funtionalized reaction partners are demonstrated, all run using environmentally benign nanoreactors in water at ambient temperatures.

Full text of DOI:10.1002/anie.201510570

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International Edition: DOI: 10.1002/anie.201510570
German Edition: DOI: 10.1002/ange.201510570
Micellar Catalysis
Hot Paper
HandaPhos: A General Ligand Enabling Sustainable ppm Levels of
Palladium-Catalyzed Cross-Couplings in Water at Room Temperature
Sachin Handa, Martin P. Andersson, Fabrice Gallou, John Reilly, and Bruce H. Lipshutz*
Abstract: The new monophosphine ligand HandaPhos has
been identified such that when complexed in a 1:1 ratio with
Pd(OAc)2, enables Pd-catalyzed cross-couplings to be run
using ꢀ 1000 ppm of this pre-catalyst. Applications to Suzuki–
Miyaura reactions involving highly funtionalized reaction
partners are demonstrated, all run using environmentally
benign nanoreactors in water at ambient temperatures. Com-
parisons with existing state-of-the-art ligands and catalysts are
discussed herein.
is typically fully recycled, creating considerable organic waste
especially at scale.
Here, we disclose a truly general, mild, efficient, and
environmentally sustainable technology based on the new
ligand, racemic “HandaPhos.” When combined in a 1:1 ratio
with Pd(OAc)2,[7] a pre-catalyst results that, via in situ
reduction, enables Pd-catalyzed Suzuki–Miyaura (SM)
cross-couplings to be run in water at room temperature
using ppm levels of palladium (Scheme 1A). In essence, the
level of ligated palladium that need be invested can be
reduced by 1–2 orders of magnitude. No other technology of
this generality and environmental attractiveness applied to
couplings of this type is currently known.
L
igated palladium remains among the most enthusiastically
utilized catalysts in synthetic and materials chemistry.[1] The
Nobel Prize awarded to Heck, Negishi, and Suzuki in 2010
serves to encourage further use and applications of these
transition metal-mediated reactions.[2] Unfortunately, the
worldꢀs supply of economically accessible palladium is
limited; i.e., it is an endangered element.[3] Hence, aside
from its status as a precious and, therefore, costly metal, there
is considerable incentive to address this issue from the
perspective of sustainability. Perhaps of equal impact, espe-
cially for the pharmaceutical industry, is the amount of
residual palladium found in the products, which typically
requires special processing to reduce to FDA-approved levels.
Two options include a move away from palladium entirely, or
use of palladium at especially low levels, and preferably, with
recycling. While alternative transition metals, such as nickel[4]
and copper,[5] may be attractive for certain applications,
palladium remains the metal of choice. Traditional uses of
palladium catalysts under homogeneous conditions in organic
solvents tend to employ catalyst loadings in the range of 1–
5 mol %. While there are isolated examples in the literature
where ppm,[6] and even ppb,[6c–e] levels have been reported,
none is of sufficient generality and in virtually all cases,
forcing conditions are required. Moreover, regardless of the
extent of Pd invested per reaction, neither catalyst nor solvent
À
Scheme 1. A ligand-based sustainable approach to Pd-catalyzed C C
bond formation.
[*] Dr. S. Handa, Prof. Dr. B. H. Lipshutz
Department of Chemistry and Biochemistry
University of California Santa Barbara
Santa Barbara, CA 93106 (USA)
Traditional Pd-catalyzed sp2–sp2 bond formations carried
out in organic solvents rely on ligands cleverly crafted based
on crucial steric, conformational, and stereoelectronic prop-
erties.[8] Upon completion, most, if not all, of the active
palladium catalyst is either discarded as waste or re-processed
in efforts to recover spent precious metal. Rarely is there any
attention directed towards recovery/recycling of costly
ligands, especially significant at higher catalyst loadings.
Indeed, the cost associated with such ligands can oftentimes
be more than that for palladium. Moreover, considerable
amounts of Pd are usually present within the isolated product,
leading to additional metal losses and necessitating further
purification.[9] This latter situation can dictate whether Pd-
E-mail: lipshutz@chem.ucsb.edu
Prof. Dr. M. P. Andersson
Nano-Science Center, Department of Chemistry, University of
Copenhagen (Denmark)
Dr. F. Gallou
Novartis Pharma AG, Basel (Switzerland)
Dr. J. Reilly
Novartis Institute for Medical Research
Cambridge, MA 02139 (USA)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201510570.
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catalyzed couplings are even eligible for use at later stages of
a synthesis en route to an active pharmaceutical ingredient
(API). By contrast, reactions run in size- and shape-
controlled nanomicelles feature much higher substrate and
catalyst concentrations within their inner cores than those
found in organic solvent-based solution. This hydrophobic
environment offers a unique opportunity to increase the
effective catalyst concentration (i.e., its binding constant)
based on its lipophilicity, in addition to adjustments to other
standard reaction parameters.[10] Thus, by increasing the time
spent by the catalyst in close proximity to the coupling
partners, less catalyst should be needed to achieve coupling
within the same or shorter time period.
