Syntheses of new 1,2-, 1,3-, and 1,4-diazine derivatives. 2. Hydrolysis and alkylation of diazinylphenylacetonitriles

Article abstract of DOI:10.1007/s10593-006-0242-8

A number of aryldiazinyl acetonitriles were subjected to hydrolysis, methylation, and benzylation reactions. They resulted in the formation of aryldiazinylacetamides, diazinylmethylacetonitriles, and benzyldiazinylacetonitriles, respectively.

Full text of DOI:10.1007/s10593-006-0242-8

Chemistry of Heterocyclic Compounds, Vol. 42, No. 10, 2006
SYNTHESES OF NEW 1,2-, 1,3-, AND 1,4-DIAZINE
DERIVATIVES. 2*. HYDROLYSIS AND ALKYLATION
OF DIAZINYLPHENYLACETONITRILES
K. Wisterowicz and H. Foks
A number of aryldiazinyl acetonitriles were subjected to hydrolysis, methylation, and benzylation
reactions. They resulted in the formation of aryldiazinylacetamides, diazinylmethylacetonitriles, and
benzyldiazinylacetonitriles, respectively.
Keywords: 2-benzylpyrazines, diazinylphenylacetamides, diazinylphenylacetonitriles, alkylation,
hydrolysis, decarboxylation.
The continuation of previously reported syntheses of new pyridazine, pyrimidine, and pyrazine
derivatives containing an active methine fragment [1] is described in the present paper.
Aryldiazinylacetonitriles were the substrates subjected to hydrolysis action of concentrated sulfuric acid.
This gave a series of aryldiazinylacetamides, as shown below:
R1
R1
H2SO4
R
CH
R
CH
CN
∆
CONH2
1–10
Diazinylacetonitrile derivatives with unsubstituted methine hydrogen atom were then exposed to
methylation and benzylation reactions. These proceeded in 50% aqueous sodium hydroxide/dimethyl sulfoxide
medium under the action of methyl iodide in methylation, and benzyl chloride in benzylation reactions,
respectively. The diazinylmethylacetonitriles 11, 12 and diazinylbenzylacetonitriles 13-15 were the products
obtained, as shown below:
R2
R
N
N
C
R
R1
N
N
CH
R1
R2X
11–15
_______
* For Communication 1, see [1].
__________________________________________________________________________________________
Department of Organic Chemistry, Medical University of Gdansk, 80-416 Gdansk, Poland; e-mail:
hfoks@amg.gda.pl. Published in Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1534-1540, October,
2006. Original article submitted January 25, 2005; revision submitted June 8, 2006.
0009-3122/06/4210-1325©2006 Springer Science+Business Media, Inc.
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TABLE 2. IR and 1H NMR data for compounds 1-10
Com-
pound
IR spectrum, cm-1
1H NMR spectrum, δ, ppm*
1
2
1700 (C=O), 3070 (CH aromatic),
3340 (NH2)
7.50 (5H, m, 2H pyridazine and 3H phenyl);
5.75 (1H, s, CH)
1660 (C=O), 2960 (CH alkyl),
3060 (CH aromatic),
6.90 (3H, m, pyrimidine); 5.90 (4H, m, phenyl);
4.50 (1H, s, CH)
3380, 3330 (NH2)
3
1660 (C=O), 2940 (CH alkyl),
3050 (CH aromatic),
7.50 (6H, m, 3H pyrimidine and 3H phenyl);
5.50 (1H, s, CH); 4.20 (2H, s, NH2)
3420, 3240 (NH2)
4
5
6
7
8
9
1680 (C=O), 2960 (CH alkyl),
3080 (CH aromatic), 3350 (NH2)
6.90 (3H, m, pyrimidine); 5.70 (3H, m,
phenyl); 4.15 (1H, s, CH); 3.10 (6H, s, 2CH3)
1650 (C=O), 2940 (CH alkyl),
3060 (CH aromatic), 3360 (NH2)
6.90 (3H, m, pyrazine); 6.05 (3H, m, phenyl);
4.40(1H, s, CH); 2.75 (2H, s, NH2)
1670 (C=O), 2930 (CH alkyl),
3060 (CH aromatic), 3340 (NH2)
1680 (C=O), 2920 (CH alkyl),
3020 (CH aromatic), 3340 (NH2)
6.90 (3H, m, pyrazine); 6.10 (3H, m, phenyl);
4.20 (1H, s, CH)
6.90 (3H, m, pyrazine); 5.90 (3H, m, phenyl);
4.70 (1H, s, CH)
1650 (C=O), 2980 (CH alkyl),
3080 (CH aromatic), 3380 (NH2)
6.80 (3H, m, pyrazine); 6.10 (7H, m, naphthyl);
4.30 (1H, s, CH); 2.75 (2H, s, NH2)
1690 (C=O), 2960 (CH alkyl),
3060 (CH aromatic), 3320 (NH2)
6.65 (1H, s, pyrazine); 5.95 (3H, m, phenyl);
4.25 (1H, s, CH); 2.70 (2H, s, NH2);
2.0(6H, m, 2 CH3)
10
1680 (C=O), 2960 (CH alkyl),
3050 (CH aromatic), 3330 (NH2)
6.60 (1H, s, pyrazine); 5.80 (3H, m, phenyl);
4.70 (1H, s, CH); 1.90 (6H, s, 2CH3)
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* Compounds 1, 2, 4, 7, 10 – in CDCl3, compounds 3, 5, 6, 8, 9 – in DMSO-d6.
Some pyrazinylacetonitriles, viz. 4-chlorophenyl-2-pyrazinylacetonitrile, 3',4'-dichlorophenyl-2-
