Direct C-3-alkenylation of quinolones via palladium-catalyzed C-H functionalization

Article abstract of DOI:10.1002/adsc.201000364

An unprecedented C-3-alkenylation of quinolones was reported through palladium-catalyzed C-H functionalization with 1% catalyst loading. This method provides an efficient route to a variety of new quinolone derivatives.

Full text of DOI:10.1002/adsc.201000364

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DOI: 10.1002/adsc.201000364
Direct C-3-Alkenylation of Quinolones via Palladium-Catalyzed
À
C H Functionalization
Mingzong Li,a Liangxi Li,a and Haibo Gea,*
a
Department of Chemistry and Chemical Biology, Indiana University–Purdue University Indianapolis, Indianapolis,
Indiana 46202-3274, USA
Fax : (+1)-317-274-4701; e-mail: geh@iupui.edu
Received: May 8, 2010; Published online: September 24, 2010
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000364.
Abstract: An unprecedented C-3-alkenylation of
C-3-alkenylation of quinolones via palladium-cata-
lyzed C H functionalization is reported.
À
quinolones was reported through palladium-cata-
À
lyzed C H functionalization with 1% catalyst load-
The investigation was initiated by coupling N-
ing. This method provides an efficient route to a va-
riety of new quinolone derivatives.
methyl-4(1H)-quinolone[7] (1a) with tert-butyl acrylate
(2a) in the presence of 20 mol% Pd
ACHTUNGRTEN(NUNG OAc)2 with stoi-
chiometric Cu(OAc)2 as an oxidant (Table 1). After
AHCTUNGTRENNUNG
À
Keywords: alkenylation; C H functionalization;
palladium; quinolones
extensive solvent screening, the mixture of 1,4-diox-
ane and DMSO (7.5:1, v/v) gave the optimal result
for this reaction, and the desired product (3a) was iso-
lated in modest yield (42%, entry 1). It was also
noted that the coupling reaction gave no product
without Pd
Carbon-carbon bond formation through transition obtained without Cu
metal-catalyzed cross-coupling reactions remains one study showed that the loading of PdAHCUTNGTRENNUNG
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
of the most powerful methods in organic synthesis, reduced to 10% (entry 4). Encouraged by these re-
and is widely used in both academic and industrial sults, different Pd sources were screened, and it was
laboratories.[1] Oxidative-coupling reactions, particu- found that both PdCl2 and Pd
N
À
larly palladium-catalyzed direct C H functionaliza- lyzed the reaction (entries 5 and 6). It was also no-
tion,[2] have attracted considerable attention over ticed that, unlike Pd
N
the past decade, and significant progress has been from 10% to 5% did not affect the yield with PdCl2
achieved in recent years.[3] Unfortunately, these meth- (entries 7 and 8). Next, the amount of oxidant in the
ods often require high catalyst loading and/or stoi- coupling reaction was investigated and it was demon-
chiometric oxidants, which reduce their potential ap- strated that the reaction worked efficiently with a cat-
plication compared to traditional cross-coupling reac- alytic amount of Cu
ACHTUNGRTEN(NUNG OAc)2 (10 mol%, entry 9). En-
tions. couraged by these results, the amount of PdCl2 was
Our interest in developing catalytic processes for further reduced from 5% to 1%, but, in this case, the
the synthesis of biologically active compounds yield was significantly reduced (entry 10). However,
À
prompted us to explore palladium-catalyzed direct C
even at 1% PdCl2, the yield of product was improved
H functionalization on quinolone systems. The quino- by increasing either the reaction concentration to
lone moiety is an important structural unit in medici- 0.3M (entry 11) or the reaction time (30 h, entry 12),
nal chemistry and many compounds with this scaffold or by using O2 as a co-oxidant (entry 13) instead of
have shown impressive biological activity in a variety air. Optimal conditions provided the desired product
of drug targets.[4] Although numerous efforts have in 90% yield using a 0.5M concentration in 16 h
been made to modify quinolones,[5] currently there under an O2 atmosphere (entry 14). It is noted that
À
are no examples of either metal-catalyzed C H func- the reaction could even be carried out with 0.5%
tionalization or direct alkenylation on this moiety. In- PdCl2 loading, which gave a modest yield of product
spired by recent studies of oxidative Heck reactions (entry 15). Reducing the amount of Cu
ACHTUNGRTEN(NUNG OAc)2 to
on enaminones[3h] and pyridones,[6] herein an efficient 5 mol% significantly reduced the yield (entry 16).
