CC BY-ND-NC 4.0 · SynOpen 2018; 02(04): 0285-0292
DOI: 10.1055/s-0037-1610388
paper
Copyright with the author

Novel Synthesis of 1,2-Substituted 4-Quinolones

Sreenivasulareddy Bandatmakuru
,
R&D Centre, Suven Life Sciences Ltd, Plot No#18, Phase-III, IDA, Jeedimetla, Hyderabad-500055, India   Email: reddyvenis@rediffmail.com
› Author Affiliations
Further Information

Publication History

Received: 21 August 2018

Accepted after revision: 25 October 2018

Publication Date:
21 November 2018 (online)

 

Abstract

An efficient method for the straightforward synthesis of N-functionalized 4-quinolones and 1,2-substituted 4-quinolones from simple 2-aminoacetophenones has been developed.


#

Nitrogen-containing heterocycles are frequently found in a variety of biologically active molecules that can be used in therapeutic areas.[1] Specifically, 4-quinolone derivatives have attracted considerable attention because of their diverse biological activities. Several quinolone compounds, such as oxolinic acid, Ciprofloxacin, Pefloxacin, and Ofloxacin, have emerged as potent antibiotics (Figure [1]).[2]

Zoom Image
Figure 1 Representative potent antibiotics containing the 4-quinolone moiety

More recently, 4-quinolone derivatives have been explored for their antibacterial,[3] antitumor,[4] antimalarial,[5] antidiabetic,[6] antiviral[7] and HIV-1 integrase inhibition properties.[8] Given the importance of these heterocycles in medical chemistry, the development of synthetic methodology to access 4-quinolone derivatives remains an imperative. To date, numerous methods have been reported for the synthesis of quinolones.[9] The most frequently used approaches are based on various cyclocondensation strategies, such as the Camps,[10] Conrad–Limpach,[11] Gould–Jacobs,[12] and Niementowski cyclizations.[13] Often these synthetic methods are carried out under extremely harsh conditions, including temperatures up to 250 °C or the use of strong acids such as polyphosphoric acid or Eaton’s reagent. As a result, the harsh conditions dramatically limit the substrate scope of these transformations. To develop milder processes for construction of the 4-quinolone framework, much effort has been focused on the development of transition-metal-catalyzed (Pd,[14] Cu,[15] and Au[16]) cyclization methodologies during the past decade. Despite significant progress, transition-metal-catalyzed synthetic methods often require specially designed ligands. Another disadvantage is the need to remove metal-related impurities from products, which is an important issue in the synthesis of pharmaceutical molecules.

Some quinolones have been found to be active as mammalian topoisomerase-II inhibitors, including a series of 3-unsubstituted compounds.[17] 1-Methyl-1,4-dihydroquinolin-4-one, echinopsine,[18] is a nontoxic alkaloid from Echinops species that regulates the function of the parasympathetic autonomous nervous system.[19] Several 1-alkyl-3-unsubstituted derivatives have been prepared by decarboxylation of the corresponding 3-carboxylic acids.[20] This method usually requires high temperatures and the reported yields are generally low to medium. Some 1-aryl-3-unsubstituted 1,4-dihydroquinolin-4-ones have also been prepared by this method but the yields are also generally low.[17] Thermal rearrangement of 4-methoxy- and 4-ethoxyquinoline derivatives can be used for the synthesis of the corresponding 1-methyl- and 1-ethyl-1,4-dihydroquinolin-4-ones, respectively.[21] This method usually requires high temperatures (300–350 °C) and the yields are again usually low. Lower temperatures and higher yields were reported when the rearrangement was carried out in the presence of the appropriate iodoalkane,[22] alkyl tosylate,[23] or trialkyl phosphate.[23] 1-Alkyl-3-unsubstituted 1,4-dihydroquinolin-4-ones having a primary alkyl group at the 1-position can also be prepared by N-alkylation of the corresponding 1-unsubstituted 1,4-dihydroquinolin-4-ones.

It is known that amino-substituted acetophenones are valuable precursors for the synthesis of medicinally important substances such as 2-arylquinolin-4(1H)-ones and their analogues.[24] [25] In recent years, interest in these compounds has prompted extensive studies into their properties, such as toxicity to human tumor cell lines and tubulin polymerization inhibition.[4a,26] The method most widely used to prepare 2-aryl-2,3-dihydroquinolin-4(1H)-ones includes a two-step sequence consisting of base-catalyzed aldol condensation of 2-aminoacetophenones and aldehydes and then acid-catalyzed cyclization of the corresponding 2-aminochalcones thus formed via an intramolecular aza-Michael reaction.[25] [26] [27] Other groups have also investigated the synthesis of 4-quinolones from 2-aminoacetophenones,[28] 2-bromoacetophenones,[14d] 2-halophenones,[15a] and 2-iodoanilines,[29] as well as the reactions of isatoic anhydrides with aryl ketones[30a] or alkynes[30b] using transition-metal catalysts. Tambe and co-workers used copper-mediated N-cyclopropylation on substituted fused or unfused pyridinol systems to generate N-cyclopropyl quinolones in moderate yields (Equation 1).[31]

Zoom Image
Equation 1

Kumar et al. synthesized N-aryl quinolones from quinolone and diaryliodonium salts in good yields (Equation 2).[32]

Zoom Image
Equation 2

Ueno et al. prepared N-alkyl quinolones by the nickel-catalyzed intramolecular amination of 2-(N-alkylamino)propiophenones at the β-carbon in good yields (Equation 3).[18j]

Zoom Image
Equation 3

Shao et al.[9h] prepared N-cyclopropyl quinolones from trimethylsilyl substituted substrates and cyclopropyl amine in good yields (Equation 4).

Zoom Image
Equation 4

However, especially for structure–activity studies, the need for new methods for the preparation of the 3-unsubstituted compounds remains. This is particularly true for 1-sec-alkyl, 1-tert-alkyl, and 1-aryl-1,4-dihydroquinolin-4-ones.

At the outset, when we attempted the reaction of 1-(2-cyclopropylaminophenyl)ethanone[33] with dimethylformamide dimethylacetal (DMFDMA) as both reactant and solvent, the desired product 2a was not observed (Table [1]). However, product 2a was formed in 90% yield when para-toluenesulfonic acid (PTSA, 0.1 mol) in ortho-xylene was employed (entry 10). The yields were not improved by using other acids such as methanesulfonic acid, benzenesulfonic acid, camphor sulfonic acid, conc. HCl or sulfuric acid (entries 11–15). A survey of reaction media showed that the use of polar solvents such as DMSO, DMF, and DMA provided better results than those obtained in either toluene or 1,4-dioxane (entries 16–21).

Table 1 Optimization of One-Pot Tandem Reaction Conditions of 2a

Entry

Solvent

Catalyst

Temp (°C)

Time (h)

Yield (%)

1

DMFDMA

80

24

NR

2

DMFDMA

100

24

NR

3

DMFDMA

130

24

NR

4

ortho-xylene

PTSA

80

40

10

5

ortho-xylene

PTSA

100

38

25

6

ortho-xylene

PTSA

110

38

33

7

ortho-xylene

PTSA

120

38

42

8

ortho-xylene

PTSA

130

12

63

9

ortho-xylene

PTSA

130

20

82

10

ortho-xylene

PTSA

130

24

90

11

ortho-xylene

methanesulfonic acid

130

24

10

12

ortho-xylene

benzenesulfonic acid

130

24

15

13

ortho-xylene

camphorsulfonic acid

130

24

15

14

ortho-xylene

Conc. HCl

130

24

50

15

ortho-xylene

Conc. H2SO4

130

24

NR

16

DMF

PTSA

130

24

65

17

DMSO

PTSA

130

24

65

18

chlorobenzene

PTSA

130

24

55

19

toluene

PTSA

110

24

trace

20

dioxane

PTSA

100

24

NR

21

DMA

PTSA

130

24

trace

A series of experiments were then carried out to reveal the crucial role of the reaction temperature (Table [1], entries 4–9). The results showed that increasing reaction temperature led to higher yields (90% at 130 °C vs. 25% at 100 °C; entries 10 and 5). Investigation of the effect of time on the reaction showed that higher yields can be obtained by prolonging the reaction time from 8 to 24 hours (entries 8–10). Thus, optimal conditions used 1a and DMFDMA in the presence of PTSA in ortho-xylene at 130 °C (entry 10).