Our attention was directed towards oxaphosphole-con-
taining ligands in the BI-DIME family, first introduced and
extensively studied by Tang et al., and found to be very useful
as their derived Pd complexes as catalysts in SM couplings in
aqueous toluene using 2–5 mol % of palladium.[11] Since these
catalysts, however, are ineffective under micellar conditions
at the 1000 ppm level (0.1 mol %; see below), a structurally
related monophosphine with enhanced activity was envi-
sioned based on increased lipophilicity and donicity, while
maintaining optimal coordination properties achieved via
conformational rigidity, as well as stereoelectronic and steric
effects. An extensive investigation of various carbon-based
appendages at the 2-position (e.g., L2–L8, Scheme 1B)
included racemic derivative L8 bearing a 2,4,6-triisopropyl-
phenylmethyl residue. Remarkably, in a ꢁ 1:1 combination
with typically ꢀ 1000 ppm of Pd(OAc)2, this new catalyst
efficiently mediates SM cross-couplings at RT. When run in
aqueous nanomicelles composed of the inexpensive and
commercially available designer surfactant Nok,[12] along
with 1.5–2.0 equivalents of Et3N, a wealth of functionality in
either reaction partner is tolerated. Excellent yields of cross-
coupling products are obtained, and no special precautions in
catalyst handling are needed insofar as sensitivity towards air
and moisture. Moreover, as the extensive survey of products
3–35 illustrates in Scheme 2, this technology is amenable to
substrates bearing chloride (e.g., 5, 8, and 9), bromide or
iodide as leaving group, although chlorides may require mild
heating to 458C to reach full conversion. Likewise, the source
of boron is especially broad, including boronic acids, Bpin or
B(MIDA) derivatives, and BF3K salts. Noteworthy observa-
tions regarding these examples include: a) biaryl products
such as 12, 33, 34 can be fashioned, notwithstanding their
congested state, which might otherwise be very challenging to
form in organic solvents at room temperature using even
much higher levels of known catalysts; b) alkenylboron
derivatives readily participate with equal effectiveness (14
and 23).
Doubly protected nitrogen, as found in products 36–38
(Scheme 3A), and other sensitive groups, remain intact under
these basic albeit especially mild conditions, where
ꢁ 1000 ppm of (HandaPhos)Pd suffices to afford products
36–44. Couplings based on other hydridizations at carbon (sp
and sp3) are also amenable (Scheme 3B). Attempted coupling
using a state-of-the-art catalyst, e.g., (SPhos)palladacycle,
under literature conditions (5 mol %, 50000 ppm)[13] led
predominantly to loss of the Boc protecting group (Sche-
Scheme 2. Representative examples using (HandaPhos)Pd. Unless
otherwise mentioned, [Pd]=1000 ppm (see Supporting Information
for details); *Y=added in two equal portions after 12 h at 458C.
HandPhos: SigmaAldrich catalog number 799580.
me 3C). Similar direct comparisons of Pd ligated by Handa-
Phos at the 1000 ppm level with other highly acclaimed
catalysts clearly documented their limited utility under these
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Scheme 3. Substrates with sensitive functionality and/or sp and sp3
carbon-based reaction partners. Reaction conditions for (A) and (B):
0.5 mmol ArX, 0.53–0.6 mmol Ar’BR2, 1000 ppm Pd(OAc)2 0.01 m in
toluene, 1020 ppm HandaPhos, 0.75–1.0 mmol Et3N, 1.0 mL 2 wt%
Nok in H2O, RT. Unless otherwise mentioned, RT=room temperature.
For part (B), reaction temperature is 458C. *Y was added in two
portions at 12 h intervals (see Supporting Information, pages S17–S18
for a general procedure).
Scheme 4. A) Comparative studies with state-of-the-art ligands;
B) levels of Pd in products; C) recycle studies.
Given that organic solvents constitute the vast majority of
organic waste created by the chemical enterprise,[15] in
general, an E Factor[16] calculated based on this reaction
variable, therefore, approaches zero; i.e., the reaction from
start to finish involves no organic solvent. In addition, all of
the water is re-used in subsequent reactions. Future incorpo-
ration of HandaPhos into a palladacycle should assist with
mechanistic investigations, as well as further reductions in
catalyst loadings.
A representative sequence of reactions performed in
a single pot is illustrated in Scheme 5 (top). An initial double
SM coupling on a bis-MOM-protected 3,3’-dibromo-BINOL
is followed by hydrolysis of both MOM residues to afford
BINOL 51 in 92% overall yield, highlighting the use of both
micellar and the surrounding aqueous media. Prospects for
HandaPhos-ligated Pd to mediate analogous Pd-catalyzed
Sonogashira couplings, in the absence of copper, were also
tested leading to unsymmetrical alkyne 52 (85%), likewise
formed in water. Adduct 52 bears several functional groups
suggesting that these same mild coupling conditions will allow
for considerable scope in the alkyne partner as well.
conditions, as little, if any, biaryl product was found in all cases
(Scheme 4A). Reactions can be run at global concentrations
of 0.5m or higher; hence, minimal amounts of water are
involved. Thus, after in-flask extraction followed by filtration
through silica, ICP analysis for Pd content in the product
indicated levels on the order of ꢀ 9 ppm, which compares very
favorably with levels observed using traditional coupling
conditions (Scheme 4B).
