Transition metal-free one-pot synthesis of 2-substituted 3-carboxy-4-quinolone and chromone derivatives

Article abstract of DOI:10.1039/c3cc41690a

A novel one-pot synthesis of the 2-substituted 3-carboxy-4-quinolone/ chromone derivatives from readily available 3-oxo-3-arylpropanoates and amides/acyl chlorides is reported, without any transition metal aid. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c3cc41690a

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Transition metal-free one-pot synthesis of 2-substituted
3-carboxy-4-quinolone and chromone derivatives†
Cite this: DOI: 10.1039/c3cc41690a
Jian-Ping Lin and Ya-Qiu Long*
Received 6th March 2013,
Accepted 21st April 2013
DOI: 10.1039/c3cc41690a
www.rsc.org/chemcomm
A novel one-pot synthesis of the 2-substituted 3-carboxy-4-quinolone/ 3-carboxy-4-quinolone derivatives with disadvantages of multi-
chromone derivatives from readily available 3-oxo-3-arylpropanoates steps (Scheme 1b),9 rare substrates10 or use of protecting
and amides/acyl chlorides is reported, without any transition metal aid. groups.11 The yields from these methods were usually low and thus
limited their application in the preparation of derivatives. However,
3-Carboxy-4-quinolones are among the most common scaffolds
2-substituted 4-quinolone derivatives have increasingly shown
present in drugs and bioactive compounds.1 Besides constituting
attractive biological activities, and the nature of 2-substituent
specifies the biological profile.12 Thus a convenient and efficient
an important category of marketed antibacterial agents (e.g., Cipro-
floxacin, Levofloxacin and Moxifloxacin), the 3-carboxy-4-quinolone
synthesis for this class of quinolones would warrant an extensive
derivatives have been found to exhibit a broad and potent spectrum
medicinal chemistry investigation and further drug development
of pharmacological activities, such as antitumor,2 anxiolytic,3 anti-
based on the drug-like scaffold.
viral,4 anti-HIV-1 integrase,5 and cannabinoid receptor 2 agonist/
Herein, we design and develop a novel one-pot transition metal-
antagonist activities.6 All these make the scaffold a valuable
free synthesis involving a tandem C–C bond and C–N bond formation
synthetic target and continuously promote the efforts to develop
to afford structurally diverse 2-substituted 3-carboxy-4-quinolone
new efficient synthetic strategies enabling rapid functionalization
derivatives from 3-oxo-3-arylpropanoates and amides (Scheme 1c).
and diversification. Among these methods, the Grohe–Heitzer
Furthermore, when the amide is changed to the acyl chloride, this
reaction7 (Scheme 1a) and the Gould–Jacobs reaction8 have
approach delivers 2-substituted 3-carboxy-4-chromone derivatives,
been widely applied. However, it is still difficult to introduce
which represent another versatile bioactive scaffold in drug
discovery.13 Distinct from traditional Buchwald–Hartwig amination14
a variable substituent at position 2 through those methods,
and Ullmann-type coupling reaction,15 our methodology employed a
presumably due to the steric hindrance of the carboxyl group at
position 3. Few syntheses have been reported for 2-substituted
base-promoted intramolecular N-arylation or O-arylation to achieve
the annulation. To the best of our knowledge, this is the first
synthesis of 2-substituted 3-carboxy-4-quinolone derivatives by a
one-pot condensation using readily accessible amides and 3-oxo-3-
arylpropanoates as starting materials, providing a simple and
convenient alternative to the classical quinolone syntheses.
Based on the imine–enamine tautomerism, we envisioned that the
condensation of halogen-substituted 3-oxo-3-arylpropanoate 1 and
amide 2 would lead to the 2-substituted quinolone 4 via a tandem
addition–elimination reaction (C–C coupling)/nucleophilic aromatic
substitution reaction (C–N coupling) through an imine–enamine
intermediate (A and C), as illustrated in Scheme 2. The competitive
O-acylation (B) might occur. To accelerate the C–C coupling, the amide
could be transformed into more reactive imidoyl chloride 3by reacting
with SOCl2 in situ. Considering both couplings need base, we reasoned
that the two-step reactions can be performed in one pot. Therefore, we
chose K2CO3 as the base and DMF as the solvent to initiate the
reaction. Because the fluoro group can serve as a handle to introduce
further substituents and itself possesses a special nature in pharma-
cology, ethyl 3-oxo-3-(2,3,4,5-tetrafluorophenyl)propanoate (1a) and
Scheme 1 Strategies for the synthesis of 4-quinolone-3-carboxylates.
CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica,
Chinese Academy of Sciences, Shanghai, 201203, P. R. China.
