Synthesis of some Acetylenic Amines Derivatives by Mannich Reaction

Some acetylenic amine derivatives containing nitrogen bases (cytosine, uracil) were synthesized through Mannich reaction which involved reaction of N-propargyl cytosine or uracil with paraformaldehyde and secondary amines. The structure of synthesized compounds have been confirmed depending on the physical and spectral data.


INTRODUCTION
Mannich-reaction have been employed in the organic synthesis of natural compounds such as peptides, nucleotides, antibiotics, and alkaloids (e.g.tropinone), other applications were in agro chemicals such as plant growth regulators (da Rosa et al., 2003), also used in the synthesis of medicinal compounds e.g.rolitetracycline, flaoxetine and tolmetin (antiinflammatory drugs) (Mitsumori et al., 2006).
PDF created with pdfFactory Pro trial version www.pdffactory.comOn the other hand, many compounds containing cytosine nucleus were found to possess human anti-tumor activity (Creasy et al., 2006), other compounds containing uracil group were found to be as a new type of anticancer agents (Yamamoto, 1981).Accordingly, we described here an approach to synthesize some aminoacetylenic compounds containing Cytosine(4-amino-2-hydroxypyrimidine) and Uracil (2,4-dihydroxypyrimidine) moieties to improve the expected biological activities of such compounds.

EXPERIMENTAL
Melting point were determined using electrothermal 9300 melting point apparatus and are uncorrected.IR. spectra were recorded by Pye-Unicam SP1100 Spectrophotometer as (KBr) disc.UV.Spectra were recorded on shimadzu (UV-160) UV-visible spectrophotometer using absolute ethanol as a solvent.

Preparation of N-(4-substitutedaminobut-2-ynyl) cytosine ( Ia-e ): General method (Mannich Reaction) (Afaf et al., 2000):
A mixture of paraformaldehyde (0.9 gm, 0.001 mole) and appropriate secondary amine (0.015 mole) in absolute ethanol (10 ml) was refluxed till clear solution was obtained.Compound (I) (0.59 gm, 0.004 mole) was heated in absolute ethanol (10 ml), then added to the first reaction mixture and refluxed for (2 hrs).The mixture was concentrated by heating and the separated product was filtered off and recrystallized form chloroformpetroleum ether (80-100 o C) to give the desired compounds (Ia-e).The physical and spectral data of compounds (Ia-e) were listed in Table (1).

Preparation of 3-(N-propargyl) uracil (II) (Sheat and Dawood, 2004):
A cooled solution of sodium hydroxide (1.36 gm, 0.034 mole) in ethanol (50 ml) was added to a cooled solution of uracil (3.8 gm, 0.034 mole) in ethanol (50 ml) with stirring and cooling at 0 o C. Propargyl bromide (4 gm, 0.034 mole) was added dropwise with stirring.After the addition is completed, the reaction mixture was refluxed for (3 hrs) with continuous stirring , then extracted with chloroform (2 × 50 ml).The chloroform extracts were dried with anhydrous magnesium sulphate, then filtered and the solvent was removed in vacuum.The precipitate was recrystallized from benzene-petroleum ether PDF created with pdfFactory Pro trial version www.pdffactory.com(80-100 o C) to afford compound (II) as white crystals of (75%) yield and m.p. (132-133 o C).

RESULTS AND DISCUSSION
It is well known that many acetylenic amines derivatives are pharmaceutically active compounds.This fact was confirmed from the mentioned previous studies in the introduction.Accordingly, the synthesis of acetylenic amines derivatives containing cytosine and uracil moieties may show characteristic biological activity.
Therefore, two series of acetylenic amines derivatives have been synthesized using cytosine and uracil as a starting material in the Mannich synthesis as shown in scheme (1).
The synthesized acetylenic amines derivatives (Ia-e & IIa-e) have been investigated according to their physical and spectroscopic data (IR and UV) (Parikh, 1974).Other supporting evidence is the positive Tollen test for the acetylenic hydrogen in proporgyl compounds (I ,II) which became negative test in Mannich products.
The IR. spectra of compounds (Ia-e) showed strong absorption bands at (1646-1655) cm -1 for the amidic carbonyls frequencies, another strong absorption bands for the two bands (C=N & C=C) which overlapped at the region (1614-1636) cm -1 .While the broad absorption bands at (3418-3446) cm -1 is due to υN-H.The broad band at 3169 cm -1 which appeared for the acetylenic hydrogen in compound (I) is disappeared in Mannich products (Ia-e) as shown in Table (1).
The IR. Spectra of compounds (IIa-e) showed two strong absorption bands at the regions (1711-1735) cm -1 and (1656-1669) cm -1 due to the asymmetric and symmetric stretching vibrations of the imidic carbonyl groups, strong absorption bands appeared at (1618-1625) cm -1 for υC=C, a broad absorption band appeared at (3433-3455) cm -1 for the amidic hydrogen.Also the strong band at 3236 cm -1 which appeared for the acetylenic hydrogen in compound (II) is disappeared in Mannich products (IIa-e) as shown in Table (1).
The UV. spectra of compounds (Ia-e and IIa-e) showed higher λmax.values as compounds with those of compounds (I and II).This is due to the appearance of conjugation effect which increase λmax values and cause bathochromic shift in the n π * transition of these compounds.
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Table 1 :
physical and spectral data of the synthesized compounds (Ia-e , IIa-e) * All the compounds were of white color.PDF created with pdfFactory Pro trial version www.pdffactory.com