π-Allylpalladium Species in Micelles of FI-750-M for Sustainable and General Suzuki-Miyaura Couplings of Unactivated Quinoline Systems in Water

Article abstract of DOI:10.1002/cctc.201800958

General, clean, and sustainable Suzuki-Miyaura cross-couplings of 2-and 4-quinoline and isoquinoline systems have been demonstrated with use of π-allyl Pd catalyst in the nanomicelles of environmentally benign, proline-derived surfactant FI-750-M. Optimiz

Full text of DOI:10.1002/cctc.201800958

DOI: 10.1002/cctc.201800958
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p-Allylpalladium Species in Micelles of FI-750-M for
Sustainable and General Suzuki-Miyaura Couplings of
Unactivated Quinoline Systems in Water
[a]
# [a]
# [a]
[b]
Sachin Handa,* Faisal Ibrahim , Tharique N. Ansari , and Fabrice Gallou
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General, clean, and sustainable Suzuki-Miyaura cross-couplings
of 2-and 4-quinoline and isoquinoline systems have been
demonstrated with use of p-allyl Pd catalyst in the nanomicelles
of environmentally benign, proline-derived surfactant FI-750-M.
Optimized reaction conditions mostly provided good-to-excel-
lent yields up to gram-scale with high selectivity and functional
group tolerance. Control studies revealed the long-term stability
of the catalyst in FI-750-M. Both the catalyst and micellar
reaction medium have been recycled. The behavior of the
nanomicelles has been elucidated with DLS and cryo-TEM
measurements, and mechanistic investigations have revealed
the reversible binding of quinoline nitrogen with palladium that
competitively inhibits reaction rate.
potent catalysts and making them commercially available,
cross-coupling chemistry is viable for any chemist. The Lipshutz
group has made noteworthy contributions to the sustainability
[11]
of this chemistry,
exemplified by the development of
[12]
[13]
HandaPhos ligand and ppm Pd-doped Fe nanoparticles,
which enable these couplings in environmentally benign nano-
micelles with virtually no palladium. Due to these salient
features, micellar palladium catalysis has gained significant
[14]
attention from industrial chemists.
Despite such advancements in cross-coupling chemistry,
sustainable cross-couplings of quinoline and isoquinoline
[15]
systems is underdeveloped.
These fragments are highly
valuable in diverse areas, especially in pharmaceuticals with
antibacterial, antifungal, anticancer, antiviral, and anti-inflamma-
[16]
tory activities. Cross-couplings of 2- and 4-bromo quinoline
and isoquinoline systems are more complicated than corre-
Before the discovery of Suzuki-Miyaura, Heck, Negishi, and
[17]
Sonogashira cross-couplings, catalytic CÀC bond formation was
sponding 3-bromo systems. In addition to use of highly toxic
organic solvents such as DMF, 1,4-dioxane, etc., high catalyst
loading, excess of coupling partners, expensive ligands, and
harsh reaction conditions may be required (Scheme 1). On top
[
1]
quite challenging. These transformations are categorized as
the most valuable class of reactions in catalytic organometallic
[
1c,2]
chemistry due to their wide applications,
easy reaction
[
3]
protocols, mechanistic insights gained from behavior of
[4]
transition metal-based catalytic intermediates involved, high
[
5]
reaction reproducibility, reliable scalability, etc. Their contin-
ued evolution even after the 2010 Nobel Prize is a testament to
[6]
their popularity, especially in the pharmaceutical industry. This
evolution largely has been driven by mechanistic insights
gained from the behavior of transition metal-based catalytic
[
7]
intermediates. Leveraging fundamental knowledge about the
nature of ligated palladium species in each step of the catalytic
cycle, chemists have developed many novel kinds of trans-
[8]
formations, especially those involving remote CÀH activation.
