HETEROCYCLES

Short Paper | Special issue | Vol. 84, No. 2, 2012, pp. 1277-1284
Received, 15th June, 2011, Accepted, 20th July, 2011, Published online, 28th July, 2011.
DOI: 10.3987/COM-11-S(P)38

■ A Facile and Convenient Method for the Synthesis of 6,8-Bis(trifluoroacetyl)quinolin-5-amines

Dai Shibata, Maurice Médebielle, Mizuki Hatakenaka, and Etsuji Okada*

Department of Chemical Science and Engineering, Graduate School of Engineering, Kobe University, 1-1 Rokkodai-cho, Nada-ku, Kobe 657-8501, Japan

Abstract

New 6,8-bis(trifluoroacetyl)quinolin-5-amines (6) were easily prepared in moderate to high yields by the aromatic nucleophilic nitrogen-nitrogen exchange reaction of N,N-dimethyl-6,8-bis(trifluoroacetyl)-quinolin-5-amine (5) with various aliphatic and aromatic amines.

The quinoline skeleton has a ubiquitous presence in many natural products having significant biological activities and quinoline derivatives have wide applications in medicinal chemistry.1 In particular, many quinoline amines, which are represented by quinolin-4-amines such as chloroquine and amodiaquine, are recognized as pharmaceutically important compounds.2 Similarly, quinolin-5-amines have also been found to have interesting biological activities such as 5-HT1 receptor antagonist3a-c and NHE-1 inhibitor.3d Furthermore, quinolin-5-amines could be converted to many quinoline-fused polycyclic heterocyclic compounds, for example pyrrolo[2,3-f]qunolines4a and 1,7-phenanthrolines,5a,5b which also indicate a variety of biological properties,4,5 by using various ring formation reactions. Besides, significant attention in recent years has been focused on the development of new methodologies for the syntheses of many kinds of fluorine-containing heterocycles, since these compounds are now widely recognized as valuable materials showing interesting biological activities and for their potential use in medicinal and agricultural scientific fields.6 Therefore, the development of new efficient synthetic methods for fluorine-containing quinolin-5-amine derivatives is very meaningful due to not only their own bioactivities, but also the availability as building blocks of fluorine-containing heterocycles.
Previously, we have reported that N,N-dimethyl-2,4-bis(trifluoroacetyl)naphthalen-1-amine (1) and N,N-dimethyl-5,7-bis(trifluoroacetyl)quinolin-8-amine (2) undergo novel aromatic nucleophilic substitutions with amines under mild conditions to give the corresponding N-substituted 2,4-bis(trifluoroacetyl)naphthalen-1-amines (3)7 and 5,7-bis(trifluoroacetyl)quinolin-8-amines (4),8 respectively (Scheme 1). Moreover, we succeeded in extending this type of aromatic nucleophilic substitution to the simple syntheses of various trifluoromethyl-containing heterocycles with naphthalene9 and quinoline10 skeletons.

Herein, we now wish to report the facile and convenient synthesis of new 6,8-bis(trifluoroacetyl)quinolin-5-amines (6), which are greatly expected to be utilized as novel bioactive compounds and novel building blocks for the construction of fluorine-containing heterocycles having quinoline skeleton, by the SNAr reaction of N,N-dimethyl-6,8-bis(trifluoroacetyl)quinolin-5-amine (5)11 with various alkyl- and arylamines.
The requisite starting material (5) was easily prepared in moderate yield in three steps by reduction,12 N,N-dimethylation,13 and bis(trifluoroacetylation) of commercially available 5-nitroquinoline.11 The aromatic nucleophilic substitution of 5 with various amines was examined, as shown in Scheme 1 and summarized in Table 1. The reaction of 5 with aqueous ammonia proceeded at 80 °C in acetonitrile to give 6,8-bis(trifluoroacetyl)quinolin-5-amine (6a) in 82% yield (entry 1). Primary aliphatic amines such as methyl-, isopropyl-, tert-butyl-, benzyl-, and propargylamines also reacted cleanly to provide the desired amine exchange products (6b-f) in 56-91% yields (entries 2-6). In the case of propargylamine,11

the pyridine-ring formation reaction of the desired product (6f)11,14 with dimethylamine, which was generated by the elimination of the dimethylamino group from 5, also occurred in situ to afford
1-(3-dimethylaminomethyl-4-trifluoromethyl-1,7-phenanthrolin-6-yl)-2,2,2-trifluoroethane-1,1-diol as a by-product in 34% yield. In addition, the reaction of 5 with secondary amine, pyrrolidine, also took place to give the desired pyrrolidino derivative (6g) in 62% yield (entry 7). Less nucleophilic aromatic amines such as p-anisidine, aniline, and p-chloroaniline were also found to be usable for this type of exchange reaction and thus the introduction of arylamino groups into the 5-position of quinoline system was readily achieved (entries 8-10).
It was also found that there is a great difference in reactivity among three substrates, naphthalen-1-amines (1), quinolin-8-amines (2), and quinolin-5-amines (5). For example, the results of the amine exchange reaction of 1, 2, and 5 with pyrrolidine were shown in Scheme 3. The reactivities decreased in the following order, quinolin-8-amines (2) > naphthalen-1-amines (1) > quinolin-5-amines (5). The difference between quinolin-8-amines (2) and naphthalen-1-amines (1) is expectedly and depends on the