pyrazinylacetonitrile, 2'-naphthyl-2-pyrazinylacetonitrile (syntheses described in [1]), as well as compounds 14
and 15 were subjected to hydrolysis, followed by decarboxylation. These reactions gave 2-benzylpyrazine
derivatives 16-20, as shown below:
R1
R
R1
C
N
N
N
CH
R2
∆, HCl
R2
N
16–20
The yields, physical properties of the reactions as well as the results of IR and 1H NMR spectral analyses
are given in Tables 1, 2 (for compounds 1-10), and 3, 4 (for compounds 11-20).
EXPERIMENTAL
Melting points were determined with a Boetius apparatus and are uncorrected. The IR spectra were taken
1
with a Satellite spectrophotometer (KBr pellets), and H NMR spectra – with a Varian Gemini 200 apparatus
(200 MHz) with TMS as an internal standard.
Syntheses of Diazinylacetamides 1-10. (General Method). 2,4-Dichlorophenylpyrazinylacetonitrile
(0.53 g, 2 mmol) was heated on the water bath with concentrated H2SO4 (1.9 ml) for 10 min. Then the reaction
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TABLE 4. IR and 1H NMR Data for Compounds 11-20
Com-
pound
IR spectrum, cm-1
1H NMR spectrum (DMSO-d6), δ, ppm (J, Hz)
11
3100 (CH aromatic), 2980,
2940 (CH alkyl), 2250 (C≡N)
7.10 (1H, s, pyrazine); 6.99 (2H, s, pyrazine);
6.05 (4H, m, phenyl); 1.80 (3H, s, CH3)
12
3090 (CH aromatic),
2940 (CH alkyl), 2270 (C≡N)
7.00 (3H, m, pyrazine); 6.40,
6.10 (7H, m, 4H and 3H naphthalene);
1.85 (3H, s, CH3)
13
14
15
3040 (CH aromatic), 2960,
2920 (CH alkyl), 2260 (C≡N)
7.00 (3H, m, pyrazine); 6.65 (9H, m, phenyl);
2.70 (2H, s, CH2)
3080 (CH aromatic), 2980,
2920 (CH alkyl), 2260 (C≡N)
3060 (CH aromatic), 2960,
2920 (CH alkyl), 2260 (C≡N)
6.85 (3H, m, pyrazine); 5.90 (8H, m, phenyl);
2.70 (2H, s, CH2)
7.00 (3H, m, pyrazine); 6.40, 6.10, 5.70 (12H,
m, 5H phenyl and 7H naphthalene);
2.70 (2H, s, CH2)
16
17
18
19
20
3040 (CH aromatic), 2980,
2920 (CH alkyl), 1580, 1540,
1500 (phenyl ring)
6.90 (3H, m, pyrazine); 5.95 (4H, m, phenyl);
2.70 (2H, s, CH2)
3100 (CH aromatic), 2940,
2880 (CH alkyl), 1590, 1540,
1500 (phenyl ring)
6.80 (3H, m, pyrazine); 5.95 (3H, m, phenyl);
2.70 (2H, s, CH2)
3080(CH aromatic), 2940,
2880(CH alkyl), 1590, 1550,
1440(phenyl ring)
6.90 (3H, m, pyrazine);
6.40, 6.00 (7H, m, naphthalene); 2.70 (2H, s, CH2)
3100 (CH aromatic), 2980,
2940 (CH alkyl), 1640, 1540,
1490 (phenyl ring)
6.90 (3H, m, pyrazine); 5.85 (8H,
m, phenyl); 3.95 (1H, m, CH); 2.70 (2H, s, CH2)
3080 (CH aromatic), 2940,
2880 (CH alkyl), 1600, 1540,
1490 (phenyl ring)
6.85 (3H, m, pyrazine);
6.15, 5.70 (12H, m, naphthalene and phenyl);
3.85 (1H, m, CH); 2.70 (2H, s, CH2)
mixture was poured into ice water and alkalized with 25% aqueous ammonia. The precipitated product was
crystallized from methanol. Compound 5 (0.23g, mp 179-181°C) was obtained; compounds 1-4 and 6-10 were
obtained analogously.
Syntheses of Diazinylmethylacetonitriles and Diazinylbenzylacetonitriles 11-15. (General Method).
To 2-naphthylopyrazinylacetonitrile (0.49 g, 2 mmol) DMSO (1 ml), methyl iodide (0.2 ml, 2 mmol), and 50%
aqueous NaOH (0.5 ml) were added. The whole was heated on the water bath at 70°C for 1 h with vigorous
stirring. Then the reaction mixture was poured into ice water, acidified with concentrated HCl to pH 3, and
extracted thrice with chloroform. The extracts were dried with anhydrous MgSO4 and thickened under reduced
pressure. The residue was crystallized from methanol. Compound 12 was obtained (0.18 g). Compounds 11 and
13-15 were obtained analogously.
Syntheses of Benzylpyrazines 16-20. (General Method). To 2-(4'-chlorophenyl)cyanomethylpyrazine
(0.5 g, 2 mmol) concentrated HCl (5 ml) was added and the whole heated for 5 h. Then the reaction mixture was
poured into ice water, alkalized with 25% aqueous ammonia and extracted thrice with chloroform. The extract
was evaporated to dryness under vacuum and the residue crystallized from diethyl ether. Compound 16 (0.36 g)
was obtained. Other benzylpyrazines 17-20 were obtained analogously.
REFERENCES
1.
K. Wisterowicz and H. Foks, Khim. Geterotsikl. Soedin., 1346 (2006). [Chem. Heterocycl. Comp., 42,
1168 (2006)].
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