Sonogashira Couplings Catalyzed by Fe Nanoparticles Containing ppm Levels of Reusable Pd, under Mild Aqueous Micellar Conditions

Article abstract of DOI:10.1021/acscatal.9b00007

Nanoparticles derived from FeCl₃ containing the ligand XPhos and only 500 ppm Pd effect Sonogashira couplings in water between rt and 45 °C. The entire aqueous reaction medium can be easily recycled using an "in-flask" extraction. Several tande

Full text of DOI:10.1021/acscatal.9b00007

Research Article
Cite This: ACS Catal. 2019, 9, 2423−2431
pubs.acs.org/acscatalysis
Sonogashira Couplings Catalyzed by Fe Nanoparticles Containing
ppm Levels of Reusable Pd, under Mild Aqueous Micellar Conditions
,
‡,†
†
‡
†
§
∥
⊥
Sachin Handa,*
Bo Jin, Pranjal P. Bora, Ye Wang, Xiaohua Zhang, Fabrice Gallou, John Reilly,
,
†
and Bruce H. Lipshutz*
†
Department of Chemistry & Biochemistry, University of California, Santa Barbara, California 93106, United States
Department of Chemistry, University of Louisville, Louisville, Kentucky 40292, United States
PHT International, Inc., Shanghai, 200336 China
‡
§
∥
Novartis Pharma AG, 4056 Basel, Switzerland
⊥
Novartis Institute of Medical Research, Cambridge, Massachusetts 02129, United States
S Supporting Information
*
ABSTRACT: Nanoparticles derived from FeCl containing the ligand
3
XPhos and only 500 ppm Pd effect Sonogashira couplings in water
between rt and 45 °C. The entire aqueous reaction medium can be
easily recycled using an “in-flask” extraction. Several tandem processes
in one pot are illustrated, including a sequence involving five steps (10
reactions) in good overall yield.
KEYWORDS: micellar catalysis, green chemistry, cross-couplings, multistep sequences, chemistry in water
otwithstanding the 2010 Nobel Prizes awarded in
recognition of the extraordinary value of Pd catalysis in
And yet, as unequivocally established by control reactions,
couplings were indeed mediated by this platinoid, the
minimum amount of which required for catalysis was found
to be ca. 320 ppm. While the most effective embedded ligand
N
modern organic synthesis, many challenges remain in keeping
with the times since the 1970s when the Suzuki, Heck, and
1
3
Negishi couplings were first reported. Among these
for these SM couplings was found to be SPhos, the
challenges, sustainability figures prominently, encouraging
evaluation of the impact of such chemistry on the
environment. Increased attention is now being paid to issues
such as catalyst recovery, cost-effectiveness, status of
endangered metals, operational safety and complexity,
regulatory requirements, energy consumption, product
contamination with residual metals, etc. To begin to address
these issues, new Fe-based nanoparticles (NPs) were recently
disclosed that effectively catalyze highly useful Suzuki−
Miyaura (SM) reactions under very mild aqueous micellar
likelihood that other Pd-catalyzed C−C bond-forming
reactions are amenable to use of these same NPs at the
same loading of Pd and/or ligand was not high. Moreover, in
altering the NPs to function as catalysts for Sonogashira
couplings, new questions arose, including: (i) Are Fe/ppm Pd
NPs stable when ligands other than SPhos are used? (ii)
With a change of ligand, is the shape and/or size of the
resulting NPs impacted such that reactivity is maintained?
(iii) Does leaching of Pd become an issue? (iv) Should these
Fe/ppm Pd NPs be prepared in the exact same fashion for
use in other Pd-catalyzed reactions? We now report on a
new, general nanoparticle technology for effecting heteroge-
neously Pd-catalyzed Sonogashira couplings under environ-
mentally responsible conditions.
2
conditions. Strikingly, these NPs were prepared from
inexpensive FeCl that naturally contained enough palladium
3
(
i.e., as an “impurity”) for them to function catalytically when
prepared in the presence of a ligand. The majority of the
chemical makeup of these NPs (>97%) consisted of atoms
derived from both the added Grignard reagent (Mg and Cl,
from MeMgCl) and the solvent (C, H, and O, from THF)
utilized in their formation. The amount of iron present,
therefore, was relatively low (<1.5%), while the palladium
content was below the detection limit using XPS analysis.
The preparation of these modified Fe/ppm Pd NPs is
straightforward: FeCl , Pd(OAc) , and XPhos are dissolved in
3
2
Received: January 2, 2019
Revised: January 31, 2019
©
XXXX American Chemical Society
2423
DOI: 10.1021/acscatal.9b00007
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Research Article
instrumental in enabling these heterogeneous couplings to
take place under such uncharacteristically mild conditions.