With the optimized reaction conditions established, we then studied the scope of the cyclization of DMFDMA with a series of other aminoacetophenones, as shown in Scheme [1]. First, we examined the effect of substitution with electron-donating groups and electron-withdrawing groups (EWGS) on the phenyl ring. Both were well tolerated and gave the corresponding quinolones in good to excellent yields (60–90%). All ortho-, meta- and para-substituted aminoacetophenones were smoothly transformed into the desired products, which indicates that steric bulk and electronic effects did not significantly alter the reactivity.

Zoom Image
Scheme 1 One-pot synthesis of N-substituted-4-quinolone derivatives

To explore substrate scope still further, we next examined variations in the nitrogen substituent R2. When R2 was cyclic (cyclopentyl, cyclohexyl), all substrates examined were smoothly converted into the corresponding quinolones 2hk (Scheme [2]). The method was successfully utilized in the synthesis of echinopsine 2l. Changing R2 to an aryl group led to quinolones 2mu in good yields. Substrates possessing N-aryl substituents containing either electron-donating or electron-withdrawing groups also reacted efficiently.

Zoom Image
Scheme 2 Synthesis of N-substituted-4-quinolone derivatives

We also evaluated the possibility of synthesizing 1,2-disubstituted 4-quinolones 4a directly from 2-aminoacetophenone 1a and benzoyl chloride, using TEA as the catalyst and THF as the solvent. Subsequently, the intermediate was cyclized with DMF and K2CO3 and the desired product 4a was formed in 87% yield (Scheme [3]).

Quinolones 4 were useful synthetic precursors; for example, the corresponding 3-functionalized quinolones can be readily generated by using well-documented amination,[34] cyanation,[35] Heck,[5a] [36] Sonogashira,[37] and Suzuki–Miyaura­[14e,38] reactions from 3-halogenated quinolones prepared by direct halogenation of products 4.[14e] [38b]

In summary, we have developed an efficient method for the straightforward synthesis of N-functionalized 4-quinolones and 1,2-substituted 4-quinolones from 2-aminoacetophenones. By using this method, N-alkyl and N-aryl aminoacetophenones can be successfully transformed into the corresponding 4-quinolones. This approach provides one of the simplest methods for the synthesis of this class of compounds, and a wide range of multisubstituted 4-quinolones can be generated accordingly.

Zoom Image
Scheme 3 Synthesis of 2-aryl-2,3-dihydroquinolin-4(1H)-one 4

Preparation of 1-Cyclopropyl-1H-quinolin-4-one (2a); Typical Procedure

A mixture of 1-(2-cyclopropylamino-phenyl)ethanone 1 (1.0 gm, 5.71 mmol), dimethylformamide dimethylacetal (2.0 mL), and PTSA (100 mg, 0.571 mmol) in o-xylene (30 mL) was heated to reflux for 24 h. After completion of reaction (monitored by TLC), the reaction mixture was allowed to cool and then diluted with o-xylene (10 mL). Water (20 mL) was added and the organic phase was separated. The aqueous layer was then extracted further with o-xylene (10 mL) and the combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give 2a.

Yield: 950 mg (90%); yellow solid; mp 79.8–81.4 °C.

IR (KBr): 3488, 1610, 1620, 1565, 1485, 1299, 762 cm–1.

1H NMR (400 MHz, CDCl3): δ = 1.03–1.12 (q, 2 H), 1.23–1.30 (q, 2 H), 3.36–3.42 (m, 1 H), 6.23 (d, J = 7.92 Hz, 1 H), 7.37–7.41 (m, 1 H), 7.66–7.70 (m, 2 H), 7.91 (d, J = 8.6 Hz, 1 H), 8.42 (dd, J 1 = 0.84, J 2 = 0.88 Hz, 1 H).

13C NMR (100 MHz, CDCl3): δ = 8.19, 33.61, 109.89, 116.91, 123.75, 126.67, 131.96, 141.51, 142.51, 178.33.

Anal. Calcd for C12H11NO: C, 77.81; H, 5.99; N, 7.56; Found: C, 77.80; H, 5.97; N, 7.53.


#

7-Chloro-1-cyclopropyl-6-fluoro-1H-quinolin-4-one (2b)

Yield: 396 mg (76%); yellow solid; mp 195.6–197.2 °C.

IR (KBr): 3100, 3027, 1633, 1610, 1589, 1477, 1259, 971, 893, 824 cm–1.

1H NMR (400 MHz, CDCl3): δ = 1.05–1.09 (q, 2 H), 1.29–1.34 (q, 2 H), 3.34–3.39 (m, 1 H), 6.20 (d, J = 7.92 Hz, 1 H), 7.66 (d, J = 7.92 Hz, 1 H), 7.97 (d, J = 5.92 Hz, 1 H), 8.14 (d, J = 9.12 Hz, 1 H).

13C NMR (100 MHz, CDCl3): δ = 8.27, 33.83, 109.72, 112.69, 118.52, 126.42, 138.23, 142.73, 153.55, 156.05, 176.76.

Anal. Calcd for C12H9ClFNO: C, 60.65; H, 3.82; N, 5.89; Found: C, 60.66; H, 3.80; N, 5.90.


#

6-Chloro-1-cyclopropyl-1H-quinolin-4-one (2c)

Yield: 445 mg (85%); white solid; mp 168.4–174.1 °C.

IR (KBr): 3075, 3012, 1630, 1582, 1473, 1287, 1144, 823 cm–1.

1H NMR (300 MHz, CDCl3): δ = 1.03–1.09 (q, 2 H), 1.26–1.33 (q, 2 H), 3.35–3.42 (m, 1 H), 6.24 (d, J = 7.8 Hz, 1 H), 7.60 (dd, J 1 = 2.4, J 2 =2.4 Hz, 1 H), 7.67 (d, J = 7.8 Hz, 1 H), 7.85 (d, J = 9.0 Hz, 1 H), 8.39 (d, J = 2.4 Hz, 1 H).

13C NMR (75 MHz, CDCl3): δ = 8.31, 33.80, 110.25, 118.10, 126.09, 127.77, 130.08, 132.27, 140.02, 142.68, 177.6.

Anal. Calcd for C12H10ClNO: C, 65.61; H, 4.59; N, 6.38; Found: C, 65.59; H, 4.57; N, 6.40.


#

1-Cyclopropyl-7-methoxy-1H-quinolin-4-one (2d)

Yield: 419 mg (80%); yellow solid; mp 78.1–82.4 °C.

IR (KBr): 3010, 1614, 1569, 1460, 1264, 1016, 827 cm–1.

1H NMR (300 MHz, CDCl3): δ = 1.05–1.08 (q, 2 H), 1.23–1.28 (q, 2 H), 3.30–3.36 (m, 1 H), 3.94 (s, 3 H), 6.17 (d, J = 7.8 Hz, 1 H), 6.97 (dd, J 1 = 2.4, J 2 = 2.1 Hz, 1 H), 7.62 (d, J = 8.1 Hz, 1 H), 8.34 (d, J = 9.0 Hz, 1 H).

13C NMR (75 MHz, CDCl3): δ = 8.21, 33.60, 55.62, 99.03, 109.88, 112.36, 121.03, 128.69, 142.39, 143.35, 162.65, 177.92.

Anal. Calcd for C13H13NO2: C, 72.54; H, 6.09; N, 6.51; Found: C, 72.55; H, 6.07; N, 6.53.


#

1-Cyclopropyl-6-methyl-1H-quinolin-4-one (2e)

Yield: 421 mg (80%); yellow solid; mp 96.4–100.7 °C.

IR (KBr): 3032, 3008, 1633, 1604, 1582, 1488, 1341, 1296, 1154, 835 cm–1.

