A general palladium-catalyzed sonogashira coupling of aryl and heteroaryl tosylates

Article abstract of DOI:10.1002/chem.201001524

Coupled up: A new general palladium-catalyzed procedure for the cross-coupling of aryl and heteroaryl tosylates is described. This highly versatile and efficient process can be used for the synthesis of a wide variety of functionalized alkynes (see scheme).

Full text of DOI:10.1002/chem.201001524

DOI: 10.1002/chem.201001524
A General Palladium-Catalyzed Sonogashira Coupling of Aryl and
Heteroaryl Tosylates
Omar Rꢀkyek, Nis Halland, Andreas Lindenschmidt,* Jorge Alonso, Peter Lindemann,
Matthias Urmann, and Marc Nazarꢁ*[a]
Aryl alkynes are important synthetic precursors for a
wide variety of target compounds.[1] The most straightfor-
ward and reliable method for the regioselective construction
of these intermediates is the palladium-catalyzed Sonoga-
shira coupling.[2] Considerable efforts have been made to en-
hance the efficiency and generality of this reaction. Several
palladium catalyst systems have been developed that enable
the reaction to proceed at room temperature,[3] without re-
quiring copper(I) as a cocatalyst,[4] and expanding the sub-
strate range to aryl triflates and aryl chlorides.[5] However,
the course of the reaction, presumably due to the competing
oligomerization of the alkyne at higher concentration. Thus,
slow addition of the alkyne substrate over 8 h and high
purity of the tosylate were prerequisites for a successful
transformation. To the best of our knowledge, no general
procedure for the Sonogashira coupling of nonactivated or
ortho-substituted aryl tosylates or heteroaryl tosylates has
been reported so far. Herein, we report a general, efficient,
and robust catalyst system for the Sonogashira coupling of
diverse aryl and heteroaryl tosylates.[10]
À
the use of tosylates as coupling partners for the Csp2 Csp
We initiated our investigation by searching for conditions
under which the coupling reaction of ortho-(acetamido-
phenyl) tosylate and alkyl alkynes proceeded efficiently.
This was attractive because it gives access to the extremely
useful alkyne precursors of the Larock indole synthesis,[11]
yet the substrate is also a challenging one because there it
contains a potentially interfering acetamido group in close
proximity to the reacting tosylate moiety.[12]
bond formation has remained almost unexplored until re-
cently.[6] The use of aryl tosylates as electrophiles is attrac-
tive, since they can be prepared from the large number of
readily available phenols with less expensive reagents than
the corresponding triflates. Furthermore, aryl tosylates are
more convenient to use because they are highly crystalline
solids with a significantly higher hydrolytic stability than tri-
flates.[7] These properties allow aryl tosylates to be used as
inert protecting groups during a multistep synthesis, permit-
ting several orthogonal transformations and then their trans-
formation through Sonogashira coupling at an appropriate
stage in the synthetic sequence.[8] Conversely, the greater
stability of aryl tosylates makes this functionality less reac-
tive towards palladium-catalyzed processes. Recently, the
Sonogashira coupling of strongly activated, electron-defi-
cient para- and meta-substituted aryl tosylates was reported
using the monodentate X-Phos (2-dicyclohexylphosphino-
2’,4’,6’-triisopropylbiphenyl) ligand.[9] This catalyst system
was only successful when the alkyne was added slowly over
A screening of phosphine ligands, including PACHTUNGTRENNUNG(tBu)3,
P(Cy)3, and X-Phos, revealed that 1-dicyclohexylphosphino-
2-(di-tert-butylphosphinoethyl)ferrocene (CyPF-tBu)[13] in
combination with PdACHTUNRGTNE(UNG TFA)2 and K3PO4 effectively catalyzed
this reaction in tBuOH at 858C
to form alkyne 3 (Table 1, en-
tries 1 and 2; see also Table S-1
in the Supporting Information).
