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Nitriles in Heterocyclic Synthesis: The Reaction of 2-Thiocarbamoyl Cinnamonitriles with Active Methylene Reagents Abdel Moneim El-Torgoman, Salah Mohamed El-Kousy Chemistry Department, Faculty of Science, Menoufiya University, Menoufia, Egypt

Zaghloul El-Shahat Kandeel* Chemistry Department, Faculty of Science, Cairo University, Giza, Egypt

Z. Naturforsch. 42b, 107-111 (1987); received March 25/July 31, 1986

Heterocyclic Synthesis, 2-Thiocarbamoyl Cinnamonitriles

Substituted pyridin-2-thiones, 2-pyridones, thiopyrans and pyranoazoles could be synthesized via the reaction of 2-thiocarbamoyl cinnamonitriles with some active methylene reagents.

a,/?-Unsaturated nitriles are versatile reagents that have been extensively used in heterocyclic synthesis [1]. Recently the reaction of a-substituted cinnamo-nitriles with active methylene reagents has been utilized for the synthesis of a variety of otherwise not readily accessible polyfunctionally substituted heterocycles [2—4].

Whereas Daboun and Raid [5] have claimed the isolation of dihydropyridines from the reaction of cinnamonitriles with cyanothioacetamide, Soto and Co-workers [6] have reported that the products of this reaction are pyridin-2-thiones. Recently [7] it has been shown that thiopyrans are the kinetically formed reaction products and their thermal re-arrangements affords pyridin-2-thiones. Since we were interested to see if the reaction of cinnamoni-trile, with cyanothioacetamide can be extended to afford differently substituted thiopyrans and py-ridines, we studied the behaviour of 2-thiocarbamoyl cinnamonitriles ( la , b) towards a variety of active methylene reagents. The work has resulted in the synthesis of several new polyfunctionally substituted pyridinthione, thiopyrane, pyranoazoles and other not readily accessible heterocycles.

It has been found that l a reacts with cy-anothioacetamide (2 a) to yield a product of molecu-lar formula C14H10N4OS. Two isomeric structures (c/. structures 3 and 4) seemed possible for the reaction product (cf. Scheme 1). Structure 3 was however

* Reprint requests to Dr. Z . E . Kandeel.

Verlag der Zeitschrift für Naturforschung. D-7400 Tübingen 0340 - 5087/87/0100 - 0107/$ 01.00/0

readily eliminated as the reaction product proved to be different from the product of the reaction of anisaldehyde or p-chlorobenzaldehyde with 4,6-diamino-3-cyano-5,5-dihydro-pyridin-2-thione (5), prepared via self condensation of 2 a as has recently described [8]. Thus structure 4 a was established for the reaction product. The formation of 4a from l a and 2 a is assumed to proceed via initial addition of the active methylene in 2a to the double bond in l a . The Michael adduct may then cyclize to yield either the thiopyrane 6 or the pyridinthione 4. The possibil-ity that 6 is first formed and then rearranges into 4, was ruled out, as 6, synthesized from l a and malononitrile did not rearrange into 4 a under the reaction conditions. Compound 6 recently synthe-sized underwent ring opening and recyclization into pyridinethiones only in aqueous ethanol in presence of base as has been reported [7]. Similarly l b reacted with 2a to yield the pyridin-2-thione 4b.

Compound l a reacted with 2-cyanoacetamide (2 b) to yield a yellow product of molecular formula C14H10N2O4. Again two theoretically possible struc-tures can be suggested for this reaction product (cf. Scheme 2). However, structure 7 was established on the basis of *H NMR which revealed a pattern that can be interpreted in terms of structure 7 but not 8 (cf. Table II). Compound 7 is assumed to be formed via addition of the amide to the double bond in l a , cyclization via hydrogen sulphide elimination and then aromatization under the reaction conditions [9]. Synthesis of 7 via addition of 2-cyanoacetamide (2 b) to anisylidenemalononitrile ( l c ) was unsuccessful. This confirms the reported [10] inactivity of l c to-wards 2 b which is in contrast to a recent report [5].

108 A. M. El-Torgoman et al. • Nitriles in Heterocyclic Synthesis

Ar X

H ^ " ^ C N

1a;Ar« 4 - C H 3 0 - C 6 H 4 ;X= C S N H 2

1 b : AR « A - C I - C 6 H A ; X = C S N H 2

1 c : Ar« A - C H 3 0 - C 6 H 4 ; X= CN

.CN

H 2 C \ \

2 a : Y = C S N H 2

2 b : Y = C O N H 2

2c: Y = CN

N H 2

ArHC -W CN y.Z O. A s

N NH 2

NH Ar HC CN

H N N S

3 ^ Ar CHO N H .

CN

1a,b + 2a

NaOEt

\

4 a : AR= C 5 H ^ - O C H 3 ( P )

A b : Ar = C 6 H A - C I ( P )

2a H , N N S

Scheme 1.