1H NMR (300 MHz, CDCl3): δ = 1.05–1.07 (q, 2 H), 1.23–1.27 (q, 2 H), 2.47 (s, 3 H), 3.35–3.40 (m, 1 H), 6.21 (d, J = 7.8 Hz, 1 H), 7.49 (d, J = 7.8 Hz, 1 H), 7.65 (d, J = 7.8 Hz, 1 H), 7.80 (d, J = 8.7 Hz, 1 H), 8.23 (s, 1 H).

13C NMR (75 MHz, CDCl3): δ = 8.16, 20.95, 33.63, 109.65, 116.17, 126.11, 126.65, 133.42, 133.70, 139.65, 142.13, 178.29.

Anal. Calcd for C13H13NO: C, 78.36; H, 6.58; N, 7.03; Found: C, 78.34; H, 6.59; N, 7.04.


#

6-Bromo-1-cyclopropyl-1H-quinolin-4-one (2f)

Yield: 488 mg (94%); yellow solid; mp 166.3–169.8 °C.

IR (KBr):3075, 3010, 1630, 1580, 1469, 822 cm–1.

1H NMR (300 MHz, CDCl3): δ = 1.03–1.08 (q, 2 H), 1.25–1.32 (q, 2 H), 3.34–3.41 (m, 1 H), 6.22 (d, J = 8.0 Hz, 1 H), 7.67 (d, J = 7.8 Hz, 1 H), 7.75–7.81 (2 H, m), 8.55 (d, J = 1.8 Hz, 1 H).

13C NMR (75 MHz, CDCl3): δ = 8.29, 33.75, 110.32, 117.69, 118.31, 128.02, 129.22, 134.93, 140.35, 142.72, 176.89.

Anal. Calcd for C12H10BrNO: C, 54.57; H, 3.82; N, 5.30; Found: C, 54.56; H, 3.79; N, 5.32.


#

6,8-Dichloro-1-cyclopropyl-1H-quinolin-4-one (2g)

Yield: 364 mg (70%); pale-yellow solid; mp 127.4–132.8 °C.

IR (KBr): 3068, 1633, 1623, 1457, 1336, 1270, 820 cm–1.

1H NMR (300 MHz, CDCl3): δ = 0.91–0.96 (q, 2 H), 1.17–1.24 (q, 2 H), 4.04–4.11 (m, 1 H), 6.21 (d, J = 8.1 Hz, 1 H), 7.68 (d, J = 2.4 Hz, 1 H), 7.73 (d, J = 8.1 Hz, 1 H), 8.31 (d, J =2.4 Hz, 1 H).

13C NMR (75 MHz, CDCl3): δ = 11.52, 38.96, 110.57, 123.63, 125.60, 129.81, 130.60, 135.16, 138.28, 146.10, 176.37.

Anal. Calcd for C12H9Cl2NO: C, 56.72; H, 3.57; N, 5.51; Found: C, 56.69; H, 3.58; N, 5.48.


#

6-Chloro-1-cyclohexyl-1H-quinolin-4-one (2h)

Yield: 436 mg (84%); white solid; mp 126.8–131.2 °C.

IR (KBr):3061, 2929, 2861, 1621, 1587, 1479, 1353, 1326, 1210, 1170, 827, 805 cm–1.

1H NMR (300 MHz, CDCl3): δ = 1.23–1.36 (m, 1 H), 1.48–1.52 (m, 2 H), 1.68–1.76 (m, 2 H), 1.83–1.87 (m, 1 H), 2.00–2.05 (m, 1 H), 2.11–2.15 (m, 2 H), 4.29–4.36 (m, 1 H), 6.30 (d, J = 8.1 Hz, 1 H), 7.47 (d, J = 9.0 Hz, 1 H), 7.57 (dd, J 1 =2.1, J 2 =2.4 Hz, 1 H), 7.71 (d, J = 8.1 Hz, 1 H), 8.46 (d, J = 2.1 Hz, 1 H).

13C NMR (75 MHz, CDCl3): δ = 25.41, 26.00, 32.76, 58.93, 110.35, 116.56, 126.65, 128.64, 129.59, 132.25, 138.25, 138.53, 176.53.

Anal. Calcd for C15H16ClNO: C, 68.83; H, 6.16; N, 5.35; Found: C, 68.85; H, 6.17; N, 5.32.


#

1-Cyclohexyl-1H-quinolin-4-one (2i)

Yield: 428 mg (82%); white solid; mp 145.3–148.4 °C.

IR (KBr): 3080, 2934, 2860, 1623, 1605, 1581, 1485, 1359, 1209, 1175, 833 cm–1.

1H NMR (300 MHz, CDCl3): δ = 1.23–1.32 (m, 1 H), 1.49–1.57 (m, 2 H), 1.69–1.77 (m, 2 H), 1.83–1.87 (m, 1 H), 2.00–2.04 (m, 2 H), 2.12–2.16 (m, 2 H), 4.35–4.43 (m, 1 H), 6.31 (d, J = 7.8 Hz, 1 H), 7.35 (t, J = 7.5 Hz, 1 H), 7.53 (d, J = 8.7 Hz, 1 H), 7.64 (t, J = 7.5 Hz, 1 H), 7.72 (d, J = 8.1 Hz, 1 H), 8.49 (d, J = 7.8 Hz, 1 H).

13C NMR (75 MHz, CDCl3): δ = 25.53, 26.10, 32.86, 58.54, 110.20, 114.63, 123.44, 127.51, 127.70, 132.09, 138.10, 140.18, 177.85.

Anal. Calcd for C15H17NO: C, 79.26; H, 7.54; N, 6.16; Found: C, 79.24; H, 7.55; N, 6.14.


#

1-Cyclopentyl-1H-quinolin-4-one (2j)

Yield: 440 mg (84%); yellow solid; mp 104.6–107.8 °C.

IR (KBr): 3067, 2963, 1625, 1606, 1579, 1488, 1354, 1210, 1179, 838 cm–1.

1H NMR (300 MHz, CDCl3): δ = 1.80–1.93 (m, 6 H), 2.25–2.29 (m, 2 H), 4.94 (m, 1 H), 6.31 (d, J = 7.8 Hz, 1 H), 7.36 (t, J = 7.2 Hz, 1 H), 7.60–7.70 (m, 3 H), 8.48 (d, J = 7.8 Hz, 1 H).

13C NMR (75 MHz, CDCl3): δ = 24.05, 32.29, 60.61, 110.10, 115.43, 123.49, 127.27, 127.57, 132.01, 138.22, 140.73, 177.94.

Anal. Calcd for C14H15NO: C, 78.84; H, 7.09; N, 6.57; Found: C, 78.85; H, 7.10; N, 6.54.


#

6-Chloro-1-cyclopentyl-1H-quinolin-4-one (2k)

Yield: 448 mg (86%); white solid; mp 141.7–143.2 °C.

IR (KBr): 3079, 2954, 2877, 1626, 1585, 1483, 1206, 1008, 845, 823 cm–1.

1H NMR (300 MHz, CDCl3): δ = 1.85–1.93 (m, 6 H), 2.25–2.27 (m, 2 H), 4.87–4.88 (m, 1 H), 6.29 (d, J = 8.1 Hz, 1 H), 7.54–7.61 (m, 2 H), 7.65 (d, J = 7.8 Hz, 1 H), 8.45 (d, J = 1.5 Hz, 1 H).

13C NMR (75 MHz, CDCl3): δ = 24.03, 32.28, 60.98, 110.36, 117.31, 126.56, 128.63, 129.78, 132.25, 138.36, 139.15.

Anal. Calcd for C14H14ClNO: C, 67.88; H, 5.70; N, 5.65; Found: C, 67.86; H, 5.67; N, 5.67.


#

1-Methyl-1H-quinolin-4-one (2l)

Yield: 373 mg (70%); white solid; mp 144.6–148.1 °C.

IR (KBr): 3061, 3017, 1625, 1576, 1493, 1237, 759 cm–1.

1H NMR (400 MHz, CDCl3): δ = 3.81 (s, 3 H), 6.28 (d, J = 7.6 Hz, 1 H), 7.41 (t, J = 3.4 Hz, 2 H), 7.52 (d, J = 7.6 Hz, 1 H), 7.71 (t, J = 7.8 Hz, 1 H), 8.48 (d, J = 8.0 Hz, 1 H).

