HETEROCYCLES

Paper | Regular issue | Vol. 89, No. 10, 2014, pp. 2303-2317
Received, 7th August, 2014, Accepted, 27th August, 2014, Published online, 29th August, 2014.
DOI: 10.3987/COM-14-13070

■ Efficient Syntheses of Fluorine-Containing Pyrimido[5,4-c]quinolines and Benzo[h][1,6]naphthyridines by Condensation Reactions of 3-Trifluoro-acetylquinolin-4-amine with Aldehydes and Ketones

Etsuji Okada,* Mizuki Hatakenaka, Shiro Nakano, Takushi Sakaemura, Takashi Mori, and Terukazu Terauchi

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

Abstract

3-Trifluoroacetylquinolin-4-amine reacted easily with various aldehydes in the presence of aqueous ammonia to afford mainly trifluoromethylated pyrimido[5,4-c]quinoline derivatives in moderate to high yields. In contrast, the use of ketones instead of aldehydes under almost the same conditions, mostly gave benzo[h][1,6]naphthyridine derivatives in excellent combined yields.

INTRODUCTION
It is common knowledge that pyrimido[5,4-c]quinolines are important systems that are encountered in a number of natural products and have wide applications for a variety of purposes such as biological materials, drugs, and agrochemicals because they indicate various biological activities such as analgesic,1 anticonvulsant,1,2 antipsychotic,1 antibacterial,3 antitumor,2,4 antioxidant,5 and PDK-1 inhibitory activities.6,7
Similarly, benzo[h][1,6]naphthyridines have attracted much attention because of their biological properties. For example, they have demonstrated potential applications as topoisomerase IIα8 and CK29 inhibitors with anticancer properties, analgesic,10 antimalarial,11 and bactericide12 activities, 5-HT4 receptor antagonist,13,14 and poly ADP-ribose polymerase-1 inhibitor.15
Besides, in recent years, the development of new methodologies for the synthesis of many kinds of fluorine-containing heterocycles has been the subject of much attention because of their importance and potential as the organic materials showing interesting biological activities in medicinal and agricultural scientific fields.16-18
However, there has been only one report about compounds directly introduced fluorine atom or perfluoroalkyl to pyrimido[5,4-c]quinoline skelton.7 Moreover the synthesis of only two example of 7-fluoro13 and 2-trifluoromethyl17-19 derivatives has been achieved in the benzo[h][1,6]naphthyridine system.
Because of the reasons mentioned above, it is really worth to develop the facile synthetic methods of fluorine-containing pyrimido[5,4-c]quinolines and benzo[h][1,6]naphthyridines, which would be expected to present new activities and functionalities.
Previously, we have reported the facile synthetic methods of novel heterocycles bearing trifluoromethyl groups by using our originally developed fluorine-containing building blocks. For example, we carried out applying the novel aromatic nucleophilic substitutions (N-N, N-S, and N-O exchanges) of N,N-dimethyl-2,4-bis(trifluoroacetyl)-1-naphthylamine20 and N,N-dimethyl-5,7-bis(trifluoroacetyl)-8-quinolylamine21 with various N-, S-, and O-nucleophiles and the subsequent acid catalyzed cyclizations to the simple syntheses of naphthalene- and quinoline-fused heterocycles bearing trifluoromethyl groups. Moreover, we also succeeded in utilizing trifluoroacetylated 1-naphthyl-,22 8-quinolyl-,23 and 5-quinolylamines24 for the simple syntheses of fluorine-containing naphthalene- and quinoline-fused heterocycles by the use of their three-component condensation and pyridine-ring formation reactions.
In continuation of our works, we use 3-trifluoroacetylquinolin-4-amine (1) as a new fluorine-containing building block, and herein wish to present simple and efficient syntheses of the title compounds (2, 3, 6). That is to say, 1 underwent the three-component condensation reaction with aldehydes in the presence of aqueous ammonia to give the pyrimido[5,4-c]quinoline derivatives (2, 3), and in the case of aliphatic aldehydes, benzo[h][1,6]naphthyridine derivatives (4) were also obtained by Friedländer-type cyclization. Under the quite similar conditions, the reaction of 1 with ketones gave benzo[h][1,6]naphthyridine derivatives (6) selectively. As identified above, these novel fluorinated compounds are powerfully expected to show interesting biological properties.

RESULTS AND DISCUSSION
3-Trifluoroacetylquinolin-4-amine (1), the new fluorine-containing building block, was easily synthesized in high yield by the dimethylamino-amino exchange reaction of N,N-dimethyl-3-trifluoroacetylquinolin-4-amine with aqueous ammonia (Scheme 1).25
Initially, we attempted to synthesize the novel fluorine-containing pyrimido[5,4-c]quinoline derivatives (2 and 3) by the reaction of 1 with various aldehydes and aqueous ammonia, and the results are shown in Scheme 2 and summarized in Table 1. The three-component condensation reaction of 1 with

acetaldehyde (5 eq) in the presence of aqueous ammonia (10 eq) proceeded quickly at 50 °C in acetonitrile to give the corresponding fluorine-containing dihydropyrimido[5,4-c]quinoline (2a), which is the precursor of expected pyrimido[5,4-c]quinoline (3a), in 46% yield, together with benzo[h][1,6]naphthyridine derivative (4a) in 31% yield (entry 1). The latter product 4a would be formed by Friedländer-type cyclization,26 in which the ammonia works not as a nucleophile but as a base. Similarly in the case of propionaldehyde, 2b and 4b were obtained in the presence of 3 eq of aqueous ammonia in 58% and 20% yields, respectively (entry 2). In the cases of other linear aliphatic aldehydes, such as n-butyraldehyde, n-valeraldehyde, n-hexylaldehyde, and n-heptylaldehyde, we solely obtained the corresponding dihydropyrimido[5,4-c]quinolines (2c,e,h,i) in moderate to good yields (entries 3, 5, 8, 9). Isobutyraldehyde, isovaleraldehyde, and 2-methylbutyraldehyde also reacted to afford 2d, 2f, and 2g exclusively and Friedländer-type cyclization was not occurred due to difficulty of deprotonation at sterically hindered α-position (entries 4, 6, 7). The reaction of 1 with aromatic aldehydes, such as p-substituted benzaldehydes, and aqueous ammonia gave dihydropyrimido[5,4-c]quinolines (2j-n) in good to high yields (entries 10-14). In the cases with p-tolualdehyde, benzaldehyde, and p-chlorobenzaldehyde, the dehydrogenated products of 2l-n, pyrimido[5,4-c]quinolines (3l-n) were also obtained in 10-18% yields (entries 12-14).27
Treatment of dihydropyrimido[5,4-c]quinolines (2a-n) with DDQ at room temperature for 1 h led to successful dehydrogenation to give fluorine-containing pyrimido[5,4-c]quinolines (3a-n) in 80-100% yields (Scheme 3).
