Indian Journal of Chemistry Vol. 40B, July 2001 , pp. 608-61 1

Note

Synthesis of 2,6-dimethyl-4-substituted pyridine-3,5-dicarbonitriles from

B-aminoacrylonitriles

F AI-Omran* & A A EI-Khair

Department of Chemistry, Faculty of Science, University of Kuwait, P.O. Box 5969 Safat, 1 3060, Kuwait

Received 10 November 1 999; accepted (revised) 12 May 2000

!3-Aminoacrylonitrile reacts with aldehydes or cinnamaldehyde in the presence of HC) to give 2,6-dimethyl-4-substituted pyridine-3,5-dicarbo/nitrites 2a-c. 2a-b on condensation with DMF/DMA afford Sa-b. Reaction of 2b with 4-N,N­dimethylaminobenzaldehyde yields Sc. The structures of the newly synthesized compounds have been elucidated by elemental analyses and spectral data.

Pyridine derivatives are very interesting class of heteroaromatics because of their significant biological activities such as antitumor, antibiotics I , herbicides2

and insecticides3 . As a part of our studies aimed at developing simple and efficient syntheses of polyfunctional heteroaromatics from readily obtained starting materials4-9, we report herein the synthesis of 2,6-dimethyl-4-substituted pyridine-3,5-dicarbo­nitriles 2a-c utilizing p-aminoacrylonitrile 1 as a starting material.

Thus, treatment of p-aminoacrylonitrile 1 in ethanol with equimolar amount of acetaldehyde or benzaldehyde in the presence of equimolar amount of hydrochloric acid at room temperature afforded 2,6-dimethyl-4-substituted pyridine-3,5-dicarbonitriles 2a-b in excellent yield (Scheme I). On the other hand, refluxing of cinnamaldehyde with two moles of p­aminoacrylonitrile in the presence of a catalytic amount of hydrochloric acid afforded compound 2co Both elemental analyses and spectral data were in complete agreement with the assigned structures. Treatment of 3-aminocrotononitrile 1 with equimolar amount of cinnamaldehyde in the presence of a catalytic mount of hydrochloric acid gave a yellow product in an excellent yield. The product, which showed absorption band at 22 14 and 1 69 1 cm-I , was assigned the structure 30 Treatment of 3 with an equimolar amount of the malononitrile in refluxing ethanol and in the presence of piperidine and HCI, afforded a yellow crystalline product, whose IR showed band at 3347 cm-I (NH str) in addition to

RCHO

I

NH2 PhCH=CHCHO + 2 r=<.

•

NC Me

! ii

ii

J PhCH=CHCHO a, R = Me

b, R = Ph

iv •

(i) 30 ml HCI I EtOH, RT

C, R = Ph-CH=CH-

ti

P

: NC CN

� I .HCl

o N Me I

H

(ii) I ml Hel / EtOH, refllux 4 (iii) I ml Hel l EtOH, RT (iv) I ml Hel / EtOH, reflux, piperidine

Scheme I

band at 1 630 cm-I (amide carbonyl), was assigned the structure 4. This was confirmed from elemental analysis and IH NMR data as well (Scheme 1)0

The reaction of 3-aminocrotononitrile 1 with p­dimethylaminobenzaldehyde in refluxing ethanol and in the presence of catalytic amount of piperidine and acetic acid afforded the corresponding cinnamonitrile 6 in excellent yield whose structure was established on the basis of spectral data (IR and IH NMR). We believe that 6 is formed by nucleophilic attack at the carbonyl group of intermediate 50 To the best of our knowledge this is the first reported acyl group cleavage (retro-aldol) in such systems (Scheme II).