13C NMR (100 MHz, CDCl3): δ = 40.61, 110.15, 115.23, 123.77, 127.06, 127.13, 132.20, 140.67, 143.62, 178.32.

Anal. Calcd for C10H9NO: C, 75.45; H, 5.70; N, 8.80; Found: C, 75.43; H, 5.68; N, 8.81.


#

1-(4-Chloro-phenyl)-1H-quinolin-4-one (2m)

Yield: 884 mg (85%); yellow solid; mp 177.2–181.5 °C.

IR (KBr): 3045, 3022, 1622, 1606, 1590, 1476, 1367, 1285, 1236, 760 cm–1.

1H NMR (400 MHz, CDCl3): δ = 6.38 (d, J = 7.6 Hz, 1 H), 6.98 (d, J = 8.4 Hz, 1 H), 7.40–7.35 (m, 3 H), 7.59–7.49 (m, 4 H), 8.46 (dd, J 1 =0.8, J 2 =0.8 Hz, 1 H).

13C NMR (100 MHz, CDCl3): δ = 110.54, 116.99, 124.10, 126.60, 126.74, 129.01, 130.61, 132.04, 135.59, 139.81, 141.20, 142.41, 178.23.

Anal. Calcd for C15H10ClNO: C, 70.46; H, 3.94; N, 5.48; Found: C, 70.47; H, 3.92; N, 5.46.


#

1-(4-Bromo-phenyl)-6-methyl-1H-quinolin-4-one (2n)

Yield: 454 mg (88%); white solid; mp 145.3–148.4 °C.

IR (KBr): 3021, 1630, 1610, 1583, 1483, 1289, 1201, 823 cm–1.

1H NMR (400 MHz, CDCl3): δ = 2.45 (s, 3 H), 6.36 (d, J = 7.6 Hz, 1 H), 6.89 (d, J = 8.8 Hz, 1 H), 7.29 (d, J = 8.4 Hz, 2 H), 7.34 (dd, J 1 = 2.0, J 2 =2.0 Hz, 1 H), 7.52 (d, J = 7.6 Hz, 1 H), 7.73 (d, J = 8.4 Hz, 2 H), 8.26 (s, 1 H).

13C NMR (100 MHz, CDCl3): δ = 20.89, 110.25, 116.91, 123.45, 126.05, 126.45, 129.24, 133.46, 133.55, 134.17, 139.20, 140.44, 141.99, 178.18.

Anal. Calcd for C16H12BrNO: C, 61.17; H, 3.85; N, 4.46; Found: C, 61.15; H, 3.87; N, 4.43.


#

1-(4-Bromo-phenyl)-1H-quinolin-4-one (2o)

Yield: 806 mg (78%); yellow solid; mp 198.1–200.1 °C.

IR (KBr): 3043, 3020, 1619, 1591, 1475, 1366, 1283, 1238 cm–1.

1H NMR (400 MHz, CDCl3): δ = 6.37 (d, J = 7.6 Hz, 1 H), 6.98 (d, J = 8.4 Hz, 1 H), 7.30 (d, J = 8.0 Hz, 2 H), 7.40 (t, J = 7.4 Hz, 1 H), 7.53 (dd, J 1 = 1.2, J 2 = 1.6 Hz, 1 H), 7.55 (d, J = 8.0 Hz, 1 H), 7.75 (d, J = 7.6 Hz, 2 H), 8.48 (dd, J 1 = 0.8, J 2 = 0.8 Hz, 1 H).

13C NMR (100 MHz, CDCl3): δ = 110.57, 116.98, 123.56, 124.10, 126.61, 126.75, 129.31, 132.04, 133.62, 140.34, 141.13, 142.31, 178.21.

Anal. Calcd for C15H10BrNO: C, 60.02; H, 3.36; N, 4.67; Found: C, 60.03; H, 3.34; N, 4.64.


#

1-(4-Isopropyl-phenyl)-1H-quinolin-4-one (2p)

Yield: 893 mg (86%); yellow solid; mp 44.7–46.5 °C.

IR (KBr): 2964, 1620, 1585, 1291, 760 cm–1.

1H NMR (400 MHz, CDCl3): δ = 1.34 (d, J = 6.8 Hz, 6 H), 3.00–307 (m, 1 H), 6.38 (d, J = 8.0 Hz, 1 H), 7.04 (d, J = 8.4 Hz, 1 H), 7.31 (d, J = 8.4 Hz, 2 H), 7.38 (t, J = 7.6 Hz, 1 H), 7.44 (d, J = 8.0 Hz, 2 H), 7.49 (t, J = 8.4 Hz, 1 H), 7.61 (d, J = 7.6 Hz, 1 H), 8.48 (dd, J 1 = 1.2, J 2 = 1.2 Hz, 1 H).

13C NMR (100 MHz, CDCl3): δ = 23.94, 33.95, 110.11, 117.45, 123.81, 126.52, 126.60, 127.35, 128.25, 131.77, 138.99, 141.52, 142.93, 150.49, 178.29.

Anal. Calcd for C18H17NO: C, 82.10; H, 6.51; N, 5.32; Found: C, 82.08; H, 6.52; N, 5.30.


#

6-Methyl-1-phenyl-1H-quinolin-4-one (2q)

Yield: 887 mg (85%); white solid; mp 113.2–115.7 °C.

IR (KBr): 3030, 1584, 1486, 1286, 830, 808, 765, 695 cm–1.

1H NMR (300 MHz, CDCl3): δ = 2.46 (s, 3 H), 6.36 (d, J = 7.5 Hz, 1 H), 6.92 (d, J = 8.7 Hz, 1 H), 7.301 (d, J = 8.4 Hz, 1 H), 7.39 (d, J = 6.3 Hz, 2 H), 7.56–7.60 (m, 4 H), 8.27 (s, 1 H).

13C NMR (75 MHz, CDCl3): δ = 21.00, 110.03, 117.34, 125.98, 126.57, 127.65, 129.53, 130.37, 133.39, 133.99, 139.57, 141.60, 142.50, 178.35.

Anal. Calcd for C16H13NO: C, 81.68; H, 5.57; N, 5.95; Found: C, 81.66; H, 5.58; N, 5.97.


#

6-Bromo-1-phenyl-1H-quinolin-4-one (2r)

Yield: 827 mg (80%); yellow solid; mp 158–162.8 °C.

IR (KBr): 3054, 3043, 1630, 1584, 1471, 1292, 818, 698 cm–1.

1H NMR (300 MHz, CDCl3): δ = 6.39 (d, J = 7.5 Hz, 1 H), 6.88 (d, J = 9.0 Hz, 1 H), 7.37 (d, J = 7.5 Hz, 2 H), 7.54–7.61 (m, 5 H), 8.61 (s, 1 H).

13C NMR (75 MHz, CDCl3): δ = 110.68, 117.85, 119.39, 127.53, 127.94, 129.25, 129.91, 130.61, 134.96, 140.26, 141.09, 143.03, 177.04.

Anal. Calcd for C15H10BrNO: C, 60.02; H, 3.36; N, 4.67; Found: C, 60.00; H, 3.32; N, 4.65.


#

6-Chloro-1-phenyl-1H-quinolin-4-one (2s)

Yield: 832 mg (80%); white solid; mp 161.5–164.7 °C.

IR (KBr): 3042, 1630, 1590, 1473, 1294, 817, 702 cm–1.

1H NMR (300 MHz, CDCl3): δ = 6.37 (d, J = 7.8 Hz, 1 H), 6.95 (d, J = 9.0 Hz, 1 H), 7.38–7.44 (m, 3 H), 7.58–7.62 (m, 4 H), 8.44 (d, J = 2.4 Hz, 1 H).

13C NMR (75 MHz, CDCl3): δ = 110.58, 119.20, 126.05, 127.56, 127.65, 129.90, 130.23, 130.60, 132.28, 139.90, 141.16, 142.97, 177.16.

Anal. Calcd for C15H10ClNO: C, 70.46; H, 3.94; N, 5.48; Found: C, 70.47; H, 3.92; N, 5.46.