Next, we examined the reaction of 1 with formaldehyde in the presence of aqueous ammonia. In contrast to the results mentioned in Scheme 2 and Table 1, there was no incorporation of the nitrogen atom of ammonia into products in the reaction of 1 with formaldehyde and fluorine-containing 2,4-dihydro-1H-[1,3]oxazino[5,4-c]quinoline (5) was solely obtained in 73% yield without any formation of the corresponding dihydropyrimido[5,4-c]quinoline derivative. These phenomena were also observed in our previous experiment of the naphthalene system (Scheme 4).22

Furthermore, the present cyclization reaction was applied to a variety of ketones, and we carried out the syntheses of novel fluorine-containing benzo[h][1,6]naphthyridines (6) (Scheme 5, Table 2). Reaction of 1 with acetone took place cleanly at 50 °C in acetonitrile in the presence of aqueous ammonia to afford the corresponding benzo[h][1,6]naphthyridine (6a) in high yield without any formation of pyrimido[5,4-c]quinoline derivative (entry 1). In the case of diethyl ketone, the prolonged time (96 h) and more elevated temperature (130 °C) were required for completion of the reaction and 6b was obtained in 63% yield, together with 37% yield of the product incorporated the nitrogen atom of ammonia, pyrimido[5,4-c]quinoline (7b) (entry 2). The reaction with asymmetric ketones such as ethyl methyl ketone, isopropyl methyl ketone, and acetophenone, occurred easily to give the corresponding 2-(alkyl or aryl)-benzo[h][1,6]naphthyridines (6c-e) in high yields (entries 3-5). Although two products were possible in the case of ethyl methyl ketone, only 2-ethyl derivative (6c) was obtained selectively. Moreover, the reactions with aliphatic cyclic ketones yielded heterotetracyclic compounds (6f-i) in moderate to high yields, except for the case of cyclohexanone, which afford spiro-substituted dihydropyrimido[5,4-c]quinoline derivative (7g) (39%) together with 6g (59%).

In summary, we succeeded in utilization of 1 as a new fluorine-containing building block and could present a simple and efficient synthetic method for novel fluorine-containing pyrimido[5,4-c]quinolines (2, 3, and 7), and benzonaphthyridines (4, 6), which are not easily accessible by other methods. Moreover, we could obtain the fluorine-containing 2,4-dihydro-1H-[1,3]oxazino[5,4-c]quinoline (5) instead of expected pyrimido[5,4-c]quinoline by the reaction of 1 with formaldehyde. Evaluation of biological activities for 2-7 is now underway

EXPERIMENTAL
All reagents and solvents were purchased as reagent grade and used without further purification. Melting points were determined on an electrothermal digital melting point apparatus and are uncorrected. 1H NMR spectra were obtained with JEOL PMX 60SI (60 MHz) and Bruker Avance 500 (500 MHz) spectrometers and 13C NMR spectra were obtained with a Bruker Avance 500 (125 MHz) spectrometer; TMS was used as an internal standard. IR spectra were recorded on Hitachi EPI-G3 and PerkinElmer Spectrum ONE spectrophotometers. Microanalyses were taken with a Yanaco CHN-Coder MT-5 analyzer.
Three-Component Condensation Reaction of 1 with Aldehydes in the Presence of Ammonia; General Procedure
The appropriate aldehydes (5.00 mmol) and 28% (w/w) aq NH3 (3.00 to 10.00 mmol) were added to a soln of 1 (240 mg, 1.00 mmol) in MeCN (7 mL), and the mixture was stirred at 50 °C for 24-96 h. Evaporation of the solvent in vacuo gave a crude mixture which was subjected to column chromatography (silica gel, n-hexane-EtOAc, 23:1 to 0:1) to give the corresponding 2a-n, 3l-n, and 4a,b.
Dehydrogenation of 2a-n with DDQ; General Procedure
DDQ (1.05 mmol) was added to a soln of the appropriate 2a-n (1.00 mmol) in MeCN (8 mL), and the mixture was stirred at rt for 1 h. The solvent was evaporated under reduced pressure, and EtOAc (50 mL) was added to the residue. The solution was washed with sat. aq Na2CO3 (50 mL), and dried (Na2SO4). Evaporation of the solvent in vacuo gave the corresponding pure 3a-n.
2-Methyl-4-(trifluoromethyl)-1,2-dihydropyrimido[5,4-c]quinoline (2a): mp 181-182 °C (n-hexane-EtOAc); IR (KBr): 3261, 1198, 1128 cm-1; 1H NMR (500 MHz, CD3CN-CDCl3): δ = 8.73 (s, 1H), 7.98 (d, J = 7.7 Hz, 1H), 7.77 (d, J = 7.7 Hz, 1H), 7.73 (t, J = 7.7 Hz, 1H), 7.49 (t, J = 7.7 Hz, 1H), 5.91-5.36 (br, 1H), 5.58 (q, J = 5.9 Hz, 1H), 1.69 (d, J = 5.9 Hz, 3H); 13C NMR (CD3CN-CDCl3): δ = 152.3 (q, JCF = 35.3 Hz), 149.8, 149.1, 146.5, 131.7, 129.7, 125.8, 121.2, 117.0, 116.3 (q, JCF = 273.1 Hz), 101.8, 65.9, 22.3. Anal. Calcd for C13H10F3N3: C, 58.87; H, 3.80; N, 15.48. Found: C, 58.79; H, 4.18; N, 15.54.
2-Ethyl-4-(trifluoromethyl)-1,2-dihydropyrimido[5,4-c]quinoline (2b): mp 165-166 °C (n-hexane-EtOAc); IR (KBr): 3001, 1189, 1111 cm-1; 1H NMR (60 MHz, CD3CN-CDCl3): δ = 8.65 (q, J = 2.0 Hz, 1H), 8.09-7.34 (m, 4H), 6.90-5.25 (br, 1H), 5.45 (br t, J = 6.0 Hz, 1H), 2.19-1.73 (m, 2H), 1.07 (t, J = 7.0 Hz, 3H). Anal. Calcd for C14H12F3N3: C, 60.21; H, 4.33; N, 15.05. Found: C, 60.34; H, 4.34; N, 14.97.
2-Propyl-4-(trifluoromethyl)-1,2-dihydropyrimido[5,4-c]quinoline (2c): mp 171-172 °C (n-hexane-EtOAc); IR (KBr): 3063, 1189, 1120 cm-1; 1H NMR (60 MHz, CD3CN-CDCl3): δ = 8.80-8.60 (m, 1H), 8.17-7.44 (m, 4H), 6.90-6.13 (br, 1H), 5.53 (br t, J = 5.0 Hz, 1H), 2.17-1.20 (m, 4H), 1.20-0.56 (m, 3H). Anal. Calcd for C15H14F3N3: C, 61.43; H, 4.81; N, 14.33. Found: C, 61.43; H, 4.91; N, 14.61.
