Direct dehydrative cross-coupling of tautomerizable heterocycles with alkynes via Pd/Cu-catalyzed phosphonium coupling

Article abstract of DOI:10.1039/b917777a

The first chemoselective direct dehydrative cross-coupling of tautomerizable heterocycles with alkynes has been achieved via C-H/C-OH bond activations with direct C(sp²)-C(sp) bond formation, which is in line with ideal synthesis using readily

Full text of DOI:10.1039/b917777a

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Direct dehydrative cross-coupling of tautomerizable heterocycles with
alkynes via Pd/Cu-catalyzed phosphonium couplingwz
Fu-An Kang,* James C . Lanter, Chaozhong Cai, Zhihua Sui and William V. Murray
Received (in Cambridge, UK) 28th August 2009, Accepted 11th December 2009
First published as an Advance Article on the web 11th January 2010
DOI: 10.1039/b917777a
The first chemoselective direct dehydrative cross-coupling of
tautomerizable heterocycles with alkynes has been achieved via
C–H/C–OH bond activations with direct C(sp2)–C(sp) bond
formation, which is in line with ideal synthesis using readily
available materials.
Organic synthesis is the art and science of molecular engineering.
‘‘What for? From what? How?’’ are constant challenges that
motivate synthetic chemists1 in the development of ideal
syntheses to advance life and material sciences. ‘‘Ideal synthesis’’
is defined as green, efficient and atom-economic processes that
generate products in high yields using readily available materials
with minimal wastes.2 Readily available materials are inexpen-
sive, inert, unactivated and unprotected (IIUU) molecules,
which are in contrast to the conventional expensive, reactive,
activated and protected intermediates in traditional synthesis.
Carbon–carbon (C–C) bond formation plays a central role in
organic synthesis.3 Metal-catalyzed cross-coupling reactions for
C–C bond formations are important components in the modern
chemical technology toolbox. Traditional demetal halide cross-
couplings4 (Scheme 1) have been indispensable methodologies to
effect C–C bond formation from small-scale synthesis in drug
discovery to large-scale manufacture of commercial medicines.
These technologies, however, often involve the coupling of
activated carbon–halogen (C–X) and carbon–metal (C–M)
intermediates. Preparation of these chemically reactive and
Scheme 1 Traditional vs. direct cross-couplings.
usually unstable intermediates normally requires multiple steps,
The key in designing such a novel process relies on the unique
combination of catalysts and additives, which should not only
chemoselectively and regioselectively activate and merge the two
molecules, but also maintain an efficient catalytic cycle under
mild conditions. To this end, direct dehydrogenative cross-
couplings8 have recently emerged as promising and powerful
technologies for C–C bond formations. These reactions employ
two IIUU molecules via C–H/C–H bond activations in the
presence of a catalyst (metal salt) and an additive (oxidant).
Another conceptually similar approach is the direct dehydrative
cross-coupling between two IIUU molecules via C–H/C–OH
bond activations. Herein, we report the first chemoselective
direct dehydrative cross-coupling of tautomerizable heterocycles
with alkynes via Pd/Cu-catalyzed phosphonium coupling.
Phosphonium coupling is a mild efficient chemoselective
and versatile methodology for the direct C–C, C–N, C–O
and C–S bond formations of tautomerizable heterocycles.7,9
It proceeds through in situ C–OH bond activation of a
tautomerizable heterocycle with a phosphonium reagent,
e.g. PyBroP (bromotris(pyrrolidino)phosphonium hexafluoro-
phosphate),7,9 followed by subsequent functionalization of the
in situ formed ‘‘pseudo-aryl halide’’9c,10 with either a nucleophile
which are not only expensive, but also generate wastes.
In recent years, development of direct cross-couplings, such
as dehydrohalide,5 demetal hydride6 and demetal hydroxide7
cross-couplings, have received considerable attention. These
new technologies replace one of the expensive unstable
coupling partners (C–X or C–M) with IIUU molecules, and
enable the C–C bond formations via C–H or C–OH bond
activations. Therefore, direct cross-couplings are becoming
highly attractive approaches in terms of efficiency, economy
and environmental impact.