That is, the MPEG-terminated nanomicelles housing the
5
reaction partners in high concentrations are delivered to the
metal NPs, as the catalyst (containing Fe) is known to be
6
stabilized by the (M)PEG serving as a ligand. This “nano-to-
7
nano” effect, nonexistent in traditional organic solvents and
yet seen previously in multiple systems of this type and
8
confirmed by cryo-TEM analyses, leads to product alkynes
in very good isolated yields (Table 1).
Several of the examples to be found within Table 1 are
worthy of note. For example, heteroaromatics within either
the electrophilic or nucleophilic partner appear to be well
tolerated (7−9, 11, 12, 17−20). The presence of fluorinated
educts, where fluorine is either within a CF residue (11, 14)
3
or present on the ring (6, 10), does not affect the coupling.
Enyne derivatives can also be smoothly fashioned (6, 9). Aryl
bromides and iodides are the most reactive coupling partners,
leaving heteroaryl chlorides intact (9). When highly
crystalline materials are involved and, hence, solubility issues
may arise, use of small percentages of a cosolvent (e.g., THF;
9
see 17, 20) may prove beneficial. Notably, a free arylamine
residue leading to product 5 did not participate in potentially
competitive amination reactions. The presence of both
thiophene (8) and benzothiophene (11) rings also displayed
good reactivity without observable polymerization. Coupling
partners containing ester functionality were also used with
impunity given the mildness of the basic aqueous conditions
Figure 1. Preparation and application of Fe/ppm Pd nanoparticles
(
NPs) as a catalyst for Sonogashira couplings.
(
10, 20).
Reactivity differences between aryl iodides and bromides
toward this NP catalyst could be used to great advantage.
Selective reactions with substrates bearing both iodide and
bromide are facile. As illustrated in Scheme 1, highly
functionalized acetylenic products 24 and 21 were obtained
in excellent yields independent of the original location of the
bromide. Notably, for both transformations, aged (2 weeks)
NPs were used as catalyst. With freshly prepared NPs, no
differences in reaction times and/or yields were observed.
Multiple Sonogashira couplings on a single educt could
also be achieved involving suitably halogenated precursors.
Three representative examples are shown in Scheme 2, where
aryl dihalides 27a or 27b, and 30, each undergo double
couplings to afford products 29 and 31, respectively. 1,3,5-
Tribromobenzene reacts with excess TMS-acetylene in a
triple Sonogashira reaction to afford an initial product of
trisubstitution. This adduct could be treated, without
isolation, with added carbonate to afford the all-terminal
trialkyne in 88% isolated overall yield from this one-pot
process. Product 32 is of considerable general interest in
Figure 2. “Nano-to-nano” effect; the MPEG in nanomicelles delivers
the reaction partners to the NP catalyst.
dry THF. MeMgBr in THF is then added at rt (Figure 1).
After 20 min, quenching with trace amounts of water is
followed by evaporation of solvent under reduced pressure,
followed by trituration with pentane to give the NPs. These
can be used directly in a reaction or isolated via filtration and
stored on the shelf at ambient temperatures. NPs containing
10
materials chemistry.
To demonstrate an application of this new technology, the
disubstituted subsection of the antitumor agent ponatinib was
targeted. As illustrated in Scheme 3, coupling between aryl
bromide 33 and triethylsilylacetylene catalyzed by these Fe/
ppm Pd NPs afforded the adduct 34 in 92% isolated yield.
Desilylation led to terminal alkyne 35 (94%), which
underwent a second Sonogashira coupling with heteroar-
omatic iodide 36 to give the desired alkyne 37 (84%).
One particularly noteworthy advantage characteristic of
chemistry enabled by aqueous micellar catalysis is the
opportunity to effect sequential reactions of the same or
different type, in a single flask and without introduction of
additional NPs, given that the reaction medium for each
one of several other ligands (e.g., PPh , t-BuBrettPhos,
3
SPhos) as well as sources of palladium (e.g., PdCl ) or other
2
metals in place of Pd (e.g., Ni(OAc) ) were all examined,
2
leading to an optimized procedure (see the Supporting
Information for details).
Sonogashira reactions catalyzed by these NPs proceeded
smoothly in water at temperatures between rt and 45 °C.
4
The presence of the designer surfactant TPGS-750-M
(Figure 2; only 2 wt %, or 0.016 mmol/mL water) was
2
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a
Table 1. Representative Examples of Sonogashira Couplings Catalyzed by Fe/ppm Pd NPs
a
Conditions. (i) FeCl (5 mol %), XPhos (3 mol %), Pd(OAc) (500 ppm), MeMgBr (10 mol %); (ii) Ar−X (0.5 mmol), alkyne (0.75 mmol),
3
2
Et N (1.0 mmol), 1 mL 2 wt % TPGS-750-M/H O, rt −45 °C, Ar.