2-Isopropyl-4-(trifluoromethyl)-1,2-dihydropyrimido[5,4-c]quinoline (2d): mp 170-171 °C (n-hexane-EtOAc); IR (KBr): 3061, 1190, 1126 cm-1; 1H NMR (60 MHz, CD3CN-CDCl3): δ = 8.63 (q, J = 2.0 Hz, 1H), 8.05-7.33 (m, 4H), 7.05-5.57 (br, 1H), 5.35 (br d, J = 6.5 Hz, 1H), 2.43-1.86 (m, 1H), 1.07 (d, J = 6.5 Hz, 6H). Anal. Calcd for C15H14F3N3: C, 61.43; H, 4.81; N, 14.33. Found: C, 61.41; H, 4.67; N, 14.22.
2-Butyl-4-(trifluoromethyl)-1,2-dihydropyrimido[5,4-c]quinoline (2e): mp 194-195 °C (n-hexane-EtOAc); IR (KBr): 3061, 1190, 1115 cm-1; 1H NMR (60 MHz, CD3CN-CDCl3): δ = 8.93-8.67 (m, 1H), 8.23-7.43 (m, 4H), 6.83-6.37 (br, 1H), 5.57 (br t, J = 6.0 Hz, 1H), 2.17-0.63 (m, 9H). Anal. Calcd for C16H16F3N3: C, 62.53; H, 5.25; N, 13.67. Found: C, 62.37; H, 5.29; N, 13.78.
2-Isobutyl-4-(trifluoromethyl)-1,2-dihydropyrimido[5,4-c]quinoline (2f): mp 158-159 °C (n-hexane-EtOAc); IR (KBr): 3062, 1191, 1125 cm-1; 1H NMR (60 MHz, CD3CN-CDCl3): δ = 8.83-8.63 (m, 1H), 8.23-7.33 (m, 4H), 7.00-6.33 (br, 1H), 5.60 (br t, J = 6.0 Hz, 1H), 2.27-1.63 (m, 3H), 1.47-0.67 (m, 6H). Anal. Calcd for C16H16F3N3: C, 62.53; H, 5.25; N, 13.67. Found: C, 62.93; H, 5.21; N, 13.52.
2-sec-Butyl-4-(trifluoromethyl)-1,2-dihydropyrimido[5,4-c]quinoline (2g): mp 148-149 °C (n-hexane-EtOAc); IR (KBr): 3203, 1186, 1124 cm-1; 1H NMR (60 MHz, CD3CN-CDCl3): δ = 8.83-8.73 (m, 1H), 8.27-7.40 (m, 4H), 7.00-6.32 (br, 1H), 5.56-5.40 (br, 1H), 2.17-0.73 (m, 9H). Anal. Calcd for C16H16F3N3: C, 62.53; H, 5.25; N, 13.67. Found: C, 62.73; H, 5.42; N, 13.30.
2-Pentyl-4-(trifluoromethyl)-1,2-dihydropyrimido[5,4-c]quinoline (2h): mp 171-172 °C (n-hexane-EtOAc); IR (KBr): 3060, 1186, 1129 cm-1; 1H NMR (60 MHz, CD3CN-CDCl3): δ = 8.83-8.70 (m, 1H), 8.17-7.33 (m, 4H), 7.00-6.27 (br, 1H), 5.50 (br t, J = 6.0 Hz, 1H), 2.07-0.63 (m, 11H). Anal. Calcd for C17H18F3N3: C, 63.54; H, 5.65; N, 13.08. Found: C, 63.61; H, 5.48; N, 12.85.
2-Hexyl-4-(trifluoromethyl)-1,2-dihydropyrimido[5,4-c]quinoline (2i): mp 141-142 °C (n-hexane-EtOAc); IR (KBr): 3062, 1190, 1130 cm-1; 1H NMR (60 MHz, CD3CN-CDCl3): δ = 8.83-8.57 (m, 1H), 8.20-7.47 (m, 4H), 6.97-6.20 (br, 1H), 5.50 (br t, J = 6.0 Hz, 1H), 2.13-0.57 (m, 13H). Anal. Calcd for C18H20F3N3: C, 64.46; H, 6.01; N, 12.53. Found: C, 64.63; H, 6.03; N, 12.33.
4-(4-(Trifluoromethyl)-1,2-dihydropyrimido[5,4-c]quinolin-2-yl)phenol (2j): mp 210-211 °C (n-hexane-EtOAc); IR (KBr): 3363, 3261, 1199, 1124 cm-1; 1H NMR (60 MHz, CD3CN-CDCl3): δ = 8.92-8.62 (m, 1H), 8.55-6.85 (m, 9H), 6.55 (s, 1H), 6.25-5.28 (br, 1H). Anal. Calcd for C18H13F3N3O: C, 62.97; H, 3.52; N, 12.24. Found: C, 62.97; H, 3.91; N, 11.85.
2-(4-Methoxyphenyl)-4-(trifluoromethyl)-1,2-dihydropyrimido[5,4-c]quinoline (2k): mp 166-167 °C (n-hexane-EtOAc); IR (KBr): 3423, 1193, 1131 cm-1; 1H NMR (60 MHz, CD3CN-CDCl3): δ = 8.64 (q, J = 2.0 Hz, 1H), 8.03-7.33 (m, 6H), 6.90 (d, J = 9.0 Hz, 2H), 6.48 (br s, 1H), 4.37-3.00 (br, 1H), 3.77 (s, 3H). Anal. Calcd for C19H14F3N3O: C, 63.86; H, 3.95; N, 11.76. Found: C, 64.09; H, 4.06; N, 11.41.
2-p-Tolyl-4-(trifluoromethyl)-1,2-dihydropyrimido[5,4-c]quinoline (2l): mp 185-186 °C (n-hexane-EtOAc); IR (KBr): 3434, 1192, 1125 cm-1; 1H NMR (60 MHz, CD3CN-CDCl3): δ = 8.63 (q, J = 2.0 Hz, 1H), 8.04-7.09 (m, 8H), 6.49 (br s, 1H), 3.36-1.68 (br, 1H), 2.33 (s, 3H). Anal. Calcd for C19H14F3N3: C, 66.86; H, 4.13; N, 12.31. Found: C, 67.00; H, 4.18; N, 12.33.
2-Phenyl-4-(trifluoromethyl)-1,2-dihydropyrimido[5,4-c]quinoline (2m): mp 168-169 °C (n-hexane-EtOAc); IR (KBr): 3412, 1191, 1138 cm-1; 1H NMR (60 MHz, CD3CN-CDCl3): δ = 8.69 (q, J = 2.0 Hz, 1H), 8.08-7.33 (m, 9H), 6.55 (br s, 1H), 6.22-3.85 (br, 1H). Anal. Calcd for C18H12F3N3: C, 66.05; H, 3.70; N, 12.84. Found: C, 65.88; H, 3.99; N, 12.71.
