Efficient route to 4-substituted-2(5H)-furanones, 2(1H)-quinolones, and pyrones by nickel-catalyzed cross-coupling of arenesulfonates with organozinc reagents

Article abstract of DOI:10.1246/cl.2005.796

Nickel(II)-catalyzed cross-coupling reactions of 4-tosyl-2(1H)-quinolone, pyrone, and 2(5H)-furanone with various organozinc reagents provide an efficient and practical method for the high-yielding synthesis of 4-substituted 2(1H)-quinolones, pyrones, and 2(5H)-furanones. Copyright

Full text of DOI:10.1246/cl.2005.796

796
Chemistry Letters Vol.34, No.6 (2005)
Efficient Route to 4-Substituted-2(5H)-furanones, 2(1H)-quinolones, and pyrones
by Nickel-catalyzed Cross-coupling of Arenesulfonates with Organozinc Reagents
Jie Wu,Ã Xiaoyu Sun, and Liang Zhang
Department of Chemistry, Fudan University, 220 Handan Road, Shanghai 200433, P. R. China
(Received March 14, 2005; CL-050342)
Nickel(II)-catalyzed cross-coupling reactions of 4-tosyl-
reagent as substrate under palladium-catalyzed cross-coupling
conditions. (Scheme 1)
2(1H)-quinolone, pyrone, and 2(5H)-furanone with various
organozinc reagents provide an efficient and practical method
for the high-yielding synthesis of 4-substituted 2(1H)-quino-
lones, pyrones, and 2(5H)-furanones.
OTs
[Pd]
+
C5H11
ZnI
H3C
N
O
C5H11
N
O
CH3
1a
2aa
2(1H)-quinolones A, pyrones B, and 2(5H)-furanones C are
important structural units in naturally occurring products, thera-
peutics, and synthetic analogues with interesting biological ac-
tivities.1–3 (Figure 1) For example, Rofecoxib is an anti-inflam-
matory drug launched by Merck and approved by FDA.2k Rubro-
lides A–F are potent antibiotics.2g
Scheme 1.
Initial studies were performed by using different palladium
catalyst (Pd(PPh3)4, PdCl2(PPh3)2, Pd(OAc)2, PdCl2, PdCl2-
(MeCN)2, PdCl2(PhCN)2, and Pd2(dba)3) in the reaction of
compound 1a with 4-pentylphenylzinc iodide. To our delight,
we observed the formation of the corresponding product 2a,
albeit in low yield (10–30%). However, addition of ligand or
changing solvents or temperature did not improve the reaction
yield. Since C–O bond would undergo oxidative addition during
the reaction process, we thus shifted our focus to other transi-
tion-metal catalyst, such as nickel, which in most cases, is more
active than palladium.
R2
R1
R2
R3
R1
O
R2
O
R1
N
O
O
H3C
O
R4
A
B
C
Figure 1.
As expected, in the reaction of compound 1a with 4-pentyl-
phenylzinc iodide using NiCl2(dppp) (5 mol %) as the catalyst,
71% yield of the desired product 2a was afforded in 12 hours
at 50 ꢀC. After further survey of different nickel catalysts, sol-
vents, and temperature, NiCl2(dppe) was identified to be the best
catalyst and 84% yield of 2a was obtained after 12 hours when
the reaction was performed in THF at about 50–60 ꢀC. Although
we routinely conduct these cross-coupling at 50 ꢀC, they can in
fact be accomplished at room temperature, although a long reac-
tion time is needed.
To demonstrate the generality of this method, we next inves-
tigated the scope of this reaction and the results are summarized
in Table 1. The operation is simple: Organozinc reagent (2.0
equiv.) was added to a solution of substrate 1 (0.25 mmol) and
NiCl2(dppe) (5 mol %) in THF (2.0 mL) under argon atmo-
sphere. The reaction mixture was stirred overnight at about
50–60 ꢀC. After the reaction was completed and monitored by
TLC, the mixture was separated directly by flash column chro-
matography (silica gel) to afford the corresponding product.
These conditions have proved to be useful for coupling
a range of tosylates with an array of organozinc reagents
(Table 1). For compound 1a, various organozinc reagents are
suitable substrates. Both electron-rich and electron-poor arylzinc
reagents gave similar yields. The reactions were very clean and
the desired products were afforded in good yields. It is notewor-
thy that not only aryl- or vinylzinc reagents but also alkylzinc re-
agents were suitable for this reaction. For example, when cyclo-
hexylzinc bromide was employed in the reaction, 68% yield of
the corresponding product 2j was obtained. When 4-tosyloxy-
6-methyl-pyrone 1b and 4-tosyloxy-2(5H)-furanones 1c were
Recently, we have witnessed the important progress of using
arenesulfonates as electrophiles for the cross-coupling reactions
since arenesulfonates are more easily handled and considerably
less expensive than the corresponding triflates.4–9 In this field,
we also reported the applications of 4-hydroxycoumarin-derived
4-tosyloxycoumarin as a unique replacement for its correspond-
ing triflate in palladium-catalyzed cross-coupling reactions with
acetylenes,5b organozinc reagents,5b and arylboronic acids,4h,4i
respectively, in the synthesis of various 4-substituted coumarins.
The structural similarity of 4-hydroxycoumarin and 4-hydroxy-
2(1H)-quinolone, 4-hydroxy-pyrone, and 4-hydroxy-2(5H)-
furanone led us to envisage that these tosylates also could be
employed in transition metal-catalyzed cross-coupling reactions
as an ideal alternative compared with triflate in terms of their sta-
bility, as well as cost and commercial availability of reagents.
Herein, we would like to report a novel and efficient route to
4-subsituted-2(5H)-furanones, 2(1H)-quinolones, and pyrones
via nickel-catalyzed cross-coupling of 4-tosylates with organo-
zinc reagents.
These tosylates were prepared simply from the correspond-
ing 4-hydroxy species with p-toluenesulphonyl chloride in the
presence of triethylamine. At the outset of our research, 4-tosyl-
oxy-1-methyl-2(1H)-quinolone 1a was selected for model stud-
ies. Due to their easy handling and long shelf life, arylboronic
acid derivatives would be the starting materials of choice. How-
ever, when 4-tosyloxy-1-methyl-2(1H)-quinolone 1a was em-
ployed in the palladium-catalyzed Suzuki-type cross-coupling
reactions under several conditions, no product was detected at
all. We, therefore, investigated the possibility of utilizing zinc
Copyright Ó 2005 The Chemical Society of Japan

