Sustainable ppm level palladium-catalyzed aminations in nanoreactors under mild, aqueous conditions

Article abstract of DOI:10.1039/c9sc03710a

A 1?:?1 Pd?:?ligand complex, [t-BuXPhos(Pd-π-cinnamyl)]OTf, has been identified as a highly robust pre-catalyst for amination reactions leading to diarylamines, where loadings of metal are typically at 1000 ppm Pd, run in water at temperatures between rt and 45 °C. The protocol is exceptionally simple, is readily scaled, and compares very favorably vs. traditional amination conditions. It has also been shown to successfully lead to key intermediates associated with several physiologically active compounds.

Full text of DOI:10.1039/c9sc03710a

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Sustainable ppm level palladium-catalyzed
aminations in nanoreactors under mild, aqueous
Cite this: Chem. Sci., 2019, 10, 10556
conditions†
Yitao Zhang,a Balaram S. Takale,
All publication charges for this article
have been paid for by the Royal Society
of Chemistry
a
b
Fabrice Gallou,
John Reillyc
a
*
and Bruce H. Lipshutz
A 1 : 1 Pd : ligand complex, [t-BuXPhos(Pd-p-cinnamyl)]OTf, has been identified as a highly robust pre-
catalyst for amination reactions leading to diarylamines, where loadings of metal are typically at
1000 ppm Pd, run in water at temperatures between rt and 45 ꢀC. The protocol is exceptionally simple,
is readily scaled, and compares very favorably vs. traditional amination conditions. It has also been shown
to successfully lead to key intermediates associated with several physiologically active compounds.
Received 27th July 2019
Accepted 19th September 2019
DOI: 10.1039/c9sc03710a
rsc.li/chemical-science
platinoids.8 Hence, a procedure that is not only general and
mild but can also be used under environmentally responsible
Introduction
conditions would be highly desirable, perhaps encouraging
further use of this approach to C–N bond formation. Towards
this goal, we and others have identied ligand scaffolds that
complex Pd forming catalysts that mediate such couplings
under mild, micellar conditions in water.9 However, the crucial
reaction parameters involving reduction in the amount of
endangered metal required for catalysis to a sustainable level
had yet to be achieved; indeed, in addition to high loadings
being the norm, even greater amounts of privileged ligands are
required. To begin to convert Pd-catalyzed aminations to truly
sustainable processes, we have endeavored to develop, and this
contribution report on, a general protocol that takes place in
water, requires little-to-no investment in energy other than that
Ligated palladium has been and continues to be a privileged
catalyst in the realm of organic synthesis.1 In particular, the
widespread application of Heck, Suzuki–Miyaura, and Negishi
coupling reactions earned them the highest appreciation in
chemistry.2 Palladium-catalyzed aminations have also been
pursued enthusiastically in elds ranging from pharmaceuti-
cals and agrochemicals to others in the ne chemical industry.3
The versatility and utility of such aminations has also made it
among the more reliable methods for construction of C–N
bonds that are so prevalent in many target molecules.4 Since the
mid 1990's, extensive ligand design as well as mechanistic
investigations have emerged, leading to commonly employed
phosphine ligands that tend to be monodentate, bidentate, or
dialkylbiarylphosphines.5 Development of pre-catalysts that
generate active Pd(0) species in the reaction mixture have been
also actively investigated.6 Notable examples include Pd/
phosphine ligand complexes, palladacycles, and NHCs,
among others.6 Several generations of pre-catalysts have been
developed, with each system allowing a seemingly broader
substrate scope.7 Nonetheless, much of the literature suggests
that conditions typically used for these aminations are generally
harsh, involving high boiling organic solvents (e.g., toluene,
dioxane, DMF, etc.) as the reaction medium, oentimes
requiring extended reaction times.3 Moreover, catalyst loadings
in the 2–10 mol% range of Pd are not uncommon,4e represent-
ing a non-sustainable scenario given the endangered status of
ꢀ
available between room temperature and 45 C, and is partic-
ularly mindful of the endangered status of palladium.8,10
Reducing the loading of a Pd catalyst by 1–2 orders of
magnitude requires a signicant net increase in reagent activity.
