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Pyrroloquinolines, Part III [1] Synthesis of lH-Pyrrolo(2,3-b)quinolines

M. Murugesan Department of Chemistry, P. S. G. College of Arts and Science, Coimbatore-641014, India

and

K. Ramasamy, and P. Shanmugam*

Department of Chemistry, Madras University Postgraduate Centre, Coimbatore-641041, India

Z. Naturforsch. 35b, 746-748 (1980); received June 25, 1979 2 -Chloro - 3 - vinyl quinolines, 2 - Amino - 3 - vinyl quinolines, 2 - Acetamido - 3 - viny lquinolines, 2-Chloro-3-( r,2'-dibroethyl)quinolines, 1 H-Pyrrolo(2,3-b)quinolines

A new route to synthesis of pyrrolo(2,3-b)quinolines is described based on the use of 2-chloro-3-vinylquinolines as well as 2-chloro-3-(l',2'-dibromoethyl)quinolines.

In continuation of our earlier work [1] on the synthesis of 1 H-pyrrolo(2,3-b)quinolines [2] (3) we wish to report another but a still more elegant route to the synthesis of the same system. The method utilizes 2-chloro-3-vinylquinolines [3, 4] (1) as pre-cursors.

In our attempts to convert the chloroquinoline (1) into the aminoquinoline (2), as a possible way of arriving at the synthesis of 3, we treated 1 with various reagents [5] such as ethanolic ammonia in a sealed tube, ammoniated zinc chloride in a sealed tube, sodamide in an inert solvent and ammonia gas in the presence of phenol. In all these cases the expected amino compound 2 a could not be ob-tained. But heating an intimate mixture of 1 a and p-aminobenzenesulphonamide [5, 6] at 180-200 °C and hydrolysing the resulting mass with aqueous sodium carbonate afforded 2 il 3/S cl pasty mass, readily characterized as its acetyl derivative. Addition of bromine to the amine 2 a in chloroform solution, and heating the reaction mixture there-after with triethylamine afforded 3 a as crystalline solid, identical in all respects with the authentic sample [1]. Extension of this technique to lb [3b], 1 c [3 a], 1 d [3 b], 1 e [3 b] and 1 f [3 b] led respectively to the pyrroloquinolines 3b, 3c [1], 3d[l], 3e and 3f.

As an alternative attempt to synthesise the pyrroloquinoline from 1, we prepared the bromine-adduct 5a from la and fused it with p-amino-benzenesulphonamide. Hydrolysis of the resulting mass afforded, interestingly, 3a in 60% yield

* Reprint requests to Dr. P. Shanmugam. 0340-5087/80/0600-0746/$ 01.00/0

identical wit 3 a, obtained by the above, as well as by the previously reported method [1]. Extension of this procedure to 1 b to 1 d gave respectively the pyrroloquinolines 3b to 3d. The 2-chloro-3-(r,2'-dibromoethyl)quinoline (5g) derived from 3-vinyl -2-quinoline by modified procedure [8] gave rise to the parent 1 H-pyrrolo(2,3-b)quinoline (3g) on heating with p-aminobenzenesulphonamide followed by hydrolysis. Since 3-vinyl-2-quinolones [3, 7] are available in several varieties it is expected that this method would provide a new convenient route to a wide range of pyrrolo(2,3-b)quinolines.

Compound Ri R 2

a c h3

H

b c h3

Br c c

6h

5 H

d CßHö Cl e CeHs Br f c h

3 N 0

2

g H H

Experimental Melting points were determined on a Boetius

microheating Table and are uncorrected. The NMR spectra were determined on a varian T-60 spectro-meter (TMS as internal standard) and IR spectra on a Beckman IR-20 spectrophotometer.

2-Amino-3-vinylquinolines (2) An intimate mixture of 2-chloro-3-vinyl-4-methyl-

quinoline (la, 2.03 g) and pure p-aminobenzene-sulphonamide (0.86 g) is fused at 180 °C for 4 h, in an oil bath. The black solidified mass is cooled and digested with hot ethanol. The solution after cooling,

M. Murugesan et al. • Pyrroloquinolines 747

is poured into 10% acqueous sodium carbonate (100 ml) and tbe aqueous solution is then heated on a steam bath for 2 h. It is cooled and extracted with chloroform. The chloroform extract is washed with water (3 X 50 ml), dried (Na2SC>4) and then evaporated. When 2 a is obtained as a pasty mass, compounds 2 b to 2f are obtained in a similar manner. The amines are readily characterized as their acetyl derivative. The amine is used without purification for the subsequent experiment.

