Micelle-enabled palladium catalysis for convenient sp2-sp3 coupling of nitroalkanes with aryl bromides in water under mild conditions

Article abstract of DOI:10.1021/acscatal.7b02663

The efficacy of custom surfactant FI-750-M, designed to mimic polar solvents such as DMF and 1, 4-dioxane, has been demonstrated with the palladium-catalyzed sp²-sp³ coupling of nitroalkanes to aryl bromides using a heteroleptic palladium catalyst under unprecedentedly mild conditions. Optimized reaction conditions mostly provided good yields up to gram scale, with high selectivity and functional group tolerance for a wide scope of aryl bromides. Use of surfactant FI-750-M makes water the gross reaction medium and enables in-flask recycling. The behavior of the surfactant has been elucidated with DLS and cryo-TEM measurements, and mechanistic investigations have revealed the importance of the π-allyl ligand in the catalytic cycle.

Full text of DOI:10.1021/acscatal.7b02663

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Letter
Micelle-Enabled Palladium Catalysis for Convenient sp2-sp3 Coupling
of Nitroalkanes with Aryl Bromides in Water Under Mild Conditions
Jeremy Brals, Justin Douglas Smith, Faisal Ibrahim, Fabrice Gallou, and Sachin Handa
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.7b02663 • Publication Date (Web): 22 Sep 2017
Downloaded from http://pubs.acs.org on September 22, 2017
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MicelleꢀEnabled Palladium Catalysis for Convenient sp2ꢀsp3 Couꢀ
pling of Nitroalkanes with Aryl Bromides in Water Under Mild
Conditions
Jeremy Brals,† Justin D. Smith,† Faisal Ibrahim,† Fabrice Gallou,‡ and Sachin Handa†*
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†Department of Chemistry, 2320 S. Brook St., University of Louisville, Louisville, KY 40292 (USA)
‡Novartis Pharma AG, Basel CHꢀ4002 Switzerland
ABSTRACT: The efficacy of custom surfactant FIꢀ750ꢀM, designed to mimic polar solvents such as DMF and 1,4ꢀdioxane, has been
demonstrated with the palladiumꢀcatalyzed sp2ꢀsp3 coupling of nitroalkanes to aryl bromides using a heteroleptic palladium catalyst under
unprecedentedly mild conditions. Optimized reaction conditions mostly provided good yields up to gram scale, with high selectivity and
functional group tolerance for a wide scope of aryl bromides. Use of surfactant FIꢀ750ꢀM makes water the gross reaction medium and enaꢀ
bles inꢀflask recycling. The behavior of the surfactant has been elucidated with DLS and cryoꢀTEM measurements, and mechanistic invesꢀ
tigations have revealed the importance of the πꢀallyl ligand in the catalytic cycle.
KEYWORDS micellar catalysis, green chemistry, crossꢀcouplings, E factor, amphiphiles.
While tracing back the history of the 2010 Nobel Prize in
Chemistry, Colacot and Snieckus found palladium catalyzed
crossꢀcouplings to be the most heavily used reactions in multiple
arenas.1 Although such reactions can be achieved with other tranꢀ
sitionꢀmetal catalysts,2 palladium is still considered as a first
choice for synthetic organic chemists.3 The reasons behind this
prevailing preferential approach are ease of handling, broader
substrate scope, greater functional group tolerance, mild reaction
conditions, high reproducibility at industrial scale, etc.4 Unfortuꢀ
nately, palladium is an endangered element and its current accesꢀ
sible supply is limited.5 Options to prolong its supply are to comꢀ
pletely move away from pallidum or to use it at a reasonably low
level with an opportunity to recycle and reꢀuse without any addiꢀ
tional investment of resources. Uozumi and coꢀworkers have
demonstrated highly efficient catalysis with very intelligently
designed nanocatalysts and amphiphilic palladium species.6 Very
recently, Lipshutz and coꢀworkers have significantly contributed
in this area, especially for sustainable and practical Suzukiꢀ
Miyaura (SM) crossꢀcouplings, by developing Feꢀppm Pd nanoꢀ
particles and a highly potent ligand.2f, 6 However, these two apꢀ
proaches are only applicable to SM, Sonogashira couplings, and
nitro reductions.7 Along the same lines, Colacot and coꢀworkers
have developed very potent phosphineꢀbased πꢀallylpalladium
complexes with versatile activity in crossꢀcoupling chemistry,8
although these complexes are highly active only under inert atꢀ
mosphere in organic solvents, mostly at elevated temperature.