difference in electron-withdrawing abilities between the pyridine and benzene rings being fused into the benzene ring where the amine exchange reaction takes place. However, in striking contrast to the
expected increase in reactivity of quinolin-8-amines (2), the reactivity of quinolin-5-amines (5) was dramatically decreased and became lowest among three substrates. It is noteworthy that there is an exceedingly great difference between quinolin-8-amine system (2) and quinolin-5-amine one (5), although the reason is not known at present.
In summary, we have demonstrated a facile and convenient approach for the syntheses of various 6,8-bis(trifluoroacetyl)quinolin-5-amines (6) which are not easily accessible by other methods, by the amine exchange reaction of N,N-dimethyl-6,8-bis(trifluoroacetyl)quinolin-5-amine (5) as a key step, starting from commercially available 5-nitroquinoline. Evaluation of biological activities of new fluorine-containing compounds (6) and the investigations of their synthetic applications are now under way.

EXPERIMENTAL
Melting points were determined on an electrothermal digital melting point apparatus and are uncorrected. 1H NMR spectra were measured on a Bruker Avance 500 spectrometer (1H at 500 MHz, 13C at 126 MHz); TMS was used as an internal standard. IR spectra were recorded on a PerkinElmer Spectrum ONE spectrophotometer. Microanalyses were obtained with a Yanaco CHN-Coder MT-5 analyzer.
Aromatic Nucleophilic Substitution of N,N-Dimethyl-6,8-bis(trifluoroacetyl)quinolin-5-amine (5) with Amines; General Procedure
The appropriate amine (0.3-3 mmol) was added to a solution of 5 (109 mg, 0.3 mmol) in MeCN or PrCN (2.4 mL), and the mixture was stirred at 50 °C, at 80 °C or under reflux for 1-24 h. Evaporation of the solvent in vacuo gave a crude mixture, which was subjected to column chromatography (silica gel, n-hexane-EtOAc, 5:1 to 1:1) to give the corresponding 6a-j, 7.
6,8-Bis(trifluoroacetyl)quinolin-5-amine (6a): mp 220 °C (n-C6H14/EtOAc); IR (KBr): 3520, 3323, 1662, 1623 cm-1; 1H NMR (CDCl3): δ (monohydrate form) 8.89 (d, J = 4.5 Hz, 1H, H-2), 8.60-8.03 (br, 2H, NH or OH), 8.56 (d, J = 9.0 Hz, 1H, H-4), 8.40 (s, 1H, H-7), 7.63 (br s, 2H, NH or OH), 7.54 (dd, J = 4.5, 9.0 Hz, 1H, H-3). Anal. Calcd for C13H6F6N2O2・H2O: C, 44.08; H, 2.28; N, 7.91. Found: C, 43.90; H, 2.48; N, 7.68.
N-Methyl-6,8-bis(trifluoroacetyl)quinolin-5-amine (6b): mp 138-139 °C (n-C6H14/EtOAc); IR (KBr): 3311, 1643, 1616 cm-1; 1H NMR (CDCl3): δ (monohydrate form) 10.65 (br s, 1H, NH), 8.83-8.81 (m, 2H, H-2, H-4), 8.42 (s, 1H, H-7), 7.44 (dd, J = 4.5, 9.0 Hz, 1H, H-3), 7.23 (br s, 2H, OH), 3.57 (d, J = 5.5 Hz, 3H, CH3). Anal. Calcd for C14H8F6N2O2・H2O: C, 45.66; H, 2.74; N, 7.61. Found: C, 45.47; H, 2.87; N, 7.68.
N-Isopropyl-6,8-bis(trifluoroacetyl)quinolin-5-amine (6c): mp 106-107 °C (n-C6H14/EtOAc); IR (KBr): 3336, 1644, 1609 cm-1; 1H NMR (CD3CN): δ (monohydrate form) 10.15-9.63 (br, 1H, NH), 8.72-8.47 (m, 2H, H-2, H-4), 8.23-7.85 (m, 3H, H-7,OH), 7.37 (dd, J = 5.0, 9.0 Hz, 1H, H-3), 4.70-3.92 (m, 1H, CH), 1.38 (d, J = 6.0 Hz, 6H, CH3). Anal. Calcd for C16H12F6N2O2・H2O: C, 48.49; H, 3.56; N, 7.07. Found: C, 48.45; H, 3.78; N, 6.89.