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Mingzong Li et al.
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Table 1. Optimization of reaction conditions.[a]
Entry
PdX2 (mol%)
Cu
(OAc)2 (mol%)
Gas 1 atm
Time [h]
Yield [%][b]
1
Pd
–
Pd
Pd
G
200
200
–
200
200
200
200
200
10
10
10
10
10
air
air
air
air
air
air
air
air
air
air
air
air
O2
O2
O2
O2
16
16
16
16
16
16
16
16
16
16
16
30
16
16
16
16
42
0
2[c]
3[d]
4
5
6
7
8
9
10
11[e]
12
13[f]
14[f]
15[f]
16[f]
29
41
96
97
95
70
93
54
75
64
75
90
68
40
PdCl2 (10)
Pd(TFA)2 (10)
PdCl2 (5)
Pd(TFA)2 (5)
PdCl2 (5)
PdCl2 (1)
PdCl2 (1)
PdCl2 (1)
PdCl2 (1)
PdCl2 (1)
PdCl2 (0.5)
PdCl2 (1)
10
10
5
[a]
Reaction conditions: 1a (1 equiv.), 2a (2 equiv.), PdX2, CuACHTNUTRGNENUG(OAc)2, 1,4-dioxane/DMSO (7.5/1, v/v; c=0.1M unless other-
wise noted), air or O2 (1 atm), 16 h unless otherwise noted.
Isolated yield based on quinolone.
Without palladium.
Without CuACHTUNGTRENNUNG(OAc)2
c=0.3M.
c=0.5M.
[b]
[c]
[d]
[e]
[f]
Next, the scope of alkenes was explored using the tolerated under these reaction conditions and high
optimal reaction conditions described above yields were produced with 6-fluoro- (5h), 6-chloro-
(Table 2). As expected, all terminal acrylates gave the (5i) and 6-bromo-substituted (5j) quinolones. Further
corresponding products in high yield (3b–d, 90–94%). investigation showed that C-8 substituted quinolones
In addition, N,N-dimethylacrylamide also provided a worked in the same fashion as those with C-6 subsitu-
high yield (3e, 94%) while a modest yield was pro- tion, generally with lower yields, which could arise
duced with acrylic acid (3f, 70%). The reaction was from a steric effect (5k–n). Finally, it was found that
also successful in reasonable yield with the sterically 6,7-(methylenedioxy)-substituted quinolone also gave
hindered acrylates, diethyl fumarate and methacrylo- a modest yield of product (5o).
nitrile (3g–j, 43–66%). Quinolone phosphonate 3k
In summary, a novel and efficient approach for the
and quinolone sulfone 3l were prepared using vinyl direct C-3 alkenylation of quinolones has been devel-
phosphonate and methyl vinyl sulfone in modest to oped. Considering the abundance of the quinolone
good yields while high yields were obtained with sty- moiety in a variety of biologically active compounds,
rene and 2-vinylnaphthalene (3m and 3n).
this procedure will be attractive for the preparation of
The investigation of quinolone (1) compatibility new quinolone libraries for biological evaluation.
was studied next (Table 3). It is noted that a substitu-
ent is required on the nitrogen; coupling of free (NH)
quinolone with acrylate 2a gave no product. Methyl is
Experimental Section
not a necessary group and it could be replaced by
benzyl (4) without significant loss of yield (5a, 85%).
As expected, electron-donating groups at the C-6 po-
sition provided high yields (5b and 5c) while electron-
withdrawing groups gave lower yields (5d–f). Interest-
ingly, a high yield was obtained with the 6-CF3-substi-
General Procedure for Reaction Conditions
Optimization under Air Atmosphere
A 20-mL oven-dried pressure tube was charged with Pd
source, oxidant, 1-methyl-4-quinolone (1a), tert-butyl acry-
tuted quinolone (5g). Not surprisingly, halogens are late (2a) and mixed solvents (1,4-dioxane/DMSO=7.5:1,
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À
Direct C-3-Alkenylation of Quinolones via Palladium-Catalyzed C H Functionalization
[a]
À
Table 2. Scope of alkenes in C H functionalization.
