Heck couplings at room temperature in nanometer aqueous micelles

Article abstract of DOI:10.1021/ol702755g

(Chemical Equation Presented) A nonionic amphiphile such as Triton X-100 or the vitamin E-based PTS, both of which form nanomicelles in water, promotes Heck crosscouplings of non-water-soluble partners at ambient temperatures. These are the first examples of Heck reactions conducted in water (as the only solvent) at room temperature.

Full text of DOI:10.1021/ol702755g

ORGANIC
LETTERS
2008
Vol. 10, No. 7
1329-1332
Heck Couplings at Room Temperature
in Nanometer Aqueous Micelles†
Bruce H. Lipshutz* and Benjamin R. Taft
Department of Chemistry & Biochemistry, UniVersity of California,
Santa Barbara, California 93106
lipshutz@chem.ucsb.edu
Received November 14, 2007
ABSTRACT
A nonionic amphiphile such as Triton X-100 or the vitamin E-based PTS, both of which form nanomicelles in water, promotes Heck cross-
couplings of non-water-soluble partners at ambient temperatures. These are the first examples of Heck reactions conducted in water (as the
only solvent) at room temperature.
Ideally, organic synthesis would be performed at ambient
temperature in water as the only solvent. Catalyzed reactions
would allow facile product isolation using recoverable
organic solvents, while the aqueous phase containing the
active catalyst would be recyclable. Such concepts broadly
applied to organometallic chemistry, in general, may be far
from reality, although considerable efforts to identify such
processes on a reaction-by-reaction basis are ongoing, and
a great deal of progress has been made.1 One approach is to
consider inexpensive amphiphiles as potential additives that,
upon self-assembly into micelles, accommodate otherwise
insoluble organic substrates and catalysts within the lipophilic
cores.2 Although ostensibly a dilute solution in water, the
effective concentration within the micelle could be quite high,
and hence, reaction rates might be increased relative to those
normally observed in organic media. While these con-
cepts are well-grounded in micellar catalysis,2 there are
many parameters that must be “matched” to the reaction
under study. With respect to Heck couplings in particular,3
factors such as (1) the nature of the surfactant (cationic,
anionic, or nonionic), (2) palladium catalyst, and (3) base
must be controlled in the search for an effective aqueous
milieu. Existing methods in water require considerable
heating in the absence of cosolvents.4 Herein we describe
the use of selected nonionic micelle-forming carriers that
allow, for the first time, Heck cross-couplings to be run at
room temperature, in water as the only solvent.
A survey was conducted of several commercially available
nonionic amphiphiles, including Triton X-1005a (1), Brij-
305b (2), and TPGS6 (3, m ≈ 21). Also included were known
species PTS7 (4, m ≈ 13) and PSS7 (5), as well as the
common salt SDS5c (6) (Figure 1). Heck couplings between
lipophilic aryl iodides and acrylates, using Et3N as base,
(3) (a) Whiting, A.; Knowles, J. P. Org. Biomol. Chem. 2007, 5, 31. (b)
Jones, W. C.; Sluys, M.; Phan, N. AdV. Synth. Catal. 2006, 348, 609. (c)
Yus, M.; Beletskaya, I. P.; Alonso, F. Tetrahedron 2005, 61, 11771. (d)
Beletskaya, I. P.; Cheprakov, A. V. In Handbook of Organopalladium
Chemistry for Organic Synthesis; Negishi, E., Ed.; Wiley: New York, NY,
2002; Vol. 2, pp. 2957-3006. (e) Beletskaya, I. P.; Cheprakov, A. V. Chem.
ReV. 2000, 100, 3009.
(4) (a) Alacid, E.; Najera, C. Synlett 2006, 2959. (b) Schonfelder, D.;
Nuyken, O.; Weberskirch, R. J. Organomet. Chem. 2005, 690, 4648. (c)
Schonfelder, D.; Fischer, K.; Schmidt, M.; Nuyken, O.; Weberskirch, R.