Despite the high value of αꢀarylated/heteroarylated nitroalꢀ
kanes,9 among sp2ꢀsp3 crossꢀcoupling reactions catalytic but susꢀ
tainable arylations of nitroalkanes are yet underexplored;10 there
Figure 1. Advances facilitated by a sustainable micellar approach
is not a single report focusing on avoidance of organic solvents,
use of low palladium loading, inꢀflask recycling and reꢀuse of
catalyst and reaction medium, or reactions under ambient condiꢀ
tions. Typically, these couplings are achieved using up to 10
mol% palladium e.g., (Pd2dba3) in toxic organic solvents such as
1,4ꢀdioxane at elevated temperature under very dry conditions.
Accordingly, current methods are not sustainable (Figure 1).
for arylation of nitroalkanes.
had observed in our previous work.2g To solve this critical probꢀ
lem, we decided to develop an environmentally benign amꢀ
phiphile that, when dissolved in water, would form micelles with
slightly polar inner micellar cores in order to mimic DMF and
1,4ꢀdioxane, and thus could easily accommodate relatively polar
nitroalkanes, as polar as nitroethane. This technology also would
enable the chemistry to be conducted in water under ambient conꢀ
ditions without use of toxic organic solvent. The second important
consideration was choice of a catalyst demonstrating high comꢀ
patibility with micellar arrays as well as optimal stereoelectronic
properties and potency.6 A key determinant here is catalyst lipoꢀ
philicity. In essence, the longer the catalyst spends inside the miꢀ
To avoid the use of organic solvents and achieve catalysis with
low palladium loading, we suspected that micellar catalysis may
be the better approach.11 However, substrates with high to moderꢀ
ate polarity including nitroalkanes, potentially present a challenge,
particularly in accommodating these types of molecules in a miꢀ
cellar core—a requisite for the optimal catalytic activity that we
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celle, the more catalysis that takes place, so more lipophilic cataꢀ
lysts should enable lower catalyst loadings.
source. Compared to aryl bromides and chlorides, poor converꢀ
sions were observed with aryl iodides. Preꢀcomplexation of tꢀ
BuXphos with Pd(OAc)2 or Pd2dba3 did not show catalytic activiꢀ
ty comparable to corresponding πꢀallyl palladium complex 12,
suggesting that the allyl (η2 or η3) component is an active ligand
in the catalytic cycle. Other variables for optimal catalytic activity
were FIꢀ750ꢀM as surfactant, K3PO4 as base, 1–2.5 mol% of
catalyst 12, and 45 oC as reaction temperature (See SI). Low
catalyst loading and no use of glovebox at any stage are
noteworthy.
Here we disclose the results of this strategy: a general,
efficient,
mild,
and
sustainable
method
for
arylation/heteroarylation of nitroalkanes. Our study began with
design of FIꢀ750ꢀM, a prolineꢀbased environmently benign nonꢀ
ionic surfactant with a moderately polar inner core, that, when
mixed with nitroalakanes, exponentially increases the size of
micelles to accomodate reaction components for effective
catalysis. During initial catalyst screening for a model reaction
between 1 and 2 using K3PO4 as a base in a 3 wt% aqueous
solution of FIꢀ750ꢀM, various palladium catalysts and ligands that
are highly active in routine crossꢀcoupling reactions including
HandaPhos,6 biaryl phosphines,1,12 and Feꢀppm Pd nanoparticles2f
were unable to provide fruitful results. Only traces of desired
product were identified (for details, see Supporting Information).
