Well-defined air-stable palladium HASPO complexes for efficient Kumada-Corriu cross-couplings of (Hetero)aryl or alkenyl tosylates

Article abstract of DOI:10.1002/chem.201002386

Palladium complexes of representative heteroatom-substituted secondary phosphine oxide (HASPO) preligands were synthesized and fully characterized, including X-ray crystal structure analysis. Importantly, these well-defined complexes served as highly efficient catalysts for Kumada-Corriu cross-coupling reactions of aryl, alkenyl, and even heteroaryl tosylates. Particularly, an air-stable catalyst derived from inexpensive PinP(O)H displayed a remarkably high catalytic efficacy, which resulted in cross-couplings at low catalyst loadings under exceedingly mild reaction conditions with ample scope.

Full text of DOI:10.1002/chem.201002386

FULL PAPER
DOI: 10.1002/chem.201002386
Well-Defined Air-Stable Palladium HASPO Complexes for Efficient
Kumada–Corriu Cross-Couplings of (Hetero)Aryl or Alkenyl Tosylates
Lutz Ackermann,*[a] Anant R. Kapdi,[a] Sabine Fenner,[a] Christoph Kornhaaß,[a] and
Carola Schulzke[b]
Abstract: Palladium complexes of rep-
resentative heteroatom-substituted sec-
ondary phosphine oxide (HASPO) pre-
ligands were synthesized and fully char-
acterized, including X-ray crystal struc-
ture analysis. Importantly, these well-
defined complexes served as highly ef-
ficient catalysts for Kumada–Corriu
cross-coupling reactions of aryl, alken-
yl, and even heteroaryl tosylates. Par-
ticularly, an air-stable catalyst derived
from inexpensive PinP(O)H displayed
a remarkably high catalytic efficacy,
which resulted in cross-couplings at
low catalyst loadings under exceedingly
mild reaction conditions with ample
scope.
Keywords: catalysis
·
cross-cou-
pling · ligand · palladium · tosylate
Introduction
coupling reactions between organomagnesium reagents and
unactivated aryl tosylates were elegantly accomplished with
a palladium complex derived from an electron-rich analogue
of the Josiphos ligand.[7–9] Unfortunately, heterocyclic[10] to-
sylates bearing Lewis-basic nitrogen-containing functionali-
ties proved to be detrimental to the catalytic activity of the
Josiphos-based palladium complex.[7,8] We, on the contrary,
devised an in situ generated catalyst of air-stable heteroa-
tom-substituted[11] secondary phosphine oxide (HASPO)[12]
preligands for challenging arylations of inter alia aryl bro-
mides, chlorides, and fluorides,[13] which notably proved to
be amenable to Kumada-Corriu coupling reactions of unac-
tivated aryl tosylates as well.[14] Thus, particularly complexes
generated from inexpensive PinP(O)H (4a) displayed a high
catalytic activity (Scheme 1), even when using more de-
manding Lewis-basic N-heteroaromatic tosylates.
Despite this remarkable recent progress in the use of
HASPO preligands for catalytic cross-coupling reac-
tions,[12–14] the coordination chemistry of catalytically rele-
vant HASPOs has thus far not been explored. Moreover,
structurally characterized HASPO complexes have, to the
best of our knowledge, previously not been employed as
well-defined catalysts for cross-coupling reactions.[12] There-
fore, we became interested in preparing novel isolated
HASPO transition-metal complexes and in probing their
performance in catalytic arylation reactions. As a result of
our efforts, we disclose herein the synthesis of fully charac-
terized palladium complexes of representative HASPO pre-
ligands and their use as catalysts in challenging Kumada–
Corriu cross-coupling reactions of unactivated aryl and het-
eroaryl tosylates. Importantly, these studies also represent a
first application of secondary phosphine oxides as preligands
for cross-couplings of alkenyl tosylates.
Transition-metal-catalyzed cross-coupling reactions between
organic halides and organometallic or main-group-element
nucleophiles are among the most valuable tools for regiose-
[1,2]
À
lective C C bond formations.
Due to their mild reaction
conditions, these transformations found widespread applica-
tions in various research areas, such as crop protection, ma-
terial sciences, or medicinal chemistry. Traditionally, aryl io-
dides, triflates, bromides, and more recently chlorides[3,4]
served as organic electrophiles for the regioselective synthe-
sis of substituted (hetero)arenes.[3,5] On the contrary, the use
of aryl or alkenyl tosylates in cross-coupling chemistry is
highly desirable, since they can be prepared from readily
available phenols or ketones using inexpensive reagents, and
because they are usually highly crystalline as well as stable
towards hydrolysis.[3] Unfortunately, the remarkable stability
of these user-friendly electrophiles translates into a signifi-
cantly diminished reactivity in metal-catalyzed coupling re-
actions. As a result, palladium-catalyzed functionalizations
of electronically unactivated aryl tosylates usually required
the use of specifically designed stabilizing ligands.[3,6] Thus
far, this ligand design mainly focused on electron-rich terti-
ary phosphines, which can be prone to undergo oxidation.