NH- C g H ^ O C H3 ( p )

C P ) H 3 C O - H 4 C 6 H C CN N C ^ ^ N S ^ C N

- H I - l a • 2 b — - F II N ^ O 0 N N H ,

H L

o Scheme 2.

Compound l a reacted with ethyl acetoacetate to yield a product which was formulated as the 2-hy-droxypyridine derivative 9 based on the IR spectrum which revealed the absence of absorption for ring CO group. The possibility that 9 was formed through the intermediacy of the pyran 11 was ruled out as 11, synthesized via reaction of ethyl acetoacetate and l c could not be rearranged under similar conditions.

l a reacted also with acetylacetone to yield the thiopyrane 12 as was inferred from its analytical and spectral data and is assumed to be formed via the sequence in Scheme 3.

l a reacted with 3-methylpyrazol-5-one (13) to yield the thiopyrane 15. The formation of 15 is as-sumed to take place via the intermediacy of the Michael adduct 14 which cyclizes via water elimina-tion. The formation of thiopyrano[2,3-c]pyrazoles in this manner contributes an interesting approach for this ring system. Only very few derivatives of this ring system are known. Similarythethiopyrano[2,3-c]-isoxazole 17 was obtained from l a and 3-methyl-isoxazol-5-one (16).

In contrast to the behaviour 13 and 16, l-phenyl-3-methyl-2-pyrazolin-5-one (18) afforded the py-

109 A. M. El-Torgoman et al. • Nitriles in Heterocyclic Synthesis

NC NH NC NH,

-CCH 3 N '

15a: AR« p - CH3OC6HA

15b: AR= p- CI-C6HA

| -H 2 O NC V ,NH2

6 5

C O } (P)H3COC6H4 .

r - f °

CH3-^n,N-C6H5

19

18a / o 1Q CH3-C-CH2C02Et

0 1 C VCH 3CO) 2CH 2

EtO

0 CgH OCH3 CN

H3C ^ C R NH2

11

0 C6HAOCH3(p)

1 1

H-IC

0 C 6H^OCH 3(p)

CN EtO

OH

0 CGHAOCH3(p) -CN

H3CVO S^NH2 H 3 c ^ n ^ O H

10

H,C

0 C 6 H A OCH 3 (p ) CN

Scheme 3.

rano[2,3-c]pyrazole 20 when treated with l a . It is clear that several polysubstituted pyridines, thio-pyrans, thiopyrano[2,3-c]pyrazole, and thiopyrano-[2,3-c]isoxazole, are now available from easily pre-pared starting materials and under simple experi-mental conditions.

Experimental All melting points are uncorrected. IR spectra

were measured as KBr discs using a Pye-Unicam SP 1100 spectrophotometer. NMR were obtained on an EM-390, 90 MHz Spectrometer, DMSO (d6)

as a solvent and TMS as an internal standard. Ele-mental analyses (±0.3%) were performed in the Microanalytical Center in Cairo University.

6-Amino-3,5-dicyano-4-(p-methoxy phenyl) pyridin-2(lH)-thione (4a)

To a solution of 2.02 g. (10 mmole) of l a in 50 ml ethanol was added 0.86 g. (10 mmole) of cyano-thioacetamide (2a) and 3 drops of triethyl amine. The reaction mixture was then heated under reflux till H2S ceased to evolve (lead acetate paper; 2—3 h). The solvent was then removed by evaporation in vacuo and the solid product formed on standing was

110 A. M. El-Torgoman et al. • Nitriles in Heterocyclic Synthesis

C o m p d . N o .

Yield [%]

M.P. °C

Mol. Formula (M.W.)

Analysis [%] Found/Calcd C H N

4a 82 265 C 1 4 H1 0N

4O S

(282.318) 60.02 59.56

3.71 3.57

20.10 19.85

4b 71 110 C 1 3 H7N

4SC1*

(186.785) 54.60 54.45

2.50 2.46

19.70 19.54

7 84.2 205 C 1 4 H1 0N

4O ,

(266.256) 63.40 63.16

4.00 3.79

21.10 21.04

9 85.5 181- 182 C17H16N,O4 (312.318)

.65.50 65.38

5.00 5.16

9.21 8.97

12 78.4 238-•239 C16H16N,O2S (300.371)

64.10 63.98

5.18 5.37

9.51 9.33

15 a 48.9 251 C 1 5 H1 4N

4O S

(198.361) 60.50 60.38

4.61 4.73

19.00 18.78

15 b 54.6 140 C 1 4 H„N4SC1**

(302.828) 55.27 55.53

3.78 3.66

18.34 18.50

17 60.7 240 (decomp.)

