Sustainable Palladium-Catalyzed Tsuji-Trost Reactions Enabled by Aqueous Micellar Catalysis

Article abstract of DOI:10.1021/acs.orglett.0c01329

Palladium-catalyzed allylic substitution, or "Tsuji-Trost"reactions, can be run under micellar catalysis conditions featuring not only chemistry in water but also numerous combinations of reaction partners that require low levels of palladium, typically on the order of 1000 ppm (0.1 mol %). These couplings are further characterized by especially mild conditions, leading to a number of cases not previously reported in an aqueous micellar medium. Inclusion of diverse nucleophiles, such as N-H heterocycles, alcohols, dicarbonyl compounds, and sulfonamides is described. Intramolecular cyclizations further illustrate the broad utility of this process. In addition to recycling studies, a multigram scale example is reported, indicative of the prospects for scale up.

Full text of DOI:10.1021/acs.orglett.0c01329

pubs.acs.org/OrgLett
Letter
Sustainable Palladium-Catalyzed Tsuji−Trost Reactions Enabled by
Aqueous Micellar Catalysis
Nicholas R. Lee, Farbod A. Moghadam, Felipe C. Braga, Daniel J. Lippincott, Bingchun Zhu,
Fabrice Gallou, and Bruce H. Lipshutz*
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ABSTRACT: Palladium-catalyzed allylic substitution, or “Tsuji−
Trost” reactions, can be run under micellar catalysis conditions
featuring not only chemistry in water but also numerous
combinations of reaction partners that require low levels of
palladium, typically on the order of 1000 ppm (0.1 mol %). These
couplings are further characterized by especially mild conditions,
leading to a number of cases not previously reported in an aqueous
micellar medium. Inclusion of diverse nucleophiles, such as N−H
heterocycles, alcohols, dicarbonyl compounds, and sulfonamides is
described. Intramolecular cyclizations further illustrate the broad utility of this process. In addition to recycling studies, a multigram
scale example is reported, indicative of the prospects for scale up.
alladium-catalyzed allylic substitution reactions, oftentimes
Scheme 1. Approaches to Tsuji−Trost Reactions in Water
P
referred to as “Tsuji−Trost” couplings,1 have been widely
studied in organic synthesis and catalysis for decades.2 The
ability to incorporate synthetically useful allylic functionality
into various substrates under mild conditions, as well as the
potential for intramolecular cyclizations, makes it valuable as a
tool for complex molecule synthesis and for use in catalysis. The
majority of methodologies developed for this reaction are
conducted in typical organic solvents such as THF, DCM, DME,
etc. and, in general, use Pd loadings that are typically in the 1−5
mol % range, which is clearly unsustainable. The ability to use
minimal amounts of recyclable water as the bulk reaction
medium is attractive from an environmental, safety, and cost
perspective. A number of publications over the last few decades
have appeared that conduct the Tsuji−Trost reaction “in water”,
with varying approaches to facilitating the unique challenges
associated with this choice of medium (Scheme 1). Use of
“custom” ligands, such as the tetra-tertiary phosphine Tedi-
cyp,3a has achieved very high catalytic activity (up to a turnover
number of 680,000 and 1,000,000 in THF and water,
respectively), albeit requiring a lengthy synthesis for this air-
sensitive ligand’s preparation.3b Nanoparticle catalysts such as
the PdNP@PVP4 also have produced high turnover numbers (up
to 537,000) in water.
TPPTS has been employed as a water-soluble phosphine
ligand, utilized for substitution of allylic alcohols,5 albeit at high
Pd loading (i.e., 5 mol %). Immobilized Pd catalysts, such as Pd
on hydroxyapatite,6 and asymmetric ligands attached to
polystyrene beads7 have also been employed to good effect.
Of the experiments utilizing water8 as the actual solvent or bulk
reaction medium, few have utilized surfactants.9 Thus, we now
describe a general, environmentally responsible procedure for
Received: April 16, 2020
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© XXXX American Chemical Society
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a
carrying out Tsuji−Trost reactions that utilizes designer
surfactant technology in recyclable water as the reaction
medium,10 and that relies on parts per million levels (typically
1000 ppm or 0.1 mol %) of a commercially available Pd catalyst.