Finally, to our delight, πꢀallyl palladium complexes8 recently
developed by the Colacot group, displayed better catalytic
acitivity (see SI and Table 1). Further investigation revealed the
high bench stability of catalysts from this series. While screening
the catalytic activity of such πꢀallyl palladium complexes over a
model reaction, catalysts 11 and 12 were found to demonstrate the
desired activity (Table 1). Only 74% conversion was detected
with 11 while full conversion was acheived with catalyst 12. This
remarkable difference in catalytic activity fits with expectations of
the optimal lipophilicity needed to accomodate a catalyst within
the micellar core.
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Table 2. Substrate scope for catalytic arylation of nitroalkanes
Table 1. Optimizations of micelleꢀenabled catalytic arylation
of nitroalkanes
entry
catalyst
base
% yield 3*
1
2
3
4
5
6
7
8
4
5
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
8
0
6
4
7
0
8
3
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10
11
19
74
9
12
Pd(OAc)2
12
K3PO4
K3PO4
iꢀPrNEt2
NEt3
100
0
10
11
12
13
68
60
81
Conditions: unless otherwise noted Ar—Br (0.5 mmol), nitroalkane (2.5
mmol), 12 (1–2.5 mol%), base (0.6 mmol, 1.2 equiv.), 1.0 mL 3 wt% FIꢀ
12
†
o
12
K2CO3
750ꢀM, 45 °C. Reaction temperature 60 C; *reaction scale 0.25 mmol.
All listed yields are isolated.
Conditions: 1 (0.25 mmol, 43 mg), 2 (2.5 mmol, 180 µL), 12 (5 mol%),
base (0.5 mmol, 2.0 equiv.), 0.5 mL 3 wt % FIꢀ750ꢀM, 45 °C, 24 h, argon
atmosphere. *Conversions based on GCMS.
After establishing very mild optimal reaction conditions, furꢀ
ther substrate scope was explored in order to reveal the generality
of the protocol. Special attention was paid to reproducibility,
functional group tolerance, and steric and electronic parameters.
Optimization studies revealed a dependence on several variaꢀ
bles, most notably the nature of the aryl halide and the palladium
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Notably, aryl chlorides displayed very sluggish reactivity. Reꢀ
further oxidation of nitro to ketones or incompatibility of any
reaction intermediate with oxygen.
markable generality was found with respect to the nature of aryl
bromides including excellent functional group tolerance. Electron
deficient (Table 2; 13–16, 22–24, 29, 32, 34–38) as well as elecꢀ
tronꢀrich (17, 18, 20, 25–28, 31, 33, 39) aryl residues were very
well tolerated with goodꢀtoꢀexcellent yields. Ester (13, 29, 37),
nitrile (14, 36), ketone (22, 24), chloro (16, 30), fluoro (15, 23, 27,
34, 37, 38), trifluoromethyl (35), and cyclic ether (27, 39) funcꢀ
tionalities all easily survived, and no detrimental effect on outꢀ
come of the catalytic process was observed. When a substrate
with an acetyl residue was subjected to these conditions, no side
product from an Aldolꢀtype reaction was observed (22, 24). Notaꢀ
bly, in an aqueous environment and under basic pH, no ester hyꢀ
drolysis was observed (13, 29, 37) and goodꢀtoꢀexcellent yields
were obtained. Both monoꢀ and diꢀesters were well tolerated (13,
29, 37). Heteroaromatics quinoline (18), pyridine (20), benzothioꢀ
phene (25, 33), and furan (26) displayed good to excellent reactivꢀ
ity without formation of any homocoupling side product. No polꢀ
ymerized side product was observed for the benzothiazole moiety.
Furthermore, a diarylated nitro product was not observed in any
example.