E-mail: yqlong@mail.shcnc.ac.cn
† Electronic supplementary information (ESI) available: Experimental details and
characterization data for all compounds. See DOI: 10.1039/c3cc41690a
c
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Table 2 The substrate scope of the one-pot synthesis of 2-substituted-4-
quinolone derivativesa,b
Yieldc (%)
Product
Entry
1
2
4a: R1 = 6,7,8-tri-F
4b: R1 = 6-I,7-F
74
74
Scheme 2 One-pot synthesis design.
3
4
5
6
7
8
9
10
11
12
13
4c: R1 = 6-I,7-F
4d: R1 = 7-F
64
65
85
73
68
43
48
50
10
41
11
N-methylbenzamide (2a) were chosen as the model substrates to
screen the base, solvent, and temperature in air for optimized reaction
conditions.
4e: R1 = 7-NO2
4f: R1 = 6-CF3
4g: R1 = 7-CN
The reaction mixture was first cooled to 0 1C for one hour to fulfil
C–C coupling, then heated to 110 1C for another one hour to form the
C–N bond. Gratifyingly, the reaction proceeded well, and the desired
product 4a was isolated in 68% yield (Table 1, entry 1). Adding organic
base DIPEA to the reaction solution resulted in an increase in yield
(entry 2, 74%), while the yield was lowered when only DIPEA was used
as the base (entry 8, 51%). Hence the organic co-base was examined
(entries 2–4), and DIPEA was proven to be the best. We further
surveyed the inorganic bases (K2CO3, Na2CO3, Cs2CO3 and NaH),
and found that the best yield was achieved when K2CO3 was used
(entries 2, 5–7). The solvent was critical for this transformation. Use of
other aprotic solvents such as toluene and DMSO caused a substantial
drop in the yield (entries 9 and 10). Higher temperature was detri-
mental to the C–C coupling reaction (entries 11–13), owing to the
increase of the undesired O-acylation by the competitive enolization of
substrate 1a at higher temperature. Overall, entry 2 stood out as the
optimized set of conditions for this one-pot transformation.
With optimized conditions in hand, we turned to explore the
reaction scope with respect to 3-oxo-3-arylpropanoate (Table 2,
entries 1–13). A range of 3-oxo-3-arylpropanoates bearing electron-
withdrawing groups such as trifluoromethyl, cyano, nitro and halogen
4h: R1 = 6-Me
4i: R1 = 7-OMe
4j: R1 = H, X = F
4j: R1 = H, X = Cl
4j: R1 = H, X = Br
4j: R1 = H, X = I
14
15
16
17
18
19
20
21
22
4k: R2 = 4-OMe-Ph
4l: R2 = 4-F-Ph
70
66
71
77
74
72
65
81
41
4m: R2 = 4-Cl-Ph
4n: R2 = 2-I-Ph
4o: R2 = 2,6-di-Cl-Ph
4p: R2 = 3-CF3-Ph
4q: R2 = 4-NO2-Ph
4r: R2 = 2-NO2-Ph
4s: R2 = 2-furanyl
23
24
25
26
27
28d
4t: R3 = cyclopropyl
4u: R3 = isopropyl
4v: R3 = allyl
56
77
64
75
63
85
4w: R3 = n-butyl
4x: R3 = benzyl
4y: R3 = cyclohexyl
a
Reaction conditions: 1 (2 mmol), 2 (2.4 mmol), SOCl2 (12 mmol),
b
K2CO3 (6 mmol), DIPEA (4 mmol), DMF (10 mL), under air. X = F
unless otherwise specified. Values are the overall yields of isolated
products. Reaction conditions: 120 1C, 6 h for the C–N coupling step.
c
d
Table 1 Reaction conditions screeninga
group substituted on the aromatic ring were all competent nucleo-
philes in the coupling reaction with imidoyl chloride 3 and sub-
sequent cyclization to give the corresponding products in good yields
(entries 1–7). Significantly, compound 4e was successfully isolated in
85% overall yield for all three steps (entry 5). However, the electron-
donating group (i.e. methyl or methoxy) substituted on the aromatic
ring disfavored the condensation with a marked decrease in the yield
(entries 8 and 9, 43% and 48% yield, respectively). These results
indicated that the electronic effect of the substituent played an
important role in the last nucleophilic aromatic substitution step
(C–N bond formation). The electron-withdrawing group significantly
promoted the transformation, whereas the electron-donating group
exerted an adverse effect. It was also observed that ethyl propanoate
1b was more reactive than the methyl propanoate counterpart 1c with
a 10% increase in the yield. We further examined the reactivity of the
halogen substituent on the aryl ring involved in the N-arylation
reaction. Among the four halogens, fluoro was the most suitable
and bromo was the second, but chloro and iodo only gave the
corresponding products in much lower yields (entries 10–13).
