A facile Horner-Wadsworth-Emmons route to 2-quinolones

Article abstract of DOI:10.1016/j.tetlet.2008.04.088

2-Quinolones are prepared from o-aminophenylketones by N-acylation with phosphonoalkanoylchlorides, followed by an intramolecular Horner-Wadsworth-Emmons olefination. The transformation proceeds under mild conditions, is generally applicable, gives good yields and can be performed either in two steps or as a one-pot reaction.

Full text of DOI:10.1016/j.tetlet.2008.04.088

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 4029–4032
A facile Horner–Wadsworth–Emmons route to 2-quinolones
*
´
Jens-Uwe Peters , Tony Capuano, Silja Weber, Stephane Kritter, Matthias Sagesser
¨
Discovery Chemistry, Pharma Division, F. Hoffmann-La Roche Ltd, CH-4070 Basel, Switzerland
Received 12 March 2008; revised 10 April 2008; accepted 14 April 2008
Available online 18 April 2008
Abstract
2-Quinolones are prepared from o-aminophenylketones by N-acylation with phosphonoalkanoylchlorides, followed by an intra-
molecular Horner–Wadsworth–Emmons olefination. The transformation proceeds under mild conditions, is generally applicable, gives
good yields and can be performed either in two steps or as a one-pot reaction.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: N-Heterocycles; 2-Quinolones; Cyclisation; Olefination
2-Quinolones (carbostyrils) are useful starting materials
and form the core structures of a variety of bioactive sub-
stances.1 Their preparation from anilines and b-ketoesters
(Knorr synthesis) has been known for over 100 years;2
numerous alternatives have since been developed.3 A fre-
quently employed method is an intramolecular condensa-
tion of an N-acyl-o-aminophenylketone 1 as outlined in
Scheme 1. This reaction proceeds typically in high yields
if either the carboxamide a-position is suitably activated
(e.g., R3 = ester,4 aryl,5 or pyridinium6) or the ketone motif
in 1 withstands strongly basic conditions (e.g., if R2 =
aryl3,7). This method might, however, not be applicable if
the acyl a-position is not activated, and if, at the same time,
the ketone motif in 1 is readily enolised (e.g., if R2 =
R3 = alkyl). For instance, 4 gave under the conditions of
Park and Lee,3 not a 2-quinolone, but quinoline 5 as a
product of an intermolecular aldol condensation and imine
formation in a low yield (Scheme 2).
We found that this problem can be circumvented by
acylating 3 with diethyl phosphonopropionylchloride (7-
Me) to give 8, followed by an intramolecular Horner–
Wadsworth–Emmons (HWE) olefination (Scheme 3).
Somewhat surprisingly, this rather obvious approach is
unprecedented in the literature, although some methods
to make quinolones involve intermediates similar to 8: a
Cl
Cl
Cl
Cl
a
O
O
NH2
NH
R2
R2
3
O
4
R3
O
O
base
R1
R1
O
NH
N
H
Cl
Cl
R3
b
HN
O
(NaH)
N
1
2
Cl
Cl
Scheme 1. Quinolones 2 are frequently prepared from N-acyl-o-amino-
phenylketones 1.
5
Scheme 2. Compound
according to Scheme 1. Reagents and conditions: (a) EtCOCl, Et3N,
CH2Cl2, rt weekend, 83%; (b) NaH (6 equiv), THF, 20 h reflux, 15%.
3
cannot be transformed into a quinolone
*
Corresponding author. Tel.: +41 61 6882636.
E-mail address: jens-uwe.peters@roche.com (J.-U. Peters).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.04.088