Scheme 1. Control experiments and catalytically active species
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Although micellar media played a crucial role in successful reꢀ
action completion (see SI), it was still questionable whether miꢀ
celles accommodated the moderately polar nitroalkanes or not.
Dynamic light scattering (DLS) experiments revealed the existꢀ
ence of nanomicelles composed of FIꢀ750ꢀM with an average
diameter of ca. 300 nm (Figure 2) which is quite large compared
to other nonꢀionic surfactants.13 Upon addition of ca. 2% of niꢀ
troethane to the surfactant solution, particle size exponentially
increased and a more diverse population of sizes was observed (Zꢀ
average 530 nm). The increase in micelle size along with reducꢀ
tion of peak area around 300 nm supports the formation of larger
particles by merging of smaller ones and nitroethane, which ocꢀ
cured without any visual turbidity in solution.13 Size, distribution,
and shape of nanomicelles composed of FIꢀ750ꢀM were also conꢀ
firmed by cryoꢀTEM imaging and the average size was in agreeꢀ
ment with that revealed by DLS.
Conditions: unless otherwise noted, Ar—Br (0.5 mmol), niꢀ
troethane/nitropropane (2.5 mmol) and catalyst as shown in scheme, base
(0.6 mmol, 1.2 equiv.), 1.0 mL 3 wt% FIꢀ750ꢀM, argon atmosphere, 45
°C. *air balloon instead argon atmosphere
.
Arguably, such significant differences in catalytic activity beꢀ
tween 12 and tꢀBuXPhos bound to different palladium sources
may be due to different induction periods for generation of the
active palladium(0) species needed for initiation of a catalytic
cycle. The induction period could be further lowered by using the
corresponding palladacycle. Therefore, by choosing coupling
partners 40 and nitropropane, activity of palladacycle 41 was
compared with 12. Compared to 84% isolated yield with standard
conditions, relatively poor conversion (43%) was observed for the
palladacycle and 50% unreacted 40 was recovered.
Figure 2. DLS data of FIꢀ750ꢀM in water revealing particle size
growth and accommodation of relatively polar reactant niꢀ
troethane (left); cryoꢀTEM of FIꢀ750ꢀM showing large micelles
(right).
Having identified the importance of a πꢀallyl component in the
catalyst, attention was drawn to the mechanistic significance of
this system. One suspicion was that the catalytic cycle could inꢀ
volve Pd(I) and Pd(III) intermediates when using πꢀallylꢀPd as in
12. However, neither Pd(I) nor Pd(III) were detected in EPR exꢀ
periments (see SI for details). Because AgOTf was used in the
synthesis of 12, the possibility for synergistic catalysis by residual
silver was investigated. Upon control reactions using traces or a
catalytic amount of AgOTf and different palladium sources with tꢀ
ButylXPhos, no synergistic effect was observed (Scheme 2). Fiꢀ
nally, it could be inferred that the allyl group is acting as a πꢀacid
ligand and is essential for high catalytic activity. In control experꢀ
iments using catalytic amounts of propylene or allyl bromide with
tꢀButylXPhos preꢀcomplexed with palladium acetate, efficient
catalysis was achieved, revealing the role of the allyl ligand. This
result suggests that, unlike in organic solvents, in micelar media tꢀ
In order to gain insight into the nature of the catalyst, control
experiments were conducted. These revealed that tꢀBuXPhosꢀ
bound palladium is not enough for the desired level of catalytic
activity (Scheme 1). Using different palladium sources with tꢀ
BuXPhos as ligand under optimized reaction conditions, less efꢀ
fective catalysis was achieved. Palladium sources Pd(OAc)2 and
Pd2dba3 produced only 45% and 31% yield of 3, respectively.