N-tert-Butyl-6,8-bis(trifluoroacetyl)quinolin-5-amine (6d): mp 110-111 °C (n-C6H14/EtOAc); IR (KBr): 3338, 1646, 1620 cm-1; 1H NMR (CD3CN): δ 9.14-8.83 (m, 2H, H-2, H-4), 8.53 (br s, 2H, H-7, NH), 7.72 (dd, J = 4.0, 9.0 Hz, 1H, H-3), 1.36 (s, 9H, CH3). Anal. Calcd for C17H14F6N2O2・H2O: C, 49.76; H, 3.93; N, 6.83. Found: C, 49.98; H, 4.05; N, 6.73.
N-Benzyl-6,8-bis(trifluoroacetyl)quinolin-5-amine (6e): mp 207-209 °C (dec.) (n-C6H14/EtOAc); IR (KBr): 3336, 1633, 1616 cm-1; 1H NMR (CD3CN): δ (monohydrate form) 10.42-10.02 (br, 1H, NH), 8.72-8.35 (m, 2H, H-2, H-4), 8.18-7.47 (m, 3H, H-7, OH), 7.30-7.00 (m, 6H, H-3, Ph), 4.83 (d, J = 6.0 Hz, 2H, CH2). Anal. Calcd for C20H12F6N2O2・H2O: C, 54.06; H, 3.18; N, 6.30. Found: C, 54.07; H, 3.38; N, 6.25.
5-(Pyrrolidin-1-yl)-6,8-bis(trifluoroacetyl)quinoline (6g): mp 137-138 °C (n-C6H14/EtOAc); IR (KBr): 3389, 3236, 1610 cm-1; 1H NMR (CDCl3): δ 8.97 (d, J = 4.0 Hz, 1H, H-2), 8.61 (s, 1H, H-7), 8.35 (d, J = 8.0 Hz, 1H, H-4), 7.37 (dd, J = 4.0, 8.0 Hz, 1H, H-3), 3.67 (br s, 4H, NCH2), 2.08 (br s, 4H, CH2). Anal. Calcd for C17H12F6N2O2: C, 52.32; H, 3.10; N, 7.18. Found: C, 52.04; H, 3.39; N, 7.17.
N-4-Methoxyphenyl-6,8-bis(trifluoroacetyl)quinolin-5-amine (6h): mp 128-133 °C (dec.) (n-C6H14/EtOAc); IR (KBr): 3446, 1650, 1612 cm-1; 1H NMR (CDCl3): δ (monohydrate form) 11.16 (br s, 1H, NH), 8.57 (dd, J = 2.0, 4.0 Hz, 1H, H-2), 8.37 (br s, 1H, H-7), 8.12 (dd, J = 2.0, 9.0 Hz, 1H, H-4), 7.30-6.13 (br, 2H, OH), 7.12-6.68 (m, 5H, H-3, Harom), 3.80 (s, 3H, OCH3). Anal. Calcd for C20H12F6N2O3: C, 54.31; H, 2.73; N, 6.33. Found: C, 54.39; H, 2.88; N, 6.10.
N-Phenyl-6,8-bis(trifluoroacetyl)quinolin-5-amine (6i): mp 115-116 °C (n-C6H14/EtOAc); IR (KBr): 3304, 1660, 1613 cm-1; 1H NMR (CDCl3): δ 11.18 (br s, 1H, NH), 8.79 (d, J = 3.0 Hz, 1H, H-2), 8.56 (br s, 1H, H-7), 8.29 (d, J = 9.0 Hz, 1H, H-4), 7.42-7.07 (m, 6H, H-3, Harom). Anal. Calcd for C19H10F6N2O2・H2O: C, 53.03; H, 2.81; N, 6.51. Found: C, 52.98; H, 2.71; N, 6.71.
N-4-Chlorophenyl-6,8-bis(trifluoroacetyl)quinolin-5-amine (6j): mp 156-157 °C (n-C6H14/EtOAc); IR (KBr): 3336, 1660, 1615 cm-1; 1H NMR (CDCl3): δ 11.00 (br s, 1H, NH), 8.83 (d, J = 4.5 Hz, 1H, H-2), 8.57 (br s, 1H, H-7), 8.28 (d, J = 8.5 Hz, 1H, H-4), 7.30 (d, J = 8.5 Hz, 2H, Harom), 7.23 (dd, J = 4.5, 8.5 Hz, 1H, H-3), 7.00 (d, J = 8.5 Hz, 2H, Harom). Anal. Calcd for C19H9ClF6N2O2・H2O: C, 49.10; H, 2.39; N, 6.03. Found: C, 49.13; H, 2.51; N, 5.88.
Comparison of Reactivity among Naphthalen-1-amines (1), Quinolin-8-amines (2), and Quinolin-5-amines (5) in the N-N Exchange Reaction with Pyrrolidine; General Procedure
Pyrrolidine (71.1 mg, 1 mmol) was added to a solution of the appropriate substrate (1 mmol) in MeCN (8.0 mL), and the mixture was stirred at room temperature (23 °C) for 2 h. The prompt evaporation of the solvent and the remained pyrrolidine under the reduced pressure at room temperature gave a crude mixture. The conversion was determined by 1H NMR measurement of the crude reaction mixtures (calculated from integration ratio between methyl protons of dimethylamino group and methylene protons of pyrroridinyl group).

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