#

1-(4-Nitro-phenyl)-1H-quinolin-4-one (2t)

Yield: 441 mg (85%); yellow solid; mp 164.1–167.8 °C.

IR (KBr): 3354, 1682, 1594, 1504, 1330, 1304, 1111, 740 cm–1.

1H NMR (400 MHz, CDCl3): δ = 6.43 (d, J = 7.6 Hz, 1 H), 6.99 (d, J = 8.4 Hz, 1 H), 7.42 (t, J = 7.2 Hz, 1 H), 7.54–7.58 (m, 2 H), 7.65 (d, J = 8.8 Hz, 2 H), 8.49 (d, J = 8.8 Hz, 3 H).

13C NMR (100 Hz, CDCl3): δ = 111.21, 116.52, 124.59, 125.82, 126.62, 127.05, 128.73, 132.37, 140.57, 141.65, 146.58, 147.94, 178.10.

Anal. Calcd for C15H10N2O3: C, 67.67; H, 3.79; N, 10.52; Found: C, 67.62; H, 3.74; N, 10.49.


#

1-(3-Methoxy-phenyl)-1H-quinolin-4-one (2u)

Yield: 426 mg (82%); yellow solid; mp 163.5–167.1 °C.

IR (KBr): 3056, 2840, 1631, 1585, 1225, 1032, 699 cm–1.

1H NMR (400 MHz, CDCl3): δ = 3.86 (s, 3 H), 6.36 (d, J = 8.0 Hz, 1 H), 6.92 (d, J = 2.0 Hz, 1 H), 6.98 (t, J = 7.6 Hz, 1 H), 7.04–7.10 (m, 2 H), 7.36 (t, J = 7.4 Hz, 1 H), 7.47–7.52 (m, 2 H), 7.60 (d, J = 7.6 Hz, 2 H), 8.46 (d, J = 7.2 Hz, 1 H).

13C NMR (100 Hz, CDCl3): δ = 55.65, 110.17, 113.25, 115.21, 117.35, 119.59, 123.87, 126.56, 131.02, 131.85, 141.29, 142.39, 142.59, 161.00, 178.29.

Anal. Calcd for C16H13NO2: C, 76.48; H, 5.21; N, 5.57; Found: C, 76.49; H, 5.23; N, 5.56.


#

Preparation of 1-Cyclopropyl-2-phenyl-1H-quinolin-4-one (4a)

To a mixture of 1-(2-cyclopropylaminophenyl)ethanone 1 (1.0 g, 5.71 mmol) and triethylamine (2.88 g, 28.5 mmol) in THF (10 mL) at 25 °C, benzoyl chloride (0.802 g, 5.71 mmol) was added and the mixture was heated to reflux for 4 h. After completion of reaction (as monitored by TLC), the THF was removed under reduced pressure and potassium carbonate (2.36 g, 17.10 mmol) and DMF (10 mL) were added at 25 °C. The reaction mixture was then heated to 100 °C until completion of the reaction (monitored by TLC). The reaction mixture was then poured into water and extracted with EtOAc (3 × 10 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EtOAc/n-hexane to obtain 4a.


#

1-Cyclopropyl-2-phenyl-1H-quinolin-4-one (4a)

Yield: 650 mg (87%); white solid; mp 170.1–172.4 °C.

IR (KBr): 3049, 3009, 1617, 1597, 1478, 1462, 1408, 1311, 1271, 1138, 1043, 775, 758, 709 cm–1.

1H NMR (400 MHz, CDCl3): δ = 0.57–0.58 (q, 2 H), 0.91–0.95 (q, 2 H), 3.32–3.35 (m, 1 H), 6.32 (s, 1 H), 7.38 (t, J = 7.6 Hz, 1 H), 7.47–7.54 (m, 5 H), 7.68–7.72 (m, 1 H), 7.96 (d, J = 8.8 Hz, 1 H), 8.44 (dd, J 1 = 1.2, J 2 = 1.2 Hz, 1 H).

13C NMR (100 MHz, CDCl3): δ = 12.92, 32.37, 113.32, 117.82, 123.53, 126.41, 126.77, 128.36, 128.52, 129.20, 131.67, 136.96, 143.12, 155.45, 178.19.

Anal. Calcd for C18H15NO: C, 82.73; H, 5.79; N, 5.36; Found: C, 82.74; H, 5.76; N, 5.34.


#

7-Chloro-1-cyclopropyl-6-fluoro-2-phenyl-1H-quinolin-4-one (4b)

Yield: 575 mg (84%); white solid; mp 209.2–211.5 °C.

IR (KBr): 3073, 1631, 1609, 1468, 1271, 986, 840 cm–1.

1H NMR (400 MHz, CDCl3): δ = 0.58–0.59 (q, 2 H), 0.95–1.00 (q, 2 H), 3.29–3.32 (m, 1 H), 6.26 (s, 1 H), 7.49 (m, 5 H), 8.03 (d, J = 6.0 Hz, 1 H), 8.13 (d, J = 8.8 Hz, 1 H).

13C NMR (100 MHz, CDCl3): δ = 12.96, 32.66, 112.25, 112.47, 113.00, 120.18, 125.99, 126.19, 126.66, 126.72, 128.29, 128.67, 129.53, 136.38, 139.74, 153.42, 155.85, 155.89, 176.58, 176.60.

Anal. Calcd for C18H13ClFNO: C, 68.91; H, 4.18; N, 4.46; Found: C, 68.90; H, 4.17; N, 4.45.


#
#

Acknowledgment

We would like to thank Suven Life Sciences for providing analytical facilities and acknowledge CEO Mr Jasti for permission to publish this work.

