Kumada-corriu cross-couplings with 2-pyridyl grignard reagents

Article abstract of DOI:10.1002/chem.201000032

Chemical Equation Presentation SPOs meet the challenge: A palladium complex derived from air- and moisture-stable secondary phosphine oxide (SPO) (1-Ad)₂P(O)H enables general cross-coupling reactions of challenging electron-deficient 2-pyridyl Grignard reagents with ample scope (see scheme)

Full text of DOI:10.1002/chem.201000032

DOI: 10.1002/chem.201000032
Kumada–Corriu Cross-Couplings with 2-Pyridyl Grignard Reagents
Lutz Ackermann,*[a] Harish K. Potukuchi,[a] Anant R. Kapdi,[a] and Carola Schulzke[b]
Substituted heterobiaryls constitute privileged scaffolds of
compounds with activities of relevance to various research
areas, ranging from medicinal chemistry and catalysis to ma-
terial sciences.[1–4] Their regioselective syntheses rely strong-
ly on transition-metal-catalyzed cross-coupling reactions,
which have matured to being indispensable tools in modern
organic syntheses.[3,4] Since organomagnesium reagents are
more readily available than are alternative organometallic
nucleophiles,[5,6] catalytic cross-couplings of Grignard re-
agents have proven particularly useful for streamlining het-
erobiaryl synthesis.[7] Therefore, catalysts derived from vari-
ous transition metals, such as nickel,[8,9] palladium,[10]
iron,[11,12] cobalt,[13–15] or manganese,[16] were developed for
Kumada–Corriu-type[17,18] coupling reactions.[3,4,19] While this
research significantly expanded the pool of viable electro-
philes, cross-coupling reactions of electron-deficient N-het-
erocyclic nucleophiles continue to be challenging because of
their reduced nucleophilicities. Hence, a generally applicable
protocol for metal-catalyzed arylations of less nucleophilic
2-azine Grignard[20] reagents has, to the best of our knowl-
edge, proven elusive.[2,21,22] As part of our program directed
towards the use of air-stable secondary phosphine oxides
(SPO) as preligands in transition-metal catalysis,[23,24] we
noted that efficient cross-couplings with 2-pyridyl organo-
magnesium compounds could be accomplished, provided
that palladium catalysts derived from air- and moisture-
stable SPOs[23] were employed as preligands. Herein, we
report on these findings, which highlight the unique reactivi-
ty profile of SPO preligands.
At the outset of our studies, we probed various transition-
metal complexes and ligands in the cross-coupling of chal-
lenging 2-pyridyl Grignard 1a with aryl bromide 2a
(Table 1). Unfortunately, monodentate phosphines 4a–4d
provided unsatisfactory results (Table 1, entries 2–5), as did
bidentate ligands 4e–4g or phosphite 5 (Table 1, entries 6–
9). Further, in situ generated (Table 1, entries 10 and 11) or
preformed, well-defined palladium N-heterocyclic carbene
complexes (Table 1, entries 12 and 13) did not deliver the
desired product 3a.
Table 1. Optimization of palladium-catalyzed coupling with 2-pyridyl
Grignard 1a.[a]
Entry
L
Yield [%]
1
2
3
4
5
6
7
8
–
<2[b]
<2[b]
7[b]
PPh3
PCy3
[HP
X-Phos
dppp
dppf
BINAP
P
IPrHCl
4a
4b
4c
4d
4e
4 f
4g
5
6a
6b
6c
6d
7a
7b
7c
(tBu)3]BF4
<2[b]
<2[b]
<2[b]
14
11
9
(OEt)3
<2[b]
<2[b]
<2[b]
<2[b]
<2[b]
27
10
11
12
13
14
15
16
17
18
19
SIPrHCl
(allyl)Cl][c]
[PdACTHNUGRTENNUG(SIPr)ACHTUGNTRENNUGN
Pd-PEPPSI-SIPr[c]
Ph2P(O)H
[a] Prof. Dr. L. Ackermann, H. K. Potukuchi, Dr. A. R. Kapdi
Institut fꢀr Organische und Biomolekulare Chemie
Georg-August-Universitꢁt
Mes2P(O)H
T
8
47
Tammannstrasse 2, 37077 Gçttingen (Germany)
Fax : (+49)551-39-6777
E-mail: Lutz.Ackermann@chemie.uni-goettingen.de
67
A
7d
64[d]
93[e]
[b] Prof. Dr. C. Schulzke
[a] Reaction conditions: 1a (1.5 mmol), 2a (1.0 mmol), [Pd2ACHTUNGTRENNUNG(dba)3]
Institut fꢀr Anorganische Chemie
Georg-August-Universitꢁt
Tammannstrasse 4, 37077 Gçttingen (Germany)
(2.0 mol%), L (8.0 mol%), THF (1.0 mL), 608C, 20 h, yields of isolated
products; X-Phos=2-dicyclohexyl phosphino-2’,4’,6’-triisopropylbiphenyl;
(S)IPrH=N,N’-bis-(2,6-diisopropylphenyl)imidazol(in)ium; Pd-PEPPSI-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200100032.
SIPr=[Pd
AHCTUNGTRENNUNG
ACHUTGTNRNE(NUG SIPr)CAHTUNGTREN(NUGN 3-Clpy)Cl2]. [b] GC-conversion. [c] Instead of [Pd2-
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Chem. Eur. J. 2010, 16, 3300 – 3303