[a]
Reaction conditions: 1a (1 equiv.), 2 (2 equiv.), PdCl2 (1 mol%), CuACTHUNRGTNEUNG(OAc)2
(10 mol%), 1,4-dioxane/DMSO (7.5/1, v/v; c=0.5M), O2 (1 atm), 16 h unless
otherwise noted.
[b]
[c]
[d]
[e]
[f]
Isolated yield based on quinolone.
trans-Methyl crotonate was used.
trans-Diethyl fumarate was used.
40 h.
1
Determined by H NMR analysis of crude product.
v/v) with the designated amount of quinolone (0.1-mmol
scale of quinolone when c=0.1M, and 0.3-mmol scale of
quinolone when c=0.3M). The reaction tube was then
sealed and the mixture was heated to 1158C for the time
noted. Upon the completion of the reaction, the reaction
mixture was cooled to room temperature, diluted with
Adv. Synth. Catal. 2010, 352, 2445 – 2449
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Mingzong Li et al.
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[a]
À
Table 3. Scope of quinolones in C H functionalization.
[a]
Reaction conditions: 1 or 4 (1 equiv.), 2a (2 equiv.), PdCl2 (1 mol%), CuACHTNUTRGNE(UNG OAc)2 (10 mol%),
1,4-dioxane/DMSO (7.5/1, v/v; c=0.5M), O2 (1 atm), 16 h or as otherwise noted.
Isolated yield based on quinolone.
40 h.
[b]
[c]
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À
Direct C-3-Alkenylation of Quinolones via Palladium-Catalyzed C H Functionalization
CH2Cl2, and purified after removal of the solvents with flash
chromatography column (MeOH/CH2Cl2: 0–1%, v/v) to give
the product 3a.
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General Procedure for Reaction Conditions
Optimization under O2 Atmosphere
A 30-mL oven-dried Schlenk tube was charged with PdCl2,
CuACHTUNGTRENNUNG(OAc)2, 1-methyl-4-quinolone (1a), tert-butyl acrylate
(2a) and mixed solvents (1,4-dioxane/DMSO=7.5:1, v/v)
with designated amount of quinolone (0.1-mmol scale of
quinolone when c=0.1M, and 0.35-mmol scale of quinolone
when c=0.5M). The reaction tube was then degassed under
vacuum and refilled with O2 (balloon, 3 times), and then
sealed. The mixture was heated to 1158C for the time noted.
Upon the completion of the reaction, the mixture was
cooled to room temperature, diluted with CH2Cl2, and puri-
fied after removal of the solvents with flash chromatography
column (MeOH/CH2Cl2: 0–1%, v/v) to give the product 3a.
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General Procedure for C-3-Alkenylation of
Quinolones with Alkenes under the Optimal
Conditions
A 30-mL oven-dried Schlenk tube was charged with PdCl2
(0.6 mg, 0.0035 mmol), CuACTHNUTRGNE(NUG OAc)2 (6.3 mg, 0.035 mmol), qui-
nolones (1 or 4) (0.35 mmol), alkenes (2, 0.7 mmol) and
mixed solvents (1,4-dioxane/DMSO=7.5:1, v/v, 0.7 mL)
unless otherwise noted. The reaction tube was then degassed
under vacuum and refilled with O2 (balloon, 3 times) and
sealed. The mixture was allowed to stir at 1158C for the
time noted. Upon the completion of the reaction, the mix-
ture was cooled to room temperature, diluted with CH2Cl2,
and purified after removal of the solvents with flash chro-
matography column (MeOH/CH2Cl2: 0–1%, v/v) to give the
product 3 or 5.
Acknowledgements
We gratefully acknowledge Indiana University–Purdue Uni-
versity Indianapolis for financial support. The Bruker
500 MHz NMR was purchased using funds from an NSF-
MRI award (CHE-0619254).
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