2-(4-Chlorophenyl)-4-(trifluoromethyl)-1,2-dihydropyrimido[5,4-c]quinoline (2n): mp 198-199 °C (n-hexane-EtOAc); IR (KBr): 3399, 1197, 1134 cm-1; 1H NMR (60 MHz, CD3CN-CDCl3): δ = 9.08-8.00 (br, 1H), 8.63 (br s, 1H), 8.43-8.23 (m, 1H), 7.99-7.29 (m, 7H), 6.58 (br s, 1H). Anal. Calcd for C18H11ClF3N3: C, 59.76; H, 3.07; N, 11.62. Found: C, 59.57; H, 3.23; N, 11.52.
2-Methyl-4-(trifluoromethyl)pyrimido[5,4-c]quinoline (3a): yield 98%; mp 173-174 °C (n-hexane-EtOAc); IR (KBr): 1192, 1137 cm-1; 1H NMR (60 MHz, CD3CN-CDCl3): δ = 9.22 (q, J = 2.0 Hz, 1H), 9.13-8.98 (m, 1H), 8.32-7.59 (m, 3H), 3.05 (s, 3H). Anal. Calcd for C13H8F3N3: C, 59.32; H, 3.06; N, 15.96. Found: C, 59.33; H, 3.33; N, 16.03.
2-Ethyl-4-(trifluoromethyl)pyrimido[5,4-c]quinoline (3b): yield 99%; mp 172-173 °C (n-hexane-EtOAc); IR (KBr): 1196, 1142 cm-1; 1H NMR (60 MHz, CD3CN-CDCl3): δ = 9.57 (q, J = 2.0 Hz, 1H), 9.23-9.06 (m, 1H), 8.31-7.68 (m, 3H), 3.33 (q, J = 7.0 Hz, 2H), 1.55 (t, J = 7.0 Hz, 3H). Anal. Calcd for C14H10F3N3: C, 60.65; H, 3.64; N, 15.16. Found: C, 60.26; H, 3.56; N, 15.01.
2-Propyl-4-(trifluoromethyl)pyrimido[5,4-c]quinoline (3c): yield 87%; mp 114-115 °C (n-hexane-EtOAc); IR (KBr): 1189, 1137 cm-1; 1H NMR (500 MHz, CD3CN-CDCl3): δ = 9.62 (s, 1H), 9.19 (d, J = 7.6 Hz, 1H), 8.25 (d, J = 7.6 Hz, 1H), 8.01 (t, J = 7.6 Hz, 1H), 7.85 (t, J = 7.6 Hz, 1H), 3.29 (t, J = 7.3 Hz, 2H), 2.16-2.03 (m, 2H), 1.11 (t, J = 7.3 Hz, 3H); 13C NMR (CD3CN-CDCl3): δ = 171.0, 154.6, 154.2 (q, JCF = 33.7 Hz), 147.5, 147.1, 132.9, 129.6, 128.4, 124.2, 123.0, 121.0 (q, JCF = 275.2 Hz), 111.2, 41.6, 21.4, 13.6. Anal. Calcd for C15H12F3N3: C, 61.85; H, 4.15; N, 14.43. Found: C, 62.11; H, 4.22; N, 14.10.
2-Isopropyl-4-(trifluoromethyl)pyrimido[5,4-c]quinoline (3d): yield 96%; mp 116-117 °C (n-hexane-EtOAc); IR (KBr): 1194, 1134 cm-1; 1H NMR (60 MHz, CD3CN-CDCl3): δ = 9.54 (q, J = 2.0 Hz, 1H), 9.18-9.02 (m, 1H), 8.25-7.58 (m, 3H), 3.56 (hept, J = 7.0 Hz, 1H), 1.54 (d, J = 7.0 Hz, 6H). Anal. Calcd for C15H12F3N3: C, 61.85; H, 4.15; N, 14.43. Found: C, 61.81; H, 4.11; N, 14.51.
2-Butyl-4-(trifluoromethyl)pyrimido[5,4-c]quinoline (3e): yield 96%; mp 92-93 °C (n-hexane-EtOAc); IR (KBr): 1193, 1139 cm-1; 1H NMR (500 MHz, CD3CN-CDCl3): δ = 9.58 (s, 1H), 9.14 (d, J = 7.4 Hz, 1H), 8.21 (d, J = 7.4 Hz, 1H), 7.98 (t, J = 7.4 Hz, 1H), 7.82 (t, J = 7.4 Hz, 1H), 3.30 (t, J = 6.7 Hz, 2H), 2.09-1.93 (m, 2H), 1.60-1.47 (m, 2H), 1.03 (t, J = 6.7 Hz, 3H); 13C NMR (CD3CN-CDCl3): δ = 171.1, 154.4, 154.1 (q, JCF = 34.8 Hz), 147.3, 146.9, 132.7, 129.4, 128.2, 124.1, 122.9, 120.8 (q, JCF = 277.7 Hz), 111.0, 39.3, 30.0, 22.1, 13.5. Anal. Calcd for C16H14F3N3: C, 62.95; H, 4.62; N, 13.76. Found: C, 63.00; H, 4.69; N, 13.64.
2-Isobutyl-4-(trifluoromethyl)pyrimido[5,4-c]quinoline (3f): yield 98%; mp 96-97 °C (n-hexane-EtOAc); IR (KBr): 1192, 1141 cm-1; 1H NMR (500 MHz, CD3CN-CDCl3): δ = 9.61 (s, 1H), 9.18 (d, J = 7.3 Hz, 1H), 8.24 (d, J = 7.3 Hz, 1H), 8.01 (t, J = 7.3 Hz, 1H), 7.84 (t, J = 7.3 Hz, 1H), 3.19 (t, J = 6.0 Hz, 2H), 2.60-2.48 (m, 1H), 1.07 (d, J = 6.0 Hz, 6H); 13C NMR (CD3CN-CDCl3): δ = 170.6, 154.7, 154.3 (q, JCF = 35.7 Hz), 147.6, 147.2, 133.0, 129.7, 128.5, 124.4, 123.2, 121.1 (q, JCF = 277.7 Hz), 111.3, 48.7, 28.2, 22.4. Anal. Calcd for C16H14F3N3: C, 62.95; H, 4.62; N, 13.76. Found: C, 63.06; H, 4.64; N, 13.63.
2-sec-Butyl-4-(trifluoromethyl)pyrimido[5,4-c]quinoline (3g): yield 80%; mp 77-78 °C (n-hexane-EtOAc); IR (KBr): 1188, 1145 cm-1; 1H NMR (500 MHz, DMSO-d6-CDCl3): δ = 9.62 (s, 1H), 9.21 (d, J = 7.4 Hz, 1H), 8.25 (d, J = 7.4 Hz, 1H), 8.00 (t, J = 7.4 Hz, 1H), 7.85 (t, J = 7.4 Hz, 1H), 3.37 (sext, J = 7.2 Hz, 1H), 2.19-2.02 (m, 1H), 1.93-1.79 (m, 1H), 1.51 (d, J = 7.2 Hz, 3H), 0.97 (t, J = 7.2 Hz, 3H); 13C NMR (DMSO-d6-CDCl3): δ = 174.1, 154.0, 153.7 (q, JCF = 37.6 Hz), 146.9, 146.5, 132.3, 129.0, 127.8, 123.7, 122.6, 120.4 (q, JCF = 281.8 Hz), 110.7, 44.5, 28.3, 18.6, 11.2. Anal. Calcd for C16H14F3N3: C, 62.95; H, 4.62; N, 13.76. Found: C, 63.17; H, 4.75; N, 13.41.