The amount of Pd invested in each coupling can be
reduced further by recycling of the aqueous reaction medium.
As described previously in our study of SM using aryl MIDA
boronates,[14] the solid biaryl or related product(s) can be
easily obtained by dilution of the reaction mixture with water
followed by product isolation via filtration. The filtrate can
then be recycled, upon addition of surfactant (back to 2 wt
%), and ligated Pd (back to the original ppm level). As
summarized in Scheme 4C, couplings between educts 49 and
50 led to consistent isolated yields of biaryl 24 over five cycles.
To gain insight as to the key attributes associated with the
design of HandaPhos that impart the observed catalytic
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large variations in reactivity, and ultimately, yields, between
several established Pd catalysts and HandaPhos(Pd) may be
attributed, on the one hand, to the modest role of ligand
lipophilicity, while the major influence is due to synergies
between steric effects (vs. XPhos) and the electronic structure
of HandaPhos (vs. SPhos and IPr).
Overall, this work provides a significant advance in the
area of Pd catalysis, and cross-coupling chemistry in partic-
ular. Specifically, it offers the synthetic community, based on
the new ligand HandaPhos,[18] the following features now
associated with the most heavily utilized of all Pd-catalyzed
cross-couplings, the Suzuki–Miyaura reaction, most of which
are not characteristic of current methodologies: 1) uses ppm
levels of palladium (ꢀ 0.1 mol %); 2) is generally applicable
to a broad range of functionality in either reaction partner;
3) involves very mild conditions, typically room temperature
(ca. 228C); 4) utilizes an aqueous reaction medium that
avoids organic solvents, yet involves very little water—allows
for “in-flask” recycling of the surfactant, water, and catalyst;
5) leads to ppm levels of residual palladium in cross-coupling
products. The process further illustrates the synthetic poten-
tial of micellar catalysis in combination with catalyst design,
where enhancing the lipophilic and, in particular, steric and
electronic properties of the ligand chelating Pd leads to
catalyst loadings that can be reduced to ppm levels. Further
applications of HandaPhos-based technology to several other
Pd catalyzed reactions (e.g., a more extensive study on
Sonogashira couplings), as well as its use with other precious
metals (e.g., Au) at the ppm level will be reported in due
course.
Scheme 5. Top: Tandem reactions to 51, and Sonogashira coupling to
52, with ppm levels of (HandaPhos)Pd. Bottom: Occupied density of
states (DOS) projected onto the Pd d-orbitals for four mono-ligated Pd
catalysts.
activity to its in situ-derived palladium complex, density
functional theory (DFT) calculations have been performed
using the COSMO-RS implicit solvent model.[17] This allows
for analysis of thermodynamic properties such as solubility,
partitioning, interfacial tension,[18] and reaction free energies
in a two-phase system such as exists with Nok-derived
nanomicelles in an aqueous medium. Surprisingly, the
extent of partitioning of four mono-ligated Pd catalysts
containing XPhos, SPhos, IPr, or HandaPhos in this medium
is predicted to be virtually identical. Any difference, there-
fore, ascribed to hydrophobicity of the various ligands should
have a minor impact on local concentrations therein, and
hence, minimal influence on reaction rates. The electronic
structures of these ligands, however, can be quite different
(Scheme 5, bottom; also, see Supporting Information). The
center of the occupied states projected onto Pd d-orbitals
correlates linearly with the reaction energy leading to a stable
intermediate from the oxidative addition step. Reaction
energy differences span ca. 140 kJmolÀ1, implying dissim-
ilarity in resulting catalyst activity as a function of ligand.
XPhos and HandaPhos, however, have essentially the same
occupied d-orbital center, with only 20 kJmolÀ1 between
them. Therefore, the potential role of sterics was investigated
by calculating the reaction energy in Nok micelles for binding
a second ligand of HandaPhos and XPhos to mono-ligated Pd.
The free energy of formation between the mono- and di-
ligated complexes is + 66 kJmolÀ1 for HandaPhos, and
À62 kJmolÀ1 for XPhos. This strongly suggests that Handa-
Phos forms an exclusively mono-ligated complex with Pd0,
while XPhos prefers the (less active) di-ligated state. Thus, the
Acknowledgements
Financial support provided by Novartis is warmly acknowl-
edged. The palladium used in this study was generously
supplied by Dr. Thomas Colacot at Johnson Matthey.
Technical assistance provided by R. Linstadt and Dr. Ye
Wang is appreciated. We are also grateful for support by the
NIH in the form of
(1S10OD012077-01A1).
a
Shared Instrument Grant
Keywords: E Factor · green chemistry · ligand design ·
micellar catalysis · Suzuki–Miyaura coupling
How to cite: Angew. Chem. Int. Ed. 2016, 55, 4914–4918
Angew. Chem. 2016, 128, 4998–5002
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Received: November 14, 2015
Published online: February 29, 2016
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