Palladium-catalyzed Sonogashira coupling of aryl mesylates and tosylates

Article abstract of DOI:10.1002/chem.201001269

Up to speed: The first general and mild protocol for the Sonogashira coupling of aryl mesylates is presented (see scheme). The coupling intermediate also provides facile access to 2-substituted isoquinolines.

Full text of DOI:10.1002/chem.201001269

DOI: 10.1002/chem.201001269
Palladium-Catalyzed Sonogashira Coupling of Aryl Mesylates and ACTHUNRGTNETNUG osylates
Pui Ying Choy, Wing Kin Chow, Chau Ming So, Chak Po Lau, and Fuk Yee Kwong*[a]
Dedicated to Professor Albert S. C. Chan on his occasion of 60th birthday
Aryl alkynes are important synthetic precursors and subu-
nits for a range of pharmaceutically attractive and valued
materials science organic compounds.[1] One of the most
straightforward and versatile protocols for the construction
system. Thus, the use of Csp2-tosylates as coupling partners
À
in Csp2 Csp bond-forming reaction has seldom been reported.
Only vinyl tosylates were successful in this transformation.[8]
Recently, the Sonogashira coupling of strongly activated and
electron-deficient para- and meta-substituted aryl tosylates
was disclosed using the Pd/X-Phos (X-Phos=2-dicyclohexyl-
phosphino-2’,4’,6’-triisopropylbiphenyl) complex in propioni-
trile at reflux.[9] These pioneering examples required the
slow addition of diluted alkyne substrates for 8 h over the
course of reaction. Moreover, it was found that a high purity
of the aryl tosylates was a prerequisite for these successful
couplings. To the best of our knowledge, an operationally
simple and general procedures for Sonogashira coupling of
nonactivated aryl and heteraryl tosylates remains sporadical-
ly reported to date. A European patent described the appli-
À
of Csp2 Csp bond is the palladium-catalyzed cross-coupling of
aryl halides/sulfonates and terminal alkynes, namely, Sono-
gashira coupling.[2] This methodology features a modular ap-
proach to assemble an array of diversified compounds from
commonly available electrophilic and nucleophilic part-
ners.[3]
A number of palladium catalyst systems have been devel-
oped for facilitating the Sonogashira coupling to proceed
even without CuI cocatalyst and at room temperature,[4,5] as
well as showing the applicability of aryl chloride sub-
strates.[6] Although the alkyne coupling of aryl halides has
been extensively established, the popularity of aryl triflates
has been limited. These constraints are possibly due to the
high cost of the triflating agent (e.g., Tf2O),[7] and the low
hydrolytic stability of aryl triflates under basic coupling re-
action conditions. In fact, it is worth developing methods for
phenolic compound derivatives to be used as electrophiles.
Since they usually offer different or unique substituted
groups in the aromatic ring, in which the corresponding aryl
halides are not commonly available, or require additional
synthetic steps to manipulate the pattern of complementary
substitution. Thus, the exploration of less expensive, yet
more stable, aryl arenesulfonates in Sonogashira coupling is
highly favorable. Nevertheless, the higher stability of aryl
arenesulfonate (e.g., aryl tosylate) makes this less reactive
when used for oxidative addition under palladium catalytic
cation of a PdACHTNUGTRENUNG(TFA)2/Josiphos-type (Josiphos=1-[2-(dicyclo-
hexylphosphino)ferrocenyl]ethyldiphenylphosphine) ligand
system for this reaction.[10] Herein, we report a general and
À
efficient catalyst system for aryl tosylates in Csp2 Csp cou-
plings. In particular, we also uncover the first examples of
more difficult, but more atom-economical aryl mesylate cou-
plings with alkynes.
We embarked on developing a general protocol for Sono-
gashira coupling of aryl tosylates by using an unactivated 4-
tert-butylphenyl tosylate and 1-heptyne as the model sub-
strates (Table 1). Alcoholic solvents such as tBuOH were
our preference instead of nitrile solvents. Commonly well-
recognized and commercially available phosphine ligands,[11]
such as DitBuPF, cataCXium A, cataCXium PCy, and X-
Phos, were initially screened to test the feasibility of the aryl
tosylate–alkyne coupling (Table 1, entries 1–4). Moderate
substrate conversions and fair product yields were afforded
by using biaryl-type monodentate phosphines as the sup-
porting ligands (Table 1, entries 3 and 4). A combination of
[a] P. Y. Choy, W. K. Chow, C. M. So, Prof. Dr. C. P. Lau,
Prof. Dr. F. Y. Kwong
State Key Laboratory of Chiroscience and
Department of Applied Biology and Chemical Technology
The Hong Kong Polytechnic University, Hung Hom
Kowloon, Hong Kong (Hong Kong)
Fax : (+852)2364-9932
E-mail: bcfyk@inet.polyu.edu.hk
PdACTHNUTRGNEUNG
(OAc)2 with CM-phos[12] was found to be the best catalyst
system for this tosylate coupling (Table 1, entry 5). A survey
of often used inorganic bases revealed that K3PO4 and
K3PO4·H2O were equally efficient (Table 1, entries 5–8). The
best Pd/CM-phos ratio was found to be 1:3 (Table 1, en-
tries 5, 10, and 11).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201001269.
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Chem. Eur. J. 2010, 16, 9982 – 9985