2-Pentyl-4-(trifluoromethyl)pyrimido[5,4-c]quinoline (3h): yield 98%; mp 73-74 °C (n-hexane-EtOAc); IR (KBr): 1191, 1136 cm-1; 1H NMR (500 MHz, DMSO-d6-CDCl3): δ = 9.61 (s, 1H), 9.19 (d, J = 7.9 Hz, 1H), 8.25 (d, J = 7.9 Hz, 1H), 8.03 (t, J = 7.9 Hz, 1H), 7.86 (t, J = 7.9 Hz, 1H), 3.30 (t, J = 7.0 Hz, 2H), 1.68-1.22 (m, 6H), 0.95 (t, J = 7.0 Hz, 3H); 13C NMR (DMSO-d6-CDCl3): δ = 171.2, 157.1, 154.2 (q, JCF = 38.3 Hz), 148.3, 147.4, 132.8, 129.5, 128.3, 124.2, 122.4, 120.8 (q, JCF = 277.5 Hz), 111.1, 39.6, 31.2, 27.6, 22.2, 13.7. Anal. Calcd for C17H16F3N3: C, 63.94; H, 5.05; N, 13.16. Found: C, 63.94; H, 5.12; N, 13.10.
2-Hexyl-4-(trifluoromethyl)pyrimido[5,4-c]quinoline (3i): yield 89%; mp 76-77 °C (n-hexane-EtOAc); IR (KBr): 1193, 1137 cm-1; 1H NMR (500 MHz, DMSO-d6-CDCl3): δ = 9.60 (s, 1H), 9.16 (d, J = 7.6 Hz, 1H), 8.23 (d, J = 7.6 Hz, 1H), 8.00 (t, J = 7.6 Hz, 1H), 7.84 (t, J = 7.6 Hz, 1H), 3.30 (t, J = 7.2 Hz, 2H), 2.02 (quint, J = 7.2 Hz, 2H), 1.53-1.18 (m, 6H), 0.91 (t, J = 7.2 Hz, 3H); 13C NMR (DMSO-d6-CDCl3): δ = 171.0, 154.4, 154.0 (q, JCF = 35.7 Hz), 147.3, 146.9, 132.6, 129.3, 128.2, 124.0, 122.8, 120.7 (q, JCF = 277.5 Hz), 110.9, 39.5, 31.2, 28.5, 27.7, 22.1, 13.5. Anal. Calcd for C18H18F3N3: C, 64.85; H, 5.44; N, 12.61. Found: C, 64.95; H, 5.44; N, 12.51.
4-(4-(Trifluoromethyl)pyrimido[5,4-c]quinolin-2-yl)phenol (3j): yield 98%; mp 309-310 °C (n-hexane-EtOAc); IR (KBr): 3076, 1183, 1127 cm-1; 1H NMR (500 MHz, DMSO-d6-CDCl3): δ = 9.76 (br s, 1H), 9.57 (s, 1H), 9.27 (d, J = 7.4 Hz, 1H), 8.67 (d, J = 8.5 Hz, 2H), 8.24 (d, J = 7.4 Hz, 1H), 8.00 (t, J = 7.4 Hz, 1H), 7.86 (t, J = 7.4 Hz, 1H), 7.05 (d, J = 8.5 Hz, 2H); 13C NMR (DMSO-d6-CDCl3): δ = 160.9, 160.3, 152.8, 152.1 (q, JCF = 35.7 Hz), 145.7, 145.0, 131.1, 129.4, 127.7, 126.5, 124.9, 122.3, 121.5 (q, JCF = 277.5 Hz), 121.2, 118.1, 108.9. Anal. Calcd for C18H10F3N3O: C, 63.35; H, 2.95; N, 12.31. Found: C, 63.29; H, 2.99; N, 12.33.
2-(4-Methoxyphenyl)-4-(trifluoromethyl)pyrimido[5,4-c]quinoline (3k): yield 93%; mp 182-183 °C (n-hexane-EtOAc); IR (KBr): 1182, 1130 cm-1; 1H NMR (60 MHz, CDCl3): δ = 9.43 (q, J = 2.0 Hz, 1H), 9.11-8.95 (m, 1H), 8.55 (d, J = 9.0 Hz, 2H), 8.21-7.54 (m, 3H), 6.92 (d, J = 9.0 Hz, 2H), 3.84 (s, 3H). Anal. Calcd for C19H12F3N3O: C, 64.23; H, 3.40; N, 11.83. Found: C, 64.15; H, 3.58; N, 11.58.
2-p-Tolyl-4-(trifluoromethyl)pyrimido[5,4-c]quinoline (3l): yield 94% (from 2l); mp 187-188 °C (n-hexane-EtOAc); IR (KBr): 1195, 1139 cm-1; 1H NMR (60 MHz, CDCl3): δ = 9.44 (q, J = 2.0 Hz, 1H), 9.08-8.93 (m, 1H), 8.41 (d, J = 8.0 Hz, 2H), 8.31-7.51 (m, 3H), 7.17 (d, J = 8.0 Hz, 2H), 2.36 (s, 3H). Anal. Calcd for C19H12F3N3: C, 67.25; H, 3.56; N, 12.38. Found: C, 67.14; H, 3.68; N, 12.39.
2-Phenyl-4-(trifluoromethyl)pyrimido[5,4-c]quinoline (3m): yield 100% (from 2m); mp 167-168 °C (n-hexane-EtOAc); IR (KBr): 1189, 1139 cm-1; 1H NMR (60 MHz, CDCl3): δ = 9.57 (q, J = 2.0 Hz, 1H), 9.21-9.04 (m, 1H), 8.76-8.56 (m, 2H), 8.26-7.41 (m, 6H). Anal. Calcd for C18H10F3N3: C, 66.46; H, 3.10; N, 12.92. Found: C, 66.46; H, 3.37; N, 12.83.
2-(4-Chlorophenyl)-4-(trifluoromethyl)pyrimido[5,4-c]quinoline (3n): yield 94% (from 2n); mp 186-187 °C (n-hexane-EtOAc); IR (KBr): 1188, 1146 cm-1; 1H NMR (60 MHz, CDCl3): δ = 9.49 (q, J = 2.0 Hz, 1H), 9.09-8.93 (m, 1H), 8.59 (d, J = 9.0 Hz, 2H), 8.26-7.68 (m, 3H), 7.40 (d, J = 9.0 Hz, 2H). Anal. Calcd for C18H9ClF3N3: C, 60.10; H, 2.52; N, 11.68. Found: C, 60.09; H, 2.52; N, 11.74.
