Eleventh International Electronic Conference on Synthetic Organic Chemistry (ECSOC-11), http://www.mdpi.net/ecsoc-11, November 1-30, 2007


Reactions of Acetoacetates With Electron-deficient Anilines

Wolfgang STADLBAUER *, and Naresh S. BADGUJAR


Institut für Chemie, Organic Synthesis Group,
Karl-Franzens-University of Graz
Heinrichstrasse 28, A-8010 Graz (Austria)



Received: #00th #00 2007


  1. Abstract
  2. Introduction
  3. Synthesis of Acetanilides and Azomethines
  4. Ring Closure Reactions
  5. Experimental
  6. Acknowledgement
  7. References


The reaction of anilines, having electron-withdrawing substituents such as chloro- or trifluoromethyl groups, with acetoacetates was studied. Using the "watering protocol" [5], mainly acetanilides were obtained which were intended ty cyclize to 2-quinolones. However, in contrast to electron-rich anilides, it was not possible to obtain cyclized products from electron-deficient anilides.

intro scheme

4- And 2-trifluoromethyl quinolone derivatives (5, 6; R = CF3) are useful intermediates and their synthesis and reactions were studied in the last years extensively [1-8]. The synthesis from anilines 1 and acetoacetates 2 gives in the first step isomeric acetanilides 3 or azomethines 4, depending on the reaction conditions and substituents, which cyclize then in a further step, a reaction type known as Konrad-Limpach or as Knorr synthesis [9, 10].

We have shown that 4-trifluoromethyl-2-quinolones 5 with suitable substituents either in the aromatic or in the heteroaromatic ring (e.g. X = 6- and 7-OMe) show excellent fluorescence properties [1] which can be used as fluorescence markers for biological polymers such as proteins or amino-carbohydrates [3, 4].

Anilines 1 with electron donating substituents such as methoxy- or amino groups give excellent yields in the condensation and subsequent ring closure to both 2- and 4-quinolones 5, 6 (R = CF3) [1-4, 8]. Less reactive anilines with halogen substituents were investigated by several workgroups [5-7] and some success was obtained by dedicated reaction conditions ("watering protocol" of the Schlosser group [5] or temperature and catalyst control [7]).

Synthesis of Acetoacetanilides and Azomethines
formula scheme

For further studies of fluorescence properties we started a synthesis project which should lead from trifluoromethyl or dichloro substituted anilines to the corresponding quinolones.
Among the reported syntheses, only by the "watering protocol" of the Schlosser group [5] fluoro, chloro, bromo and iodo derivatives were obtained. Other syntheses were restricted to fluoro derivatives only [7]. By Schlosser's watering protocol, the 2-quinolone derivatives should be favored.

We performed the reactions from anilines 1a-c having trifluoromethyl groups as substituents in 2-,3- and 4-position, with acetoacetate 2a (R = Me) without solvent by heating to 130 °C for some hours and added some Milliliters of water in periodic intervals. By this reaction we obtained the acetoacetanilide intermediates 3a-c in good yields.

formula scheme

Trifluoroacetoacetate 2b (R = CF3) reacted at the same reaction conditions with anilines 1a-c by addition of water to slightly different anilide isomers. Spectral and and analytical data, revealed, that addition of water took place and stable ketone-hydrates were isolated. This seems to be also the main reason, why Schlosser's watering protocol [5] leads to anilide isomers: because of protected keto groups.

formula scheme

When 3-Chloro- or 2,3-dichloroaniline (1d,e was brought to reaction with acetoacetate 2a in the presence of water, very low yields were obtained from a product, which was assigned by spectral and analytical data as the enamine of the reaction product of acetoacetate with 2 molecules of aniline, on both reaction centers, the ester and the keton moiety.

formula scheme

The reaction of 1-phenylaniline 1f, having a phenyl group as desacivating substituent, with trifluoroacetoacetate 2b gave in low yields the anilide 3d, which exists according to spectral data predominantly as the enol tautomer.

Ringclosure Reactions
formula scheme

formula scheme

Recently we have published the synthesis of 6,7-dimethoxy-4-trifluoromethylquinolones [3,4] in a one pot reaction from anilines 1g, h by thermal condensation to an about 9:1 mixture of 3 and 4, which were subsequently cyclized by heating in 75% sulfuric acid. After recrystallization pure, isomer-free 2-quinolones 5g,h were obtained; the yields were ranging between 85-95%.