Realization of this goal becomes all the more challenging in
that high levels of reaction conversion must be realized within
reasonable timeframes. Among the many catalysts screened for
this study, some of which are shown in Scheme 1, we took
special note of reports by Colacot and co-workers describing two
new classes of p-allylpalladium complexes containing biar-
ylphosphine ligands.6d,f
Though mechanistic aspects of these studies were not
investigated in aqueous media, in organic solvents it was shown
that active “L-Pd(0)” species could be generated from either
neutral or cationic ligated frameworks that are both air- and
moisture-stable.6f These preformed monoligated-Pd complexes
are particularly appealing as they avoid use of excess ligands
which are formally unnecessary for the catalytic cycle, ulti-
mately generate organic waste, and can add cost to the overall
process. Moreover, such catalyst precursors help ensure
aDepartment of Chemistry and Biochemistry, University of California Santa Barbara,
Santa Barbara, CA 93106, USA. E-mail: lipshutz@chem.ucsb.edu
bNovartis Pharma AG, Basel, Switzerland
cNovartis Institutes for BioMedical Research (NIBR), Cambridge, MA, USA
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c9sc03710a
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Scheme 1 Defined LPd complexes used at 1000 ppm loading level
(see ESI† for the complete list of pre-catalysts screened).
consistent results between batches, which has obvious advan-
tages over in situ preparations both at an early stage of discovery
as well as in future applications, especially at scale.11
Results and discussion
A model reaction between 3-bromoanisole (1) and indoline (2)
was initially used to screen for catalyst activity, where only
1000 ppm (i.e., 0.10 mol%) of the Pd-containing catalyst was
invested. All reactions were run using nanomicelles derived
from TPGS-750-M in water between rt and 45 ꢀC. While several
pre-catalysts failed to deliver any detectable product, systems
featuring a biarylphosphine scaffold proved more active, as
noted previously by the Schmitt group.9e Among t-BuXPhos-
based complexes, the three cationic species [t-BuXPhos(Pd-p-
allyl)]OTf (C8), [t-BuXPhos(Pd-p-crotyl)]OTf (C9) and [t-BuX-
Phos(Pd-p-cinnamyl)]OTf (C10) each led with high efficiency to
the desired amination product. The most lipophilic pre-catalyst,
C10, afforded the diarylamine 3 in close to quantitative yield.
Use of triate salts was crucial, as the corresponding chlorides
were less effective, presumably due to their tendency to form
dimeric complexes via bridging chloride ions, species that are
apparently catalytically inferior.6d–f
Scheme 2 Representative examples of aminations under sustainable
aqueous micellar conditions. Unless otherwise mentioned: X ¼ Br,
[LPd] ¼ 1000 ppm [t-BuXPhosPd(cinnamyl)]OTf, temp ¼ 45 ꢀC, time ¼
16 h; KO-t-Bu or K3PO4$H2O used as inorganic base in 2 wt% TPGS-
750-M at 0.5 M global concentration (see ESI† for additional details).
*Product isolated by simple filtration.
Having identied C10 as the most effective pre-catalyst
under micellar conditions at the 1000 ppm level of Pd, we
evaluated the scope of this C–N coupling chemistry between
anilines/aniline-like amines and aryl bromides (Scheme 2).
Primary and secondary anilines reacted efficiently between rt
and 45 ꢀC with aryl bromides bearing electron-donating,
highly functionalized heterocyclic bromide from the Merck
Informer Library X3 (ref. 12) also participated to give the desired
product 18.13 Aryl chlorides were totally inert under these
conditions (e.g., 8), and hence, complete selectivity for
-withdrawing, or neutral substituents (products 3–20).