4-(Trifluoromethyl)benzo[h][1,6]naphthyridine (4a): mp 125-126 °C (n-hexane-EtOAc); IR (KBr): 1192, 1122 cm-1; 1H NMR (500 MHz, CD3CN-CDCl3): δ = 9.62 (s, 1H), 9.33 (d, J = 7.0 Hz, 1H), 9.18 (d, J = 7.8 Hz, 1H), 8.24 (d, J = 7.8 Hz, 1H), 7.99-7.87 (m, 2H), 7.83 (t, J = 7.0 Hz, 1H); 13C NMR (CD3CN-CDCl3): δ = 153.1, 149.3, 147.8, 146.2, 134.8 (q, JCF = 33.2 Hz), 131.1, 129.4, 128.2, 124.5, 124.0, 123.0 (q, JCF = 274.9 Hz), 119.0 (q, JCF = 5.3 Hz), 115.4. Anal. Calcd for C13H7F3N2: C, 62.91; H, 2.84; N, 11.29. Found: C, 63.09; H, 3.06; N, 11.37.
3-Methyl-4-(trifluoromethyl)benzo[h][1,6]naphthyridine (4b): mp 132-133 °C (EtOAc); IR (KBr): 1159, 1124 cm-1; 1H NMR (60 MHz, CDCl3): δ = 9.61 (q, J = 2.0 Hz, 1H), 9.18-8.95 (m, 2H), 8.28-7.55 (m, 3H), 2.71 (q, J = 4.0 Hz, 3H). Anal. Calcd for C14H9F3N2: C, 64.12; H, 3.46; N, 10.68. Found: C, 63.96; H, 3.46; N, 10.77.
4-(Trifluoromethyl)-2,4-dihydro-1H-[1,3]oxazino[5,4-c]quinolin-4-ol (5)
Aq. HCHO (5.00 mmol) and 28% (w/w) aq NH3 (5.00 mmol) were added to a soln of 1 (240 mg, 1.00 mmol) in MeCN (7 mL), and the mixture was stirred at 50 °C for 96 h. The solvent was evaporated under reduced pressure, and EtOAc (80 mL) was added to the residue. The solution was washed with H2O (20 mL), and dried (Na2SO4). After removal of the solvent, the crude mixture was subjected to column chromatography (silica gel, EtOAc) to give 5. mp 237-238 °C (n-hexane-EtOAc); IR (KBr): 3416, 3071, 1192, 1125 cm-1; 1H NMR (500 MHz, DMSO-d6-CDCl3): δ = 8.83 (s, 1H), 8.16-7.60 (br, 1H), 7.98 (d, J = 7.4 Hz, 1H), 7.97 (d, J = 7.4 Hz, 1H), 7.68 (t, J = 7.4 Hz, 1H), 7.50 (t, J = 7.4 Hz, 1H), 7.28 (br s, 1H), 4.99 (qAB, J = 7.6 Hz, Δδ = 0.09 ppm, 2H); 13C NMR (DMSO-d6-CDCl3): δ = 147.9, 146.8, 146.6, 129.6, 128.1, 124.9, 122.8 (q, JCF = 287.8 Hz), 121.1, 118.0, 107.6, 92.1 (q, JCF = 32.5 Hz), 67.3. Anal. Calcd for C12H9F3N2O2: C, 53.34; H, 3.36; N, 10.37. Found: C, 53.18; H, 3.42; N, 10.52.
Condensation Reaction of 1 with Ketones in the Presence of Ammonia; General Procedure
The appropriate ketones (3.00 or 5.00 mmol) and 28% (w/w) aq NH3 (1.20 or 5.00 mmol) were added to a soln of 1 (240 mg, 1.00 mmol) in MeCN (7 mL), and the mixture was stirred at 50 °C for 24-168 h. In the case of diethylketone and acetophenone, the mixture was heated 100 °C and 130 °C in PrCN and BuCN in a sealed tube, respectively. Evaporation of the solvent in vacuo gave a crude mixture which was subjected to column chromatography (silica gel, n-hexane-EtOAc, 30:1 to 1:1) to give the corresponding 6a-i and 7b,g.
2-Methyl-4-(trifluoromethyl)benzo[h][1,6]naphthyridine (6a): mp 129-130 °C (n-hexane); IR (KBr): 1193, 1120 cm-1; 1H NMR (60 MHz, CDCl3): δ = 9.45 (q, J = 2.0 Hz, 1H), 9.27-8.93 (m, 1H), 8.18-7.57 (m, 4H), 2.76 (s, 3H). Anal. Calcd for C14H9F3N2: C, 64.12; H, 3.46; N, 10.68. Found: C, 64.08; H, 3.73; N, 10.64.
2-Ethyl-3-methyl-4-(trifluoromethyl)benzo[h][1,6]naphthyridine (6b): mp 158-159 °C (n-hexane); IR (KBr): 1159, 1129 cm-1; 1H NMR (60 MHz, CDCl3): δ = 9.67 (q, J = 2.0 Hz, 1H), 9.33-9.08 (m, 1H), 8.29-7.73 (m, 3H), 3.14 (q, J = 7.0 Hz, 2H), 2.63 (q, J = 2.0 Hz, 3H), 1.50 (t, J = 7.0 Hz, 3H). Anal. Calcd for C16H13F3N2: C, 66.20; H, 4.51; N, 9.65. Found: C, 66.01; H, 4.58; N, 9.58.
2-Ethyl-4-(trifluoromethyl)benzo[h][1,6]naphthyridine (6c): mp 112-113 °C (n-hexane); IR (KBr): 1183, 1130 cm-1; 1H NMR (60 MHz, CDCl3): δ = 9.57 (q, J = 2.0 Hz, 1H), 9.27-9.10 (m, 1H), 8.30-7.70 (m, 4H), 3.13 (q, J = 7.0 Hz, 2H), 1.47 (t, J = 7.0 Hz, 3H). Anal. Calcd for C15H11F3N2: C, 65.21; H, 4.01; N, 10.14. Found: C, 64.92; H, 3.92; N, 9.99.
2-Isopropyl-4-(trifluoromethyl)benzo[h][1,6]naphthyridine (6d): mp 110-111 °C (n-hexane); IR (KBr): 1156, 1130 cm-1; 1H NMR (60 MHz, CDCl3): δ = 9.68 (q, J = 2.0 Hz, 1H), 9.45-9.27 (m, 1H), 8.45-7.78 (m, 4H), 3.53 (hept, J = 7.0 Hz, 1H), 1.65 (d, J = 7.0 Hz, 6H). Anal. Calcd for C16H13F3N2: C, 66.20; H, 4.51; N, 9.65. Found: C, 66.25; H, 4.70; N, 9.41.