Specifically, generally applicable palladium-catalyzed cross-
[a] Prof. Dr. L. Ackermann, Dr. A. R. Kapdi, Dipl.-Chem. S. Fenner,
Dipl.-Chem. C. Kornhaaß
Institut fꢀr Organische und Biomolekulare Chemie
Georg-August-Universitꢁt
Tammannstrasse 2, 37077, Gçttingen (Germany)
Fax : (+49)551-39-6777
E-mail: lutz.ackermann@chemie.uni-goettingen.de
[b] Dr. C. Schulzke
School of Chemistry, Trinity College Dublin
College Green, Dublin 2 (Ireland)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201002386.
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1b (Scheme 3). Notably, the
isolated complex 5a displayed
an activity that was significantly
improved over the one of the in
situ generated catalytic system.
Furthermore, palladium com-
plexes 5b and 5c required a
higher catalyst loading to
ensure satisfactory yields of
products 3ao and 3ap.
Scheme 1. Kumada–Corriu cross-coupling of aryl tosylates 1 with an in situ generated complex of HASPO pre-
ligand 4a.
A
A
Results and Discussion
Cross-couplings of alkenyl tosy-
lates with an in situ generated
catalytic system: In situ gener-
ated transition-metal complexes
of air-stable (HA)SPO preli-
gands were thus far solely em-
ployed for cross-coupling reac-
tions of aryl sulfonates.[12]
Therefore, we probed at the
outset of our studies the appli-
cation of the in situ generated
catalytic system of PinP(O)H
(4a) for the diastereoselective
synthesis of tri- and tetrasubsti-
tuted alkenes
3
(Table 1).
Thereby, a variety of differently
substituted alkenes 3 was ac-
cessed with excellent chemose-
lectivities (Table 1, entries 1–
12). Importantly, the catalytic
system turned out not to be
limited to cyclic alkenyl tosy-
Scheme 2. Synthesis of novel HASPO palladium complexes 5a–5c.
lates 1, but also enabled the efficient and selective synthesis
of acyclic olefins 3am and 3an (Table 1, entries 13, and 14).
Synthesis of well-defined palladium complexes: Despite the
outstanding catalytic activity and wide applicability exerted
by in situ generated HASPO complexes, the coordination
chemistry of catalytically relevant derivatives has thus far
not been explored.[12] Therefore, we set out to prepare well-
defined palladium complexes 5a–5c by employing represen-
tative air-stable preligands 4a–4c (Scheme 2).
Importantly, the molecular structures of homobimetallic
complex 5b and monometallic complex 5c revealed the hy-
drogen-bond stabilized nature of the quasi-bidentate ligand
(Figure 1 and 2, respectively).[15] Furthermore, it is notewor-
thy that novel palladium complex 5c displays a monomeric
k-acetato-ligand.[16]
Figure 1. Molecular structure of [(m-ClPdACHTUNTGRNENUG{(iPrO)2POH}ACHTUNGTRNE{NUGN (iPrO)2PO})2]
(5b). Thermal ellipsoids are shown at 50% probability. H atoms are
omitted for clarity except for H1O, which was found and refined freely.
Well-defined isolated catalysts for cross-couplings with aryl
tosylates: With well-defined palladium complexes 5a–5c in
hand, we tested their catalytic efficacy in the Kumada–
Corriu cross-coupling of electron-rich aryl tosylates 1a and
Subsequently, we explored the scope of the optimal cata-
lyst 5a in Kumada–Corriu cross-coupling reactions of substi-
tuted aryl tosylates (Table 2). Thus, diversely decorated aryl
tosylates were efficiently functionalized, even when being
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Cross-Couplings of (Hetero)Aryl or Alkenyl Tosylates
FULL PAPER
Table 1. Kumada–Corriu cross-coupling of alkenyl tosylates 1 with an in
situ generated complex of HASPO 4a.[a]
Entry
1
1
3
Yield [%]
65
3aa
3ab
Figure 2. Molecular structure of k2-acetato palladium complex 5c. Ther-
mal ellipsoids are shown at 50% probability. H atoms and solvent are
omitted for clarity. Only one of two orientations of the disordered mole-
cule is shown.
2
3
77[b]
78[b]
3ac
4
5
3ad
3ae
72
73
6
7
3af
72
3ag
80[b]
8
3ah
82[b]
9
3ai
3aj
65
82
10
11
12
3ak
3al
62[b]
78[b]
13
14
3am 54
Scheme 3. Catalytic activity of isolated complexes 5 versus in situ gener-
ated catalyst.