Again, only corresponding πꢀallyl palladium species 12 was cataꢀ
lytically efficient and highly active. However, use of 12 in the
presence of atmospheric oxygen significantly dropped its activity,
and only 40% desired product was obtained, which may be due to
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ButylXPhos may be acting merely as a monodentate ligand withꢀ
Figure 3. Plausible mechanism and reaction selectivity.
out any nonꢀclassical metalꢀarene ligation.14
Next, selectivity of this process was explored by choosing a
coupling partner 42 having an activated polyfluoroaryl residue
that could easily undergo SNAr reaction to form a dialkylated
product or polymerize (Scheme 3b). However, due to very mild
reaction conditions, no such side product was observed and 43
was obtained with 59% isolated yield. Desired reaction was
somewhat sluggish and remaining starting material was recovꢀ
ered.
Scheme 2. Effect of silver as a coꢀcatalyst/trace impurity and
πꢀacid ligand
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Finally, gramꢀscale reproducibility and sustainability of this
micelleꢀenabled transformation were assessed (Scheme 3). Using
1.25 mol% catalyst loading, 3 was obtained with 90% isolated
yield (Scheme 3a). Attempts at full recycling of the catalyst reꢀ
sulted in slow conversions. A recycling study with partial palladiꢀ
um and full reaction medium recycling resulted in a very low E
factor15 of 5.3 with recovery of solvent used in chromatography
and 18.4 without recovery in the last cycle, demonstrating the
greenness of this process (Scheme 3b).
Scheme 3. Gram scale reaction and recycle studies
Conditions: 1 (0.5 mmol, 85 mg), 2 (2.5 mmol, 180 µL), [Pd] (3 mol%)
K3PO4 (0.6 mmol, 1.2 equiv.), 1.0 mL 3 wt% FIꢀ750ꢀM, 45 oC, 24 h,
argon atmosphere. Propylene was used as a 0.1 M solution (0.2 mL, 4
mol%) in hexanes. *100 ppm AgOTf was used as a coꢀcatalyst. **Pd2dba3
loading was 1.5 mol%.
In light of these revelations, we propose a mechanism that inꢀ
volves in situ formation of an η2 allyl palladium(0) complex that
undergoes oxidative addition to form intermediate A (Figure 3a).
Under basic conditions, the bromide group is slowly replaced by
nucleophilic attack from the αꢀcarbon of the nitro coupling partner
to form intermediate B followed by reductive elimination to genꢀ
erate the product and active catalyst for the next cycle.
In summary, this work demonstrates the development of an enꢀ
vironmentally benign amphiphilic molecule that mimics polar
solvents such as DMF and 1,4ꢀdioxane along with a significant
advance in the area of palladium catalysis and crossꢀcoupling
chemistry, in particular for sp2ꢀsp3 couplings. Specifically, it ofꢀ
fers the synthetic community a palladium catalyzed arylation of
nitroalkanes that is noteworthy for: (1) low palladium loading; (2)
general applicability to a broad range of functionalities; (3) very
mild conditions; and (4) use of an aqueous reaction medium that
avoids organic solvents, requires very little water, and allows for
inꢀflask recycling of the surfactant, water, and catalyst.
ASSOCIATED CONTENT
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(3) (a) Beletskaya, I. P.; Cheprakov, A. V. Organometallics, 2012, 31,
Supporting Information
7753ꢀ7808. (b) Johansson Seechurn, C. C. C.; Li, H.; Colacot, T. J. in
New Trends in Cross-Coupling: Theory and Applications, The Royal
Society of Chemistry, London, 2015, pp. 91ꢀ138.
The Supporting Information is available free of charge on the
ACS Publications website at XXX.
Reaction optimization, details of cryoꢀTEM, DLS, controlꢀ
experiments, analytical data of compounds, and NMR data.
