A Novel Synthesis of Polyfunctionally Substituted Pyrrole Derivatives

Nitriles in Heterocyclic Synthesis: A Novel Synthesis of Polyfunctionally Substituted Pyrrole Derivatives Fathy Mohamed A bdelrazek * 3 and A hm ed Ali Faddab a D epartm ent of Chem istry. Faculty of Science, Cairo University, Giza. A. R. Egypt b D ept, of C hem ., Fac. of Sei., M ansoura University. Egypt Z. Naturforsch. 41b, 499—501 (1986); received March 1/Septem ber 18, 1985 /3-Thiocyanatomethyl C innam onitrile, R eductive Cleavage, Pyrrole Derivatives /3-Thiocyanatomethyl cinnam onitrile derivatives coupled with aromatic diazonium salts to afford the corresponding azo com pounds, which undergo reductive cyclization into pyrrole derivatives.

The utility of organic cyano com pounds in heterocyclic synthesis has recently received consider able attention [1, 2], Our group has been involved in the last years in a program aiming to develop effi cient procedures for synthesis of polyfunctionally substituted azoles [3, 4], azines [5, 6 ] and their con densed derivatives [7, 8 ] utilizing simple and readily obtainable polyfunctionally substituted nitriles. D u ring this phase of our research we could show that whereas ethylidenem alononitrile derivative l a does not couple with aromatic diazonium salts, the pre sence o f cyano substituent on the methyl m oiety (as in lb ) sufficiently activates the adjacent m ethylene group for coupling [9], The resulting hydrazones could be utilized for synthesis of pyridazine- 6 -imine derivatives [10]. It seem ed to us of value to see if the presence of other functional substituent on the methyl m oiety in 1 can effect similar activation. In the present paper we report synthesis of /?-thiocyanatomethyl cinnamonitrile derivatives l c , e and their conversion into 2-substituted 3-cyano-4-phenyl5-thiocyanatopyrrole derivatives 5a, b. Thus, it has been found that Id reacts with potassium thiocyanate to yield the thiocyanato derivative l c . C om pound l c has been previously obtained [ 1 1 ] via reac tion of phenacylthiocyanate with malononitrile under conditions very similar to those reported in a recent patent [ 12 ] in which it is suggested that the reaction affords the thiazole derivative 2. Com pound I f reacts similarly with KSCN to afford the thio cyanato derivative l e . C om pound l e has also been previously reported by us [13] via another route but in a very poor yield.

* R eprint requests to Dr. F. M. A bdelrazek. Verlag der Zeitschrift für N aturforschung, D-7400 Tübingen 0340 - 5087/86/0400- 0499/$ 01.00/0

Compound l c coupled with aromatic diazonium salts to yield the corresponding coupling products which may be formulated as the hydrazone 3 or the azo derivatives 4 a—c. NC

1a: 1b: 1c: 1d: 1e: 1f:

X

X

NC.

^CN SCN

Ph

r = c h 3 , r ' = c 6h 5 , x = c n r = c h 2c n . r ' = n h 2 , x = c n

HN

I

r = c h 2s c n . r ' = c 6h 5 , x = c n

Ar

R = C H 2Br, R'= C6H5 , X = CN r

=C H j S C N , r ' =

3

c 6h 5 , X =C 0 2Et

R = C H , B r . R ' = C fiH , . X = C 0 7 Et

Ph

i=

S CN

r

sr 4b: Ac: Ad:

A r = C 6H 4 C H 3 - p , X : C N Ar = C6H4 C I- p , X = C N A r = CgHg, X = C 0 2 Et

A e : A r = C 6H 4 C H 3 - p , X = C 0 2 E t A f : A r = C 6H 4 C I - p , X = C 0 2 E t

'H NM R spectra revealed that the reaction pro duct exists mainly in the arylazo form 4. Thus ‘H NM R revealed aromatic multiplet at d 7.35 —8.40 ppm. If this product is the hydrazone 3, at least three of the aromatic protons, being shielded by resonance of hydrazone lone electrons on the aromatic ring, should have appeared at d value higher than 7.3 ppm. The assigned structure finds further support from chemical reactivity of the reac tion product. Thus com pounds 4 a —c did not cyclize into either pyridazin-6 -imine or thiadiazoles at condi tions reported to effect cyclizations of hydrazones of structures very similar to that of 3.