4030
J.-U. Peters et al. / Tetrahedron Letters 49 (2008) 4029–4032
OEt
Cl
Cl
Cl
a, b
c
7 -Me
Cl
O
O
O
(add to 3)
74%
PO(OEt)2
PO(OEt)2
7-Me
O
N
H
Cl
NH2
6
3
9
Cl
Cl
Cl
Cl
MeO
MeO
d
O
MeO
MeO
7 -Me
O
(DBU / LiCl)
72%
NH
N
H
O
O
N
NH2
H
O
10
11
PO(OEt)2
8
9
Scheme 3. Compound 3 can be transformed into quinolone 9 by acylation
with 7-Me, followed by an intramolecular olefination. Reagents and
conditions: (a) KOH, EtOH, H2O, 16 h rt, 90%; (b) (ClCO)2, DMF,
CH2Cl2, 6 h rt, quant.; (c) add to 3, CH2Cl2, 0 °C to rt, 2 h, 82%; (d) DBU,
LiCl, THF, 2 h rt, 86%.
7 -Pr
O
52%
O
N
NH2
H
OH
OH
12
13
Scheme 4. One-pot reactions exploring the scope of the acylation–
olefination sequence. Typical reaction conditions: add 7-Me to 3, DBU
(5 equiv), THF, 0 °C to rt, 6 h, then LiCl, rt overnight.
phosphonate ketene reagent was used to prepare N-
methyl-phenylquinolin-2-one.8 Carbamoylmethylphospho-
nates were transformed into 2-quinolon-3-yl phosphonates
in a Knoevenagel-type condensation.9 The possibility of a
HWE olefination was mentioned in this Letter, but was
not demonstrated. In another instance, a 2-quinolone was
prepared in a low yield by a HWE reaction with concomi-
tant amide formation.10 The latter method had the disad-
vantage that it gave rise to the trans-olefin as the major
product, which did not undergo cyclisation. 3-Unsubstitut-
ed 2-quinolones have been obtained in intramolecular
Wittig reactions, either by the addition of an o-amino-
phenylketone to the Bestmann ylide, Ph3P@C@C@O11,12
or from a phosphonium salt with NaH as a base.13
We obtained phosphonopropionylchloride 7-Me from
commercial 6 in two steps under standard conditions in
high yields. The acylation of aminophenylketone 3 with
this reagent led to 8. When subjected to the mildly basic
Masamune–Roush conditions (LiCl/DBU),14 this interme-
diate underwent an intramolecular HWE olefination to
give quinolone 9 in high overall yield (71% from 3).
To investigate if this acylation–olefination sequence can
also be performed as a one-pot reaction, we carried out the
initial acylation step in THF as a solvent, using an excess of
DBU as a base to trap liberated HCl (Scheme 4). After the
near-complete consumption of 3 (ꢀ6 h), LiCl was added.
Upon completion of the reaction, quinolone 9 was isolated
in a yield comparable to the two-step process. During this
and similar reactions, we found that 5 equiv of DBU are
necessary for the olefination step in the one-pot setting.
To explore if this method is equally applicable to elec-
tron-rich aminophenylketones, we converted 10 and the
unprotected phenolic compound 12 with phosphonopropi-
onylchloride 7-Me or phosphonopentanoylchloride 7-Pr
into the corresponding 2-quinolones (Scheme 4). 7-Me
and 7-Pr were used in amounts that were necessary for a
complete acylation of the aminoketone starting materials
(ꢀ1.5 equiv). Compound 11 was obtained in good yields,
whereas 13 was isolated in a somewhat lower yield, possi-
bly due to the reactivity of the free OH group and the
formation of by-products with the excess of acid chloride
reagent.
The acid-sensitive 14-NHBoc15 was transformed into
quinolone 15 in two steps, using EDC as a condensation
agent for the initial amide formation (Scheme 5). We
observed that both EDC and 14-NHBoc, which are water
soluble and therefore easily removed during workup, are
best used in a 2-fold excess for a complete conversion of
the aminoketone starting material. The amide intermediate
(not shown) then gave the desired 2-quinolone 15 in good
yields.
Piperidine has been used as a base to prepare 2-quino-
lone-3-phosphonic acids from unsubstituted phos-
phonoacetylchlorides as a result of an intramolecular
Knoevenagel condensation.9 This prompted us to test if a
Knoevenagel pathway might be preferred over the desired
HWE olefination pathway with unsubstituted HWE
reagents under the Masamune–Roush conditions. Indeed,
when we transformed aminoketone 16 into a quinolone
using the unsubstituted HWE reagent 14-H,16 we isolated
exclusively the Knoevenagel product 17 (Scheme 6). For
comparison, the methyl-substituted 14-Me16 cannot lead
to a Knoevenagel reaction and formed, under the same
conditions, the HWE olefination product 18 as expected.
Analogously, the heterocyclic aminoketone 19 reacted with
14-H to give the Knoevenagel product 20, whereas with
OH
NHBoc
a, b
NHBoc
O
PO(OMe)2
N
H
O
15
14-NHBoc
Scheme 5. An EDC-mediated amide condensation was used to obtain
quinolone 15 from the acid-sensitive 14-NHBoc. Reagents and conditions:
(a) o-aminoacetophenone (0.5 equiv), EDC, DMF, rt, overnight, 73%; (b)
DBU, LiCl, THF, 4 h rt, 88%.