(4) (a)Torborg, C.; Beller, M. Adv. Synth. Catal. 2009, 351, 3027ꢀ
3043. (b) Biajoli, A. F. P.; Schwalm, C. S.; Limberger, J.; Claudino,
T. S.; Monteiro, A. L. J. Braz. Chem. Soc. 2014, 25, 2186ꢀ2214.
(5) (a) Davies, E.; Renner, R. Chem World, 2011, 1, 50ꢀ54. (b) Mike,
P. New Sci. 2011, 2,2799.
AUTHOR INFORMATION
Corresponding Author
9
(6) (a) Hamasaka, G.; Muto, T.; Andoh, Y.; Fujimoto, K.; Kato, K.;
Takata, M.; Okazaki, S.; Uozumi, Y. Chem. Eur. J., 2017, 23, 1291.
(b) Handa, S.; Andersson, M. P.; Gallou, F.; Reilly, J.; Lipshutz, B. H.
Angew. Chem., Int. Ed. 2016, 55, 4914ꢀ4918. (c) Yamada, Y. M. A.;
Sarkar, S. M.; Uozumi, Y. J. Am. Chem. Soc., 2012, 134, 3190ꢀ3198.
(d) Sarkar, S. M.; Uozumi, Y.; Yamada, Y. M. A. Angew. Chem., Int.
Ed. 2011, 50, 9437ꢀ9441. (e) Hamasaka, G.; Muto, T.; Uozumi, Y.
Angew. Chem., Int. Ed. 2011, 50, 4876ꢀ4878. (f) Soule, JꢀF.; Miyamuꢀ
ra, H.; Kobayashi, S. J. Am. Chem. Soc., 2011, 133, 18550ꢀ18553.
*Eꢀmail: sachin.handa@louisville.edu
Notes
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The authors declare competing financial interest for the surfactant
FIꢀ750ꢀM and their derivatives
.
ACKNOWLEDGMENT
This research work was supported in part by an award from Kenꢀ
tucky Science and Engineering Foundation as per grant agreement
#KSEFꢀ148ꢀ502ꢀ17ꢀ396 with the Kentcuky Science and Techꢀ
nolgy Corporation. We also acknowledge the University of Louꢀ
isville for partial support. We warmly thank JohnsonꢀMatthey 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 MATꢀ95XP mass
spectrometer purchased with NIH grant 1S10RR016657ꢀ01. We
thank Prof. Martin O’Toole and Dr. Rajat Chauhan for their help
in determining particle size of FIꢀ750ꢀM using DLS and Dr. Aiꢀ
dan Taylor from UCSB for obtaining cryoꢀTEM images.
(7) (a) Feng, J.; Handa, S.; Gallou, F.; Lipshutz, B. H. Angew. Chem.,
Int. Ed. 2016, 128, 9125ꢀ9128. (b) Gabriel, C. M.; Parmentier, M.;
Riegert, C.; Lanz, M.; Handa, S.; Lipshutz, B. H.; Gallou, F. Org.
Process Res. Dev. 2017, 21, 247ꢀ252.
(8) DeAngelis, A. J.; Gildner, P. G.; Chow, R.; Colacot, T. J. J. Org.
Chem. 2015, 80, 6794ꢀ6813.
(9) (a) Ono, N. The Nitro Group in Organic Synthesis. John Wiley &
Sons, Inc.: 2001, 392ꢀ415pp. (b) Ballini, R.; Palmieri, A.; Righi, P.
Tetrahedron 2007, 63, 12099ꢀ12121. (c) MarquesꢀLopez, E.; Merino,
P.; Tejero, T.; Herrera, R. P. Eur. J. Org. Chem. 2009, 15, 2401ꢀ2420.
(10) (a) Bellina, F.; Ross, R. Chem. Rev. 2010, 110, 1082ꢀ1146. (b)
Walvoord, R. R.; Kozlowski, M. C. J. Org. Chem., 2013, 78, 8859ꢀ
8864. (c) Yang, X.ꢀF.; Yu, W.ꢀH.; Ding, C.ꢀH.; Ding, Q.ꢀP.; Wan, S.ꢀ
L.; Hou, X.ꢀL.; Dai, L.ꢀX.; Wang, P.ꢀJ.; J. Org. Chem., 2013, 78,
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