Macromolecules 2005, 38, 254.
† Dedicated with greatest respect and admiration to Professor E. J. Corey,
Nobel Laureate, on the occasion of his 80th birthday.
(1) (a) Li, C.-J.; Chen, L. Chem. Soc. ReV. 2006, 35, 68. (b) Shaughnessy,
K. H. Eur. J. Org. Chem. 2006, 1827. (c) Li, C.-J. Chem. ReV. 2005, 105,
3095. (d) Shaughnessy, K. H.; DeVasher, R. B. Curr. Org. Chem. 2005, 9,
585. (e) Aqueous-Phase Organometallic Catalysis, 2nd ed.; Cornils, B.,
Herrmann, W. A., Eds.; Wiley-VCH: Weinheim, Germany, 2004.
(2) Oehme, G.; Paetzold, E.; Dwars, T. Angew. Chem., Int. Ed. 2005,
44, 7174.
(5) Sigma-Aldrich catalog #’s (a) 234729, (b) P4391, (c) L3771.
(6) PCI-102B Eastman Vitamin E TPGS NF - Applications and Proper-
ties. http://www.eastman.com/NR/rdonlyres/A2FE037B-0778-4A90-A0FC-
5D07BE51064A/0/PCI102.pdf (accessed August 2007).
10.1021/ol702755g CCC: $40.75
© 2008 American Chemical Society
Published on Web 03/12/2008

level of conversion was observed.9 PEG-400 in water (entry
3) was less effective. Several other control reactions served
to highlight the crucial role of the surfactant. Thus, reactions
run in neat Et3N (entry 8) or in DMF with Et3N (entry 9),
indicated that the added base is not functioning as solvent
and that the corresponding reaction in a purely organic
medium does not occur at room temperature, as expected.10d
Results using pH 10 buffer alone (entry 10), or PTS/H2O +
pH 10 buffer (entry 11), suggest that an aqueous basic
medium is problematic. When using 15 wt % of PTS
solutions, strong, vigorous stirring is required to en-
sure adequate mixing. Reactions conducted in 2 wt % of
PTS led to better mixing but marginal product formation (en-
try 12). The decrease in conversion was attributed to a lack
of catalyst stability, as black and purple solids precipitated
from the reaction mixture. In an attempt to increase catalyst
lifetime, various additives were used (entries 13-15), but
ultimately, the level of conversion was unsatisfactory.
Interestingly, when a more sterically hindered aryl iodide
was employed under similar conditions, several differences
were noted. In this case, Triton X-100 out-performed all other
amphiphiles (entry 17), while PTS led to a somewhat slower
but still effective coupling (entry 16). Most notably, the
reaction conducted “on water”9 produced only a limited
amount of the desired stilbene (entry 21). This data suggests
that such reactions run in the absence of surfactant can be
substrate-dependent.11
Figure 1. Various amphiphiles studied and catalyst used.
could most successfully be carried out using either Triton
X-100 or more generally, PTS.
As indicated in Table 1, PTS (entry 1) was somewhat more
effective than Triton X-100 (entry 2). When run “on water”8
(entry 7), a surprising (albeit substrate-dependent; vide infra)
Use of commercially available Johnson-Matthey catalyst
(dtbpf)PdCl212 (7; Figure 1) proved to be the most effective
of those screened to date (Pd(OAc)2, PdCl2, or Pd(dba)2 with
bisphosphine). By simply taking a preformed solution of PTS
in water (15 wt %; “stored on the benchtop”) and adding 2
mol % of (dtbpf)PdCl2 (7), Et3N (3 equiv), aryl iodide (1
equiv), and acrylate (2 equiv), Heck couplings take place,
in general, at room temperature with reaction times ranging
from 1 to 24 h. A typical reaction mixture appears hetero-
geneous during the first 20-30 min but becomes pseudo-
homogeneous thereafter (Figure 2). Product isolation is
straightforward following a standard extractive workup or
filtration through a pad of silica gel (see the Supporting
Information).