COMMUNICATION
Table 1. Initial screenings of Pd-catalyzed Sonogashira couplings of aryl
tosylates.[a]
Table 2. Palladium-catalyzed Sonogashira coupling of aryl and heteroaryl
tosylates.[a]
Entry
Ligand[b]
Base
Yield[c] [%]
1
2
3
4
5
6
7
8
ditBuPF
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4·H2O
Cs2CO3
K2CO3
K3PO4
K3PO4
K3PO4
K3PO4
4
0
30
39
90
89
59
trace
32
93
cataCXium A
cataCXium PCy
X-Phos
CM-phos
CM-phos
CM-phos
CM-phos
CM-phos
CM-phos
CM-phos
CM-phos
9[d]
10[e]
11[f]
12[g]
62
59
[a] Reaction conditions: ArOTs (0.5 mmol), alkyne (1.0 mmol), Pd-
ACHTUNGTRENNUNG(OAc)2 (2.0 mol%), (Pd/ligand=1:4), base (1.5 mmol), and tBuOH
(2.0 mL) under N2 at 1108C for 24 h (reaction time was not optimized).
[b] cataCXium A=di(1-adamantyl)-n-butylphosphine, cataCXium PCy=
2-(dicyclohexylphosphino)-1-phenyl-1H-pyrrole, CM-phos=N-methyl-2-
(2’-dicyclohexylphosphinophenyl)indole. [c] GC yields were reported.
[d] 0.5 mol% of PdACHTUNGTRENNUNG(OAc)2 was used. [e] A ratio of Pd/CM-phos=1:3 was
used. [f] A ratio of Pd/CM-phos=1:2 was used. [g] 0.6 mmol of the corre-
sponding alkyne was used.
Having the optimized reaction conditions in hand, we ex-
amined a variety of aryl tosylate coupling partners with 1-
heptyne (Table 2). Common functional groups such as me-
thoxy, cyano, keto, ester, and aldehyde were compatible
under the stated reaction conditions. Heterocyclic benzo-
thiazolyl and quinolinyl tosylates furnished the correspond-
ing coupling products smoothly. Alkenyl tosylate coupled
with phenylacetylene to afford the product in good yield. 1-
Ethynylcyclohex-1-ene could serve as an effective nucleo-
phile for tosylate coupling (Table 2).
[a] Reaction conditions: ArOTs (1.0 mmol), alkyne (2.0 mmol), Pd-
AHCTUNGTREN(GUNN OAc)2 (2.0 mol%), (Pd/CM-phos=1:3), K3PO4 (3.0 mmol), and tBuOH
(2.0 mL) under N2 at 1008C for 18 h (reaction time for each substrate
was not optimized). Isolated yields were reported.
In view of commonly used sulfonate leaving groups, the
mesylate can be regarded as the most inert group, since the
pKa of the corresponding conjugate acid is the highest
among the others (Scheme 1). Nevertheless, mesylate pro-
vides the best atom efficiency when compared with tosylate
and triflate. Inspired by its intrinsic attractiveness, we turned
to examine the possibility of using more difficult, yet more
beneficial aryl mesylates as the electrophilic partners in So-
nogashira coupling.
Scheme 1. A comparison of aryl mesylate, tosylate, and triflate leaving
groups.
Gratifyingly, the Pd/CM-phos catalytic system was found
to be effective in promoting the Sonogashira coupling of
aryl mesylates (Table 3). An array of aryl mesylates were ex-
amined in this coupling reaction using 1-hexyne as the nu-
cleophile. Heteroaryl mesylates were also compatible in this
system. Aryl alkyne and conjugated alkyne were found to
be capable coupling partners (Table 3). These examples rep-
resent the first aryl mesylate–alkyne coupling reaction.
To further show the application of this coupling process, a
tandem reaction was investigated. The tosylate Sonogashira
approach provided a facile access to nitrogen heterocycles,
Chem. Eur. J. 2010, 16, 9982 – 9985
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F. Y. Kwong et al.
Table 3. Palladium-catalyzed Sonogashira coupling of aryl and heteroaryl