The state of the art of direct cross-couplings in ideal
synthesis is arguably the coupling of two IIUU molecules, in
which a C–C bond formation between them does not occur
until a catalyst and an additive are added into the reaction.
Johnson & Johnson Pharmaceutical Research and Development, LLC,
Welsh and McKean Roads, Spring House, PA 19477, USA.
E-mail: fkang@its.jnj.com; Fax: +1 215 540 4627;
Tel: +1 215 628 7895
w Dedicated to Professors Cheng-Lie Yin and Li-Xin Dai on the
occasions of their 80th and 85th.
z Electronic supplementary information (ESI) available: Experimental
details and analytical data. See DOI: 10.1039/b917777a
ꢀc
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Chem. Commun., 2010, 46, 1347–1349 | 1347

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Table 1 Screening of conditions
Table 2 Direct dehydrative cross-coupling
Entry Ar–OH
1
RCC–H
Ar–CCR
Yield (%)
78a
Entry
Catalyst (mol%)
Base
Yield (%)
2
80a
1
2
3
4
5
6
7
8
None
None
CuI (10)
PdCl2(PPh3)2 (5)
PdCl2(PPh3)2 (1)
PdCl2(PPh3)2 (5), CuI (10)
PdCl2(PPh3)2 (1), CuI (2)
PdCl2[P(o-Tol)3]2 (5), CuI (10)
PdCl2(dppf)(CH2Cl2) (5), CuI (10)
Pd(OAc)2 (5), CuI (10)
Pd(OAc)2(PPh3)2 (5), CuI (10)
Pd(PPh3)4 (5), CuI (10)
Et3N
NaOtBu
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
0a
0a
0b
15b
12b
82b
78c
60b
55b
48b
67b
73b
3
4
5
6
7
49,a 78c
72a
9
10
11
12
68a
a
Condition A: 2-quinoxalinone (0.5 mmol), PyBroP (1.2 eq) and Et3N
(6 eq) in 1,4-dioxane (5 mL), then p-tolylacetylene (2 eq) and base
b
(1.5 eq) at r.t. for 18 h. Condition B: 2-quinoxalinone (0.5 mmol),
70a
PyBroP (1.2 eq) and Et3N (6 eq) in 1,4-dioxane (5 mL), then
p-tolylacetylene (2 eq), Pd catalyst and/or CuI at r.t. for 18 h.
82a
through SNAr displacement or an organometallic through metal-
catalyzed cross-coupling. Its featured operational simplicity,
functionality compatibility, broad substrate scope, and protecting-
group-free synthesis11 have led to the facile access to many
biologically important heterocyclic compounds in recent years.9c
As phosphonium coupling has addressed direct
C(sp2)–C(sp3) and C(sp2)–C(sp2) bond formations,7,9 we
envisioned that it could also enable direct C(sp2)–C(sp) bond
formation via direct dehydrative cross-coupling between tauto-
merizable heterocycles and alkynes, which are both typical IIUU
molecules. Direct dehydrative cross-coupling of 2-quinoxalinone
and p-tolylacetylene was studied under various base-promoted
(Et3N, NaOBut) and metal-catalyzed (Pd, Cu, Pd–Cu) phos-
phonium coupling conditions at room temperature (Table 1).
No coupling products were observed under the based-promoted
or Cu-catalyzed conditions. However, the Cu-free Pd-catalyzed
reaction was found to undergo slowly with low conversion.