Supporting Information

  • References

  • 1 Pozharskii AF, Soldatenkov AT, Katritzky AR. Heterocycles in Life and Society . Wiley; Chichester, UK: 1997: 135
    • 2a Mitscher LA. Chem. Rev. 2005; 105: 559
    • 2b Cheng G, Hao H, Dai M, Liu Z, Yuan Z. Eur. J. Med. Chem. 2013; 66: 555
    • 3a Chen Y.-L, Fang K.-C, Sheu J.-Y, Hsu S.-L, Tzeng C.-C. J. Med. Chem. 2001; 44: 2374
    • 3b Asahina Y, Iwase K, Iinuma F, Hosaka M, Ishizaki T. J. Med. Chem. 2005; 48: 3194
    • 3c Odagiri T, Inagaki H, Sugimoto Y, Nagamochi M, Miyauchi RN, Kuroyanagi J, Kitamura T, Komoriya S, Takahashi H. J. Med. Chem. 2013; 56: 1974
    • 4a Li L, Wang H.-K, Kuo S.-C, Wu T.-S, Mauger A, Lin CM, Hamel E, Lee K.-H. J. Med. Chem. 1994; 37: 3400
    • 4b Nakamura S, Kozuka M, Bastow KF, Tokuda H, Nishino H, Suzuki M, Tatsuzaki J, Natschke SL. M, Kuo S.-C, Lee K.-H. Bioorg. Med. Chem. 2005; 13: 4396
    • 4c Chang Y.-H, Hsu M.-H, Wang S.-H, Huang L.-J, Qian K, Morris-Natschke SL, Hamel E, Kuo S.-C, Lee K.-H. J. Med. Chem. 2009; 52: 4883
    • 5a Cross RM, Monastyrskyi A, Mutka TS, Burrows JN, Kyle DE, Manetsch R. J. Med. Chem. 2010; 53: 7076
    • 5b Cross RM, Namelikonda NK, Mutka TS, Luong L, Kyle DE, Manetsch R. J. Med. Chem. 2011; 54: 8321
    • 5c Zhang Y, Clark JA, Connelly MC, Zhu F, Min J, Guiguemde WA, Pradhan A, Iyer L, Furimsky A, Gow J, Parman T, Mazouni FE, Phillips MA, Kyle DE, Mirsalis J, Guy RK. J. Med. Chem. 2012; 55: 4205
  • 6 Edmont D, Rocher R, Plisson C, Chenault J. Bioorg. Med. Chem. Lett. 2000; 10: 1831
  • 7 Lucero BdA, Gomes CR. B, Frugulhetti IC. de P. P, Faro LV, Alvarenga L, Souza MC. B. V, de Souza TM. L, Ferreira VF. Bioorg. Med. Chem. Lett. 2006; 16: 1010
    • 8a Cecchetti V, Parolin C, Moro S, Pecere T, Filipponi E, Calistri A, Tabarrini O, Gatto B, Palumbo M, Fravolini A, Palu G. J. Med. Chem. 2000; 43: 3799
    • 8b Sato M, Motomura T, Aramaki H, Matsuda T, Yamashita M, Ito Y, Kawakami H, Matsuzaki Y, Watanabe W, Yamataka K, Ikeda S, Kodama E, Matsuoka M, Shinkai H. J. Med. Chem. 2006; 49: 1506
    • 8c Pasquini S, Mugnaini C, Tintori C, Botta M, Trejos A, Arvela RK, Larhed M, Witvrouw M, Michiels M, Christ F, Debyser Z, Corelli F. J. Med. Chem. 2008; 51: 5125
    • 9a Reitsema RH. Chem. Rev. 1948; 43: 43
    • 9b López SE, Rebollo O, Salazar J, Charris JE, Yánez C. J. Fluorine Chem. 2003; 120: 71
    • 9c Boteva AA, Krasnykh OP. Chem. Heterocycl. Compd. 2009; 45: 757
    • 9d Romek A, Opatz T. Eur. J. Org. Chem. 2010; 5841
    • 9e Liu Q.-L, Li Q.-L, Fei X.-D, Zhu Y.-M. ACS Comb. Sci. 2011; 13: 19
    • 9f Zhao J, Zhao Y, Fu H. Org. Lett. 2012; 14: 2710
    • 9g Iaroshenko VO, Knepper I, Zahid M, Dudkin S, Kuzora R, Villinger A, Langer P. Org. Biomol. Chem. 2012; 10: 2955
    • 9h Shao J, Huang X, Hong X, Liu B, Xu B. Synthesis 2012; 44: 1798
    • 9i Victor NJ, Muraleedharan KM. Adv. Synth. Catal. 2014; 356: 3600
    • 9j Ji X, Wang Z, Tan M, Huang H, Deng GJ. Asian J. Org. Chem. 2018; 7: 711
    • 9k Wang D, Sun P, Jia p, Peng J, Yue Y, Chen C. Synthesis 2017; 49: 1851
    • 9l Xu X, Zhang X. Org. Lett. 2017; 19: 4984
  • 10 Camps R. Ber. Dtsch. Chem. Ges. 1899; 32: 3228
  • 12 Gould RG, Jacobs WA. J. Am. Chem. Soc. 1939; 61: 2890
    • 13a Niementowski S. Ber. Dtsch. Chem. Ges. 1894; 27: 1394
    • 13b Fuson RC, Burness DM. J. Am. Chem. Soc. 1946; 68: 1270
    • 13c Son JK, Kim SI, Jahng Y. Heterocycles 2001; 55: 1981
    • 14a Kalinin VN, Sbostakovsky MV, Ponomaryov AB. Tetrahedron Lett. 1992; 33: 373
    • 14b Torii S, Okumoto H, Xu LH, Sadakane M, Shostakovsky MV, Ponomaryov AB, Kalinin VN. Tetrahedron 1993; 49: 6773
    • 14c Haddad N, Tan J, Farina V. J. Org. Chem. 2006; 71: 5031
    • 14d Huang J, Chen Y, King AO, Dilmeghani M, Larsen RD, Faul MM. Org. Lett. 2008; 10: 2609
    • 14e Zhao T, Xu B. Org. Lett. 2010; 12: 212
    • 14f Takahashi I, Morita F, Kusagaya S, Fukaya H, Kitagawa O. Tetrahedron: Asymmetry 2012; 23: 1657
    • 14g Iaroshenko VO, Knepper I, Zahid M, Kuzora R, Dudkin S, Villinger A, Langer P. Org. Biomol. Chem. 2012; 10: 2955
    • 14h Fei X.-D, Zhou Z, Li W, Zhu Y.-M, Shen J.-K. Eur. J. Org. Chem. 2012; 3001
    • 14i Iaroshenko VO, Zahid M, Mkrtchyan S, Gevorgyan A, Altenburger K, Knepper I, Villinger A, Sosnovskikh VY, Langer P. Tetrahedron 2013; 69: 2309
    • 14j Wang Y, Liang H, Chen C, Wang D, Peng J. Synthesis 2015; 47: 1851
    • 15a Jones CP, Anderson KW, Buchwald SL. J. Org. Chem. 2007; 72: 7968
    • 15b Bernini R, Cacchi S, Fabrizi G, Sferrazza A. Synthesis 2009; 1209
  • 16 Seppänen O, Muuronen M, Helaja J. Eur. J. Org. Chem. 2014; 4044
  • 17 Radl S, Dax S. Curr. Med. Chem. 1994; 1: 262
    • 18a Alvarez M, Salas M, Rigat L, de Veciana A, Joule JA. J. Chem. Soc., Perkin Trans. 1 1992; 351
    • 18b Bichovski P, Haas TM, Kratzert D, Streuff J. Chem. Eur. J. 2015; 21: 2339
    • 18c Biswas K, Peterkin TA. N, Bryan MC, Arik L, Lehto SG, Sun H, Hsieh F.-Y, Xu C, Fremeau RT, Allen JR. J. Med. Chem. 2011; 54: 7232
    • 18d Hirano J, Hamase K, Zaitsu K. Tetrahedron 2006; 62: 10065
    • 18e Ji X, Li D, Wang Z, Tan M, Huang H, Deng GJ. Eur. J. Org. Chem. 2017; 6652
    • 18f Li M, Li L, Gea H. Adv. Synth. Catal. 2010; 352: 2445
    • 18g Markees DG, Schwab LS. Helv. Chim. Acta 1972; 55: 1319
    • 18h Stanislav R, Iva O. Collect. Czech. Chem. Commun. 2014; 69: 822
    • 18i Taylor NJ, Emer E, Preshlock S, Schedler M, Tredwell M, Verhoog S, Mercier J, Genicot C, Gouverneur VR. J. Am. Chem. Soc. 2017; 139: 8267
    • 18j Ueno S, Shimizu R, Maeda R, Kuwano R. Synlett 2012; 23: 1639
  • 19 The Merck Index . 13th ed. Merck & Co; Whitehouse Station, USA: 2001: p. 618
    • 20a Price JR. Aust. J. Sci. Res., Ser. A 1949; 2: 272
    • 20b Maslova MM, Marchenko NB, Polshakov VI, Glushkov RG. Khim.-Farm. Zh. 1993; 27: 57
    • 20c Reuman M, Eissenstat MA, Weaver JD. Tetrahedron Lett. 1994; 35: 8303
    • 21a Conrad M, Limpach L. Ber. Dtsch. Chem. Ges. 1887; 20: 944
    • 21b Conrad M, Eckhardt F. Ber. Dtsch. Chem. Ges. 1889; 22: 73
    • 21c Meyer H. Monatsh. Chem. 1906; 27: 255
    • 22a Knorr L, Fertig E. Ber. Dtsch. Chem. Ges. 1897; 30: 937
    • 22b Troeger J, Dunker E. J. Prakt. Chem. 1926; 112: 196
    • 22c Troeger J, Müller W. Arch. Pharm. (Weinheim, Ger.) 1914; 252: 459
  • 23 Frank J, Mészáros Z, Kömives T, Márton AF, Dutka F. J. Chem. Soc., Perkin Trans. 2 1980; 401
    • 24a Dobrowolski JC, Katen A, Fraser BH, Bhadbhade M, Black DStC, Kumar N. Tetrahedron Lett. 2016; 57: 5442
    • 24b Pan G.-F, Su L, Zhang Y.-L, Guo S.-H, Wang Y.-Q. RSC Adv. 2016; 6: 25375
  • 25 Derabli C, Mahdjoub S, Boulcina R, Boumoud B, Merazig H, Debache A. Chem. Heterocycl. Compd. 2016; 52: 99
    • 26a Xia Y, Yang Z.-Y, Xia P, Bastow KF, Tachibana Y, Kuo S.-C, Hamel E, Hackl T, Lee K.-H. J. Med. Chem. 1998; 41: 1155
    • 26b Xia Y, Yang Z.-Y, Xia P, Bastow KF, Nakanishi Y, Lee K.-H. Bioorg. Med. Chem. Lett. 2000; 10: 699
    • 27a Saito K, Moriya Y, Akiyama T. Org. Lett. 2015; 17: 3202
    • 27b Bunce RA, Nammalwar B. J. Heterocycl. Chem. 2011; 48: 613
    • 27c Wang J.-F, Liao Y.-X, Kuo P.-Y, Gau Y.-H, Yang D.-Y. Synlett 2006; 2791
  • 28 Ding D, Li X, Wang X, Du Y, Shen J. Tetrahedron Lett. 2006; 47: 6997
  • 29 Genelot M, Dufaud V, Djakovitch L. Tetrahedron 2011; 67: 976
    • 30a Coppola GM. J. Heterocycl. Chem. 1982; 19: 727
    • 30b Yoshino Y, Kurahashi T, Matsubara S. J. Am. Chem. Soc. 2009; 131: 7494
  • 31 Tambe YB, Somesh S, Arunendra P, Reddy LR. Synth. Commun. 2012; 42: 1341
  • 32 Mehra MK, Mukund PT, Arun V, Kumar I, Dalip K. Org. Biomol. Chem. 2017; 15: 4956
  • 33 Arava VR, Bandatmakuru SR. Synthesis 2013; 45: 1039
  • 34 Audisio D, Messaoudi S, Peyrat J.-FO, Brion J.-D, Alami M. J. Org. Chem. 2011; 76: 4995
  • 35 Carr RM, Sutherland DR. J. Labelled Compd. Radiopharm. 1994; 34: 961
    • 36a Almeida AI. S, Silva AM. S, Cavaleiro JA. S. Synlett 2010; 462
    • 36b Cross RM, Monastyrskyi A, Mutka TS, Burrows JN, Kyle DE, Manetsch R. J. Med. Chem. 2010; 53: 7076
  • 37 Venkataraman S, Barange DK, Pal M. Tetrahedron Lett. 2006; 47: 7317
    • 38a Zhao T, Xu B. Org. Lett. 2010; 12: 212
    • 38b Hessian KO, Flynn BL. Org. Lett. 2005; 8: 243
    • 38c Cross RM, Manetsch R. J. Org. Chem. 2010; 75: 8654