J.-U. Peters et al. / Tetrahedron Letters 49 (2008) 4029–4032
4031
HOOC
PO(OEt)2
HOOC
PO(OEt)2
1 4 -H
1 4 -Me
PO(OEt)2
O
O
a (90%), b (58%)
a (90%), b (87%)
N
H
N
H
O
NH2
17
16
18
PO(OEt)2
S
S
S
O
1 4 -H
1 4 -Me
N
N
N
O
NH2
O
N
N
H
a (44%), b (14%)
a (50%), b (quant.)
H
20
Knoevenagel product
19
21
HWE olefination product
Scheme 6. Reagents and conditions: (a) 14 (2 equiv), EDC (2 equiv), DMF, rt, overnight, (b) DBU, LiCl, THF, 1 h rt. 19 was only partially converted in
the initial amide-forming step despite an excess of reagents, which is the main reason for the relatively low yields in step (a). The amide intermediates
(omitted for clarity) were isolated and characterised in all the cases.
2. Knorr, L. Justus Liebig’s Ann. Chem. 1886, 236, 69–115.
3. A compilation of current methods can be found in: Park, K. K.; Lee,
14-Me, the HWE olefination product 21 was formed. Thus,
at least when using the Masamune–Roush conditions for
J. J. Tetrahedron 2004, 60, 2993–2999.
the olefination step, this synthetic method seems to be
4. (a) Robl, J. A. Synthesis 1991, 56–58; (b) Sasakura, K.; Sugasawa, T.
limited to the preparation of 3-substituted quinolones.
Synth. Commun. 1987, 17, 741–753.
In summary, this Letter describes a convenient method
to prepare 2-quinolones from aminophenylketones under
mild conditions, which complements existing methods.
The transformation can be carried out in two steps or as
a one-pot reaction. 2-Quinolones with electron-donating
as well as –withdrawing substituents (9, 11, 13, 15, and
18) and a heterocyclic quinolone analogue (21) could be
prepared in generally good yields. Experimental details
for the preparation of 11 as a typical example can be found
in Ref. 17. The method is limited to the use of a-substituted
HWE reagents, as the a-unsubstituted phosphonate 14-H
gave rise to Knoevenagel-type products rather than HWE
olefination products.
5. (a) Blackburn, T. P.; Cox, B.; Guildford, A. J.; Le Count, D. J.;
Middlemiss, D. N.; Pearce, R. J.; Thornber, C. W. J. Med. Chem.
1987, 30, 2252–2259; (b) Camps, R. Arch. Pharm. (Weinheim, Ger.)
1901, 591–610.
6. (a) Hewawasam, P.; Chen, N.; Ding, M.; Natale, J. T.; Boissard, C.
G.; Yeola, S.; Gribkoff, V. K.; Starrett, J.; Dworetzky, S. I. Bioorg.
Med. Chem. Lett. 2004, 14, 1615–1618; (b) Rehwald, M.; Bellmann,
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Esteve, M. E.; Gaozza, C. H. J. Heterocycl. Chem. 1981, 18, 1061–
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7. (a) Goodell, J. R.; Puig-Basagoiti, F.; Forshey, B. M.; Shi, P.-Y.;
Ferguson, D. M. J. Med. Chem. 2006, 49, 2127–2137; (b) Angibaud,
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Lezouret, P.; Ligny, Y.; Mannens, G.; Damsch, S.; Mevellec, L.;
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Acknowledgement
This work was performed as a project of the internship
program ‘Schweizer Jugend forscht’.
References and notes
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17. Preparation of 11: (a) Phosphonopropionyl chloride 7-Me: A solution
of KOH (5.48 g, 84 mmol) in EtOH (12.5 ml) and H2O (5 ml) was
and the mixture was stirred for 5.5 h at rt. The solvent was evaporated
under reduced pressure and the residue was kept under vacuum
overnight to remove residual DMF. The product (1.3 g, quant.) was
used in the next step without further purification. (b) 4-Ethyl-6,7-
dimethoxy-3-methyl-2-quinolone (11): DBU (1.09 g, 7.17 mmol) and
phosphonopropionyl chloride 7-Me (490 mg, 2.15 mmol) were added
dropwise to
a solution of o-aminophenylketone 10 (300 mg,
1.43 mmol) in THF (8 ml). After stirring overnight at rt, HPLC
monitoring indicated the completion of the acetylation step. LiCl
(91 mg, 2.1 mmol) was added and the mixture was stirred for an
additional 4.5 h, after which HPLC analysis indicated the completion
of the olefination step. The volatiles were evaporated, the residue was
taken up in ethyl acetate, and washed with HCl (1 N) and satd
NaHCO3. After drying (Na2SO4) and evaporation of the solvent, the
title compound (254 mg, 72%) was isolated from the residue by
column chromatography (silica gel, CH2Cl2/MeOH = 100:0–90:10).
1H NMR (DMSO-d6): d 1.14 (3H, t), 2.08 (3H, s), 2.84 (2H, q), 3.79
(3H, s), 3.82 (3H, s), 6.86 (1H, s), 7.12 (1H, s), 11.48 (1H, br s).
added dropwise to triethyl 2-phosphonopropionate
6 (20.00 g,
84 mmol) and the mixture was stirred at rt over the weekend. The
volatile EtOH was evaporated, and the aqueous mixture was
extracted with Et2O. The aqueous layer was separated, acidified with
6 N HCl (pH 1), saturated with NaCl, and extracted several times
with CH2Cl2. The combined organic layers were dried (Na2SO4),
filtered and evaporated. The crude phosphonocarboxylic acid
(15.51 g, 88%) was chlorinated without further purification: Oxalyl-
chloride (870 mg, 7 mmol) was added dropwise to a solution of the
obtained acid (1.20 g, 6 mmol) in CH2Cl2 (8 ml) and DMF (0.4 ml),