3
2
remains the same. Hence, workup and further processing
after each reaction can be minimized, saving time and
(27a), a double Fe/ppm Pd NP-catalyzed Sonogashira
coupling with TMS-acetylene led to the initial adduct 39.
Removal of the TMS moieties, normally done in a separate
pot using K CO in an aqueous cosolvent medium, now
1
1
materials. For example, sequential Sonogashira couplings
initially involving o-iodoaniline derivative 25 and bromoar-
ene-containing alkyne 26 afford product 21 (Scheme 4).
Without isolation, a second Sonogashira coupling could be
effected by simply adding alkyne 28 to the reaction vessel.
After workup, an 80% isolated yield of diyne 38 was
obtained.
The effectiveness of this one-pot strategy is further
illustrated in Scheme 5, in this case arriving at a potentially
new ligand containing the nonracemic binaphthyl core.
Starting with 3,3′-diiodo-BINOL as its bis-MOM derivative
2
3
utilizes the water present and the dynamic state of exchange
5
associated with all species in the micellar medium. That is,
while charged ions such as carbonate are unlikely to gain
entry into the hydrophobic micellar inner core, the exchange
processes involving all occupants (i.e., substrates, products,
etc.) and the surfactant itself occurring between micelles
through the surrounding water allow for double desilylation.
The resulting terminal alkynes are then available to
participate in a double, region-controlled Cu-catalyzed click
2
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Scheme 1. Representative Examples of Selective Sonogashira Couplings
Scheme 2. Double and Triple Fe/ppm Pd NP-Catalyzed Sonogashira Couplings
1
2
reaction to generate the bis-N-benzylated triazole 40. In
anticipation of introduction of an alternative group on both
nitrogen atoms, debenzylation was achieved by a novel
dealkylation upon introduction of inexpensive PMHS. This
silane, in the aqueous medium, generates hydrogen gas that
can be absorbed by the Pd present on the surface of the Fe/
ppm Pd NPs, thereby effecting hydrogenolysis of the two N-
benzyl groups to afford 41. Once complete, the desired
alkylating agent, a seemingly highly water-sensitive benzylic
a few minutes of gentle stirring at rt, removal of the organic
layer followed by standard processing leads to the purified
product. Removal and collection of the organic solvent allows
for its recycling in future extractions, while the aqueous
reaction mixture left in the reaction vessel is also ready for
reuse. A recycling study, as shown in Scheme 6, is suggestive
of the options not only for the water containing the
surfactant but for the NPs as well. Determination of an E
factor associated with these couplings, based on the organic
1
3
14
bromide, can be added to the same flask, ultimately arriving
at nonracemic BINOL derivative 42. This single-pot sequence
of five steps involves a total of 10 reactions and affords the
product in an overall yield of 75%.
solvent used, was 4.1, which is roughly the expected order
of magnitude drop in waste generation compared to that
typically found from similar reactions run in organic
15
solvents.
Since the typical workup for reactions run under aqueous
To gain insight regarding the nature of this new catalyst,
extensive analytical data was obtained. Cryo-TEM analysis of
in situ prepared nanoparticles in the presence of aqueous
TPGS-750-M revealed a needle-like shape (Figure 3a). Their
14
micellar conditions is of the “in-flask” nature, here, too,
product isolation involves simply adding minimum amounts
of a single solvent (e.g., EtOAc) for extraction purposes. After
2
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a
Scheme 3. Use of Fe/ppm Pd NPs for the Synthesis of Ponatinib Intermediate 37
a
Conditions: Step A: 33 (1.0 equiv), (triethylsilyl)acetylene (1.5 equiv), Fe/ppm Pd NPs (500 ppm Pd), Et N (3.0 equiv), 0.5 M in 2 wt % TPGS-
3
7
50-M/H O, 50 °C, argon, 14 h. Step B: 34 (1.0 equiv), K CO (20 mol %), 0.5 M in 1:1 MeOH/THF, 45 °C, 5 h. Step C: Imidazo[1,2-
2
2
3
b]pyridazine (1.0 equiv), N-iodosuccinimide (1.2 equiv), 0.53 M in DMF, 80 °C, argon, overnight. Step D: 36 (1.0 equiv), 35 (1.2 equiv), Fe/ppm
Pd NPs (1000 ppm Pd), Et N (3.0 equiv), 0.5 M in 2 wt % TPGS-750-M/H O, 50 °C, argon, 43 h.