Table 1. Survey of Reaction Conditions
Figure 2. Appearance of a Heck coupling (Table 1, entry 1): (A)
t ) 0, note heterogeneous appearance; (B) t ) 1 min; (C) t ) 30
min, note pseudo-homogeneous appearance; (D) t ) 3 h.
1330
Org. Lett., Vol. 10, No. 7, 2008

Scheme 1. Heck Coupling of an Aryl Bromide15
Table 2. Heck Couplings of Aryl Iodides with Acrylatesa
expected, the reactions are more sluggish, likely due to the
nature of substitution on the aromatic ring. Efforts to increase
rates using various additives (e.g., NaCl, LiCl, NaBr,
NH4BF4, B(OH)3, Zn0, LiI, NaI, and TBAI) met with limited
success. By simply warming to 50 °C, however, reactions
take place. To highlight the potential for mild, aqueous Heck
couplings with aryl bromides, 4-chloro-2-nitrobromobenzene
was coupled to ethyl acrylate yielding cinnamate15 9, a
known intermediate en route to Pfizer’s COX-2 inhibitor16
10 (Scheme 1).
Table 3. Heck Couplings of Aryl Iodides with Styrenesa
a Reactions carried out at rt for 3-8 h using aryl iodide (1 equiv), acrylate
(2 equiv), triethylamine (3 equiv), (7) (2 mol %), and 15 wt % of PTS/H2O
(∼0.5 M). b Product was inseparable from excess acrylate. c Aryl iodide (2
equiv) and acrylate (1 equiv). d Run at 50 °C.
A more extensive survey of Heck couplings in 15 wt %
of PTS/water13 is presented in Table 2, featuring isolated
yields for (E)-cinnamates using acrylates as cross-coupling
partners. Commercially available tert-butyl and 2-ethylhexyl
acrylate appear to be more effective than less lipophilic
methyl and benzyl ester analogues. “Greasy” aryl iodides
and acrylates were chosen as substrates to emphasize the
solubilizing power of PTS in water. Notably, highly lipophilic
cholesteryl acrylate is compatible with these aqueous condi-
tions, leading to highly functionalized indole derivative 8.
To expand the scope of this method, intial attempts were
made to couple aryl bromides10 at room temperature.14 As
(7) (a) Borowy-Borowski, H.; Sikorska-Walker, M.; Walker, P. R. Water-
Soluble Compositions of Bioactive Lipophilic Compounds. U.S. Patent 6,-
045,826, Apr 4, 2000. (b) Borowy-Borowski, H.; Sikorska-Walker, M.;
Walker, P. R. Water-Soluble Compositions of Bioactive Lipophilic Com-
pounds. U.S. Patent 6,191,172, Feb 20, 2001. (c) Borowy-Borowski, H.;
Sikorska-Walker, M.; Walker, P. R. Water-Soluble Compositions of
Bioactive Lipophilic Compounds. U.S. Patent 6,632,443, Oct 14, 2003.
(8) (a) Blackmond, D. G.; Armstrong, A.; Coombe, V.; Wells, A. Angew.
Chem., Int. Ed. 2007, 46, 3798.
(9) Narayan, S.; Muldoon, J.; Finn, M. G.; Fokin, V. V.; Kolib, H. C.;
Sharpless, K. B. Angew. Chem., Int. Ed. 2005, 44, 3275.