Nature of the ligand and the palladium oxidation state play a
[9]
significant role in any catalytic cycle. To gain access to the
ligated palladium zero species, pre-catalyst modification in the
form of palladacycle and p-allyl species have been developed
[10]
and commercialized by the Buchwald and Colacot groups.
Due to their contributions particularly in the development of
#
#
[a] Prof. S. Handa, F. Ibrahim, T. N. Ansari
Department of Chemistry
University of Louisville
Scheme 1. Micellar catalysis for general cross-couplings of problematic
quinolines. Please update Scheme 1; newer version is provided as attached png
file.
2320 S. Brook St., Louisville, KY 40292 (USA)
E-mail: sachin.handa@louisville.edu
b] Dr. F. Gallou
[
[
Novartis Pharma AG
Basel CH-4002 Switzerland
#
of these drawbacks, other associated challenges may include
competitive dehalogenation, homo-couplings, and slow reac-
]
Both authors equally contributed.
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/cctc.201800958
ChemCatChem 2018, 10, 1–6
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ꢀ 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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tion rate due to coordination of coupling partner’s nitrogen
atom with palladium, especially in 2-quinoline systems.
Our environmentally benign surfactant FI-750-M is specially
Table 1. Optimizations of micelle-assisted catalytic cross-coupling of 4-
bromoquinoline .
[a]
[18]
designed to mimic DMF, NMP, and 1,4-dioxane solvents.
Successful development of a protocol for clean cross-couplings
of 2- and 4-bromo (iso) quinoline fragments in aqueous FI-750-
M would both provide access to these useful and challenging
products, and also incorporate valuable sustainability features,
including mild reaction conditions, low catalyst loading,
recyclability of catalyst and reaction medium, and use of
inexpensive ligands. Thus, we set out to provide a single set of
tools for constructing CÀC bonds in challenging quinolines and
isoquinoline systems in a sustainable fashion.
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*
Entry
Catalyst
Base
Yield [%]
1
2
3
4
5
6
7
8
9
4
5
6
7
8
9
10
11
K PO ·H O
3
3
3
3
4
4
4
4
2
2
2
2
82
90
54
91
traces
100
94
13
84
K
K
K
PO
PO
PO
·H
·H
·H
O
O
O
For this purpose, one strategy is to enhance the catalysis
with instantaneous generation of Pd(0) species and clean
oxidative addition without prolonged induction time and
protodeborylation side reaction. Palladacycle and p-allylpalla-
K PO ·H O
3
3
3
3
4
4
4
4
2
2
2
2
K
K
K
PO
PO
PO
·H
·H
·H
O
O
O
[10d]
dium precatalysts are specially designed for this purpose.
Although so far palladacycles are not as effective in micellar
12
K PO ·H O
3
4
2
[12a]
1
0
Pd(OAc)
2
K
3
PO
4
·H
2
O
38
media (TPGS-750-M, FI-750-M) as in organic solvents,
the
1
1
1
2
9
9
i-PrNEt
NEt
2
10
15
effectiveness and micellar stability of p-allylpalladium precata-
lysts is still not known. Due to relatively less lipophilic interior
of our designer amphiphile FI-750-M, its nanomicelles could
accommodate polar quinoline and isoquinoline fragments.
Prolonged stability and high solubility of p-allyl Pd precatalysts
in the nanomicelles of FI-750-M are additional key features.
These features of FI-750-M could be harnessed for highly
potent catalysis to achieve cross-couplings of challenging
quinoline and isoquinoline fragments.
3
[
(
a] Conditions: 1 (52 mg, 0.25 mmol), 2 (52 mg, 0.3 mmol), [Pd] catalyst
3 mol%), base (0.5 mmol), 1.0 mL 3 wt% FI-750-M, 458C, argon atmo-
sphere. *Yields based on GCMS using mesitylene as internal standard. For
details, see SI.
2–3 mol% of catalyst 9, and 458C as reaction temperature (see
Supplementary Info). Although lower catalyst loading (1 mol%)
resulted in complete conversion, longer reaction time was
required.
