Sonogashira couplings of aryl bromides: Room temperature, water only, no copper

Article abstract of DOI:10.1021/ol801471f

(Chemical Equation Presented) Cross-coupling reactions between lipophilic terminal alkynes and aryl bromides can be catalyzed by ligated Pd, in the absence of copper, In pure water at ambient temperatures. Small amounts of the nonionic amphiphile PTS assi

Full text of DOI:10.1021/ol801471f

ORGANIC
LETTERS
2008
Vol. 10, No. 17
3793-3796
Sonogashira Couplings of Aryl
Bromides: Room Temperature, Water
Only, No Copper
Bruce H. Lipshutz,* David W. Chung, and Brian Rich
Department of Chemistry and Biochemistry UniVersity of California,
Santa Barbara, California 93106
lipshutz@chem.ucsb.edu
Received June 29, 2008
ABSTRACT
Cross-coupling reactions between lipophilic terminal alkynes and aryl bromides can be catalyzed by ligated Pd, in the absence of copper, in
pure water at ambient temperatures. Small amounts of the nonionic amphiphile PTS assist by virtue of nanometer micelles formed spontaneously
in an aqueous medium.
Among the leading “name” reactions in organic synthesis,1
Sonogashira couplings2 rank especially high given the
intrinsic value and flexibility of a newly introduced acetylenic
moiety.3 Traditionally, these cross-couplings rely on the
presence of both palladium and copper to contribute to
catalysis,4 although much effort of late has gone into
effecting such C-C bond constructions in the absence of
one5 or the other metal6 or by virtue of alternative method-
ologies that accomplish the same net aryl-alkyne bond.7
Aryl iodides are frequently used in organic media, usually
at elevated temperatures.8 The corresponding bromides and
especially chlorides are less prone to participate, requiring
more forcing conditions,9 the extent to which depends upon
levels of halide activation and specifics of ligand choice.10
While Sonogashira couplings under mixed organic/aqueous
conditions are common, reactions in water alone place
significant demands on substrates and catalyst solubilities
(5) Absence of Cu: (a) Nguefack, J.-F.; Bolitt, V.; Sinou, D. Tetrahedron
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4850. (c) Liu, F.; Ma, D. Chem. Commun. 2004, 1934–1935. (d) Colacino,
E.; Da¨ıch, L.; Martinez, J.; Lamaty, F. Synlett 2007, 1279–1283. (e) Biffis,
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10.1021/ol801471f CCC: $40.75
Published on Web 08/07/2008
2008 American Chemical Society

and, hence, are rare.11 Indeed, an aryl bromide-terminal
acetylene cross-coupling in water at ambient temperatures
is unprecedented to our knowledge. In this paper, we describe
a new method that, for the first time, allows Sonogashira
couplings to occur in the absence of both copper and organic
solvents and at room temperature using commercially avail-
able reagents.
The key to success was anticipated to derive from micellar
catalysis12 using the lipophilic vitamin E core (in red) of
the nanomicelle-forming amphiphile PTS (1; Scheme 1),13
in effect, as solvent. As recently shown in related Pd-
catalyzed Heck14 and Suzuki15 couplings, otherwise water-
insoluble substrates and catalysts out of the bottle react in
commercially available PTS/H2O16 to afford the desired
products in high isolated yields. Variables such as the ligand
on palladium and the choice/amount of base play crucial
roles, requiring that conditions be “matched” not only to the
educts but to the micellar environment.
Figure 1. Ligand/catalysts examined in this study.
prior to mixing with PTS to prevent ligand oxidation.
Reactions, therefore, are best run under inert atmosphere. A
model system composed of bromobenzene and phenylacety-
lene led to the desired product diarylacetylene in good
isolated yield (100% conversion; 83% isolated yield; Scheme
2), while the corresponding reaction “on water”18 (i.e.,
Scheme 1. Overall Conversion in Water Using PTS
Scheme 2
.
Impact of Amphiphile PTS on a Model
Cross-Coupling
without PTS) gave noticeably inferior results (34% conver-
sion) within the same time frame (5 h). Inclusion of copper
salts proved to be unnecessary. Other catalysts were screened
early in this study [including dppf analogue 3,19 Umicore’s
CX-31 (4),20 and PdCl2(Ph3P2)] with the Pd(II)/X-Phos
complex found to be the most effective.
Aromatic acetylenes could be constructed from aryl
bromides and 1-alkynes at room temperature using a 3% (by
weight) PTS/H2O solution, excess Cs2CO3 as base, and
X-Phos17 (2; Figure 1) as ligand in the presence of catalytic
PdCl2(CH3CN)2. The H2O used as solvent is briefly degassed
Significant sensitivity to base was also noted. Among
heterogeneous bases, Cs2CO3 gave excellent results (Table
1). Several soluble amine bases under otherwise identical
conditions led to considerable variation in levels of conver-
sion and isolated yields. Ultimately, Et3N emerged as the
base of choice (e.g., see entries 1b, 2b, 3, and 4) relative to
pyrrolidine, i-Pr2NEt, and DBU. Cross-coupling of hindered
bromides such as educt 5 with enyne 6 was also achieved
using Et3N as base, although in this case pyrrolidine worked
equally well. Deactivated substrate 7 reacted readily with
phenylacetylene (entry 2a) but was slow to couple with an
alkyl-substituted acetylene 8 (entry 2b). Activated bromides
(entries 4 and 5) coupled smoothly in high yields. Both
2-bromonaphthalene (entry 6) and 9-bromophenanthrene
(entry 7) gave the corresponding unsymmetrical internal
alkynes. Unexpectedly, neither n-Bu3N nor (n-octyl)3N led
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3794
Org. Lett., Vol. 10, No. 17, 2008