(10) (a) Li, J.-H.; Hu, X.-C.; Liang, Y.; Xie, Y.-X. Tetrahedron 2006,
62, 31. (b) Najera, C.; Botella, L. J. Org. Chem. 2005, 70, 4360. (c)
Shaughnessy, K. H.; Moore, L. R.; DeVasher, R. B. J. Org. Chem. 2004,
69, 7919. (d) Hartwig, J. F.; Shaughnessy, K. H.; Stauffer, S. R.; Stambuli,
J. P. J. Am. Chem. Soc. 2001, 123, 2677.
(11) (a) Organic Reactions in Water; Lindstrom, U. M., Ed.; Blackwell
Publishing Ltd.: Oxford, UK, 2007. (b) Klijn, J. E.; Engberts, J. B. Nature
2005, 435, 746.
(12) (dtbpf)PdCl2 (CAS no. 95408-45-0) was generously supplied by Dr.
Thomas J. Colacot (E-mail: colactj@jmusa.com, Johnson-Matthey).
(13) The critical micelle concentration for PTS in water has been
determined to be 0.281 mg/g at room temperature.
a Reactions carried out at rt for 1-24 h using aryl iodide (1 equiv), styrene
(2 equiv), triethylamine (3 equiv), catalyst 7 (2 mol %), and 15 wt % of
PTS/H2O (∼0.5 M). b Isolated yield of E/Z mixture, ratio by GC. c Run at
50 °C. d 9:1 inseparable mixture of E/Z isomers.
(14) A more detailed study will be reported shortly.
Org. Lett., Vol. 10, No. 7, 2008
1331

Styrenes are more reactive coupling partners relative to
acrylates;10d both electron-rich (Table 3, entries 1, 2, 4, 5,
and 7) and electron-poor (Table 3, entry 3) aryl iodides
smoothly afforded unsymmetrical (E)-stilbenes. Styrene-like
substrates, such as water-insoluble vinyltriazole17 12, readily
coupled with highly functionalized tetrahydroisoquinoline18
11, although this combination involving a relatively electron-
poor precursor (12) required gentle heating to 50 °C (Table
3, entry 6). By contrast, related iodide 13 reacted at 25 °C
with 4-methoxystyrene (Table 3, entry 7). Workup in some
cases involved partitioning between 2:1 brine/H2O and 3:1
hexanes/EtOAc, followed by extraction with 3:1 hexanes/
EtOAc. This protocol leaves PTS in the aqueous phase, along
with a substantial amount of the palladium catalyst. Efforts
to recycle the catalyst containing aqueous phase are ongoing.
studies on surfactant structure/functionality relationships are
clearly needed.
In summary, an operationally simple process has been
developed for carrying out traditional Heck couplings at
ambient temperatures in neutral water, without resorting to
cosolvents,21a ionic liquids,21b sonication,21c electrochemisty,21d
or water-soluble phosphines.21e Use of inexpensive PTS,22
a
nonionic amphiphile, allows cross-couplings to take place
under especially mild and environmentally attractive condi-
tions.23 Related Pd-catalyzed Suzuki-Miyaura cross-cou-
plings are discussed in the following paper in this issue, and
others (e.g., Sonogashira couplings in PTS/water) will be
reported in due course.
Acknowledgment. We are most grateful to Zymes, LLC
for financial support, as well as for providing PTS and PSS.
We also thank Dr. Thomas J. Colacot (Johnson-Matthey)
for supplying the palladium catalyst used in this study (CAS
no. 95408-45-0), Dr. Jingshan Dong (University of Min-
nesota) and Prof. Craig Hawker (UCSB) for help with the
cryo-TEM experiments, and Eastman for generously sup-
plying TPGS.
The nature of the micelles formed upon dissolution of PTS
(4) in water was investigated using both dynamic light
scattering (DLS)19 and low-temperature transmission electron
microscopy (cryo-TEM).20 Particle size was determined by
DLS to be distributed from ca. 10-50 nm, with an average
of 22 nm. Cryo-TEM data revealed a mixture of smaller
spherical micelles, together with larger wormlike structures
(Figure 3). Interestingly, Triton X-100 (1) and TPGS (3) in
Supporting Information Available: Experimental pro-
cedures, characterization data, and copies of 1H and 13C NMR
spectra for new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
OL702755G
(15) Palladacycle [{(o-tol)3P}Pd(OAc)]2 (CAS no. 172418-32-5) was
used instead of 7, improving selectivity (GC yield 89 vs 71%).