Application of the watering method followed by a cyclization in 95% sulfuric acid as described in ref. [5] did neither improve the isomer ratio nor the yields, because after recrystallization only 40% was obtained. Maybe the application of 95% sulfuric acid is not suitable for the methoxy groups.

Attempts to cyclize the desactivated anilides 3 and 7 to corresponding quinolones 5, using 75% or 95% sulfuric acid, failed, because either no reaction took place, or - at prolonged reaction times - mainly decomposition products were obtained; probably the influence of chloro-, dichloro- or trifluoromethyl groups prevents the attack at the aromatic aniline ring.

To investigate thermal ringclosure conditions of 3a-c, thermal behavior was investigated by thermoanalytical methods. Differential thermal scanning calorimetry (DSC) shows that after the melting area (90-105 °C) another endothermic area follows (105-120 ° onset), and at about 210-250 °C an exothermix reaction is visible, in some cases followed by a further melting area at about 250-275 °C.

As an example the DSC diagram for 7a is shown left.

Attempts to transform these findings to a preparative scale, however, failed and only decomposition products were obtained.


General procedure for the preparation of acetanilides 3, 7 and 8:
A mixture of one equivalent of acetoacetate or trifluoroacetoacetate was heated to 130 °C for 1-6 hours. During this period every 20 min water (2 mL) was added). Then the mixture was cooled in an ice-bath, triturated with methanol or hexane, the solid filtered and washed with the same solvent. After crystallization from either methanol, hexane or ligroin, colorless or brownish prisms were obtained; the yield was 10-70 % for anilides 3, 25-40% for anilides 7 and 8% for enamines 8.

Typical spectroscopical signals:
IR signals for acetoacetanilides 3a-c: ketone at 1715-1730 cm1, amide at 1659-1673 cm1;
for the enolic structure of acetoacetanilide 3d: no ketone signal, amide signal at 1670 cm1;
for acetanilides 7a-c: no ketone signal, amide signal at 1644-1673 cm1;
for enamines 8: amide signal at 1650-1660 cm1

NMR signals for acetoacetanilides 3a-c: CH2 group as singlets at 3.63-3.65 ppm, methyl group as singlets at 2.35-2.36 ppm, NH group as singlets at 9.58-9.59 ppm;
for the enolic structure of acetoacetanilide 3d: CH as singlet at 5.89 ppm; OH as singlet at 10.15 ppm;
for acetanilides 7a-c: CH2 group as singlet at 2.85-2.87 ppm, OH signals as singlet at 5.20-5.36 ppm;
for the enamines 8: methyl signal as singlets at 1.90-2.02 ppm; CH signal as singlets at 4.87-5.86 ppm.


This work was supported by a 1-year-scholarship of the Austrian Academic Exchange Service for N.S.B.


[1] W. M. F. Fabian, K. S. Niederreiter, G. Uray, W. Stadlbauer , J. Mol. Structure, 477 (1999) 209-220.
[2] G.A. Strohmeier, W.M.F. Fabian, G. Uray, Helv. Chim. Acta, 87 (2004) 215-226; G. Uray, K. H. Niederreiter, F. Belaj, W. M. F. Fabian, Helv. Chim. Acta, 82 (1999) 1408-1417.
[3] N. S. Badgujar, M. Pazicky, P. Traar, A. Terec-Suciu, G. Uray, W. Stadlbauer, Eur. J. Org. Chem., 2006, 2715-2722;
[4] G. Uray, N. S. Badgujar, S. Kováková, W. Stadlbauer, J. Heterocycl. Chem., in press.
[5] M. Marull, O. Lefebvre, M. Schlosser, Eur. J. Org. Chem., (2004) 54-63;
[6] O. Lefebvre, M. Marull, M. Schlosser, Eur. J. Org. Chem., (2003) 2115-21;
M.Marull, M.Schlosser, Eur. J. Org. Chem., 2003, 1576-1588; M. Schlosser, M. Marull, Eur. J. Org. Chem., (2003) 1569-75.
[7] D.O. Berbasov, V. A. Soloshonok, Synthesis, (2003) 2005-2010.
[8] H.-K. Lee, H. Cao, T. M. Rana, J. Comb. Chem., 7 (2005) 279-284.
[9] M. Conrad, L. Limpach, Ber. Dtsch. Chem. Ges., 20 (1898) 944; 24 (1891) 2990; L. Limpach, Ber. Dtsch. Chem. Ges., 64 (1931) 970.
[10] R. Knorr, Justus Liebigs Ann. 236 (1886) 69-115