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500

F. M. A bdelrazek —A. A. Fadda • Nitriles in Heterocyclic Synthesis

Com pound l e coupled similarly with aromatic diazonium salts to afford the corresponding coupling products 4 d —f. Analytical and spectral data are in good agreem ent with these structures. Com pounds 4 a —f could be reduced with Zinc and acetic acid into the pyrrole derivatives 5. The forma tion of 5 is assumed to proceed via reductive cleavage o f the azo link follow ed by cyclization through inter nal Michael addition of N H 2 to CN to afford 5a or through loss of ethanol to afford 5b (Chart 1). The structure of com pounds 5 a, b was inferred from both analytical and spectral data (see Experimental).

Ph

A a -f

Ph

CN

NCS — ^

NCS

To a cold solution of either l c or l e (0.01 m ole) and sodium acetate (3 g) in ethanol (50 ml) was added, dropwise a solution of diazotized amine (aniline, /?-toluidine or /?-chloroaniline respectively; 0.01 m ole), while stirring. The addition took 30 min, after which stirring was continued for further 3 h. The solid precipitates formed were collected by Al teration, washed with cold water, dryed and recrys tallized from the proper solvent (cf. Table I), to af ford com pounds: 4a 2.3 g, 4b 2.6 g, 4c 1.9 g, 4d 2.2 g, 4 e 2.5 g, 4 f 2.0 g, respectively (see Table I).

Ph ___ CN

CN

-Ö -’

N H

5a: 5b:

z z

Y = NH

=n h 2 =o h

All m elting points are uncorrected. IR spectra were recorded as KBr discs using a Pye-Unicam SP-1100 spectrophotom eter. Absorption values are expressed as v cm -1. 'H NM R spectra were recorded on a Varian A -60 spectrom eter using TMS as inter nal standard. Chemical shifts are expressed in d ppm. Analytical data were obtained from the microanalytical centre at Cairo University. Preparation o f the a zo com pounds 4 a—f (general p rocedu re)

NH,

NHNHAr

Ph

Experimental

CN

NCS

^X

Compounds 5 seem to be interesting starting m ate rial for further chemical transformations as well as for biological activity studies.

Y= 0

C h a rt

Table I. Physical data of "newly prepared compounds.

Com pound

Yield [%]

m .p. [°C] solvent

M.F. M.wt.

4a

70

225 A cO H

C I8H „N ,S 329

65.65 3.34 65.50 3.55

21.28 21.70

4b

75

231 A cO H

c

I9h „ n 270 A cOH

c ,(1h |Sn 4o , s c i 410.5

58.47 3.65 58.15 3.50

13.64 13.25

5a

60

235 E tO H

c ,2h 8n 4s 240

60.00 3.33 59.70 3.50

23.33 22.93

5b

55

209 E tO H

C r H 7N,OS 241

59.75 2.90 59.50 2.70

17.43 17.00

Analysis [%] Cd Fd

C

H

N


Satisfactory chlorine analysis has been obtained.

F. M. A bdelrazek —A. A. Fadda • Nitriles in Heterocyclic Synthesis

501

Table II. IR and 'H NM R data of the newly prepared compounds. Compound

IR vcm 1 (selected bands)

'H NM R d ppm

4a

2220 and 2190 (two C N ), 2160 (SCN)

2.42 (s, 1H, C H ); 7.38—8.3 (m, 10H , arom. protons)

4b

2210 and 2190 (two CN), 2175 (SCN)

2.4 (s, 1H, C H ); 3.7 (s, 3H , C H ,); 7.35 —8.4 (two groups m. 9H , arom. protons)

4c

2215 and 2200 (CN groups). 2175 (SCN)

2.41 (s, 1H. CH); 7 .4 —8.35 (two groups m. 9H , arom. protons)

4d

2220 (CN ), 2170 (SCN), 1720 (CO )

1.9 (t. 3H , C H ,); 2.35 (q, 2H , CH 2); 2.5 (s. 1H, C H ); 7.37—8.1 (m. 10H, arom. protons)