Entry Solvent Base1
Base2
T1 [1C] T2 [1C] Yieldb [%]
1
2
3
4
5
6
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
PhMe
DMSO
DMF
DMF
DMF
K2CO3
K2CO3
K2CO3
K2CO3
Na2CO3 DIPEA
Cs2CO3 DIPEA
NaH
—
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
—
DIPEA
Et3N
0
0
110
110
110
110
110
110
110
110
110
110
110
110
110
68
74
38
19
43
58
7
0
0
0
0
Pyridine
7
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
0
0
0
0
40
80
110
8c
9
51
23
11
71
67
32
10
11
12
13
a
Reaction conditions: 1a (2 mmol), 2a (2.4 mmol), SOCl2 (12 mmol), base1
(6 mmol), base2 (4 mmol), solvent (10 mL), T1, T2 both for 1 h, in
air. b Values are the overall yields of isolated products. c Base2 (16 mmol).
c
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To further evaluate the scope of the reaction, a survey of amide DIPEA and K2CO3 as the base, and DMF as the solvent, eligible
substrates was conducted (Table 2, entries 14–28). We changed the to a broad substrate scope. Since the current modifications at
R2 group of the amide first. A range of variously substituted phenyl position 2 are rather limited for the 3-carboxy-4-quinolone and
rings were well tolerated to furnish the quinolone products in chromone, this simple and versatile methodology will be an
moderate to good yields (entries 14–22). An interesting steric hin- excellent complement for the classical methods.
drance effect was observed in this reaction, with the yields being
We thank the National Natural Science Foundation of China
increased as the steric hindrance of R2 increased (entries 17, 18, and (81021062, 81072527 and 81123004).
21 vs. entries 16, 19, and 20). Not surprisingly, only 41% yield was
obtained with N-methylfuran-2-carboxamide as the starting material
(entry 22), because of the low yield of the corresponding imidoyl
Notes and references
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expand the scope to aliphatic amides were unfruitful, mainly due to
the presence of the a-hydrogen which complicated the formation of
the precursor imidoyl chloride. Finally, we examined the R3 sub-
stituent on the amide (entries 23–28). All substrates bearing an
aliphatic or aromatic group afforded products in good yields. Similar
to the R2 group, the steric hindrance favored the formation of the
desired products. Notably, 4y was isolated in an overall yield of 85%
for all three steps (entry 28), but its C–N bond forming step required
higher temperature and longer reaction time, up to 120 1C for
5 hours. Further transformation of these quinolone carboxylates is
widely feasible, e.g., N-debenzylation of compound 4x by hydro-
genation readily afforded 4(1H)-quinolone 4z (see ESI†).
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Having established a robust synthesis of a diverse array of
2-substituted-4-quinolone-3-carboxylates, we were interested in
whether the approach could be extended to chromone synthesis
by switching N-arylation to O-arylation, namely, using a hydroxyl as
the nucleophile. To our delight, when the imidoyl chloride was
changed to acyl chloride, a variety of 2-substituted-3-carboxy-4-
chromones were generated in good yields (Table 3). Similar to the
synthesis of the quinolone, the yields increased as the steric
hindrance of aryl chloride increased. But the electronic effect
seemed to be slight. In general, aromatic acyl chloride performed
better than aliphatic acyl chloride, thus providing higher yields.
In conclusion, we have developed a convenient, practical,
and highly efficient method for the synthesis of 2-substituted-3-
carboxy quinolone and chromone derivatives. The one-pot
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Table 3 The substrate scope of the one-pot synthesis of 2-substituted-3-
carboxy-chromone derivativesa
Product
Entry
Yieldb (%)
1
2
3
4
5
6
7
8
9
6a: R2 = Ph
64
61
69
73
61
50
63
36
43
6b: R2 = 4-Me-Ph
6c: R2 = 4-F-Ph
6d: R2 = 2-Cl-Ph
6e: R2 = 2,3-di-OMe-Ph
6f: R2 = 3-NO2-Ph
6g: R2 = 2-furanyl
6h: R2 = Me
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2008, 41, 1450–1460; (e) G. Evano, N. Blanchard and M. Toumi, Chem.
Rev., 2008, 108, 3054–3131.
6i: R2 = cyclobutyl
a
Reaction conditions: 1d (2 mmol), 5 (2.4 mmol), SOCl2 (12 mmol),
b
K2CO3 (6 mmol), DIPEA (4 mmol), DMF (10 mL), in air. Values are the
overall yields of isolated products.
c
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