Herein, we disclose the results of this strategy: a general,
efficient, mild, and sustainable method for cross-couplings of 2-
and 4-bromo (iso) quinoline with (hetero) aryl boronic acids,
After obtaining optimal reaction conditions, substrate scope
was then explored to assess the generality of the reaction
protocol. Focusing on 2- and 4-quinoline fragments, reaction
reproducibility was screened in terms of yield and reaction
completion time while varying functional group presence and
steric and electronic parameters (Table 2). Chloroquinolines
displayed low reactivity compared to the corresponding
bromides and triflates. Remarkable generality was found with
respect to the nature of quinolines and boron nucleophiles.
Both 2- and 4-bromoquinolines were reactive under established
reaction protocol. No homocoupling of either quinolines or aryl
(heteroaryl) boronic acids was detected. Couplings with elec-
tron-deficient (13, 14, 16, 19, 20, 22, 23, 24, 30) as well as
electron-rich (17, 18, 25, 27, 28, 29, 31) residues were well
tolerated with good-to-excellent yields. The chloro functional
group (15, 21) was unaffected under reaction conditions, and
no side reaction was observed. Acetyl (20) and nitro (22)
functional groups were tolerated, and no detrimental effect on
the catalytic process was observed. The basic conditions did
not generate aldol type side-products when the acetyl func-
tional group was present. Heteroaromatic nucleophiles such as
furan (18), thiophene (26), benzofuran (27), and pyridine (29)
displayed good reactivity. Notably, no polythiophene side
product was observed. Good reactivity was also observed with
a highly electron-rich coupling partner with notable steric
congestion (31).
MIDA boronate esters, and BF K salts. Our study began with use
3
of FI-750-M, that, when mixed with substrate, exponentially
increases the size of micelles to accommodate reaction
components for efficient catalysis. During initial catalyst screen-
ing for a model reaction between 1 and 2 using K PO ·H O as a
3
4
2
base in a 3 wt.% aqueous solution of FI-750-M, various p-allyl
Pd precatalysts were tested. p-Allyl Pd complex 9 displayed the
best catalytic activity (Table 1), and full conversion to the
desired product was observed. While screening the catalytic
activity of other p-allylpalladium complexes with the model
reaction, catalysts 5 and 10 were found relatively active;
however, in terms of atomic mass and cost of catalyst, 9 was
preferred, despite the suspected instability of the PCy ligand in
3
water.
Optimization studies revealed a dependence of catalytic
transformation on several variables, most notably the nature of
the base, amphiphile, and the catalyst. Compared to quinolinyl
bromide, iodide, and triflate, poor conversions were observed
with quinolinyl tosylate. The background reaction with just
Pd(OAc) and inhibition of reaction with Et N (Table 1, entries 10
2
3
and 12) was indicative of ligand-like behavior of 4-bromoquino-
line. However, slight reactivity caused by just Pd(OAc) was not
2
general, and when the isoquinoline system was exposed, no
conversion was detected. Finally, variables for optimal catalytic
activity were 3 wt.% FI-750-M as surfactant, K PO ·H O as base,
3
4
2
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[a]
Table 2. Substrate scope for catalytic couplings of 2- and 4-bromoquinoli-
nes .
Table 3. Catalytic reactivity with other quinoline and isoquinoline types .
[
a]
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[a] Conditions: Bromoquinoline (0.25 mmol), arylboronic acid (0.3 mmol), 9
3 mol%), K PO ·H O (0.5 mmol), 0.5–1.0 mL 3 wt% FI-750-M, 458C, argon
atmosphere, 24–72 h. Unless otherwise noted, yields are isolated. Aryl
(
3
4
2
†
MIDA boronate ester was used instead of aryl boronic acid.
[a]
Table 4. Polarity switch and reactivity .