(16) Vazquez, E.; Caron, S.; Stevens, R.; Nakao, K.; Koike, H.;
Yoshinori, M. J. Org. Chem. 2003, 68, 4104.
(17) 1-Octyl-4-vinyl-1,2,3-triazole (12) was prepared via copper(I)-
catalyzed “click” cycloaddition of octyl-azide with but-3-ynyl methane-
sulfonate followed by sodium iodide promoted elimination.
(18) Lipshutz, B. H.; Petersen, T. B. Unpublished work.
(19) Borkovec, M. Measuring particle size by light scattering. Handbook
of Applied Surface and Colloid Chemistry; John Wiley & Sons Ltd.:
Chichester, UK, 2002; pp 357-370.
(20) Kaler, E. W.; Gonzalez, Y. Curr. Opin. Colloid Interface Sci. 2005,
10, 256.
(21) (a) Cai, C.; Jiang, J.-Z. J. Colloid Interface Sci. 2006, 299, 938. (b)
Zhou, M.-M.; Wang, Z.; Zhou, Y.; Pan, C.; Gan, C.; Zha, Z.; Zhang, Z. J.
Org. Chem. 2006, 71, 4339. (c) Moeller, K. D.; Tian, J. Org. Lett. 2005, 7,
5381. (d) Handy, S. T.; Okello, M. Tetrahedron Lett. 2003, 44, 8395. (e)
Genet, J.-P.; Savignac, M.; Michelet, V.; Genin, E.; Amengual, R. AdV.
Synth. Catal. 2002, 344, 393.
Figure 3. Cryo-TEM image of aqueous PTS (4).
(22) Available from Sigma-Aldrich in May, 2008, as an aqueous solution
(catalog #698717).
(23) (a) Representative Procedure: (E)-tert-Butyl 3-(4-methoxyphe-
nyl)acrylate. Catalyst 7 [(dtbpf)PdCl2, 13.0 mg, 0.02 mmol) and 4-io-
doanisole (234 mg, 1.0 mmol) were added under argon to a 5.0 mL
microwave vial equipped with a large stir bar and Teflon lined septum.
PTS solution (2.0 mL, 15 wt%), triethylamine (416 µL, 3.0 mmol), and
t-butyl acrylate (290 µL, 2.0 mmol) were added by syringe. The hetero-
geneous mixture was stirred vigorously at rt, becoming pseudo-homo-
geneous after 20-40 min. Reaction progress was monitored by TLC (1:
10, EtOAc/hexanes). Upon consumption of aryl iodide (∼5 h), the dark
brown mixture was diluted with EtOAc (2.0 mL) and filtered through a
pad of silica gel using EtOAc (15 mL) as eluent. The volatiles were removed
on a rotary evaporator and the crude product was purified by silica gel
chromatography (1:10, EtOAc/hexanes) to yield 215 mg (92%) of a light
tan solid. Spectral data matched that reported in the literature. (b) Tang,
Y.; Yu, Y.; Xia, W.; Song, Y. Huang, Z. J. Org. Chem. 2002, 67, 3096-
3103.
water gave DLS data indicative of a far narrower range of
smaller particles (5-6 nm). Since TPGS is structurally
related to PTS, with variations only in its diacid linker length
(4 vs 10 carbons) and PEG (1000 vs 600), the dramatic
decrease in micellar size suggests extensive coiling in water,
which may account for its lack of generality in Heck
couplings. On the other hand, Triton X-100 also forms 5-6
nm micelles in water and yet can be competitive with PTS
as a surfactant. Thus, micelle diameter is apparently not the
sole factor affecting catalysis under these conditions. Further
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Org. Lett., Vol. 10, No. 7, 2008