C15H13N3O,S (299.344)

60.05 60.19

4.50 4.39

14.15 14.04

20 91.2 210 C21H18N4O, (358.396)

70.30 70.38

5.16 5.06

15.54 15.63

Table I. Physical data for the prepared com-pounds.

Cl; Found: 12.51, Calcd: 12.38; Cl; Found: 11.50, Calcd: 11.72.

C o m p d . No.

IR [cm"1

] >H N M R [6 ppm] Table II. IR and 'H N M R spectra for the prepared compounds.

4a 3340, 3290 (-NH,), 2950 (aromatic C H ) , 2225. 2205 (two C N ) and 1650 ( C = N )

4b 3330, 3200 ( — N H2) , 2950

(aromatic C H ) , 2220 (CN) and 1640 ( C = N )

7 3240, 3100 (conj. — N H2) ,

2850 (aromatic C H ) , 2240, 2210 (two C N ) and 1690 (ring C O )

9 3480-3390 (br, O H ) , 2490 (aromatic C H ) , 2200 (CN) and 1700 (ester C O )

12 3400, 3380 (NH,), 2940 (aromatic C H ) , 2200 (CN) and 1680 (CO)

15a 3319. 3210 (NH,), 2290 (aromatic C H ) . 2220 (CN) and 1640 ( C = N )

15b 3330, 3200 (NH,), 2220

(CN) and 1650 ( C = N )

17 3300, 3280 (NH,), 2940 (aromatic C H ) , 2240 (CN) and 1680 ( C = N )

20 3450, 3360 (NH,), 2960 (aromatic C H ) . 2210 (CN) and 1640 ( C = N )

3.8 (s, 3 H , O C H3) , 7.2-7.5

(m, 4 H , aromatic protons), 7.7 (s, 2 H , N H , ) and 8.2 (s, 1 H , N H )

3.8 (s, 3 H , O C H3) , 7.2-7.7

(m, 4 H , aromatic protons), 7.8 (s, 2 H , N H

2) and 8.1 (s, 1 H , N H )

3.8 (s, 3 H , O C H3) , 7.1-7.7

(m, 4 H , aromatic protons), 7.8 (s, 2 H , N H

2) and 8.2 (s, 1 H , N H )

3.8 (s, 3 H , O C H3) , 7.2-7.5

(m, 4 H , aromatic H ) and 8.2 (s, 1 H , O H )

1.8 (s. 3 H , C H3) , 3.8 (s, 3 H . O C H

3) ,

6.6 (s, 1 H , thiopyran H-4), 7.3-7.7 (m, 4 H , aromatic protons) and 8.1, 8.2 (s, 3 H , N H and N H , )

1.8 (s. 3 H , C H3) , 3.8 (s, 3 H , O C H

3) ,

6.4 (s, 1 H , pyran. H-4). 7.2-7.5 (m. 9 H . aromatic protons) and 8.2 (s, 2 H , N H , )

111 A. M. El-Torgoman et al. • Nitriles in Heterocyclic Synthesis

collected by filtration, washed with water several times and then recrystallized from ethanol. Orange crystals, m.p. 265 °C.

Using this procedure, the compounds enlisted in Table I could be obtained via the reaction of

equimolar amounts (10 mmole) of l a with the equiv-alent amount of the methylene active reagents (2a—c), ethyl acetoacetate, acetylacetone, 3-methyl-5-pyrazolone (13), 3-methyl-isoxazol-5-one (16) and 3-methyl-l-phenyl-5-pyrazolone (18).

[1] M . H . Elnagdi, H . A . Elfahham, and G . E . H . Elgemeie, Heterocycles 20, 519 (1983).

[2] J. L. Soto, C. Seoane, P. Zamorano, M . J. Rubio, A . Monforte, and M . Quinterio, J. C h e m . Soc. Perkin Trans I 1985, 1681.

[3] F. M . Abdel Razek, Z. E. Kandeel, K . M . H . Hilmy, and M . H . Elnagdi, Synthesis 1985, 432.

[4] Z. E. Kandeel, K . H . Hilmy, F. M . Abdel Razek, and M . H . Elnagdi, C h e m . Ind. (London) 1984, 33.

[5] H . A . Daboun and B. Y . Riad, Indian J. C h e m . 23B, 675 (1984).

[6] J. L. Soto, C. Seoane, N . Martin, and M . Quenteris, Heterocycles 20, 783 (1983).

[7] G . E. H . Elgomei, M . M . Sallam, S. M . Mourad, and M . H . Elnagdi, Heterocycles 23, 3107 (1985).

[8] S. M . Fahmy and R . M . Mohareb, Tetrahedron 42, 687 (1986).

[9] Z. E. Kandeel, K . M . H . Hilmy, N . A . Ismail, and M . H . Elnagdi, J. Prakt. C h e m . 326, 248 (1984).

[10] M . J. Encinas, C. Seoane, and J. L. Soto, Liebigs A n n . C h e m . 17, 213 (1984).