Our study began by investigating the nature of the substrates
that participate in these reactions. Previous work in our group
had determined that allylic alcohols9a or allylic phenyl ethers9b
can serve as uncommon (and oftentimes challenging) electro-
philic partners for Tsuji−Trost reactions. Use of allylic alcohols
is attractive because of their atom economy, producing water as
the only byproduct. However, using an allyl alcohol as the
leaving group typically requires higher loadings of catalyst and/
or harsher conditions.9a,11 Although allylic alcohols were
reactive under our conditions, sometimes at much lower catalyst
loadings than used in the original report (i.e., 0.5−1.0 mol % of
Pd), they failed to reach completion at the desired lower parts
per million levels of Pd. Exploring leaving group (LG) efficiency
showed the following trend: O-CO2Me > O-Boc > O-Bz > O-Ac
≫ OH. Therefore, in most cases, an allylic methyl carbonate was
the preferred electrophile. However, on occasion, significant
competing hydrolysis of this residue can occur, forming the
corresponding allylic alcohol of far lower reactivity. Moreover,
again depending upon reaction partners, the undesired sym-
metrical allylic-O-allylic ether can also be generated. These
couplings were all screened using DPEphos as the ligand of
choice on palladium, which was introduced using commercially
available dimeric Pd(allyl)Cl (see the Supporting Information).
Additional screening revealed that several allylic methyl
carbonates were found to react with nitrogen-based nucleophiles
at a favorable 1000−2000 ppm Pd loading, as shown in Scheme
2. In some cases, however, couplings failed to reach complete
conversion under these conditions (typically 0.5−1.0 M, global
concentration) and, hence, as indicated, required a somewhat
higher catalyst loading.
Scheme 2. Reactions of Nitrogen Nucleophiles
Incorporation of ammonia or its equivalent as a nucleophilic
partner can be challenging. Use of ammonia itself is limited due
to its tendency for overaddition of the resulting primary amine
product with remaining allylic electrophiles. Attempts to utilize
ammonia directly, in the form of ammonium hydroxide, under
our typically concentrated reaction conditions (0.5−1.0 M)
gave only triallylated product (e.g., 1p; Scheme 2). Another
approach is the use of Boc-protected ammonia, followed by
subsequent deprotection. Unfortunately, this nucleophile
proved unreactive under these conditions. However, di-Boc
ammonia (di-tert-butyl iminodicarboxylate) reacted readily,
giving exclusively the linear product in good isolated yield for
the one example studied (1r). However, because Boc
deprotection occurs under mildly acidic conditions, di-Boc
amine derivatives appeared to be the ammonia equivalent of
choice for these reactions.
Sodium azide was found to be a competent nucleophile in
relatively simple cinnamyl-OLG cases, but more complicated
electrophiles gave inseparable linear and branched products.
Therefore, di-Boc ammonia is the preferred ammonia equivalent
under these conditions. Moreover, attempts to reduce allylic
azides to the corresponding amines under aqueous conditions
proved challenging. Reduction by PPh3 (i.e., Staudinger-type
conditions) did not afford the amine product, and sodium
borohydride alone or in combination with Fe/ppm Pd/Ni
NPs12 gave little of the desired amine. Both zinc and iron in
combination with NH4Cl and/or HCl were found to give the
desired amine, albeit in moderate yields (∼50% after
derivatization as the benzamide using benzoyl chloride).
a
b
c
Reaction conditions: nucleophile (1.0 equiv, 1.1 equiv, 1.4 equiv),
d
e
f
g
electrophile (1.1 equiv, 1.0 equiv, 1.2 equiv, 1.5 equiv, 2.2 equiv),
K2CO3 (1.5 equiv), 2 wt % TPGS-750-M/H2O (1.0 M reaction
concentration), catalyst stock solution prepared in toluene, 45 °C,
h
i
argon. Methyl formate (1 equiv) added, Et3N (3 equiv) instead of
K2CO3, j[Pd(allyl)Cl]2/ligand added as solids, k0.5 M reaction
l
concentration instead of 1.0 M, NH4OH (5 equiv) as base and
nucleophile.
Phthalimide was also found to be a suitable ammonia equivalent,
although typically lower yields were obtained and more
byproducts were seen, including undesirable and difficult to
separate mixtures of linear/branched products. In addition,
phthalimide derivatives, in general, displayed poor solubility
characteristics within the aqueous reaction mixture due to their
B
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highly crystalline nature, although solubility can be improved
with the addition of cosolvents.13
A variety of carbon nucleophiles, such as doubly activated
cases including 1,3-dicarbonyl-containing compounds such as α-
nitroketones, malonates, etc., readily participated (Scheme 3).
hydrolyzed, in situ-formed allylic alcohol to react with an allylic-
O-LG; for example, cinnamyl-O-Boc produced the cinnamyl-O-
cinnamyl dimer as the major product. However, cinnamyl-O-Bz
gave the desired unsymmetrical ether 3d in 85% yield.