3an
70
Cross-couplings of N-heteroaryl tosylates: Regioselectively
substituted N-heteroarenes are omnipresent structural
motifs of biologically active compounds, and their syntheses
by cross-coupling chemistry have received increased atten-
tion in recent years.[17] We, therefore, tested the use of air-
stable complex 5a in the Kumada–Corriu cross-coupling of
nitrogen-containing heterocyclic tosylates. Contrary to the
results obtained with a previously reported palladium cata-
[a] Reaction conditions:
(1.25 mol%), 4a (2.50 mol%), THF (2.0 mL), 22 h, 228C. [b] 608C.
1
(1.0 equiv),
2
(1.5 equiv), [Pd2ACTHNGUTERNUN(G dba)3]
electron-rich, hence for an oxidative addition electronically
deactivated. Interestingly, the general synthesis of more ster-
ically congested ortho-substituted biaryls proved also viable
at a low catalyst loading.
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L. Ackermann et al.
Table 2. Scope of Kumada-Corriu cross-coupling of aryl tosylates 1 with catalyst 5a.[a]
Entry
1
1
3
Yield
[%]
Entry
12
1
3
Yield
[%]
3ap
3aq
3ar
99
89
94
3ba 94
3bb 97
2
3
13
14
3bc
98
4
5
3as
3at
74
91
15
16
3bd 74
3be 79
6
7
3au
3av
98
97
17
18
3bf
94
92
3ao
94[c]
8
3aw 83[b]
19
3bg 84
94
9
3ax
3ay
3az
71[b]
71[b]
84
20
21
22
3bh
88[c]
10
11
3bi
3bj
97
93
[a] Reaction conditions: 1 (1.0 equiv), 2 (1.5 equiv), 5a (0.2 mol%) 1,4-dioxane (4.0 mL), 24 h, 808C. [b] 5c (2.0 mol%), 1108C. [c] 5c (2.0 mol%), 228C.
lyst,[8] excellent yields were generally obtained with
HASPO-derived catalyst 5a (Table 3), thereby furnishing re-
gioselectively decorated pyridines (Table 3, entries 1–5) and
quinolines (Table 3, entries 6–10), again at remarkably low
catalyst loading.
Alkenyl tosylates: Alkenyl tosylates are useful, yet challeng-
ing starting materials for the diastereoselective synthesis of
substituted alkenes. Hence, we were delighted to observe
that the well-defined palladium complex 5a also allowed
highly efficient cross-coupling reactions of electronically un-
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Cross-Couplings of (Hetero)Aryl or Alkenyl Tosylates
FULL PAPER
Table 3. Kumada–Corriu cross-coupling of heteroaryl tosylates 1 with
isolated complex 5a.[a]
Table 4. Kumada–Corriu cross-coupling of alkenyl tosylates 1 with com-
plex 5a.[a]
Entry
1
3
Yield
[%]
Entry
1
3
Yield
[%]
1
2
3
4
3bk
3bl
83
98
92
71
1
2
3bu
3ae
83
92
3
4
5
6
3ag
3bv
3bw
3bx
62
90
94
96
3bm
3bn
5
6
7
3bo
3 bp
3bq
72
91
92
7
3by
98
8
9
3bz
3ca
97
97
[a] Reaction conditions: 1 (1.0 equiv), 2 (1.5 equiv), 5a (0.2 mol%), 1,4-
dioxane (4.0 mL), 24 h, 808C.
8
3br
3bs
3bt
94
98
97
alcohols 1 were well tolerated by homobimetallic complex
5a as well (Table 5, entries 6 and 7). Importantly, these find-
ings finally set the stage for site-selective Kumada–Corriu
cross-couplings of dichloroarenes (Table 5, entries 8–10).
9
10
Conclusion
[a] Reaction conditions: 1 (1.0 equiv), 2 (1.5 equiv), 5a (0.2 mol%), 1,4-
dioxane (4.0 mL), 24 h, 808C.
In summary, we have reported on the synthesis of novel
well-defined palladium complexes derived from HASPO
preligands, which were fully characterized, including their
X-ray crystal structure analysis. Importantly, an air-stable
complex of PinP(O)H (4a) displayed a significantly im-
proved catalytic activity in the challenging cross-coupling of
unactivated aryl tolsylates, when compared with the in situ
generated catalytic system. The optimized catalysts remarka-
bly broad substrate scope was reflected by high-yielding
cross-couplings of alkenyl and heteroaryl tosylates at low
catalyst loadings, as well as chemo- and site-selective func-
tionalizations of hydroxyl-substituted electrophiles. More
generally, the unprecedented use of isolated HASPO com-
plexes for cross-coupling reactions has shed light on the
working mode of thus far in situ generated HASPO-based
catalytic systems.
activated alkenyl tosylates 1 (Table 4). Notably these trans-
formations proceeded with excellent stereocontrol, thereby
delivering the desired alkenes 3 as the sole products.