mesylates.[a]
mesylate group would mean that aryl mesylates could be
used as protecting groups during a multistep synthesis, al-
lowing a number of orthogonal organic transformations and
À
performing modular Csp2 Csp bond constructions at appro-
priate stages in the whole synthetic sequence. Particularly
noteworthy is that this versatile alkyne-tosylate/mesylate
coupling also provides a facile access to 2-substituted isoqui-
noline by a one-pot cascade process. Further complementary
syntheses of unique nitrogen heterocycles (other than from
aryl halide patterns) using this catalytic system are currently
underway and will be reported in due course.[13]
Acknowledgements
We thank the Research Grants Council of Hong Kong (CERG:
PolyU5012/09P) for financial support. We are grateful to Dr. Man-Kin
Wong and Karen Ka-Yan Kung of PolyU for sharing of alkyne substrates.
Keywords: alkynes
·
cross-coupling
·
palladium
·
phosphanes · Sonogashira coupling
[a] Reaction conditions: ArOMs (1.0 mmol), alkyne (2.0 mmol), Pd-
ACHTUNGTRENNUNG(OAc)2 (2.0 mol%), (Pd/CM-phos=1:3), K3PO4 (3.0 mmol), and tBuOH
(2.0 mL) under N2 at 1108C for 18 h (reaction time for each substrate
was not optimized). Isolated yields were reported. [b] 5 mol% of Pd-
ACHTUNGTRENNUNG(OAc)2 was used. [c] K2CO3 was used instead of K3PO4. [d] 3.0 mmol of
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such as isoqinoline scaffold (Scheme 2). To the best of our
knowledge, this is the first example to target isoquinoline
using a phenolic derivative (tosylate) precursor. The formyl-
phenyl tosylate and 1-heptyne was directly transformed to
2-substituted isoquinoline effectively by an operationally
simple one-pot, two-step cascade process (Scheme 2).
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In summary, we have established a general Sonogashira
coupling of aryl and heteroaryl tosylates. This finding is of
high significance because this procedure enables difficult
phenolic derivatives to be used as the electrophilic partners,
which offer different substitution patterns with respect to
aryl halides, for aromatic alkyne synthesis. Notably, we have
also succeeded in showing the first examples of even more
difficult, yet more atom-economical aryl mesylate couplings
using Sonogashira methodology. Indeed, the inertness of the
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in 2005–2006. Note: TsCl is a solid form and sold in ordinary re-
agent bottle, whereas Tf2O is a highly moisture sensitive liquid and
usually sold in an ampule.
Scheme 2. One pot synthesis of substituted isoquinoline from aryl tosy-
late. Reaction conditions: i) ArOTs (2.0 mmol), alkyne (4.0 mmol), Pd-
ACHTUNGTRENNUNG(OAc)2 (2.0 mol%), (Pd/CM-phos=1:3), K3PO4 (6.0 mmol), and tBuOH
(4.0 mL) under N2 at 1108C for 18 h. ii) Without purification/isolation
processes, ethanolic ammonia was directly added to the reaction mixture
and stirred at 808C for 18 h. Isolated yield is given over two steps.
[8] For activated vinyl tosylates, see: a) D. Steinhuebel, J. M. Baxter, M.
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Palladium-Catalyzed Sonogashira Coupling
COMMUNICATION
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Received: May 11, 2010
Published online: July 21, 2010
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9985