2
reagents that have been reported to initiate Friedel-Crafts acylation
of carboxylic acids such as polyphosphoric acid (PPA) and Eaton’s
reagent (a solution of phosphorus pentoxide solution in
methanesulfonic acid).2,5,16 PPA-initiated reactions required high
temperatures at 120-140 °C and at those temperatures the
monoanilide intermediate 2 underwent rapid decarboxylation. In
the case of Eaton’s reagent, the reactions were hard to carry out
under mild conditions due to its high viscosity, and temperatures
higher than 70 °C resulted in the decarboxylation of intermediate
2. Reagents such as acetic anhydride and methanesulfonic acid did
not yield any product. However, when the reaction was run in a
mixture of acetic anhydride and methanesulfonic acid, the product
was obtained in low yield. Fortunately, methanesulfonic acid
anhydride (MSAA) was reported as an efficient reagent for the
Friedel-Crafts acylation of aromatic compounds using carboxylic
acids as acyl donor and was found to successfully promote the
cyclization of malonic acid monoanilides to 4-hydroxy-2-
quinolinones.17 The solvent-free reactions were carried out for a
few hours as specified in Table 1 at 60 °C (conversion of 2e to 3e
was sluggish and was run at 70 °C) using 2 equivalents of MSAA.
The product was isolated by trituration with ethyl acetate in a dry
ice-acetone bath and then washed with cold water and ethyl
acetate. The reaction yields were excellent as seen in Table 1.18
under reported conditions. Mild reaction conditions for the N-
acylation and an efficient reagent (MSAA) for the intramolecular
Friedel-Crafts cyclization steps were found to give 4-hydroxy-2-
quinolinones in excellent yields. The reaction sequence worked
well for substrates with electron-donating and moderately
electron-withdrawing groups but not those with strong electron-
withdrawing groups.
Acknowledgments
This investigation was supported by grants from San Francisco
State University (T.A.) and CSU Program for Education &
Research in Biotechnology (W.W.). The NMR facility was funded
by the National Science Foundation (DBI 0521342 and DBI
1625721). We also thank Professor Ihsan Erden for helpful
discussions.
References and Notes
1.
2.
3.
Ahmed N, Brahmbhatt KG, Singh IP, Bhutani KK. J. Heterocyclic
Chem. 2011; 48: 237-240.
Gao W, Hou W, Zheng M, Tang L. Synth. Commun. 2010; 40:
732–738.
Adbou MM. Arab. J. Chem. 2017; 10: S3324-S3337 and
references cited therein.
The products were characterized using NMR spectroscopy as
compared to those reported in literature.2 In the case of
quinolinone 3f, two products were formed because the acylation
could occur at either one of the two positions adjacent to the amide
group and the product ratio (approximately 1.6:1 in favor of the
isomer from the less sterically hindered pathway) was determined
by NMR signal integration.
4.
5.
Arya K, Agarwal M. Bioorg. Med. Chem. Lett. 2007; 17: 86-93.
Zewge D, Chen C, Deer C, Dormer PG, Hughes DL. J. Org.
Chem. 2007; 72: 4276-4279.
6.
7.
Ferretti MD, Neto AT, Morel AF, Kaufman TS, Larghi EL Eur. J.
Med. Chem 2014; 81: 253-266.
Hamama WS, Hassanien AEDE, Zoorob HH Synth. Commun.
2014; 44: 1833-1858.
8.
9.
Ishida T, Kikuchi S, Yamada T Org. Lett. 2013; 15: 3710-3713.
Ahmed N, Brahmbhatt KG, Keyur G, Sadbe S, Mitra D, Singh IP,
Bhutani KK Bioorg. Med, Chem. 2010; 18: 2872-2879.
10. Jampilek J et al. Molecules 2009; 14: 1145-1159.
11. Dittmer DC, Li Q, Avilov DM J. Org. Chem. 2005; 70: 4682-
4686.
Table 1. Yields for the conversion of anilines 1 to malonic acid monoanilides
2 and their subsequent conversion to 4-hydroxy-2-quinolinones 3
12. Jung JC, Jung YJ, Park OS Synth. Commun. 2001; 31: 1195-1200.
13. Kappe TF Farmaco 1999; 54: 309-315.
14. Dodia N, Shah A Indian J. Heterocycl. Chem. 1999; 9: 139-142.
15. Sicker D, Rabe A, Zakrzewski A, Mann G J. Prak. Chem. 1987;
329: 1063-70.
Entry
Anilines(1, Y
Yield (2,
isolated)
(%)
78
Reaction time
Yield (3,
isolated)
(%)
=)
to form 3
(hours)
16. Park S, Lee J, Lee K. Bull. Korean Chem. Soc. 2007; 28: 1203-
1205.
a
b
c
d
e
f
H
3
6
90
2-methyl
4-methoxy
4-fluoro
4-chloro
3,4-dimethyl
70
90
17. Wilkinson MC. Org. Lett. 2011; 13: 2232-2235.
18. Experimental details: All reagents were obtained from commercial
sources and used without further purification. Typical
experimental procedures for the conversion of anilines 1 to
malonic acid monoanilides 2 and from 2 to quinolinones 3 are
described below using the syntheses 4-hydroxy-2-quinolinone (3a)
as an example.
77
3
91
76
10
13
3
71
75
52
72
a
83
A mixture of aniline (1a, 500 mg, 5.4 mmol) and Meldrum’s
acid (774 mg, 5.4 mmol) in a test tube was heated for 4 hours at
60 °C (reaction was complete as monitored by TLC). The reaction
mixture was partitioned between aqueous sodium bicarbonate
solution and ethyl acetate. The aqueous layer was acidified with
concentrated HCl to pH 1 and extracted with ethyl acetate (3 x 15
mL). The combined organic layer was dried over anhydrous
sodium sulfate and the solvent was removed to yield malonic acid
monoanilide 2a as a white solid (746 mg, 78%).
A 25mL two-necked round-bottom flask was flame dried,
charged with MSAA (587 mg, 3.4 mmol) , flushed with nitrogen
gas, and fitted with a drying tube containing CaCl2. The flask was
heated at 60 °C until MSAA melted. Monoanilide 2a (300 mg, 1.7
mmol) was added and the flask was flushed with nitrogen gas
again. The reaction was complete after three hours (verified by
TLC). The reaction was placed in a dry ice bath and triturated with
ethyl acetate. The solid that formed was filtered and the solid was
washed with cold water and ethyl acetate to produce quinolinone
3a as an off-white solid (244 mg, 90%).
a
Two regioisomers formed in approximately 1.6:1 ratio as
determined by NMR signal integration.
The reaction sequence gave excellent yields for anilines with
electron-donating and moderately electron-withdrawing groups.
However, the synthetic scheme did not work for aniline with
strong electron-withdrawing groups. When the strong electron-
withdrawing groups such as the cyano or nitro groups were at the
4-position, the malonic acid monoanilide did not form or was
formed in poor yields. When the strong electron-withdrawing
groups were at the 3-position, the malonic acid monoanilides were
formed but failed to undergo Friedel-Crafts acylation.
3. Conclusions
The synthetic route for 4-hydroxy-2-quinolinones through
malonic acid monoanilide intermediates was re-examined and the
intermediates were observed to readily undergo decarboxylation