2-Phenyl-4-(trifluoromethyl)benzo[h][1,6]naphthyridine (6e): mp 128-129 °C (n-hexane); IR (KBr): 1187, 1137 cm-1; 1H NMR (60 MHz, CDCl3): δ = 9.83 (q, J = 2.0 Hz, 1H), 9.60-9.45 (m, 1H), 8.65-7.77 (m, 9H). Anal. Calcd for C19H11F3N2: C, 70.37; H, 3.42; N, 8.64. Found: C, 70.23; H, 3.47; N, 8.73.
7-(Trifluoromethyl)-9,10-dihydro-8H-benzo[h]cyclopenta[b][1,6]naphthyridine (6f): mp 199-200 °C (n-hexane); IR (KBr): 1162, 1127 cm-1; 1H NMR (60 MHz, CDCl3): δ = 9.56 (q, J = 2.0 Hz, 1H), 9.22-9.08 (m, 1H), 8.27-7.57 (m, 3H), 3.55-3.12 (m, 4H), 2.48-1.93 (m, 2H). Anal. Calcd for C16H11F3N2: C, 66.66; H, 3.85; N, 9.72. Found: C, 66.64; H, 4.02; N, 9.80.
7-(Trifluoromethyl)-8,9,10,11-tetrahydro­dibenzo[b,h][1,6]naphthyridine (6g): mp 156-157 °C (n-hexane); IR (KBr): 1158, 1124 cm-1; 1H NMR (500 MHz, CDCl3): δ = 9.62 (s, 1H), 9.10 (d, J = 7.8 Hz, 1H), 8.16 (d, J = 7.8 Hz, 1H), 7.82 (t, J = 7.8 Hz, 1H), 7.72 (t, J = 7.8 Hz, 1H), 3.34-3.15 (m, 4H), 2.18-1.86 (m, 4H); 13C NMR (CDCl3): δ = 163.8, 148.5 (q, JCF = 6.9 Hz), 146.5, 145.5, 132.3 (q, JCF = 30.5 Hz), 131.2, 130.4, 129.1, 127.6, 124.8 (q, JCF = 278.8 Hz), 124.4, 123.9, 115.4, 35.0, 27.0, 22.5, 21.7. Anal. Calcd for C17H13F3N2: C, 67.54; H, 4.33; N, 9.27. Found: C, 67.15; H, 4.65; N, 9.34.
7-(Trifluoromethyl)-9,10,11,12-tetrahy­dro-8H-benzo[h]cyclohepta[b][1,6]naphthyridine (6h): mp 107-108 °C (n-hexane); IR (KBr): 1191, 1133 cm-1; 1H NMR (60 MHz, CDCl3): δ = 9.70 (q, J = 2.0 Hz, 1H), 9.17-9.03 (m, 1H), 8.27-7.65 (m, 3H), 3.47-2.97 (m, 4H), 2.03-1.60 (m, 6H). Anal. Calcd for C18H15F3N2: C, 68.35; H, 4.78; N, 8.86. Found: C, 68.10; H, 5.12; N, 8.77.
7-(Trifluoromethyl)-8,9,10,11,12,13-hexahy­dro-8H-benzo[h]cycloocta[b][1,6]naphthyridine (6i): mp 137-138 °C (n-hexane); IR (KBr): 1160, 1125 cm-1; 1H NMR (60 MHz, CDCl3): δ = 9.60 (q, J = 2.0 Hz, 1H), 9.23-9.05 (m, 1H), 8.24-7.63 (m, 3H), 3.39-3.02 (m, 4H), 2.00-1.13 (m, 8H). Anal. Calcd for C19H17F3N2: C, 69.08; H, 5.19; N, 8.48. Found: C, 69.23; H, 5.38; N, 8.14.
2,2-Dieth­yl-4-(trifluoromethyl)-1,2-dihydropyrimido[5,4-c]quinoline (7b): mp 198-199 °C (n-hexane-EtOAc); IR (KBr): 3176, 1147, 1131 cm-1; 1H NMR (500 MHz, DMSO-d6-CD3CN): δ = 8.56 (q, J = 2.0 Hz, 1H), 8.25 (d, J = 7.9 Hz, 1H), 7.87 (d, J = 7.9 Hz, 1H), 7.77 (t, J = 7.9 Hz, 1H), 7.55 (t, J = 7.9 Hz, 1H), 7.05-6.70 (br, 1H), 1.98-1.86 (m, 4H), 1.00 (t, J = 7.4 Hz, 6H); 13C NMR (DMSO-d6-CD3CN): δ = 151.0 (q, JCF = 33.9 Hz), 150.4, 149.5, 146.0 (q, JCF = 4.1 Hz), 131.6, 129.5, 125.4, 122.1, 120.3 (q, JCF = 278.1 Hz), 116.7, 99.4, 77.2, 34.5, 7.1. Anal. Calcd for C16H16F3N3: C, 62.53; H, 5.25; N, 13.67. Found: C, 62.78; H, 5.25; N, 13.42.
2-Spirocyclohexane-4-(trifluoromethyl)-1,2-dihydropyrimido[5,4-c]quinoline (7g): mp 170-171 °C (n-hexane-EtOAc); IR (KBr): 3247, 1152, 1129 cm-1; 1H NMR (500 MHz, CD3CN): δ = 8.69 (s, 1H), 7.99 (d, J = 7.4 Hz, 1H), 7.93 (d, J = 7.4 Hz, 1H), 7.70 (t, J = 7.4 Hz, 1H), 7.47 (t, J = 7.4 Hz, 1H), 6.15 (br s, 1H), 2.19-2.03 (m, 2H), 1.92-1.78 (m, 4H), 1.68-1.22 (m, 4H); 13C NMR (CD3CN): δ = 157.0, 150.7 (q, JCF = 4.4 Hz), 148.5 (q, JCF = 32.1 Hz), 147.9, 132.5, 129.0, 125.5, 122.7, 121.8 (q, JCF = 288.7 Hz), 117.7, 102.3, 71.5, 37.6, 24.8, 20.6. Anal. Calcd for C17H16F3N3: C, 63.94; H, 5.05; N, 13.16. Found: C, 63.94; H, 5.42; N, 13.16.

References

1. A. Stanczak, W. Pakulska, B. Pietrzak, and W. Lewgowd, Pharmazie, 2001, 56, 501.
2. W. Lewgowd, A. Stanczak, B. Pietrzak, and K. Rzeszowska-Modzelewska, Acta Pol. Pharm., 2005, 62, 271.
3. O. A. Fathalla, N. A. Mohamed, W. S. El-Serwy, H. F. AbdelHamid, S. I. Abd El-Moez, and A. M. Soliman, Res. Chem. Intermediates, 2013, 39, 821; CrossRef A. C. Ranade, H. R. Deshpande, and S. A. Phadke, Indian J. Microbiol., 1981, 21, 159.