Compounds 2a,b failed to react with sulfur to yield the corresponding thienopyridine under a variety of conditions, similar to those reported in the literatureJO• l l o Condensation of 2a with dimethylform­amide/dimethylacetal yielded a product that was formulated as 7 or 80 The structure 8a is preferred over 7a based on its IH NMR spectrum which indicated the presence of two non-identical methyl signals at 0 2.4 1 and 0 2.49 in addition to N,N­dimethylamino signal at 0 3 .29 while the condensa-

NC I �: M)(XMe

7

Compd Yield (%)

2a* 87

5

Scheme n

NC�CN

M)LN4R, 8

NOTES 609

6

a) R = Me ; R' - Me2N-b) R - C�s ; R' -MC2N-c) R=�Hs; R' - p-Me2NC�

tion of 2b with dimethylformamide/dimethylacetal yield the (E)-dimethylaminoethylene pyridine derivative 8b. The (E)-structure for both 8a,b is based on 'H NMR spectrum which revealed ethylene protons as two doublets at 8 5.2 and 8 8.0 ppm with J=1 3Hz. Attempted cyclization of 8a,b with hydrazine under different conditions failed. Compound 2b also condensed with p-dimethyl­aminobenzaldehyde to yield 8c in excellent yield (Table I).

Experimental Section All melting points are uncorrected. IR spectra were

recorded on a Perkin-Elmer 2000 Ff-IR spectrometer.

Table I-Characterization data of compounds 2a-c, 3, 4, 6 and 8a-c

mp Color Mol °C formula

1 16- 18 pale yellow

Found % (ca\cd) I H NMR �C--

�=H�

��N�--

69.93 (70. 15

5.37 5.30

24.80 24.55)

2.72 (3H, s, Me), 2.78 (6H, s, 2 Me)

1 64.41 (C-2 and C-6), 1 54.96 (C-4), 1 14.77(2 CN), 108.35 (C-3 and (C-5), 24.38 (2 Me), 19.8 1 (Me)

2b* 86 175-77 yellow 77.23 4.74 (77.23 4.75

1 8. 1 3 18.02)

2.84(6H, s, 2Me), 7.54(5H, s, Ar-H)

2c* 85 230-32 yellow

3** 86 1 30-32 yellow

4* 75 80-82 yellow

6a' 85

8a* 73

8b* 76 234-36

78.54 5.73 (78.74 5.62

79. 14 5.68 (79.16 5.62

CI6HI IN30. 64.30 HCI (64.53

3.88 3.69

76.60 6.79 (76.71 7.02

69.20 6.35 (69.00 6.24

74.72 (74.97

5.56 5.59

16.08 1 6.21)

7.40 7. 10)

1 3.93 14. 1 1 )

1 6.24 1 6.27)

24.98 24.76)

19.28 19.43)

2.82(6H, s, 2 Me), 7. 19-7.66 (6H, m, Ar-H and vinylic-H), 7.96 ( l H, d, 1 = 1 5 Hz vinylic-H)

2.43(3H, s, Me), 7.21 1 9 1 .02(C-2), 153.39(C-6), ( I H, d, 1=5.0 Hz. H-4). 7.26- 149.66 (C-4), 137.2, 1 30.58, 7.66 (6H. m. Ar- H and H-6), 129. 18. 127.98. 123. 14 7.83-7.96 ( l H. m. H-5) (aromatic carbons & C-5).

1 19.80 (CN). 1 15.98 (C-3). 27.78 (Me)

2. l 1 (s. 3H. Me). 6.78. (d. I H. 1=1 3 Hz. vinylic-H). 7.3 1 -7.53 (m. 6H. Ar-H and NH), 7.77 (d. IH. 1=13 Hz. vinylic-H)

3.02 (6H, s. NM�), 6.81 -7.54 (6H. m. Ar-H and vinylic-H)

2.41 (3H. s. Me). 2.49(3H. s. Me). 3.29(6H. s. NMe2). 5.25 ( I H. d. 1=1 3 Hz. vinylic-H). 8.00 ( I H. d, 1=1 3 Hz. vinylic-H)

2.58 (3H. s. Me), 3.05 (6H, s, NMe2). 5.39 ( I H. d, 1=1 3 Hz, vinylic-H), 6.90-7.50 (5H, Ar­H). 8 . 13 ( l H. d. 1=1 3 Hz, vinylic-H)

(Contd)

6 10 INDIAN J CHEM, SEC. B . JULY 2001

Table I--Characterization data of compounds 2a-c. 3, 4, 6 and 8a-c-Contd

Compd Yield mp Color Mol (%) °C formula -:::-

-..:F..:::o=:un7d:..:<7l:;..v �(c=al�cd::L) __ IH NMR C H N

8c* 79 240-42 yellow

(a) 1it. 12 m.p. 165-68°C. *in DMSO ; * *in CDCI3

78.96 5.74 (79.09 5.53

'H 1 3C and NMR spectra on a Bruker MHz-80 spectrometer with DMSO-d6 or CDCl3 as solvent and TMS as an internal standards; chemical shifts cS, ppm. Microanalysis were performed on a Leco-CHNS 932 analyzer.

