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Synthesis 2022(10): 1610-1614
DOI: 10.1055/s-2003-40531
PAPER
© Georg Thieme Verlag Stuttgart ˙ New York

Microwave-Assisted One-Pot Synthesis of 2,4-Disubstituted Quinolines under Solvent-Free Conditions

J. S. Yadav*, B. V. S. Reddy, R. Srinivasa Rao, V. Naveenkumar, K. Nagaiah
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad-500 007, India
Fax: +91(40)27160512; e-Mail: yadav@iict.ap.nic.in;

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Publication History

Received 24 April 2003
Publication Date:
08 July 2003 (online)

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Abstract

Aromatic imines derived in situ from aryl aldehydes and aryl amines undergo smoothly, cyclization with alkynes on the surface of montmorillonite clay impregnated with copper(I) bromide under solvent-free conditions to produce 2,4-disubstituted quinolines in high yields with excellent selectivity. The reaction rates and yields are significantly improved by employing microwave irradiation.

Key words

microwave - aryl imines - alkynes - substituted quinolines

Quinoline derivatives are found to possess a wide spectrum of biological activities such as antimalarial, antibacterial, antidiabetic and antiinflammatory behavior. [1] Furthermore, polyquinolines derived from quinolines are found to undergo hierarchical self-assembly into a variety of nanostructures and mesostructures with electronic and photonic functions. [2] Consequently, numerous methods such as Skraup, Doebner-von Miller, Friedlandler and Combes methods have been developed for the preparation of quinoline derivatives. [3-5] However, many of these classical methods require high temperatures, prolonged reaction times and drastic reaction conditions and also the yields reported are far from satisfactory due to the occurrence of several side reactions. Furthermore, many of these procedures involve the use of strong acids, which always demand aqueous work-up for their separation, recycling or disposal. Owing to the fascinating biological properties of quinolines, new catalytic systems are being continuously explored in search of improved efficiencies and cost effectiveness. [6] Since quinoline derivatives have become increasingly useful and important in drugs and pharmaceuticals, the development of simple, more convenient and environmentally benign approaches are desirable.

In recent years, microwave-assisted reactions are of great interest because of the simplicity in operation, enhanced reaction rates and greater selectivity. Particularly, solvent-free reactions have gained popularity as they provide an opportunity to work with open vessels. This avoids the risk of the development of high pressure and provides a possibility of scaling-up the reaction under dry conditions. Thus, microwave irradiation, which has become a powerful synthetic tool for the rapid synthesis of a variety of biologically active compounds under solvent-free conditions, is used to enhance the rates of classical organic reactions. [7] Furthermore, solid-supported reagents are advantageous as they can be easily recovered from the reaction mixture by simple filtration and can be reused after activation, thereby making the process economically viable. In many cases, heterogeneous catalysts can be recovered with only minor change in activity and selectivity so that they can be conveniently used in continuous flow reactions. Among various heterogeneous catalysts, clays are most attractive because of their reusability, environmental compatibility, low cost, non-toxicity and experimental/operational simplicity. [8]

In this paper, we wish to report a novel and efficient approach for the synthesis of 2,4-disubstituted quinolines by three-component condensation of aldehydes, amines and alkynes on the surface of montmorillonite clay impregnated with copper(I) bromide in solvent-free conditions (Scheme [1] ).