  • References

  • 1 Pozharskii AF, Soldatenkov AT, Katritzky AR. Heterocycles in Life and Society . Wiley; Chichester, UK: 1997: 135
    • 2a Mitscher LA. Chem. Rev. 2005; 105: 559
    • 2b Cheng G, Hao H, Dai M, Liu Z, Yuan Z. Eur. J. Med. Chem. 2013; 66: 555
    • 3a Chen Y.-L, Fang K.-C, Sheu J.-Y, Hsu S.-L, Tzeng C.-C. J. Med. Chem. 2001; 44: 2374
    • 3b Asahina Y, Iwase K, Iinuma F, Hosaka M, Ishizaki T. J. Med. Chem. 2005; 48: 3194
    • 3c Odagiri T, Inagaki H, Sugimoto Y, Nagamochi M, Miyauchi RN, Kuroyanagi J, Kitamura T, Komoriya S, Takahashi H. J. Med. Chem. 2013; 56: 1974
    • 4a Li L, Wang H.-K, Kuo S.-C, Wu T.-S, Mauger A, Lin CM, Hamel E, Lee K.-H. J. Med. Chem. 1994; 37: 3400
    • 4b Nakamura S, Kozuka M, Bastow KF, Tokuda H, Nishino H, Suzuki M, Tatsuzaki J, Natschke SL. M, Kuo S.-C, Lee K.-H. Bioorg. Med. Chem. 2005; 13: 4396
    • 4c Chang Y.-H, Hsu M.-H, Wang S.-H, Huang L.-J, Qian K, Morris-Natschke SL, Hamel E, Kuo S.-C, Lee K.-H. J. Med. Chem. 2009; 52: 4883
    • 5a Cross RM, Monastyrskyi A, Mutka TS, Burrows JN, Kyle DE, Manetsch R. J. Med. Chem. 2010; 53: 7076
    • 5b Cross RM, Namelikonda NK, Mutka TS, Luong L, Kyle DE, Manetsch R. J. Med. Chem. 2011; 54: 8321
    • 5c Zhang Y, Clark JA, Connelly MC, Zhu F, Min J, Guiguemde WA, Pradhan A, Iyer L, Furimsky A, Gow J, Parman T, Mazouni FE, Phillips MA, Kyle DE, Mirsalis J, Guy RK. J. Med. Chem. 2012; 55: 4205
  • 6 Edmont D, Rocher R, Plisson C, Chenault J. Bioorg. Med. Chem. Lett. 2000; 10: 1831
  • 7 Lucero BdA, Gomes CR. B, Frugulhetti IC. de P. P, Faro LV, Alvarenga L, Souza MC. B. V, de Souza TM. L, Ferreira VF. Bioorg. Med. Chem. Lett. 2006; 16: 1010
    • 8a Cecchetti V, Parolin C, Moro S, Pecere T, Filipponi E, Calistri A, Tabarrini O, Gatto B, Palumbo M, Fravolini A, Palu G. J. Med. Chem. 2000; 43: 3799
    • 8b Sato M, Motomura T, Aramaki H, Matsuda T, Yamashita M, Ito Y, Kawakami H, Matsuzaki Y, Watanabe W, Yamataka K, Ikeda S, Kodama E, Matsuoka M, Shinkai H. J. Med. Chem. 2006; 49: 1506
    • 8c Pasquini S, Mugnaini C, Tintori C, Botta M, Trejos A, Arvela RK, Larhed M, Witvrouw M, Michiels M, Christ F, Debyser Z, Corelli F. J. Med. Chem. 2008; 51: 5125
    • 9a Reitsema RH. Chem. Rev. 1948; 43: 43
    • 9b López SE, Rebollo O, Salazar J, Charris JE, Yánez C. J. Fluorine Chem. 2003; 120: 71
    • 9c Boteva AA, Krasnykh OP. Chem. Heterocycl. Compd. 2009; 45: 757
    • 9d Romek A, Opatz T. Eur. J. Org. Chem. 2010; 5841
    • 9e Liu Q.-L, Li Q.-L, Fei X.-D, Zhu Y.-M. ACS Comb. Sci. 2011; 13: 19
    • 9f Zhao J, Zhao Y, Fu H. Org. Lett. 2012; 14: 2710
    • 9g Iaroshenko VO, Knepper I, Zahid M, Dudkin S, Kuzora R, Villinger A, Langer P. Org. Biomol. Chem. 2012; 10: 2955
    • 9h Shao J, Huang X, Hong X, Liu B, Xu B. Synthesis 2012; 44: 1798
    • 9i Victor NJ, Muraleedharan KM. Adv. Synth. Catal. 2014; 356: 3600
    • 9j Ji X, Wang Z, Tan M, Huang H, Deng GJ. Asian J. Org. Chem. 2018; 7: 711
    • 9k Wang D, Sun P, Jia p, Peng J, Yue Y, Chen C. Synthesis 2017; 49: 1851
    • 9l Xu X, Zhang X. Org. Lett. 2017; 19: 4984
  • 10 Camps R. Ber. Dtsch. Chem. Ges. 1899; 32: 3228
  • 12 Gould RG, Jacobs WA. J. Am. Chem. Soc. 1939; 61: 2890
    • 13a Niementowski S. Ber. Dtsch. Chem. Ges. 1894; 27: 1394
    • 13b Fuson RC, Burness DM. J. Am. Chem. Soc. 1946; 68: 1270
    • 13c Son JK, Kim SI, Jahng Y. Heterocycles 2001; 55: 1981
    • 14a Kalinin VN, Sbostakovsky MV, Ponomaryov AB. Tetrahedron Lett. 1992; 33: 373
    • 14b Torii S, Okumoto H, Xu LH, Sadakane M, Shostakovsky MV, Ponomaryov AB, Kalinin VN. Tetrahedron 1993; 49: 6773
    • 14c Haddad N, Tan J, Farina V. J. Org. Chem. 2006; 71: 5031
    • 14d Huang J, Chen Y, King AO, Dilmeghani M, Larsen RD, Faul MM. Org. Lett. 2008; 10: 2609
    • 14e Zhao T, Xu B. Org. Lett. 2010; 12: 212
    • 14f Takahashi I, Morita F, Kusagaya S, Fukaya H, Kitagawa O. Tetrahedron: Asymmetry 2012; 23: 1657
    • 14g Iaroshenko VO, Knepper I, Zahid M, Kuzora R, Dudkin S, Villinger A, Langer P. Org. Biomol. Chem. 2012; 10: 2955
    • 14h Fei X.-D, Zhou Z, Li W, Zhu Y.-M, Shen J.-K. Eur. J. Org. Chem. 2012; 3001
    • 14i Iaroshenko VO, Zahid M, Mkrtchyan S, Gevorgyan A, Altenburger K, Knepper I, Villinger A, Sosnovskikh VY, Langer P. Tetrahedron 2013; 69: 2309