3, S-Dicyano-2, 6-dimethyl-4-substituted pyridines 2a,b. To a suspension of 1 (0.82 g, 0.01 mole) in ethanol (20 mL) and HCl (30 mL, 0.0 1 mole) was added acetaldehyde or benzaldehyde (0.01 mole). The reaction mixture was stirred at room temperature overnight and then poured onto crushed ice-water. The solid product was collected and recrystallized from ethanol.

(E)-2, 6-Dimethyl-4-styrylpyridine-3, S-dicarbo­nitrile 2c. To a suspension of I ( 1 .64 g, 0.02 mole) in ethanol (20 mL) and HCI (1 mL) was added cinnamaldehyde ( 1 . 1 3 g, 0.01 mole). The reaction mixture was refluxed for 3hr and then poured onto ice-cold water. The solid product, so formed was collected by filtration, washed with cold ethanol and recrystallized from ethanol.

2-0xo-6-phenyl-3,5-hexadiene-3-carbonitrile 3. To a suspension of 1 (0.82 g, 0.01 mole) in ethanol (30 mL) and HCI ( 1 mL) was added cinnamaldehyde ( 1 .32 g, 0.01 mole). The reaction mixture was stirred at room temperature for 24 hr, then poured onto ice­cold water. The solid product was collected by filtration, washed with cold ethanol and recrystallized from ethanol.

1, 2-Dihydro-6-methyl-2-oxo-4-styrylpyridine-3,S-dicarbonitrile hydrochloride 4. To a mixture of 3 and malononitrile (0.01 mole) in absolute ethanol a few drops of piperidine and HCI were added. The mixture was refluxed for 5-6 hr and then poured into water. The solid product was collected by filtration and recrystallized from ethanol.

3-(4-N,N-Dimethylanilino)propenonitrile 6. To a mixture of 1 (0.82g, 0.0 1 mole) and 4-N,N-

1 5.25 2.77 (3H, s. Me). 2.99, (6H. s, 15.38) NMe2). 6.75 (2H. d. 1=9 Hz.

Ar-H), 7.30 ( l H, d, 1=9 Hz, Ar-H), 7.54 (2H, d, 1=9 Hz, Ar-H), 7.59 (5H. m, Ar-H), 8.08 ( l H. d. 1=15 Hz, vinylic-H)

dimethylaminobenzaldehyde (0. 1 5 g, 0.01 mole) in toluene (50 mL) in a Dean Stark apparatus, piperidine ( 1 mL) and acetic acid (2 mL) were added. The reaction mixture was refluxed for 4 hr and then poured onto water and triturated with ethanol. The solid product so formed was collected by filtration and recrystallized from a mixture of ethanol and dioxane.

Reaction of 2a,b with dimethylformamidel dimethylacetal formation of Sa,b. A solution of 2a,b (0.47 g, 0.0 1 mole) in acetonitrile (30 mL) was treated with (DMF/DMA) (0. 1 3 g, 0.01 mole). The reaction mixture was refluxed on a water-bath for 2 hr and cooled. The solid product was collected and recrystallized from ethanol.

(E)-6-Methyl-2-[2-( 4-N,N -dimethylanilino )ethen­yl]-4-phenylpyridine-3,S-dicarbonitrile Sc. A suspension of 2b (0.23 g, 0.0 1 mole) in acetonitrile (30 mL) was treated with 4-N,N-dimethylaminobenzalde­hyde (0.0 1 mole, 0. 1 3 g) and a few drops of piperidine. The reaction mixture was refluxed on a water-bath for 4 hr and cooled. The solid product was collected and recrystallized from acetonitrile.

Acknowledgements The authors are grateful to University of Kuwait for

funding through project SC 082. We are also grate­ful to SAF facility at University of Kuwait, Chemis­try Department, for analytical and spectral measure­ments.

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