Scheme 1

Accordingly, the treatment of benzaldehyde and aniline with homopropargyl alcohol in the presence of montmorillonite clay doped with 30 mol% copper(I) bromide under microwave irradiation over 4 minutes afforded 2,4-disubstituted quinoline in 92% yield. The microwave irradiations were carried out using a BPL, BMO-800 T, domestic microwave oven. In the microwave oven, the reaction temperature was controlled by pulsed irradiation technique (1 min with 20 s off interval) at constant power. In a similar fashion, various imines (formed in situ from aldehydes and aryl amines on the surface of clay) reacted smoothly with alkynes to produce the corresponding quinoline derivatives. The reactions proceeded efficiently in solvent-free conditions and are completed within 3.0-5.0 minutes under microwave irradiation. The same reactions took 3.0-6.0 hours under thermal conditions to afford comparable yields to those obtained by microwave irradiation. Both electron rich and electron deficient aldehydes and amines afforded the corresponding quinoline derivatives in excellent yields (75-93%) with high selectivity, whereas ketones such as acetophenone, cyclohexanone and tetralone did not give the desired product under these reaction conditions. Furthermore, phenyl acetylene and hydroxy substituted alkynes gave higher yields than simple alkynes (Table [1] ). Sterically hindered amines also gave the corresponding quinolines in high yields (entries b, d, i and l). However, in the absence of clay, the products are obtained in low yields (27-45%). This is due to the rapid formation of imines from aldehydes and amines on the clay surface. It indicates that both clay and copper bromide are essential for the success of the reaction. Finally, the reactivity of various alkynes and aldimines was studied under microwave as well as conventional heating conditions. The reaction rates and yields are considerably improved by microwave irradiation. The rate enhancement may be attributed to the absorption of more microwave energy by polar media that generates heat energy as required to promote the reaction. Thus microwave promoted reactions are quick, more convenient and high yielding. The simple experimental and product isolation procedures combined with ease of recovery of this novel catalytic system are expected to contribute to the development of clean processes for the synthesis of quinoline derivatives. The scope and generality of this process is illustrated with respect to various aldehydes, amines and alkynes and the results are presented in Table [1] .

Table 1 Copper-Montmorillonite Promoted Synthesis of Quinolines under Microwave Irradiation
Entry Arylamine ArCHO Alkyne Quinolinea Microwaveb
Conventionalc
Time (min) Yield (%) Time (min) Yield (%)
a

4.0 92 3.0 89
b

’’ ’’

5.0 89 4.5 85
c

’’

3.0 90 3.5 87
d

’’

5.0 87 6.0 81
e

3.0 92 3.0 90
f

’’

4.0 88 4.5 83
g

’’

5.0 86 5.0 80
h

’’

3.0 91 4.0 87
i

’’

3.0 93 3.5 89
j

’’

5.0 85 5.5 82
k

’’

3.0 89 4.5 86
l

’’

4.0 92 3.0 89
m

’’

3.0 75 3.5 71
n

5.0 89 3.5 85
a All products were characterized by 1H NMR, IR and mass spectroscopy.
b Pulsed irradiation (1min with 20 s interval).
c Conventional heating at 80 °C.

In summary, this paper describes a novel and efficient approach for the rapid synthesis of substituted quinolines in a one-pot operation by three-component coupling of aldehydes, amines and alkynes using montmorillonite clay impregnated with copper(I) bromide as an inexpensive and environmentally benign catalytic system. The notable features of this procedure are mild reaction conditions, operational simplicity, improved yields and enhanced reaction rates, cleaner reaction profiles and simple experimental and product separation procedures making this method attractive for the synthesis of 2,4-disubstituted quinolines of biological importance.

The IR spectra were recorded on a Perkin-Elmer infracord model 337. NMR spectra were recorded on a Varian FT-200 MHz (Gemini) and a Bruker 300 MHz (Avance). Mass spectra were recorded on a Finnigan Mat 1210 or Micro Mass 7070 spectrometer at 70 eV using a direct inlet system.

Microwave Irradiation

Aldehyde (1 mmol), amine (1 mmol), alkyne (2 mmol) and CuBr (30 mol%) were admixed with KSF clay (1.0 g) and subjected to microwave irradiation, operating at 450 Watts using a BPL, BMO-800 T microwave oven for the appropriate time (Table [1] ). After completion of the reaction, as indicated by TLC, the product was separated by filtration with EtOAc (2 × 10 mL). The combined organic extracts were concentrated in vacuo and the resulting product was directly charged onto a small silica gel column and eluted (EtOAc-n-hexane, 2:8) to afford pure 2,4-disubstituted quinolines.

Conventional Method

Aldehyde (1 mmol), amine (1 mmol), alkyne (2 mmol) and CuBr (30 mol%) were admixed with KSF clay (1.0 g) and exposed to heating at 80 °C in an oil bath for the specified time as shown in Table [1] . The work-up procedure follows as described above.

2-(2-Phenylquinolin-4-yl)ethanol (4a)

Pale yellow solid, mp 98-99 °C.

IR (KBr): 3310, 3063, 2925, 1598, 1552, 1448, 1355, 1047 cm-1.

1H NMR (300 MHz, CDCl3): δ = 3.10 (t, J = 6.9 Hz, 2 H), 3.80 (t, J = 6.9 Hz, 2 H), 3.90-4.00 (br s, OH, 1 H), 7.25-7.40 (m, 5 H), 7.55 (t, J = 7.9 Hz, 1 H), 7.75 (d, J = 8.1 Hz, 1 H), 7.80 (m, 2 H), 8.0 (d, J = 8.0 Hz, 1 H).