Furthermore, it was also
found that neither slow addition nor a significant excess of
alkyne was required to obtain selective and almost quantita-
tive conversion.
The optimized reaction conditions accept a broad sub-
strate scope in both aryl tosylate and alkyne coupling part-
ners (Table 1).[14] Several diversely and, in particular, ortho-
substituted aryl tosylates (Table 1, entries 7 and 8) are toler-
ated and react with comparable efficiency. Importantly, non-
activated substrates, such as phenyl tosylate, or even deacti-
vated aryl tosylates, such as para-tolyl- or ortho-methoxy-
phenyl tosylates, were found to be reactive under these con-
ditions (Table 1, entries 9–12).
[a] Dr. O. Rꢀkyek, Dr. N. Halland, Dr. A. Lindenschmidt, Dr. J. Alonso,
P. Lindemann, Dr. M. Urmann, Dr. M. Nazarꢁ
Sanofi-Aventis Deutschland GmbH, Industriepark Hçchst
Building G878, 65926 Frankfurt am Main (Germany)
Fax : (+49)69-331-399
E-mail: Andreas.Lindenschmidt@sanofi-aventis.com
Marc.Nazare@sanofi-aventis.com
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201001524.
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COMMUNICATION
Table 1. Scope of the Sonogashira coupling with aryl tosylates.[a]
Table 2. Scope of the Sonogashira coupling with heteroaryl (Hetaryl) to-
sylates.[a]
Entry Tosylate
Product
Yield
[%][b]
Entry Tosylate
Product
Yield
[%][b]
1[c]
2[c]
3
3a 80
1[c]
6a 60
3b 71
3c 72
2
3
6b 73
6c 65
4
3d 74
4
5
6d 73
6e 67
5
6
3e 80
3 f 60
6[c]
6 f 88
6g 65
7[c]
3g 90
3h 62
7
8
9
3i 73
3j 85
3k 97
8[c]
6h 84
10
11
9
6i 73
10
6j 63
12
3l 81
[a] All reactions were performed with 4 (1.6 mmol), 5 (1.8 mmol), Pd cat-
alyst (3 mol%), CyPF-tBu (7 mol%) in tBuOH, and K3PO4 (1.4 equiv
based on tosylate 4) at 858C for 5–18 h. [b] Isolated yields. [c] Performed
by using 2 equiv of 5 (3.2 mmol) and 3.0 equiv K3PO4 (based on tosylate
4).
[a] All reactions were performed with 1 (1.6 mmol), 2 (1.8 mmol), Pd cat-
alyst (3 mol%), CyPF-tBu (7 mol%) in tBuOH, and K3PO4 (1.4 equiv
based on tosylate 1) at 858C for 5–18 h. Ts=tosyl. [b] Isolated yields.
[c] Performed by using 2 equiv of 2 (3.2 mmol) and 3.0 equiv K3PO4
(based on tosylate 1).
A number of potentially reactive functionalities, such as
ketones, aldehydes, hydroxy groups, nitriles, methyl esters,
and even a free primary amine, are compatible and remain
unaffected, which illustrates the robustness of the catalyst
system (Tables 1 and 2).
of pharmacologically relevant scaffolds. In this context, we
observed that besides functionalized aryl tosylates, heteroar-
yl tosylates, such as thienyl and pyridyl tosylates, react with
good efficiency (Table 2, entries 1–6). Moreover, the corre-
sponding tosylates of pyra- and indazolones are suitable sub-
strates under these conditions and afford the desired alkynes
in good to high yields (Table 2, entries 7–10).
An important aspect of the reaction is the applicability of
the reaction to heterocycles, which are frequently precursors
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M. Nazarꢁ et al.