COMMUNICATION
On the contrary, a promising conversion of the starting
materials was observed when employing aryl-substituted
SPO 7a (Table 1, entry 14). A catalyst derived from more
sterically hindered aryl-substituted preligand 7b, however,
proved to be less efficient (Table 1, entry 15). Interestingly,
alkyl-substituted SPO preligands 7c and 7d turned out to be
superior (Table 1, entries 16 and 17), with sterically demand-
ing, non-hygroscopic (1-Ad)2P(O)H (7d)[25] leading to opti-
mal results (Table 1, entry 17).[26,27] This catalytic system was
not restricted to aryl bromides as electrophiles, but was
found amenable to aryl triflates or iodides as well (Table 1,
entries 18 and 19).
periments revealed i) that more electron-deficient aryl hal-
ides 2 reacted preferentially, and that ii) electron-rich 2-pyr-
idyl Grignard reagents 1 were converted with higher effica-
cy.
Given the unique reactivity profile of the complex gener-
ated in situ from SPO 7d, we became interested in exploring
its coordination chemistry and working mode. Thus, palladi-
um complex 8 bearing a self-assembled bidentate ligand was
obtained in an excellent yield, when reacting preligand 7d
with PdACHTUNTGRNE(UNG OAc)2, a transformation that occurred even in the
absence of an additional external base (Scheme 2).[28]
With a highly active catalytic system in hand, we explored
its scope in cross-coupling reactions of substituted 2-pyridyl
nucleophiles 1 and aryl halides 2 (Scheme 1). Hence, elec-
Scheme 2. Synthesis of complex 8.
Importantly, the isolated, well-defined palladium complex
8 (Figure 1) exhibited a remarkably high catalytic activity in
the challenging cross-coupling of 2-pyridyl Grignard re-
agents 1 (Scheme 3). As a result, a significantly lower cata-
lyst loading turned out to be sufficient for achieving effec-
tive cross-coupling reactions.[29] Thereby, diversely substitut-
ed Grignard reagents 1 were selectively coupled with organ-
ic electrophiles 2 bearing useful functionalities.
Figure 1. Molecular structure of complex 8.
Scheme 1. Palladium-catalyzed cross-coupling of 2-pyridyl nucleophiles 1.
It is well documented that the stabilizing proton in biden-
tate complexes derived from secondary phosphine oxides
are significantly acidified.[23] Indeed, palladium complex 8
reacted with basic Grignard reagent 1a to yield heterobime-
tallic complex 9 (Scheme 4). We propose that this heterobi-
metallic structural motif enables efficient coupling reactions
with challenging 2-pyridyl nucleophiles through the forma-
tion of intermediates of type 10.
trophiles 2 bearing valuable functional groups, such as halo
or ester substituents, were chemoselectively converted to
products 3b–3p. Further, N- or S-heteroarenes were well
tolerated by the in situ generated catalytic system (3 f, 3g,
and 3j). Additionally, a variety of differently substituted 2-
pyridyl nucleophiles 1 was efficiently cross-coupled, thus de-
livering heterobiaryls 3i–3p. Intermolecular competition ex-
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L. Ackermann et al.
stirred for 10 min at ambient temperature. Compound 2a (187 mg,
1.00 mmol) was added and the suspension was stirred for a further 5 min.
Then, 1a (5.0 mL, 1.50 mmol, 0.3m in THF) was added dropwise over
3 min and the resulting suspension was stirred for 20 h at 608C. EtOAc
(50 mL) and H2O (50 mL) were added to the cold reaction mixture. The
separated aqueous phase was extracted with EtOAc (2ꢃ50 mL). The
combined organic layers were washed with H2O (50 mL) and brine
(50 mL), dried over Na2SO4, and concentrated in vacuo. The remaining
residue was purified by column chromatography on silica (n-hexane/
EtOAc 10/1) to yield 3a as a colorless solid (124 mg, 67%).
Acknowledgements
Support by the DFG, the DAAD (fellowship to H.K.P.), and the
Alexander-von-Humboldt foundation (fellowship to A.K.) is gratefully
acknowledged.
Keywords: cross-coupling
organomagnesium reagents
secondary phosphine oxides
·
heteroarenes
palladium pyridines
·
·
·
·
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Experimental Section
Representative procedure for palladium-catalyzed cross-coupling with 2-
pyridyl Grignard reagents: Synthesis of 3a (Table 1, entry 17): A suspen-
2ACHTUNGTRENNUNG(dba)3] (dba=dibenzylideneacetone; 18 mg, 0.02 mmol,
2.0 mol%) and 7d (25 mg, 0.08 mmol, 8.0 mol%) in THF (1.0 mL) was
sion of [Pd
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Kumada–Corriu Cross-Couplings with 2-Pyridyl Grignard Reagents
COMMUNICATION
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À
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[26] The remaining mass balance was unreacted electrophilic starting
material.
[27] Under otherwise identical reaction conditions the use of [Ni
(cod=1,5-cyclooctadiene), [Ni(acac)2] (acac=acetylacetonate), or
[Fe(acac)3] did not lead to formation of the desired product.
ACHTUNGTRENNUNG(cod)2]
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
[28] CCDC-713168 contains the supplementary crystallographic data for
complex 8. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
[29] Lower yields of product 3a were obtained at this catalyst loading
with in situ generated complexes: PdACTHUNGTRENNNUG
(2.0 mol%): 46%; [Pd
2ACHTUNGTRENNUNG
(1.0 mol%): 55%.
Received: January 6, 2010
Published online: February 18, 2010
Chem. Eur. J. 2010, 16, 3300 – 3303
ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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