13C NMR (75 MHz, CDCl3): δ = 36.1, 62.2, 120.5, 123.8, 124.3, 126.9, 127.8, 128.1, 128.4, 129.2, 129.5, 129.8, 129.9, 130.1, 130.3, 130.4, 156.7.

MS (EI): m/z (%) = 249 (25) [M+], 219 (30), 217 (15), 125 (10), 111 (20), 97 (35), 83 (37), 69 (62), 57 (100), 43 (90).

2-(6,8-Difluoro-2-phenylquinolin-4-yl)ethanol (4b)

Yellow oil.

IR (neat): 3440, 2928, 2864, 1632, 1552, 1280, 1216 cm-1.

1H NMR (300 MHz, CDCl3): δ = 1.90-2.00 (br s, OH, 1 H), 2.95 (t, J = 6.8 Hz, 2 H), 3.50 (t, J = 6.8 Hz, 2 H), 6.70-6.80 (m, 1 H), 7.10-7.18 (m, 1 H), 7.30-7.45 (m, 5 H), 7.55-7.60 (m, 1 H).

MS (EI): m/z (%) = 285 (100) [M+], 199 (11), 155 (13), 142 (62), 129 (25), 117 (11), 103 (20), 77 (25), 57(30), 43 (25).

2-[2-(2,5-Dimethoxyphenyl)quinolin-4-yl]ethanol (4c)

Yellow oil.

IR (neat): 3376, 2928, 2848, 1584, 1488, 1456, 1216, 1024, 768 cm-1.

1H NMR (200 MHz, CDCl3): δ = 2.10-2.30 (br s, OH, 1 H), 3.30 (t, J = 6.9 Hz, 2 H), 3.75 (s, 3 H), 3.80 (s, 3 H), 3.98 (t, J = 6.9 Hz, 2 H), 6.90 (s, 2 H), 7.40 (s, 1 H), 7.50 (t, J = 7.9 Hz, 1 H), 7.65 (t, J = 7.9 Hz, 1 H), 7.78 (s, 1 H), 8.0 (d, J = 8.0 Hz, 1 H), 8.20 (d, J = 8.0 Hz, 1 H).

MS (EI): m/z (%) = 309 (100) [M+], 291 (27), 278 (18), 264 (23), 249 (10), 204 (15), 174 (45), 156 (12), 57 (5), 43 (10).

2-[6,8-Difluoro-2-(4-fluorophenyl)quinolin-4-yl]ethanol (4d)

Yellow oil.

IR (neat): 3391, 3068, 2924, 1727, 1602, 1507, 1430, 1230, 1143 cm-1.

1H NMR (200 MHz, CDCl3): δ = 2.00-2.10 (br s, OH, 1 H), 2.98 (t, J = 6.7 Hz, 2 H), 3.40 (t, J = 6.7 Hz, 2 H), 6.60-6.70 (m, 4 H), 6.80-6.90 (m, 1 H), 7.10-718 (m, 1 H), 7.40-7.50 (m, 1 H).

MS (EI): m/z (%) = 303 (5) [M+], 141 (27), 121 (30), 117 (100), 101 (11), 82 (35), 75 (5), 47 (45), 37 (10).

[2-(2,5-Dimethoxyphenyl)quinolin-4-yl]methanol (4e)

Pale yellow solid, mp129-131 °C.

IR (KBr): 3384, 2928, 2845, 1555, 1498, 1219, 1042 cm-1.

1H NMR (200 MHz, CDCl3): δ = 3.58 (s, 3 H), 3.70 (s, 3 H), 5.0 (s, 2 H), 6.60-6.80 (m, 2 H), 7.20 (m, 1 H), 7.40 (t, J = 7.9 Hz, 1 H), 7.60 (t, J = 7.9 Hz, 1 H), 7.75-7.80 (m, 2 H), 8.10 (d, J = 8.0 Hz, 1 H).

MS (EI): m/z (%) = 295 (18) [M+], 294 (20), 277 (50), 264 (37), 249 (16), 235 (10), 207 (8), 191 (10), 160 (31), 128 (5), 117 (87), 107 (100), 82 (30), 72 (75), 47 (37).