    • 14j Wang Y, Liang H, Chen C, Wang D, Peng J. Synthesis 2015; 47: 1851
    • 15a Jones CP, Anderson KW, Buchwald SL. J. Org. Chem. 2007; 72: 7968
    • 15b Bernini R, Cacchi S, Fabrizi G, Sferrazza A. Synthesis 2009; 1209
  • 16 Seppänen O, Muuronen M, Helaja J. Eur. J. Org. Chem. 2014; 4044
  • 17 Radl S, Dax S. Curr. Med. Chem. 1994; 1: 262
    • 18a Alvarez M, Salas M, Rigat L, de Veciana A, Joule JA. J. Chem. Soc., Perkin Trans. 1 1992; 351
    • 18b Bichovski P, Haas TM, Kratzert D, Streuff J. Chem. Eur. J. 2015; 21: 2339
    • 18c Biswas K, Peterkin TA. N, Bryan MC, Arik L, Lehto SG, Sun H, Hsieh F.-Y, Xu C, Fremeau RT, Allen JR. J. Med. Chem. 2011; 54: 7232
    • 18d Hirano J, Hamase K, Zaitsu K. Tetrahedron 2006; 62: 10065
    • 18e Ji X, Li D, Wang Z, Tan M, Huang H, Deng GJ. Eur. J. Org. Chem. 2017; 6652
    • 18f Li M, Li L, Gea H. Adv. Synth. Catal. 2010; 352: 2445
    • 18g Markees DG, Schwab LS. Helv. Chim. Acta 1972; 55: 1319
    • 18h Stanislav R, Iva O. Collect. Czech. Chem. Commun. 2014; 69: 822
    • 18i Taylor NJ, Emer E, Preshlock S, Schedler M, Tredwell M, Verhoog S, Mercier J, Genicot C, Gouverneur VR. J. Am. Chem. Soc. 2017; 139: 8267
    • 18j Ueno S, Shimizu R, Maeda R, Kuwano R. Synlett 2012; 23: 1639
  • 19 The Merck Index . 13th ed. Merck & Co; Whitehouse Station, USA: 2001: p. 618
    • 20a Price JR. Aust. J. Sci. Res., Ser. A 1949; 2: 272
    • 20b Maslova MM, Marchenko NB, Polshakov VI, Glushkov RG. Khim.-Farm. Zh. 1993; 27: 57
    • 20c Reuman M, Eissenstat MA, Weaver JD. Tetrahedron Lett. 1994; 35: 8303
    • 21a Conrad M, Limpach L. Ber. Dtsch. Chem. Ges. 1887; 20: 944
    • 21b Conrad M, Eckhardt F. Ber. Dtsch. Chem. Ges. 1889; 22: 73
    • 21c Meyer H. Monatsh. Chem. 1906; 27: 255
    • 22a Knorr L, Fertig E. Ber. Dtsch. Chem. Ges. 1897; 30: 937
    • 22b Troeger J, Dunker E. J. Prakt. Chem. 1926; 112: 196
    • 22c Troeger J, Müller W. Arch. Pharm. (Weinheim, Ger.) 1914; 252: 459
  • 23 Frank J, Mészáros Z, Kömives T, Márton AF, Dutka F. J. Chem. Soc., Perkin Trans. 2 1980; 401
    • 24a Dobrowolski JC, Katen A, Fraser BH, Bhadbhade M, Black DStC, Kumar N. Tetrahedron Lett. 2016; 57: 5442
    • 24b Pan G.-F, Su L, Zhang Y.-L, Guo S.-H, Wang Y.-Q. RSC Adv. 2016; 6: 25375
  • 25 Derabli C, Mahdjoub S, Boulcina R, Boumoud B, Merazig H, Debache A. Chem. Heterocycl. Compd. 2016; 52: 99
    • 26a Xia Y, Yang Z.-Y, Xia P, Bastow KF, Tachibana Y, Kuo S.-C, Hamel E, Hackl T, Lee K.-H. J. Med. Chem. 1998; 41: 1155
    • 26b Xia Y, Yang Z.-Y, Xia P, Bastow KF, Nakanishi Y, Lee K.-H. Bioorg. Med. Chem. Lett. 2000; 10: 699
    • 27a Saito K, Moriya Y, Akiyama T. Org. Lett. 2015; 17: 3202
    • 27b Bunce RA, Nammalwar B. J. Heterocycl. Chem. 2011; 48: 613
    • 27c Wang J.-F, Liao Y.-X, Kuo P.-Y, Gau Y.-H, Yang D.-Y. Synlett 2006; 2791
  • 28 Ding D, Li X, Wang X, Du Y, Shen J. Tetrahedron Lett. 2006; 47: 6997
  • 29 Genelot M, Dufaud V, Djakovitch L. Tetrahedron 2011; 67: 976
    • 30a Coppola GM. J. Heterocycl. Chem. 1982; 19: 727
    • 30b Yoshino Y, Kurahashi T, Matsubara S. J. Am. Chem. Soc. 2009; 131: 7494
  • 31 Tambe YB, Somesh S, Arunendra P, Reddy LR. Synth. Commun. 2012; 42: 1341
  • 32 Mehra MK, Mukund PT, Arun V, Kumar I, Dalip K. Org. Biomol. Chem. 2017; 15: 4956
  • 33 Arava VR, Bandatmakuru SR. Synthesis 2013; 45: 1039
  • 34 Audisio D, Messaoudi S, Peyrat J.-FO, Brion J.-D, Alami M. J. Org. Chem. 2011; 76: 4995
  • 35 Carr RM, Sutherland DR. J. Labelled Compd. Radiopharm. 1994; 34: 961
    • 36a Almeida AI. S, Silva AM. S, Cavaleiro JA. S. Synlett 2010; 462
    • 36b Cross RM, Monastyrskyi A, Mutka TS, Burrows JN, Kyle DE, Manetsch R. J. Med. Chem. 2010; 53: 7076
  • 37 Venkataraman S, Barange DK, Pal M. Tetrahedron Lett. 2006; 47: 7317
    • 38a Zhao T, Xu B. Org. Lett. 2010; 12: 212
    • 38b Hessian KO, Flynn BL. Org. Lett. 2005; 8: 243
    • 38c Cross RM, Manetsch R. J. Org. Chem. 2010; 75: 8654

Zoom Image
Figure 1 Representative potent antibiotics containing the 4-quinolone moiety
Zoom Image
Equation 1
Zoom Image
Equation 2
Zoom Image
Equation 3
Zoom Image
Equation 4
Zoom Image
Scheme 1 One-pot synthesis of N-substituted-4-quinolone derivatives
Zoom Image
Scheme 2 Synthesis of N-substituted-4-quinolone derivatives
Zoom Image
Scheme 3 Synthesis of 2-aryl-2,3-dihydroquinolin-4(1H)-one 4