A
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a bromide over chloride is assured based on formation of are oen stable solids at ambient temperatures. Combining,
products 15, 23, 24, and 27. For reactions that proved to be therefore, a nitro group reduction followed (without isolation)
particularly sluggish, an increase in the loading of Pd (from 0.10 by a ppm level Pd-catalyzed amination would expand the appeal
to 0.25 mol%) led to the desired C–N bonds, as shown for of this methodology, especially for industrial applications. We
products 21–27. Among these, secondary alkyl amino have previously developed a nitro group reduction protocol
compounds such as morpholine (to give 21) and pyrrolidine (to using the same aqueous micellar medium, where commercially
give 25) could be used, though an excess of inorganic base was available and inexpensive carbonyl iron powder (CIP) has been
needed to achieve reasonable levels of conversion in both cases. shown to be amenable to scale-up, delivering grams of amina-
Multiple C–N cross-couplings in 1-pot could be effected leading tion products.8g As illustrated in Scheme 3A, the crude amine
to both C2-, C3-symmetric, and axially chiral amination products product from the reduction of 31, following ltration through
28–30, each in high overall yield. The latter two products Celite, could be used directly in the amination protocol to afford
required an increase to 5000 ppm of Pd catalyst, although the cross-coupling product 32 in good overall yield.
multiple C–N bonds were made in each case.
A gram-scale amination led to the preparation of diaryl-
Procedurally, this new protocol involves a very straightfor- amine 8, starting with 4-uoroaniline and 4-bromoacetophe-
ward benchtop setup, requires no glovebox operations, and the none (Scheme 3B). The almost equally effective pre-catalyst [t-
catalysts used (e.g., C8 and C10) are easily prepared and stored.6f BuXPhos(Pd-p-allyl)]OTf (C8)14 was used due to its commercial
Moreover, in many of the cases shown in Scheme 2, the solid availability. Without alteration from our optimized conditions
products formed precipitate out of the aqueous medium (vide supra), the reaction run at 100 times its original scale was
necessitating only ltration, thereby avoiding any formal complete in less than one hour. More than ve grams of pure
workup. Subsequent trituration leads to pure product without product could be collected via ltration, with an astonishingly
reliance on column chromatography, further minimizing both low E factor (<1), as a measure of waste created (see ESI† for
organic solvent and aqueous waste streams.
details).15
While the synthesis of 8 was highly efficient at the ppm level
As aniline coupling partners are susceptible to oxidation,
they are best puried prior to use. On the other hand, the cor- of catalyst under aqueous conditions, such was not the case
responding nitro group-containing derivatives, as precursors,
Scheme 3 (A) Sequential sustainable micellar catalysis leading to 32. Scheme
4 (A) Influence of reaction scale, catalyst loading and
(B) Gram scale synthesis of 8 in TPGS-750-M with easy product temperature on micellar amination (B) ICP analysis of residual Pd
isolation. (C) Comparison study on the formation of 3 and 8 in TPGS- detected in compounds prepared by ppm LPd micellar catalysis. (C)
750-M vs. in organic solvent. Conditions: 45 ꢀC, 1000 ppm LPd catalyst Recycle study of Buchwald–Hartwig amination at rt (see ESI† for
loading, 0.5 M, 16 h.
details).
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when performed in organic solvents commonly used for these reactions leads to formation of the desired amination, the same
aminations.4e Thus, in either toluene or 1,4-dioxane under net outcome could be obtained using 1250 ppm Pd simply by
ꢀ
otherwise identical conditions, none of the desired product was a 10 C increase in reaction temperature. Comparison studies
detected (Scheme 3C). NMR analyses showed a combination of leading to product 23 clearly showed that this was indeed the
the corresponding imine had formed, along with unreacted case (Scheme 4A).
bromoacetophenone in ca. a 1 : 1 ratio. A similar solvent
By virtue of the ppm level of Pd catalyst associated with these
comparison study was performed leading to amine 3, although aminations, the amount of residual metal to be found in the
low yields were obtained in this case as well. In the composite, product amines, aer standard workup and purication, is ex-
these observations highlight the potentially signicant (e.g., pected to be below the FDA-approved level of 10 ppm per dose.16
chemoselectivity) differences that can be found between tradi- As test cases, products (e.g., 5, 12, and 23; Scheme 4B) were
tional and micellar catalysis.
randomly selected and subjected to ICP-MS analyses for Pd
Although increasing the loading (e.g., from 0.10 to content. Results (see ESI† for details) indicated that each has a Pd
0.25 mol%; see Scheme 2) for especially difficult C–N coupling content #4 ppm, suggesting that additional time and cost
Scheme 5 (A) Direct comparisons between literature conditions and those using ppm level Pd catalysis in water. (B) Comparison with recent
amination of an estrone derivative. Yields refer to isolated material.