[
(
a] Conditions: Bromoquinoline (0.25 mmol), arylboronic acid (0.3 mmol), 9
3 mol%), K PO ·H O (0.5 mmol), 0.5–1.0 mL 3 wt% FI-750-M, 458C, argon
3
4
2
atmosphere, 24–48 h. Unless otherwise noted, yields are isolated.
[a] Conditions: Bromoquinoline (0.25 mmol), aryl (hetero) aryl-[B]
3 4 2
(0.3 mmol), 9 (3 mol%), K PO ·H O (0.5 mmol), 0.5–1.0 mL 3 wt% FI-750-
M, 458C, argon atmosphere, 24–72 h. Unless otherwise noted, yields are
isolated. *Reaction temperature 658C.
Beyond the 2- and 4-quinolinyl systems, compatibility of
our catalytic system for other quinoline and isoquinoline
systems was also explored. These systems worked very well
with our method, and 32–35 were obtained in good-to-
excellent yield even at such a low scale (Table 3). Notably, a free
amino group did not affect outcome of the reaction (32), and
no amination side reaction occurred.
Next, the polarity was switched between the coupling
partners. Excellent reactivity was observed in these cases (15,
30, 33) indicative of the generality of our protocol for all types
of quinoline and isoquinoline systems (Table 4).
Scheme 2. a-b) DLS data of 3 wt % FI-750-M; c) cryo-TEM of solution of 9
Nanomicelles of FI-750-M played a crucial role in the
catalysis. A dynamic light scattering (DLS) experiment revealed
the existence of micelles with ca. 107 nm average diameter
(Scheme 2a, see Supporting Information for details). Upon
addition of 2-bromoquinoline (0.01 M) to the surfactant
solution, particle size significantly increased, which was indica-
tive of substrate accommodation in the micelles (Scheme 2b).
Furthermore, long-term stability of p-allyl Pd catalyst 9 in our
micellar system was still questionable. To gain insight about its
stability, 9 was dissolved in a 3 wt% aqueous solution of FI-750-
31
(
aged, 7 days) in FI-750-M; d) P NMR of 9 to reveal stability and substrate
binding.
M and kept at room temperature up to 7 days. No difference in
the catalytic activity was observed when fresh or aged catalyst
was used. Normally, decomposition of Pd catalyst generates Pd
black. However, no Pd black was observed. In case decreased
particle size of decomposed Pd prevented its observation, a
sample was analyzed by cryo-TEM, and in this analysis, nano-
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micelles of FI-750-M were detected without the presence of any
Pd nanoparticle or Pd black, indicative of the high stability of 9
in FI-750-M (Scheme 2c). Next, 9 was extracted from aged
aqueous solution of FI-750-M and analyzed by NMR spectro-
During a recycling study at small scale (Scheme 4), attempts
at full recycling of the catalyst resulted in slow conversions. A
31
scopy. P NMR analysis of freshly prepared and aged catalyst
solutions provided identical results (Scheme 2d). Therefore, this
catalyst is bench stable in FI-750-M solution and could be used
as a nanomicellar catalytic reagent for cross-couplings, espe-
cially for (iso)quinoline systems.
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Partial catalysis was also achieved with just use of Pd(OAc)2
(Table 1, entry 10), and further extension of reaction time and
use of Cu(OAc) as a nitrogen scavenger did not improve the
2
conversion. Inhibition of the reaction by triethylamine (entry 12)
was also observed. Therefore, control experiments were
31
conducted to gain insight into the nature of catalysis. P NMR
suggested that the nitrogen of 4-bromoquinoline reversibly
binds with the catalyst 9 and blocks the catalytic site (Fig-
ure 2d). Therefore, mild heating was required for transforma-
tions. Without such a nitrogen atom, catalytic transformation
cleanly proceeded both at room temperature and 458C, i.e.,
reaction of 2-bromonaphthalene (36) with arylboronic acid (37)
to obtain 38 (Scheme 3). Addition of 1.0 equivalent of quinoline
[a]
Scheme 4. Measure of greenness by E factor and recycle study.
recycling study with partial palladium and full reaction medium
[19]
resulted in a very low E factor of 5.9 with recovery of solvent
used in chromatography and 19.9 without recovery in the last
cycle, demonstrating the greenness of this process.