[2-(4-Fluorophenyl)-6-methylquinolin-4-yl]methanol (4f)

Pale yellow solid, mp79-80 °C.

IR (KBr): 3340, 2923, 2852, 1600, 1511, 1219 cm-1.

1H NMR (300 MHz, CDCl3): δ = 1.50-1.70 (br s, OH, 1 H), 2.50 (s, 3 H), 5.10 (s, 2 H), 7.15 (t, J = 7.9 Hz, 2 H), 7.55 (t, J = 7.9 Hz, 2 H), 7.80 (s, 1 H), 8.00-8.10 (m, 2 H).

MS (EI): m/z (%) = 267 (100) [M+], 266 (40), 238 (40), 149 (16), 142 (7), 109 (16), 97 (10), 83 (41), 71 (18), 57 (35), 43 (68).

(7-Chloro-6-fluoro-2-phenylquinolin-4-yl)methanol (4g)

Pale yellow oil.

IR (neat): 3348, 2935, 2917, 1709, 1618, 1486, 1255, 1090, 887 cm-1.

1H NMR (300 MHz, CDCl3): δ = 3.60-3.80 (br s, OH, 1 H), 4.18 (s, 2 H), 6.30 (m, 1 H), 6.50 (m, 1 H), 6.80 (t, J = 7.9 Hz, 1 H), 7.15-7.25 (m, 5 H).

MS (EI): m/z (%) = 287 (5) [M+], 235 (10), 91 (100), 77 (10), 65 (20), 51 (12).

[2-(2,5-Dimethoxyphenyl)-6-methoxyquinolin-4-yl]methanol (4h)

Pale yellow solid, mp 175 °C.

IR (KBr): 3426, 2927, 2363, 1617, 1509, 1236, 1031, 866 cm-1.

1H NMR (200 MHz, CDCl3): δ = 2.10-2.30 (br s, OH, 1 H), 3.75 (s, 3 H), 3.80 (s, 3 H), 3.95 (s, 3 H), 5.05 (s, 2 H), 6.82 (s, 2 H), 7.15 (s, 1 H), 7.25-7.30 (m, 2 H), 7.85 (s, 1 H), 8.05 (d, J = 8.0 Hz, 1 H).

MS (EI): m/z (%) = 325 (9) [M+], 213 (75), 198 (68), 184 (10), 170 (17), 142 (35), 128 (18), 115 (41), 104 (37), 89 (11), 76 (100), 51 (50), 39 (65).

(5,6,7-Trimethoxy-2-phenylquinolin-4-yl)methanol (4i)

Pale yellow solid, mp 126 °C.

IR (KBr): 3232, 2928, 2816, 1616, 1584, 1424, 1248, 1104 cm-1.

1H NMR (200 MHz, CDCl3): δ = 3.00-3.20 (br s, OH, 1 H), 3.92 (s, 3 H), 3.96 (s, 3 H), 3.98 (s, 3 H), 5.20 (s, 2 H), 7.30 (s, 1 H), 7.40-7.50 (m, 3 H), 8.05 (s, 1 H), 8.20 (d, J = 8.0 Hz, 2 H).

13C NMR (50 MHz, CDCl3): δ = 55.7, 60.6, 61.1, 63.1, 104.9, 114.9, 115.4, 127.1, 128.3, 128.9, 138.7, 141.5, 145.6, 148.2, 148.5, 155.1, 155.9.

MS (EI): m/z (%) = 325 (100) [M+], 295 (15), 278 (31), 250 (25), 236 (7), 224 (12), 167 (10%), 141 (18), 127(10), 115 (8), 97 (11), 83 (25), 71 (37), 57 (65), 43 (93).

[2-(4-Bromophenyl)quinolin-4-yl]methanol (4j)

Pale yellow solid, mp 197-199 °C.

IR (KBr): 2917, 2849, 2361, 1680, 1219 cm-1.

1H NMR (300 MHz, CDCl3): δ = 3.40-3.50 (br s, OH, 1 H), 5.20 (s, 2 H), 7.50-7.55 (m, 1 H), 7.60-7.65 (m, 2 H), 7.70-7.75 (m, 1 H), 7.90 (d, J = 8.0 Hz, 1 H), 8.0 (s, 1 H), 8.05-8.15 (m, 2 H), 8.20 (d, J = 8.1 Hz, 1 H).