3
2
Scheme 4. Sequential Fe/ppm Pd NP-Catalyzed Sonogashira Couplings in Water
Scheme 5. Multistep, One-Pot Sequence in Aqueous Nanomicelles
8
average size is ca. 70 nm, and they were found, as expected,
to be surrounded by nanomicelles of surfactant. In control
experiments as illustrated in Scheme 7, NPs prepared in the
absence of Pd showed no catalytic activity, while adding ppm
Pd after their preparation did not provide active catalyst, as
only 8% product 6 was obtained. Similarly, reaction in the
presence of 1000 ppm of Pd ligated with XPhos (i.e., no
NPs), afforded only 12% product even after a prolonged
reaction time. This suggests that any leaching of Pd from
these NPs, however unlikely given the insolubility of such
2
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Scheme 6. Recycling Study and E Factor Determination
Scheme 7. Control Experiments Revealing the Importance
of Pd Integrated within the NPs
metal(s) remains intact. Isolated catalyst was highly stable at
room temperature (Figure 3c), and aged catalyst was also
tested for catalytic activity in many reactions (see Schemes
2
b and 4). Analysis of NPs via XPS revealed a binding energy
3
+
corresponding to Fe , with this metal being ligand-bound
3
1
(
Figure 3d). P NMR of these NPs also shows that XPhos
2
does not exist as a free ligand. As seen previously, the low
levels of Pd present could not be detected by XPS analysis.
The choice of reductant was crucial for bench stability of
these nanoparticles. When MeMgCl was added to the
mixture of FeCl , Pd(OAc) , and XPhos, the resulting
3
2
isolated NPs, while initially able to mediate the desired
coupling, were surprisingly catalytically far less active after 3
days in storage at rt (Scheme 8). Thus, using aged NPs,
reaction of aryl bromide 45 with alkyne 46 under typical
conditions led to product 18 in only 18% yield after 50 h.
However, when MeMgBr was introduced as a reductant, the
resulting NPs retained catalytic activity even after 3 weeks,
affording the expected product 18 in 82% yield. These
observations are in direct contrast to those associated with
2
NPs made previously and applied to SM couplings, where
both chloride ions and SPhos are essential for catalytic
activity. For Sonogashira reactions, by contrast, the chloride/
XPhos combination present within the NP architecture is far
less stable, and subject to decomposition over time.
Interestingly, when aged material was analyzed by HRTEM
(Scheme 8), the initial needle-like shape (see Figure 3a) had
completely changed, clumping into far larger, inactive
particles.
ligated Pd species in water, does not lead to an active catalyst
as compared to Fe/ppm Pd NPs.
Catalyst stability and shelf life were tested as well,
including exposing these NPs to thermal gravimetric analysis
(
1
TGA). Complete loss of THF bound to the NPs occurs at
54 °C, implying that, at this temperature, NPs lose their
integrity and catalytic activity (Figure 3b). Loss of free ligand,
however, occurs above 200 °C, while ligand bound to the
2
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Figure 3. (a) Cryo-TEM analysis of NP; (b) TGA analysis; (c) isolated NP (aged for 4 weeks); (d) XPS analysis; (e) EDX analysis.
Scheme 8. Differences between NPs Formed Using MeMgCl vs MeMgBr
To determine whether NP-bound THF is required for
catalysis, control experiments were performed at different
temperatures (Scheme 9). Reaction between 47 and 48
proceeded smoothly with aged NPs at 45 °C; after 30 h, 47
was completely consumed and product 19 was obtained in
Further testing on the potential loss of THF from these
NPs is conducted under aqueous conditions, given its water
miscibility. Aged NPs were washed several times with water
and dried under air. No change in color was observed. When
used as a catalyst for the same Sonogashira coupling between
4
7 and 48, no difference in activity was noted, indicative of a
8
1% isolated yield. On the other hand, heating the NP
strong association of THF within these NPs (Scheme 10).
In summary, new nanoparticles are described that function
as a highly effective catalyst for especially valuable, copper-
catalyst at 80 °C under a vacuum for 6 h led to loss of THF
and resulted in a dark brown solid. When tested for activity
at the same 45 °C, only 40% of product 19 was obtained,
suggesting that most of THF had been lost from the
nanostructured catalyst. External addition of THF to the
preheated, aged catalyst did not significantly improve the
yield, implying that reconstitution of the NPs does not take
place. Thus, THF appears to be an essential component of
these NPs.
1
free Sonogashira reactions. These reactions take place under
mild conditions, in water as the gross reaction medium, and
are amenable to recycling as is the entire aqueous system.
Given the commonality associated with the reaction
conditions that apply to many typical reactions in organic
1
6
synthesis,
a multitude of opportunities for tandem
1
1
sequences now exist,
as exemplified herein. Further
2
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Scheme 9. Control Experiments for Potential Catalyst
Decomposition
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ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acscatal.9b00007.
■
*
S
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AUTHOR INFORMATION
Corresponding Authors
E-mail: lipshutz@chem.ucsb.edu.
E-mail: sachin.handa@louisville.edu.
ORCID
Sachin Handa: 0000-0002-7635-5794
Bruce H. Lipshutz: 0000-0001-9116-7049
Notes
■
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*
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■
Financial support provided by the NSF (SusChEM 1561158),
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Novartis is warmly acknowledged with thanks. S.H. also
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