Table 1. Sonogashira Couplings of Aryl Bromides Using PdCl2(CH3CN)2 + Ligand 2 in 3% PTS/H2O at rt
a Isolated; fully characterized. b Isolated, chromatographically purified material. c Used as received from vendor.
to any product 9 (entry 2b), although the acetylenic partner
8 was consumed by formation of polymeric materials, as
seen previously by others in related reactions in the presence
of copper.17 Thus, increased hydrophobicity of the base (and
hence, assumed greater solubility within the micelle) is not
commensurate in this case with an increase in the desired
reaction pathway.
Three additional monophosphine ligands, 12-14, were
studied (Table 2) in an effort to find conditions that lead to
more rapid conversions, especially involving electron-rich
aryl bromides (e.g., 7; Table 1, entry 2). Coupling p-
bromoanisole (7) with alkyne 10 in the presence of catalytic
Pd (1%), X-Phos (2; 2.5%), and base (Et3N; 3 equiv) did
progress essentially to completion over the course of 3 days.
Org. Lett., Vol. 10, No. 17, 2008
3795

Table 2. Additional Ligand Study in Sonogashira Couplings
Scheme 3. Additional Couplings Using Ligand 14 in PTS/H2O
Scheme 4. Cross-Coupling Using Ligand 14 at rt in Water
The combination of Pd(OAc)2 with the recently introduced
monodentate cyclopropylphosphine 14 from Takasago,21 on
the other hand, led to >99% conversion in e10 h and,
ultimately, 96% isolated yield of product 11. Identical results
were obtained using either degassed, or nondegassed, PTS/
H2O. Related ligands 12 and 13 were also quite effective,
although coupling in the presence of 14 was cleaner. Several
additional examples using ligand 14, as illustrated in Scheme
3, document the remarkable effectiveness and generality of
this catalyst/amphiphile combination.
One further application of ligand 14 to a more highly
functionalized aryl bromide (15) was investigated (Scheme
4). Coupling of 15 with undecynol in PTS/H2O at rt led to
alkyne 16 in good isolated yield.
In summary, new technology based on micellar catalysis
using the “designer surfactant” PTS has been developed.
Sonogashira couplings can now be run with lipophilic
partners and commercial catalysts in water at ambient
temperature. Minimizing reliance on organic solvents as
reaction media in metal-based catalysis is a worthy goal in
green chemistry; PTS may help along the way.22
Acknowledgment. We warmly thank Zymes, LLC for
continued support of our programs in green chemistry. We
are indebted to Johnson Matthey for supplying ligand 3,
Umicore for their gift of ligand 4, and Takasago for a
generous supply of their newly disclosed vinyl- and cyclo-
propylmonophosphines 12-14.
Supporting Information Available: Detailed experimen-
tal procedures and spectral data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(21) (a) Suzuki, K.; Fontaine, A.; Hori, Y.; Kobayashi, T. Synlett 2007,
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Synth. Catal. 2007, 349, 2089–2091. (c) Suzuki, K.; Hori, Y.; Kobayashi,
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OL801471F
(22) Lipshutz, B. H.; Ghorai, S. Aldrichim. Acta, in press.
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