2- A cetamido-3-vinylquinolines (4) The 2-amino-3-vinyl-4-methylquinoline (2 a, 1.8g)

is heated with a mixture of glacial acetic acid (3 ml) and acetic anhydride (3 ml) on a steam bath for 1 h. The mixture is cooled, poured into ice water and neutralised with ammonium hydroxide. The solid that separated is extracted with chloroform, washed with water (2 x 50 ml) dried (Na2S(>4), evaporated and the residue is chromatographed over alumina using benzene-petrol (60-80 °C) as aluent to afford 4a as colourless crystals. Compounds 4b to 4f are

obtained in a similar manner. The results are sum-marised in Table I.

1 H-Pyrrolo(2,3-b)quinolines (3) Method A:

The pasty mass containing the amino compound 2 a (2 g) is taken in dry chloroform and stirred magnetically. To this added dropwise a chloroform solution containing sufficient amount of bromine (0.5 ml). After the addition is over the solution is kept aside for 1 h, when the dibromide slowly separates as yellow powder. To this, is added tri-ethylamine (3 ml) (freshly distilled and kept over anhydrous potassium carbonate) and the mixture heated at reflux on a water bath for 2 h. It is cooled, poured into ice water, extracted with chloroform washed with water (4 x 50 ml), dried (Na2S04) and evaporated. The residue obtained is chromato-graphed over alumina using benzene-petrol (60 to 80 °C) as the eluent to afford 3 a as colourless powder. The pyrroloquinolines 3 b to 3 f are obtained in a similar manner. The results are summarised in Table II.

Method B: l a is treated with stoichiometric amount of

bromine in chloroform to get the adduct 5 a [4]. An intimate mixture of 5 a (1 g) and p-aminobenzene-sulphonamide (2 g) is fused at 170 °C for 1 h in an oil bath. The solidified mass is cooled and digested with 5 % alcoholic K O H (10 ml) and heated at reflux for x/2 h. To this solution is added 2 ml of triethylamine and the refluxing continued for an-other 2 h. After cooling, it is poured into ice water extracted with chloroform, washed with water (3 X 50 ml) and dried (Na2S04). The residue, obtained after evaporation of the solvent, is chromatographed over alumina using benzene-petrol (60-80 °C) as eluent to afford 3 a as colourless powder. Extension of this technique to l b to Id

Table I. 2-Acetamido-3-vinylquinolines (4).

Compound m.p. Yield IR (KBr) Analysis [%] Calcd Compound [°C] [%] [cm-1] Found

4a 182-183 56 1620, 2990 C14Hi4N20 C 74.31 H 6.24 N 12.38 (Benzene) (226.27) C 74.27 H 6.20 N 12.29

4b 155—156 66 1600, 3050 Ci4Hi3N2OBr C 55.09 H 4.29 N 9.18 (Benzene) (305.18) C 55.13 H 4.31 N 9.10

4c 171-172 51 1620, 2960 CI9H16N20 C 79.14 H 5.59 N 9.72 (Benzenepetrol) (288,34) C 79.01 H 5.62 N 9.76

4d 166-167 62 1620-2950 Ci9H15N2OC1 C 70.69 H 4.68 N 8.68 (Chloroform) (322.79) C 70.58 H 4.59 N 8.64

4e 178-179 55 1630, 2980 Ci9Hi5N2OBr C 62.14 H 4.12 N 7.63 (Benzenepetrol) (367.25) C 62.00 H 4.20 N 7.59

4f 161-162 63 1610, 2990 Ci4H13N303 C 61.92 H 4.83 N 15.49 (Chloroform) 271.27) C 62.02 H 4.79 N 15.52

748 M. Murugesan et al. • Pyrroloquinolines 748

Table II. 1 H-Pyrrolo(2,3-b)quinolines (3).