Therefore, in such cases, it became necessary to diversify leaving
groups beyond the more typically seen acetates and methyl
carbonates. Allylic O-Bz derivatives were ultimately found to
give greatly enhanced yields without dimerization. Use of an
OBz leaving group may be fortuitous, as inclusion of byproduct
potassium benzoate (when K2CO3 is used as base) has
previously been found to promote Tsuji−Trost reactions in
water.11d,e
a
Scheme 3. Reactions of Carbon Nucleophiles
Whereas many intramolecular variations of this reaction have
been reported in organic solvents, they have been conspicuously
absent from reports on Tsuji−Trost reactions in water. This led
us to pursue the synthesis of various types of heterocycles via this
method. Several cyclizations could be achieved under these
aqueous conditions, each based on literature precedent in
organic solvents.14 These cyclizations occurred smoothly at 1000
ppm of Pd catalyst, forming vinyl-substituted heterocycles such
as piperazine, morpholine, dihydrofuran, and tetrahydrovinyl-
quinoxaline-containing rings in typically moderate to high yields
(Scheme 5).
a
Scheme 5. Intramolecular Cyclization Reactions
a
Reaction conditions: nucleophile (1.0 equiv, b1.1 equiv), electrophile
c
d
e
f
(1.1 equiv, 1.0 equiv, 1.5 equiv), K2CO3 (1.5 equiv, 1.0 equiv, 2.5
equiv), 2.5 equiv), 2 wt % TPGS-750-M/H2O (1.0 M reaction
concentration) catalyst stock solution prepared in toluene, 45 °C,
argon. Pd(OAc)2/PPh3 used as Pd catalyst, h1.0 equiv of methyl
g
i
j
formate added, Et3N (3.0 equiv) instead of K2CO3, [Pd(allyl)Cl]2/
ligand added as solids, (S,S)-DACH-naphthyl used as ligand instead
of DPEphos, 0.5 M (reaction concentration).
k
l
In addition, one asymmetric example using a carbon nucleophile
(2g) was explored; however, in limited testing, amine
nucleophiles failed to give significant enantioselectivities. Similar
to allylic aminations, substrates bearing additional substitution
on the allylic partner may require higher loadings of catalyst.
Although phenols proved to be competent nucleophiles at
parts per million levels of Pd, alcohols with higher pKa values
(e.g., chrysanthemyl alcohol) failed to react at those loadings
(Scheme 4). In the case of primary alcohols, the nature of the
leaving group is crucial due to the potential for dimerization of
a
Reaction conditions: nucleophile (1.0 equiv), electrophile (1.0
equiv), Et3N (3 equiv, b2.0 equiv), methyl formate (1 equiv), 2 wt %
TPGS-750-M/H2O (0.33 M, c0.25 M, d0.4 M reaction concentration),
catalyst stock solution prepared in toluene, 45 °C, argon.
a
Scheme 4. Reactions of Oxygen Nucleophiles
To demonstrate the potential for use of this method at scale
(∼25 mmol), a multigram reaction was conducted at the 1000
ppm level of palladium in water at 45 °C after precomplexing the
catalyst in a minimum of toluene (4e; Scheme 5). This trial
proceeded with a yield (4.2 g, 84%) similar to that obtained from
the initial scale trial run on 0.5 mmol.
In addition to traditional allyl alcohols, acetates, and
carbonates, vinyl epoxides were also found to be suitable
electrophiles for Tsuji−Trost couplings in water (Scheme 6).
Reactions with various nucleophiles furnish allylic alcohols that
can be further functionalized. Most combinations were
amenable under 1000 ppm Pd catalysis.
An example of a tandem two-step, one-pot sequence is shown
in Scheme 7 (top). Whereas indole gave a mixture of N-allylated
and C3-allylated products and required fairly high loadings of
palladium to achieve good conversion, indoline is especially
a
Reaction conditions: nucleophile (1.0 equiv), electrophile (1.1 equiv,
b1.2 equiv, c1.5 equiv), K2CO3 (1.5 equiv, d1.0 equiv), 2 wt % TPGS-
750-M/H2O (1.0 M reaction concentration), catalyst stock solution
d
prepared in toluene, 45 °C, argon. Methyl formate (1 equiv) added,
e[Pd(allyl)Cl]2/DPEphos added as solids.