Chemistry Letters Vol.34, No.6 (2005)
797
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Table 1. Nickel-catalyzed cross-coupling reactions of com-
pound 1 with various organozinc reagents
OTs
R
NiCl2(dppe) (5 mol%)
RZnX, THF, 50-60°C
X
O
X
O
1
2
2
RZnX
Product
RZnX
Substrate
OTs
Product
2a (84%)
2b (82%)
2c (82%)
2d (89%)
2f (80%)
C5H11
ZnI
H3CO
ZnI
CH3
ZnI
ZnI
2g (88%)
2h (85%)
N
O
ZnBr
S
CH3
1a
ZnBr
H3C
2i (83%)
2j (68%)
ZnBr
ZnBr
ZnI
H3C
F
ZnI
2e (75%)
2k (78%)
3
OTs
C5H11
H3C
ZnI
ZnBr
ZnBr
2n (86%)
2o (78%)
S
H3C
O
O
ZnI
ZnI
2l (81%)
1b
H3C
F
2m (70%)
2p (71%)
ZnBr
O
OTs
2q (75%)
2r (71%)
2s (82%)
H3C
F
ZnBr
2t (77%)
2u (69%)
ZnCl
O
4
1c
H3CO
ZnBr
ZnCl
ZnCl
S
H3CO
2v (72%)
ZnBr
employed as substrates, organozinc reagents were again suitable
partners in this process. It is noteworthy that the products 2t, 2u,
and 2v, which were synthesized from the reactions of 1c with
benzylzinc chloride in one step, were the intermediates for the
synthesis of biologically active lignan analogues. However, the
previously reported method for these compounds was from tin
reagents in multi-steps.10
In summary, the nickel(II)-catalyzed cross-coupling reac-
tions of 4-tosyloxy-2(1H)-quinolone, pyrone, and 2(5H)-fura-
none with various organozinc reagents disclosed herein repre-
sent a simple, efficient, practical synthesis of 4-substituted
2(1H)-quinolones, pyrones, and 2(5H)-furanones. The advan-
tages of this method include good substrate generality, the use
of air-stable, inexpensive tosylate under extremely mild condi-
tions, and experimental ease. Combinatorial synthesis of these
natural product-like compounds on solid support is under inves-
tigation in our research group.
5
6
7
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Hartwig, J. Am. Chem. Soc., 125, 8704 (2003). b) Iron-catalyzed cou-
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´
¨
M. Mendez, and H. Krause, J. Am. Chem. Soc., 124, 13856 (2002).
8
Stille couplings of aryl arenesulfonates: a) D. Badone, R. Cecchi, and
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Financial support from Fudan University is gratefully
acknowledged.
9
Palladium-catalyzed Negishi-type reaction of arenesulfonates: J. Wu,
Y. Liao, and Z. Yang, J. Org. Chem., 66, 3642 (2001).
References and Notes
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Published on the web (Advance View) May 7, 2005; DOI 10.1246/cl.2005.796