Hydroxyl-substituted electrophiles: Subsequently, we were
interested in the site-selective cross-coupling of dihalo-sub-
stituted arenes.[18–20] Consequently, we explored the use of
air-stable complex 5a for the functionalization of electro-
philes 1 bearing free acidic hydroxyl substituents[19,21–23] as
potential directing groups (Table 5). Notably, both aryl
chlorides as well as aryl tosylates displaying free hydroxyl
groups were converted to the desired products 3 with high
chemoselectivities (Table 5, entries 1–5). Moreover, benzyl
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L. Ackermann et al.
Table 5. Kumada–Corriu cross-coupling of hydroxyl-substituted electro-
Representative procedure for Kumada–Corriu cross-coupling reactions of
alkenyl tosylates 1 with the in situ generated catalyst: Synthesis of 3ae
philes 1.[a]
(Table 1, entry 5):
A solution of [Pd2ACHTUNTGNUER(NG dba)3] (5.80 mg, 0.006 mmol,
1.2 mol%) and PinP(O)H (4a) (2.10 mg, 0.013 mmol, 2.5 mol%) in dry
THF (2.00 mL) was stirred under N2 for 5 min at ambient temperature.
Then 2a (1.50 mL, 0.5m in THF, 0.75 mmol) was added by using a syringe
and the solution was stirred for an additional 5 min at ambient tempera-
ture. Thereafter, 4-tert-butylcyclohexen-1-yltosylate (160 mg, 0.519 mmol)
was added, and the resulting suspension was stirred for 22 h at ambient
temperature. Saturated, aqueous NH4Cl solution (50 mL) and EtOAc
(50 mL) were added, and the separated aqueous phase was extracted
with EtOAc (3ꢃ50 mL). The combined organic layers were concentrated
in vacuo and the remaining residue was purified by column chromatogra-
phy on silica gel (n-pentane) to yield 3ae (90 mg, 73%) as a colorless
solid (m.p. 77–788C).
Entry
1
3
Yield
[%]
1
2
3cb
3cc
3 cd
3cb
3cc
3ce
3cf
75
73
82
84
80
77
93
Representative procedure for the palladium-catalyzed Kumada–Corriu
cross-coupling reactions of aryl tosylates with palladium complex 5a:
Synthesis of 3ap (Scheme 3): A solution of 5a (1.8 mg, 0.002 mmol,
0.2 mol%) in dry 1,4-dioxane (4.00 mL) was stirred under N2 for 5 min at
ambient temperature. Then 2b (0.68 mL, 2.2m in THF, 1.50 mmol) was
added by using a syringe and the solution was stirred for an additional
5 min. Thereafter 1b (278 mg, 1.00 mmol) was added, and the resulting
suspension was stirred for 24 h at 808C. At ambient temperature, aque-
ous HCl (2.0 mL, 2.0m), EtOAc (10 mL), and H2O (10 mL) were added,
and the separated aqueous phase was extracted with EtOAc (2ꢃ20 mL).
The combined organic layers were concentrated in vacuo and the remain-
ing residue was purified by column chromatography (n-hexane/EtOAc:
200/1) to yield 3ap (182 mg, 99%) as a colorless solid (m.p. 88–898C).
3
4
5
6
7
Acknowledgements
Generous support by the DFG and the Alexander-von-Humboldt foun-
dation (fellowship to A.K.), and the State of Lower Saxony within the
CaSUS program (fellowship to C.K.) is gratefully acknowledged.
8
9
3cg
3ch
86
73
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Experimental Section
General remarks: Catalytic reactions were carried out under a N2 atmos-
phere using pre-dried glassware. Chemicals were obtained from commer-
cial sources, and were used without further purification. Aryl[14] and al-
kenyl[24] tosylates were prepared as previously described. 1,4-Dioxane
and THF were freshly distilled from sodium/benzophenone under N2.
Yields refer to isolated compounds, estimated to be >95% pure as deter-
mined by 1H NMR and GC analysis. Flash chromatography: Macherey–
Nagel silica gel 60 (70–230 mesh). NMR: Spectra were recorded on a
Varian-NMR 300 instrument in the solvent indicated; chemical shifts (d)
are given in ppm.
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Cross-Couplings of (Hetero)Aryl or Alkenyl Tosylates
FULL PAPER
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Received: August 18, 2010
Published online: February 3, 2011
Chem. Eur. J. 2011, 17, 2965 – 2971
ꢂ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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2971