MS (EI): m/z (%) = 315 (65) [M+], 314 (43), 313 (72), 284 (22), 205 (11), 204 (26), 139 (6), 128 (20), 111 (18), 97 (32), 85 (43), 71 (65), 57 (100), 43 (27).

(6-Methyl-2-phenylquinolin-4-yl)methanol (4k)

Pale yellow solid, mp 142 °C.

IR (KBr): 3348, 2919, 2850, 1680, 1219 cm-1.

1H NMR (300 MHz, CDCl3): δ = 1.40-1.60 (br s, OH, 1 H), 2.55 (s, 3 H), 5.15 (s, 2 H), 7.30-7.50 (m, 5 H), 7.60 (s, 1 H), 7.85 (s, 1 H), 8.05-8.15 (m, 2 H).

MS (EI, xx eV): m/z (%) = 249 (100) [M+], 220 (35), 219 (22), 115 (9), 91 (14), 71 (15), 57 (23), 43 (8).

5,6,7-Trimethoxy-2,4-diphenylquinoline (4l)

Pale yellow solid, mp 119-120 °C.

IR (KBr): 3488, 2896, 1536, 1456, 1219, 1104 cm-1.

1H NMR (200 MHz, CDCl3): δ = 3.28 (s, 3 H), 3.94 (s, 3 H), 4.15 (s, 3 H), 5.15 (s, 2 H), 7.40 (m, 7 H), 7.50 (d, J = 8.1 Hz, 1 H), 8.15 (d, J = 8.0 Hz, 2 H).

13C NMR (50 MHz, CDCl3): δ = 56.4, 60.9, 61.4, 96.5, 105.8, 116.9, 120.1, 127.3, 127.5, 127.7, 128.7, 129.1, 129.5, 139.8, 142.5, 142.6, 147.5, 147.9, 149.0, 156.0.

MS (EI): m/z (%) = 371 (100) [M+], 328 (11), 180 (12), 152 (25), 125 (11), 89 (31), 63 (11), 50 (9).

4-Butyl-6-methyl-2-phenylquinoline (4m)

Pale yellow solid, mp 79 °C.

IR (KBr): 3452, 2955, 2864, 1594, 1551, 1448, 1219, 874 cm-1.

1H NMR (200 MHz, CDCl3): δ = 1.00 (t, J = 6.9 Hz, 3 H), 1.45-1.55 (m, 2 H), 1.75-1.85 (m, 2 H), 2.60 (s, 3 H), 3.10 (t, J = 6.8 Hz, 2 H), 7.35-7.50 (m, 4 H), 7.60 (s, 1 H), 7.70 (s, 1 H), 8.05 (d, J = 8.0 Hz, 1 H), 8.10 (d, J = 8.0 Hz, 2 H).

13C NMR (50 MHz, CDCl3): δ = 13.8, 21.8, 22.7, 29.6, 32.1, 118.4, 122.2, 126.4, 127.3, 128.6, 128.8, 129.6, 130.1, 131.2, 135.5, 139.9, 146.9, 148.3, 156.0.

MS (EI): m/z (%) = 275 (67) [M+], 233 (100), 232 (27), 197 (30), 131 (10), 120 (18), 91 (77), 65 (10), 57 (8).

6-[7-Chloro-6-fluoro-2-(4-fluorophenyl)quinolin-4-yl]hexan-1-ol (4n)

Pale yellow oil.

IR (neat): 3399, 2933, 2860, 1605, 1504, 1551, 1224, 1054 cm-1.

1H NMR (300 MHz, CDCl3): δ = 1.30-1.40 (m, 4 H), 1.50-1.60 (m, 4 H), 2.20 (t, J = 6.9 Hz, 2 H), 3.55-3.65 (br s, OH, 1 H), 3.60 (t, J = 6.9 Hz, 2 H), 6.40-6.50 (m, 1 H), 6.70-6.75 (m, 1 H), 6.95 (t, J = 8.0 Hz, 1 H), 7.05 (t, J = 7.9 Hz, 2 H), 7.50-7.55 (m, 2 H).

MS (EI): m/z (%) = 374 (5) [M+], 323 (15), 233 (10), 159 (20), 135 (10), 94 (32), 93 (100), 83 (58), 43 (40).

Acknowledgments

BVSR and RSR thank CSIR, New Delhi, for the award of fellowships.

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Scheme 1