Yield [ % ] Com- m.p. Method Analysis [ % ] Calcd pound [°C] A B Found

IR (KBr) [cm-i]

1H N M R [ppm] (CDCla)

3 a 2 1 8 - 2 2 0 50 66 C I 2 H 1 0 N 2

(Chloroform) (182.22)

3 b 203-204 50 65 Ci2H9BrN2 (Benzene) (261.14)

3 c 1 8 0 - 1 8 2 5 4 64 C I 7 H 1 2 N 2

(Benzene) (244.28)

3 d 2 3 2 - 2 3 3 50 6 5 C I 7 H U N 2 C 1 (Chloroform) (278.74)

3e 143-144 40 — Ci7HnN2Br (Benzene) (323.19)

3 f 1 5 6 - 1 5 7 47 — C i 2 H 9 N 3 0 2

(Chloroform) (227.23)

3g 210-2111 — 62 CnH8N2 (Benzene) (168.19)

C 79.09 H 5.53 N 25.38 C 79.01 H 5.49 N 15.32

C 55.20 H 3.47 N 10.74 C 55.29 H 3.39 N 10.68

C 83.58 H 4.95 N 11.47 C 83.51 H 4.89 N 11.54

C 73.25 H 3.98 N 10.05 C 73.34 H 3.95 N 10.10

C 63.17 H 3.43 N C 63.11 H 3.38 N

8.67 8.58

C 63.43 H 3.99 N 18.49 C 63.40 H 3.87 N 18.53

C 78.55 H 4.79 N 16.66 C 78.58 H 4.81 N 16.59

3220, 2280 2.73 (s, 3H, CH3) 6.63 (d, 1H, H-C-3) J = 3 Hz 7.06-8.2 (m, 6H.H-C-2, -5,-6,-7,-8-NH)

3260, 2260 2.93 (s, 3H, CH3) 6.86 (d, 1H, H-C-3) J = 3 Hz 7.15-8.5 (m, 5H, H-C-2, -5,-7,-8, - N H )

3280, 2270 6.76 (d, 1H,H-C-3) J = 3 Hz 7.58-8.26 (m, 1 0 H , H - C --2,-4,-5,-6,-7,-8) 8.35 (d, 1H, NH)

3270, 2275 6.93 (d, 1H, H-C-3) J = 2.5 Hz 7.02-8.46 (m, 10H.H-C--2,-4,-5,-7,-8, - N H )

3275, 2260 6.33 (d, 1H, H-C-3) J = 2.5 Hz 7.00-8.13 (m, 10H, H-C-2,-4,-5,-7,-8,-NH)

3215,2265 2.93 (s, 3H, CH3) 6.86 (d, 1H, H-C-3) J - 2.5 Hz 7.16-8.4 (m, 5H, H-C-2, -5,-7,-8, - N H )

3210, 2280 6.7 (d, 1H, H-C-3) J = 2.5 Hz 7.31-8.33 (m, 6 H arom.) 8.55 (s, 1 H , N H )

furnished the pyrroloquinoline 3b to 3 d respectively. 5 g [9], on fashion with p-aminobenzenesulphon-amide followed by hydrolysis gave the parent pyrroloquinoline 3g. The results are summarised in Table II .

W e thank Dr. G. Mehtha, University of Hydera-bad, Hyderabad and Dr. S. R a j a p p a , C I B A

Research Centre, Bombay, for the spectral and analytical data. Our thanks are due to Professor D. K . P . Varadarajan, Principal, P . S. G. College of Arts and Science, Coimbatore, and Dr. D. Sethu Rao, Professor of Chemistry, P. S. G. College of Arts and Science, Coimbatore for the facilities and encouragement. K R thanks the U G C (India) for financial assistance.

[1] M. Murugesan, N. Soundararajan, K . Ramas-wamy, and P. Shanmugam, Synthesis 1979, in press.

[2] The other methods for constructing this system are cited in ref. [1].

[3] a) P. Shanmugam, K . Kanakarajan, N. Sounda-rarajan, and A. Gnanasekaran, Synthesis 1976, 595. b) P. Shanmugam, K . Kanakarajan, and N. Soundararajan, Z. Naturforsch. 31b, 1698 (1976).

[4] T. K . Raja, N. Soundararajan, Y . Baktavacha-

lam, and P. Shanmugam, Z. Naturforsch. 33b, 228 (1978).

[5] F. W. Bergstrom, Chem. Rev. 35, 170 (1974). [6] a) B. Bobranski, Arch. Pharm. 277, 75 (1939).

b) W. H. Gray, J. Chem. Soc. 1939, 1202. [7] P. Shanmugam, R. Palaniappan, N. Soundara-

rajan, T. K . Thiruvengadam, and K . Kanakara-jan, Monatsh. Chem. 107, 259 (1976).

[8] P. Shanmugam, N. Soundararajan, and K . Kana-karajan, J. Chem. Soc. Perkin Trans I 1977, 2024.