In summary, this work demonstrates the development of a
stable, environmentally benign, and recyclable catalytic system
of FI-750-M and p-allyl Pd catalyst. Surfactant mimics polar-
aprotic organic solvents to enable couplings of challenging
quinoline and isoquinoline systems using recyclable p-allyl Pd
catalyst. Overall, it offers a method that is noteworthy for: (1)
low catalyst loading; (2) general applicability to a broad range
of quinolines and isoquinolines; (3) very mild conditions; and (4)
use of a benign aqueous reaction medium that avoids organic
solvents, requires very little water, and allows in-flask recycling
of the surfactant, water, and catalyst.
Acknowledgements
Scheme 3. Control experiments and gram-scale reaction
This research work was supported in part by an award from the
Kentucky Science and Engineering Foundation as per grant
agreement #KSEF-148-502-17-396 with the Kentucky Science and
Technology Corporation. We also acknowledge the University of
Louisville for partial support. We also thank Novartis Pharmaceut-
icals for partial financial support. We warmly thank Johnson-
Matthey for a generous gift of palladium catalysts. High-
resolution, accurate mass spectra were recorded by Ms. Angela
Hansen at the Indiana University Mass Spectrometry Facility using
a MAT-95XP mass spectrometer purchased with NIH grant
1S10RR016657-01. We thank Dr. Aidan Taylor from UCSB for
obtaining cryo-TEM images.
in the same reaction inhibited a reaction, and very slow
conversion was observed at 458C along with homocoupling of
boronic acid. Similarly, introduction of triethylamine in a same
reaction slowed the catalysis. Thus, non-nitrogenous base and
mild heating are required to achieve effective catalysis.
Next, the gram-scale reproducibility and sustainability of
this method were assessed. Using 1.5 mol% catalyst loading, 16
was obtained with 94% isolated yield (Scheme 3b). Notably, no
extra purification was needed, and 16 was obtained by just
simple filtration, which allowed the recovery of amphiphile and
catalyst. No residual surfactant was detected in 16 after a
simple water wash.
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Conflict of Interest
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N. J. Oldenhuis, S. L. Buchwald, Angew. Chem. Int. Ed. 2013, 52, 615;
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d) A. J. DeAngelis, P. G. Gildner, R. Chow, T. J. Colacot, J. Org. Chem.
2015, 80, 6794.
The authors declare no conflict of interest.
[
11] B. H. Lipshutz, N. A. Isley, J. C. Fennewald, E. D. Slack, Angew. Chem. Int.
Ed. 2013, 52, 10952.
Keywords: green chemistry · micellar catalysis · E factor · cross-
couplings · amphiphile
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Manuscript received: June 13, 2018
Accepted Article published: July 30, 2018
Version of record online: July 30, 2018
ChemCatChem 2018, 10, 1–6
www.chemcatchem.org
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ꢀ 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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These are not the final page numbers!

Communications
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COMMUNICATIONS
Mighty micelles! p-allyl Pd species
have been found to be stable in the
moderately polar micellar interiors of
FI-750-M. The solubility of unacti-
vated (iso)quinoline in the same site
enabled challenging cross-couplings
under mild conditions. DLS studies
revealed the expansion of micelles
upon accommodation of reaction
partners. Optimized reaction condi-
tions apply to a broad range of sub-
strates and provided good-to-
Prof. S. Handa*, F. Ibrahim, T. N. Ansari,
Dr. F. Gallou
1 – 6
p-Allylpalladium Species in Micelles
of FI-750-M for Sustainable and
General Suzuki-Miyaura Couplings
of Unactivated Quinoline Systems
in Water
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excellent yields up to gram scale
with high selectivity and functional
group tolerance.