Interestingly, we found that direct dehydrative cross-coupling
indeed proceeded rapidly under the Pd/Cu-catalyzed condition
producing 2-p-tolylethynylquinoxaline in high yield.12
8
72a
75a
70a
9
10
11
12
13
14
74b
66b
70b
72b
It is noteworthy that decrease of the catalyst loading from
5/10 mol% (Pd/Cu) to 1/2 mol% (Pd/Cu) (Table 1, entries 6
and 7) led to comparable results. Screening of various Pd
catalysts suggested that PdCl2(PPh3)2 was more effective than
other tested catalysts, which was also found to be the preferred
catalyst in the Pd-catalyzed direct arylation of tautomerizable
heterocycles with aryl boronic acids.7 As shown in this study
as well as in the previous study, the in situ ‘‘pre-formation’’ of
the heterocycle–phosphonium intermediate is not necessary.13
Hence, the catalysts and the additive can be added together
along with the starting materials. In practice, however, it
always makes more mechanistic sense to add the additive
(PyBroP) shortly before the catalysts (Pd/Cu), since it is the
in situ formed heterocycle–phosphonium intermediate that
initiates the subsequent cross-coupling reaction.
15
73b
a
Condition A: ArOH (0.5 mmol), PyBroP (1.2 eq) and Et3N (6 eq) in
1,4-dioxane (5 mL), then RCCH (2 eq), PdCl2(PPh3)2 (5 mol%), CuI
b
(10 mol%) at r.t. for 18 h. Condition B: ArOH (0.5 mmol), PyBroP
(1.2 eq) and Pri2NEt (6 eq) in 1,4-dioxane (5 mL) at 50 1C for 2 h, then
RCCH (2 eq), PdCl2(PPh3)2 (5 mol%), CuI (10 mol%) at 80 1C for
18 h. Condition C: ArOH (0.5 mmol), PyBroP (1.2 eq) and Et3N
c
(6 eq) in 1,4-dioxane (5 mL), then RCCH (2 eq), PdCl2(PPh3)2
(5 mol%) at 50 1C for 18 h.
Direct dehydrative cross-coupling of 2-quinoxalinone with
other alkynes were subsequently investigated. We found that
ꢀc
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aryl alkynes, alkenyl alkynes, and alkyl alkynes all worked well
in moderate to high yields at room temperature under ambient
atmosphere using the Pd/Cu catalyzed condition. However, in
the case of an electron-deficient alkyne, the Cu-free condition at
50 1C was found to give a higher yield (Table 2, entry 3). The
unique chemoselectivity of this new methodology is clearly
demonstrated in the direct cross-couplings involving the
sensitive hydroxylated alkynes (Table 2, entries 8–10), which
would be difficult to achieve using other existing technologies.
Next, this new Pd/Cu-catalyzed phosphonium coupling
was applied to other tautomerizable heterocycles with
p-tolylacetylene. We found that the coupling reactions of these
tautomerizable heterocycles appeared to be somewhat slower
under the same conditions, probably due to their slightly
different reactivity. We found that these reactions can be
accelerated under the modified conditions using a slightly
stronger base (iPr2NEt) at higher temperatures (50–80 1C).14
We proposed the possible mechanism of the direct dehydrative
cross-coupling of 2-quinoxalinone with p-tolylacetylene via
Pd/Cu-catalyzed phosphonium coupling (Scheme 2). It may
involve the following seven-step cascade of two (Pd/Cu) catalytic
cycles via C–H/C–OH bond activations: (1) tautomerization of
2-quinoxalinone to 2-quinoxalinol in the presence of Et3N; (2)
activation of 2-quinoxalinol with PyBroP generating the hetero-
cycle-phosphonium intermediate (C–OH bond activation); (3)
oxidative insertion of Pd0 catalyst to the C–O bond of the
heterocycle-phosphonium intermediate forming the heterocycle-
PdII-phosphonium species; (4) chelation of CuI catalyst to
p-tolylacetylene affording the alkyne-CuI p-complex (C–H bond
activation); (5) abstraction of the alkynyl hydrogen by Et3N
furnishing the alkynyl-CuI species; (6) unprecedented trans-
metalation of the heterocycle-PdII-phosphonium species with
the alkynyl-CuI species resulting in the alkynyl-PdII-heterocycle
species with regeneration of the CuI catalyst and release of
TTPA; and (7) reductive elimination of the alkynyl heterocycle
product with regeneration of the Pd0 catalyst. Consequently, the
direct dehydrative cross-coupling results in a new C(sp2)–C(sp)
bond formation, where a ‘‘H2O’’ is formally eliminated from the
starting materials in this new process with the ‘‘O’’ ending up in
TTPA and the two ‘‘H’’ in Et3NꢁHX.