C
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a
Scheme 6. Vinyl Epoxides as Electrophiles
Scheme 8. Studies on Recycling and E Factor Determination
a
Reaction conditions: nucleophile (1.0 equiv), electrophile (1.0 equiv,
b1.1 equiv, c1.2 equiv), Et3N (3 equiv, d2.0 equiv), methyl formate (1
equiv), 2 wt % TPGS-750-M/H2O (0.5 M); e1.0 M reaction
concentration), catalyst stock solution prepared in toluene, 45 °C,
couplings have been found to work well using parts per million
levels of endangered Pd, complexed by DPEphos as catalyst.
Nucleophiles not previously reported were also found to work
well, including several N-heterocycles. Other notable nucleo-
philic partners shown herein to readily participate include
sulfonamide, azide, and primary alcohols. Several approaches to
delivering ammonia equivalents were also pursued, with di-Boc-
protected ammonia being the most effective. Also described for
the first time are intramolecular allylic substitutions, likewise
performed in water in the presence of parts per million loadings
of Pd. The prognosis for this new technology to be run on a
multigram scale reaction was also evaluated as was the
recyclability of the entire reaction medium. These features,
taken in their entirety, further highlight the sustainable nature of
such chemistry in water.
f
g
argon. No methyl formate, K2CO3 (2.0 equiv) instead of Et3N.
Scheme 7. Tandem, One-Pot Sequences
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c01329.
reactive in Tsuji−Trost reactions. Further dehydrogenation of
its derived initial product can be realized using a cobalt(salen)
complex in combination with t-butylhydroperoxide (TBHP) to
furnish the N-allylated indole in a single flask operation.
Attempts at dehydrogenation15 using MnO2, DDQ, or Pd@
HAP15b failed to afford appreciable amounts of the desired
indole product in TPGS-750-M solution.
An approach to functionalized vinyl morpholines using DCM
as solvent was published by Cossy and co-workers.14a This
method was also well-suited to our aqueous conditions. Upon
initial Tsuji−Trost coupling of a sulfonamide in the presence of
a vinyl epoxide, addition of a Lewis acid catalyst results in
cyclization and loss of water (Scheme 7, bottom).
To document the facility with which the aqueous reaction
mixture can be recycled, results from three cycles, in addition to
the original coupling, are illustrated in Scheme 8. Little to no
change in isolated yields was observed. Upon cooling the
reaction mixture, the product solidifies, allowing for its isolation
by simple filtration. Rinsing with water completes the “workup”,
thereby eliminating the need for extraction with organic
solvents. Not unexpectedly, therefore, the resulting E Factors,16
as a measure of “greenness” and calculated on the basis of both
organic solvent and water usage, are very low, indicative of the
environmentally responsible nature of this technology.
Experimental procedures, syntheses, and NMR spectra
(PDF)
AUTHOR INFORMATION
Corresponding Author
■
Bruce H. Lipshutz − Department of Chemistry & Biochemistry,
University of California, Santa Barbara, California 93106,
United States; orcid.org/0000-0001-9116-7049;
Email: lipshutz@chem.ucsb.edu
Authors
Nicholas R. Lee − Department of Chemistry & Biochemistry,
University of California, Santa Barbara, California 93106,
United States
Farbod A. Moghadam − Department of Chemistry &
Biochemistry, University of California, Santa Barbara, California
93106, United States
Felipe C. Braga − Department of Chemistry & Biochemistry,
University of California, Santa Barbara, California 93106,
United States
Daniel J. Lippincott − Department of Chemistry & Biochemistry,
University of California, Santa Barbara, California 93106,
United States
In conclusion, Pd-catalyzed Tsuji−Trost reactions remain
underdeveloped with respect to their use under environmentally
responsible, aqueous micellar conditions. Many of these
Bingchun Zhu − Department of Chemistry & Biochemistry,
University of California, Santa Barbara, California 93106,
United States
D
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2009, 42, 6472−6474. (c) Billamboz, M.; Mangin, F.; Drillaud, N.;
Fabrice Gallou − Novartis Pharma AG, CH-4057 Basel,
Switzerland; orcid.org/0000-0001-8996-6079
́
Chevrin-Villette, C.; Banaszak-Leonard, E.; Len, C. Micellar Catalysis
Using a Photochromic Surfactant: Application to the Pd-Catalyzed
Tsuji−Trost Reaction in Water. J. Org. Chem. 2014, 79, 493−500.
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2018, 118, 679−746. (b) Li, C.-J.; Chen, L. Organic Chemistry in
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Oehme, G. Reactions in Micellar Systems. Angew. Chem., Int. Ed. 2005,
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Advances in Catalysis in Micellar Media. Green Chem. 2015, 17, 644−
683. (e) Lamblin, M.; Nassar-Hardy, L.; Hierso, J.-C.; Fouquet, E.;
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Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c01329
Notes
The authors declare no competing financial interest.
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