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associated with further purication, contrary to that based on study was generously supplied by Dr Thomas Colacot, formerly
traditional couplings done at 10–100 times the loading of Pd, at Johnson Matthey. Y. Z. would like to express thanks to Prof.
should not be needed for products formed using this technology. David M. Chenoweth for the inspiring mentoring in the past.
Further reduction in the amount of Pd invested can be achieved
by recycling of the aqueous reaction medium. As shown in the
coupling between ethyl p-bromobenzoate (33) and p-nitroaniline
Notes and references
(34; Scheme 4C), the solid diarylamine product 35 is isolated by
simple gravity ltration. The ltrate is then reused as the reaction
medium aer supplementing with 500 ppm of ligated Pd. As
summarized in this scheme, amine 35 is formed in good yields
consistently over four additional cycles, with an average input of
only 600 ppm (i.e., 0.06 mol%) of catalyst C10 per coupling.
To document the applicability of this aqueous coupling
chemistry, direct comparisons were made by focusing on six key
intermediates associated with medicinally relevant natural
products or APIs (Scheme 5A).17 Aminations that arrive at key
intermediates 35–40 reveal that this methodology operates at
much lower catalyst loadings and temperatures, and is typically
faster than reactions in organic media. Moreover, yields tend to
be comparable to, or better than, those reported previously.
Another recent example providing further testimony to the
potential savings of precious metal is shown in Scheme 5B.18
Amination at C-2 in a 3-substituted estrone derivative afforded
product 42 using 40 times less palladium and ligand (10 mol%
¼ 100 000 ppm), run at a lower temperature (45 vs. 110 ꢀC), and
in less time (16 vs. 24 h). The level of residual Pd in the product
from both approaches led to the expected outcomes: from
amination in toluene: 165 ppm Pd, while from this ppm level
amination in water: 3 ppm Pd.
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Overall, this work provides a signicant advance in Pd-catalyzed
C–N cross-coupling chemistry. Specically, it offers the synthetic
community, based on a known and well dened 1 : 1 Pd : L
complex, aminations that: (1) rely on ppm levels of palladium; (2)
are glove-box-free and operationally simple; (3) are general, highly
efficient, and offer gram-scale capability; (4) perform under very
ꢀ
mild conditions, with temperatures at 45 C or below; (5) utilize
an aqueous reaction medium that avoids organic solvents, yet
involve very little water; (6) allow for recycling of the surfactant,
water, and catalyst; and (7) lead to ppm levels of residual palla-
dium in the amination products. The process further illustrates
the synthetic potential of pre-complexing a lipophilic ligand with
Pd that can lead to pre-catalyst loadings at the ppm level.
Extending the current technology to additional C–N cross
couplings as well as use of Fe/ppm Pd nanoparticles8a for similar
synthetic purposes are currently under study.
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Conflicts of interest
There are no conicts to declare.
Acknowledgements
Financial support provided by Novartis and the NSF (GOALI
1566212) is warmly acknowledged. The palladium used in this
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X17 (Sigma catalog 901753) failed to give the desired
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(e.g.,
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other two analogues, [t-BuXPhos(Pd-p-crotyl)]OTf and [t-
BuXPhos(Pd-p-cinnamyl)]OTf can be prepared following
a two-step sequence from ready available material, as
described in ref. 6f.
8 For prior studies on sustainable metal-catalyzed
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Workshop on Chemistry in Water, UCSB June–July, 2019.
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