In conclusion, we have developed the first Pd/Cu-catalyzed
phosphonium coupling for the first chemoselective direct
dehydrative cross-coupling of tautomerizable heterocycles with
alkynes via C–H/C–OH bond activations with direct C(sp2)–C(sp)
bond formation, which is in line with ideal synthesis using readily
available materials. The scope of this new methodology has been
shown to tolerate a variety of tautomerizable heterocycles and
alkynes, particularly substrates with sensitive hydroxyl groups.
The mechanism of the direct dehydrative cross-coupling is
proposed to proceed through a domino seven-step process of
two (Pd/Cu) catalytic cycles via C–H/C–OH bond activations
involving an unprecedented transmetalation of a heterocycle-
PdII-phosphonium species with an alkynyl-CuI species.
Notes and references
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The Science behind the Art, Royal Society of Chemistry,
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2 P. A. Wender, Chem. Rev., 1996, 96, 1.
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John Wiley & Sons, New York, 1995.
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6 (a) F. Kakiuchi, S. Kan, K. Igi, N. Chatani and S. Murai, J. Am.
Chem. Soc., 2003, 125, 1698; (b) X. Chen, C. E. Goodhue and
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(d) S.-D. Yang, C.-L. Sun, Z. Fang, B.-J. Li, Y.-Z. Li and Z.-J. Shi,
Angew. Chem., Int. Ed., 2008, 47, 1473.
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8 (a) C.-J. Li, Acc. Chem. Res., 2009, 42, 335; (b) B.-J. Li, S.-L. Tian,
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9 (a) F.-A. Kang and W. V. Murray, Abstracts of Papers, 228th
National Meeting of the American Chemical Society, Philadelphia,
PA, August, 2004, American Chemical Society, Washington DC,
2004, ORGN-702; (b) F.-A. Kang, J. Kodah, Q. Guan, X. Li and
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10 ‘‘Pseudo aryl halides’’, such as aryl sulfonates, have been widely utilized
in various cross-couplings, see: (a) D. Gelman and S. L. Buchwald,
Angew. Chem., Int. Ed., 2003, 42, 5993; (b) Z.-Y. Tang and Q.-S. Hu,
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11 I. S. Young and P. S. Baran, Nat. Chem., 2009, 1, 193.
12 Pd/Cu co-catalysts and Cu-free Pd-only catalysts have also been
widely utilized in the Sonogashira cross-couplings of aryl halides with
alkynes, see: R. Chinchilla and C. Njera, Chem. Rev., 2007, 107, 874.
13 We found that the Pd-catalyzed phosphonium coupling of
2-quinoxalinone with p-tolylboronic acid7 can be carried out without
in situ ‘‘pre-formation’’ of the heterocycle–phosphonium intermediate.
For recent direct arylations via C–OH bond activation using
p-TsCl, see: (a) L. Ackermann and M. Mulzer, Org. Lett., 2008, 10,
5043; (b) Y. Luo and J. Wu, Tetrahedron Lett., 2009, 50, 2103.
14 For tautomerizable heterocycles, the ‘‘lactam form’’ is generally
favored over the ‘‘phenol form’’ in both solution and solid states.9c
Therefore, higher temperatures and stronger bases can accelerate
tautomerization from the former to the latter, which can also facilitate
the formation of the heterocycle–phosphonium intermediates as well
as their subsequent cross-coupling reactions. The reaction conditions
could be potentially further optimized by using other Pd/Cu catalysts
and/or ligands under milder conditions.
Scheme 2 Possible mechanism of the direct dehydrative cross-coupling.
ꢀc
This journal is The Royal Society of Chemistry 2010
Chem. Commun., 2010, 46, 1347–1349 | 1349