4. F. Zhang, X. Zhai, L. Chen, J. Qi, B. Cui, Y. Gu, and P. Gong, Chin. Chem. Lett., 2011, 22, 1277; CrossRef W. Lewgowd, A. Stanczak, Z. Ochocki, U. Krajewska, and M. Rozalski, Acta Pol. Pharm., 2005, 62, 105.
5. M. Sankaran, C. Kumarasamy, U. Chokkalingam, and P. S. Mohan, Bioorg. Med. Chem. Lett., 2010, 20, 7147. CrossRef
6. Q. Li, Z. Ge, T. Cheng, and R. Li, Mol. Divers., 2012, 16, 431. CrossRef
7. A. Wissner and A. M. Venkatesan, PCT Int. Appl. WO2008109599.
8. H. Huang, Q. Chen, K. Xin, L. Meng, L. Lin, X. Wang, C. Zhu, Y. Wang, Z. Chen, M. Li, H. Jiang, K. Chen, J. Ding, and H. Liu, J. Med. Chem., 2010, 53, 3048. CrossRef
9. F. Pierre, P. C. Chua, S. E. O'Brien, A. Siddiqui-Jain, P. Bourbon, M. Haddach, J. Michaux, J. Nagasawa, M. K. Schwaebe, E. Stefan, A. Vialettes, J. P. Whitten, T. K. Chen, L. Darjania, R. Stansfield, K. Anderes, J. Bliesath, D. Drygin, C. Ho, M. Omori, C. Proffitt, N. Streiner, K. Trent, W. G. Rice, and D. M. Ryckman, J. Med. Chem., 2011, 54, 635. CrossRef
10. S. Saito, H. Ohta, T. Ishizaka, M. Yoshinaga, M. Tatsuzuki, Y. Yokobori, Y. Tomishima, A. Morita, Y. Toda, K. Tokugawa, A. Kaku, T. Murakami, H. Yoshimura, S. Sekine, and T. Yoshimizu, PCT Int. Appl. WO2006051704.
11. R. Franke and W. J. Streich, Quant. Struct. Act. Relat., 1985, 4, 51; CrossRef K. H. Kim, C. Hansch, J. Y. Fukunaga, E. E. Steller, P. Y. C. Jow, P. N. Craig, and J. Page, J. Med. Chem., 1979, 22, 366; CrossRef K. Goerlitzer, M. Bode, P. G. Jones, H. Jomaa, and J. Wiesner, Pharmazie, 2007, 62, 15.
12. G. Matusiak and W. Sliwa, Pol. PL144840.
13. E. Dubost, N. Dumas, C. Fossey, R. Magnelli, S. Butt-Gueulle, C. Ballandonne, D. H. Caignard, F. Dulin, J. Sopkova de-Oliveira-Santos, P. Millet, Y. Charnay, S. Rault, T. Cailly, and F. Fabis, J. Med. Chem., 2012, 55, 9693. CrossRef
14. A. Hinschberger, S. Butt, V. Lelong, M. Boulouard, A. Dumuis, F. Dauphin, R. Bureau, B. Pfeiffer, P. Renard, and S. Rault, J. Med. Chem., 2003, 46, 138. CrossRef
15. D. Ferraris, Y. Ko, T. Pahutski, R. P. Ficco, L. Serdyuk, C. Alemu, C. Bradford, T. Chiou, R. Hoover, S. Huang, S. Lautar, S. Liang, Q. Lin, M. X.-C. Lu, M. Mooney, L. Morgan, Y. Qian, S. Tran, L. R. Williams, Q. Y. Wu, J. Zhang, Y. Zou, and V. Kalish, J. Med. Chem., 2003, 46, 3138. CrossRef
16. E. B. Nyquist and M. M. Joullié, J. Heterocycl. Chem., 1967, 4, 539; CrossRef R. Filler and Y. Kobayashi, ‘Biomedicinal Aspects of Fluorine Chemistry,’ Kodansha & Elsevier Biomedical, Tokyo, 1982, pp. 1-240; J. T. Welch, Tetrahedron, 1987, 43, 3123; CrossRef R. Filler, Y. Kobayashi, and L. M. Yagupolskii, ‘Organofluorine Compounds in Medicinal Chemistry and Biomedical Applications,’ Elsevier, Amsterdam, 1993, pp. 1-380; K. Burger, U. Wucherpfennig, and E. Brunner, Adv. Heterocycl. Chem., 1994, 60, 1. CrossRef
17. A. S. Dey and M. M. Joullié, J. Heterocycl. Chem., 1965, 2, 120. CrossRef
18. M. Loy and M. M. Joullié, J. Med. Chem., 1973, 16, 549. CrossRef
19. A. V. London, Brit. Chem. Eng., 1965, 10, 400; D. L. Stevenson, Trans. Nation. Vac. Symp., 1963, 10, 134; A. S. Dey and M. M. Joullié, J. Heterocycl. Chem., 1965, 2, 113; CrossRef F. Yoneda, T. Miyamae, and Y. Nitta, Chem. Pharm. Bull., 1965, 13, 500. CrossRef
20. M. Hojo, R. Masuda, E. Okada, T. Tomifuji, and N. Imazaki, Synthesis, 1990, 1135; CrossRef E. Okada, R. Masuda, M. Hojo, N. Imazaki, and K. Takahashi, Synthesis, 1991, 536.
21. E. Okada, N. Tsukushi, and T. Sakaemura, Heterocycles, 1999, 51, 2697; CrossRef E. Okada and N. Tsukushi, Heterocycles, 2000, 53, 709. CrossRef
22. E. Okada, R. Masuda, M. Hojo, H. Tone, N. Gotoh, and T.-K. Huang, Heterocycles, 1995, 40, 905; CrossRef E. Okada, N. Tsukushi, T.-K. Huang, H. Tone, N. Gotoh, H. Takeuchi, and M. Hojo, Heterocycles, 1998, 48, 95. CrossRef
23. E. Okada and N. Tsukushi, Heterocycles, 1999, 51, 2471; E. Okada and N. Tsukushi, Synthesis, 2000, 499. CrossRef
24. M. Hinoshita, D. Shibata, M. Hatakenaka, and E. Okada, Synthesis, 2011, 2754.
25. E. Okada, T. Sakaemura, and N. Shimomura, Chem. Lett., 2000, 29, 50; CrossRef E. Okada, M. Hatakenaka, T. Sakaemura, N. Shimomura, and T. Ashida, Heterocycles, 2012, 86, 1177. CrossRef
26. J. Marco-Contelles, E. Pérez-Mayoral, A. Samadi, M. do C. Carreiras, and E. Soriano, Chem. Rev., 2009, 109, 2652. CrossRef
27. The condensation reactions were carried out without replacement by an inert gas, and so it is thought that the oxidative dehydrogenation and aromatization of 2l-n to 3l-n were performed by atmospheric oxygen.