Table 3. Accessing indoles via a Sonogashira coupling cyclization sequence with aryl tosylates.[a]
The tosylate Sonogashira ap-
proach also provided facile
access to various indoles and
isoquinoline heterocyles by
using N-boc- (Boc=tert-butyl-
ACHTUNGTRENNUNGoxycarbonyl) or N-acetamide-
protected ortho-(aminophenyl)
tosylates 7 and the ortho-(for-
mylphenyl) tosylate 11, respec-
tively, as starting materials. No-
tably, to the best of our knowl-
edge, this is the first example of
accessing indoles and isoquino-
lines by using a tosylate activa-
tion (Tables 3 and 4). Interest-
ingly, for the synthesis of in-
doles 10, no in situ cyclization
of the precursor 9 was observed
during the coupling reaction;
this required a subsequent hy-
droamination step through
known cyclization procedures[15]
(Table 3, entries 1–4).
In conclusion, we have devel-
oped a novel, mild, and effi-
cient protocol for the palladi-
um-catalyzed coupling of aryl
and heteroaryl tosylates. This
simple procedure is easy to
carry out and does not require
slow addition of the alkyne sub-
strate and thus provides facile
access to a variety of function-
alized aryl and heteroaryl al-
kynes in good to very good
yields. The high tolerance to-
wards many functional groups
and heterocycles combined with
the high stability of the tosylate
precursors considerably extends
the scope of aromatic and het-
Entry
1
Tosylate
Product
Yield [%][b]
67
10a
10b
2
78
72
60
3[c]
10c
10d
4[c]
[a] All reactions were performed with 7 (1.6 mmol), 8 (1.8 mmol), Pd catalyst (3 mol%), CyPF-tBu (7 mol%)
in tBuOH, and K3PO4 (1.4 equiv based on tosylate 7) at 858C for 5–18 h. [b] Isolated yields, two steps. [c] Per-
formed by using 2 equiv of 8 (3.2 mmol) and 3.0 equiv K3PO4 (based on tosylate 7).
Table 4. Accessing isoquinolines through a Sonogashira coupling cyclization sequence with aryl tosylates.[a]
Entry
1
Tosylate
Product
Yield [%][b]
62
14a
14b
14c
2
3
76
73
eroaromatic
hydroxy
com-
pounds as potential precursors
for the Sonogashira coupling
and its applicability in multistep
syntheses. Furthermore, we
have demonstrated that the So-
nogashira adducts were easily
transformed into indoles and
isoquinolines in high yields.[17]
[a] All reactions were performed with 11 (1.8 mmol), 12 (2.2 mmol), Pd catalyst (3 mol%), CyPF-tBu
(7 mol%) in tBuOH, and K3PO4 (1.4 equiv based on tosylate 11) at 858C for 5–18 h. [b] Isolated yields over
two steps.
K3PO4 (2.2 mmol), and a magnetic stirring bar. Then, tBuOH (7 mL) and
the alkyne (1.8 mmol) were added and the mixture was again purged
Experimental Section
with argon, sealed with a serum cap, and heated to 858C for 5–18 h.
After cooling, the reaction mixture was diluted with EtOAc and filtered
through a pad of Celite. The filtrate was concentrated under reduced
pressure and the crude product was purified either by chromatography
on silica gel (using heptane/EtOAc or CH2Cl2/EtOAc as eluent) or by
General: A Schlenk tube was charged under an atmosphere of argon
with the aryl tosylate or heteroaryl tosylate (1.6 mmol), palladium tri-
fluoroacetate (0.048 mmol, 3 mol%), Cy-PF-tBu (0.112 mmol, 7 mol%),
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Palladium-Catalyzed Sonogashira Coupling
COMMUNICATION
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Acknowledgements
This work was supported by the European community by a Marie Curie
Host fellowship for the transfer of knowledge (HCTMCR). We thank
Astrid Sihorsch, Silke Herok-Schçpper, and Julia Volkmar for their ex-
cellent technical assistance, as well as our colleagues from the Analytical
Sciences department for their analytical support.
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Keywords: alkynes
palladium · Sonogashira coupling
· aryl tosylates · cross-coupling ·
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DOI: 10.1002/chem.201001269.
Received: February 17, 2010
Published online: July 6, 2010
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