4e

2190 (CN), 2165 (SCN), 1718 (CO )

1.85 (t, 3H . C H ,); 2.4 (q, 2H , CH 2); 2.55 (s, 1H, C H ); 3.5 (s, 3H , C H ,j; 7.35—8.15 (two groups m, 9 H . arom. protons)

4f

2195 (CN), 2170 (SCN), 1710 (CO )

1.95 (t. 3H . C H ,); 2.42 (q, 2H . C H 2); 2.48 (s, 1 H, C H ); 7 .4 —8.2 (two groups m, 9H . arom. protons)

5a

3420-3300 (N H and N H ,), 2180 (CN ), 2.1 (s, 2 H , N H 2); 2.32 (s, 1H. N H); 7 .3 —7.6 (m, 5H , arom . protons) 2080 (SCN)

5b

3500-3280 (NH and O H ), 2175 (CN), 2095 (SCN)

3 .2 (s. 1 H, O H );7.28—7.85 (m ,5 H. arom. protons); 8.3 (s. 1 H .N H )

P reparation o f 2 -su b stitu te d 3 -c y a n o -4 -p h e n y l5 -th io c y a n a to p y rro le d eriva tives 5 a , b

To a solution of 0.01 m ole of each of the azo com pounds 4 a —f in acetic acid glacial (50 ml) was added about 3 g of Zinc dust. The reaction mixtures were refluxed for 2 h, during which time the dark azo red colour turns to pale green. The reaction mixtures were filtered while hot and left to cool to room tem perature. The precipitated solids were collected by

Alteration and recrystallized separately from ethanol. It was found that the products of the three azos 4 a —c have the same melting point, and no de pression has been observed in the mixed melting points between them. Analytical and spectral data confirmed that they are one compound — 5 a ; the products obtained from the three azos 4 d —f were found also to be the same compound 5 b (see Tables I and II).

[1] A. J. Fatiadi. in S. Patai (ed.): Preparation and Syn thetic Applications of Cyano C om pounds in the Chemistry of Functional G roups. Suppl. C, J. Wiley and Sons L td., New Y ork 1983. [2] S. M. Fahmy. N. M. A bed, R. M. M ohareb, and M. H. Elnagdi, Synthesis 1982, 490. [3] Z. E. Kandeel. K. M. H. Hilmy, F. M. A bdelrazek. and M. H. Elnagdi. Chem. Ind. (L ondon) 1984, 33. [4] M. H. Elnagdi and H. W amhoff. J. H eterocycl. Chem. 18, 1987 (1981). [5] F. M. A bdelrazek, Z. E. K andeel, K. M. H. Hilmy, and M. H. Elnagdi, Chem. Ind. (L ondon) 1983, 439. [6] N. S. Ibrahim , N. M. A bed, and Z. E. Kandeel, Heterocycles 22, 1677 (1984). [7] H. S. Elkashef, K. U. Sadek. and M. H. Elnagdi, J. Chem. Eng. D ata 27, 103 (1982).

[8] K. U. Sadek, E. A. Hafez, A. E. M ourad, and M. H. Elnagdi, Z. Naturforsch. 39b, 824 (1984). [9] M. H. Elnagdi, M. R. H. Elm oghayar, M. K. A. Ibra him, and H. H. Alnima, Z. Naturforsch. 33b, 218 (1978). [10] M. H. Elnagdi, E. M. Zayed, and S. A bdou. Heterocycles 19 (3), 559 (1982); Review on “Chemis try of Heterocyclic Diazo C om pounds” . [11] F. M. A bdelrazek, N. S. Ibrahim . Z. E. Kandeel. and M. H. Elnagdi. Synthesis 1984, 970. [12] S. G uenther. (BASF A G ) U. S. US 4.371,734 (cl. 5 4 4 -300; co 7 D 277/20) 01 Feb. 1983, D E APPL 2,801.794, 17 Jan. 1978; 6 pp. cont.-in-Part of U.S. ser. No 1.832. abandoned; C. A. 1983. V 98. pp. 198202g. [13] F. M. A bdelrazek. H. Z. Shams, A. W. E rian. and M. H. Elnagdi. J. Chem. Res. (S) 246, (M) 2774 (1985).
