Syntheses of new 1,2-, 1,3-, and 1,4-diazine derivatives. 1. Synthesis of diazinylarylacetonitriles

Article abstract of DOI:10.1007/s10593-006-0221-0

A number of diazinylarylacetonitriles were obtained in the reactions of properly substituted 3-chloropyridazine, 2-chloropyrimidine, or 2-chloropyrazine derivatives with various arylacetonitriles. Springer Science+Business Media, Inc. 2006.

Full text of DOI:10.1007/s10593-006-0221-0

Chemistry of Heterocyclic Compounds, Vol. 42, No. 9, 2006
SYNTHESES OF NEW 1,2-, 1,3-, AND
1,4-DIAZINE DERIVATIVES. 1. SYNTHESIS
OF DIAZINYLARYLACETONITRILES
K. Wisterowicz and H. Foks
A number of diazinylarylacetonitriles were obtained in the reactions of properly substituted
3-chloropyridazine, 2-chloropyrimidine, or 2-chloropyrazine derivatives with various arylacetonitriles.
Keywords: chlorodiazines, diazynylphenylacetonitriles, phenylacetonitriles, phase-transfer synthesis.
The syntheses of heterocyclic compounds with an active methine fragment in α-position to the nitrogen
atom are described in the present paper.
Compounds of this kind are of interest from both pharmaceutical and chemical points of view. As they
have an unsubstituted hydrogen atom, the existence of two tautomeric forms – the so-called CH- and NH-acids –
is possible (Scheme 1).
Scheme 1
H
H
R
CN
N
N
C
C
R
CN
The tautomerism arising from the mobile methine proton migration towards the heterocyclic nitrogen
atom was examined by many authors [1-4].
The compounds having an active methine fragment appear to be biologically active, too. Some of them
are analgesic and antiphlogistic [5-6]; others affect the secretion of gastric juices [7] or exhibit affinity to
dopamine receptors [8].
Attempts to synthesize the 1,2-, 1,3-, and 1,4-diazine derivatives were aimed at obtaining some new
potentially active therapeutics. The diazines, viz., 3,6-dichloropyridazine, 3-chloro-6-methoxypyridazine,
2-chloropyrimidine, 2,4-dichloropyrimidine, 2-chloropyrazine, and 3-chloro-2,5-dimethylpyrazine, were used as
substrates in reactions with the following substituted phenylacetonitriles: 3-chloro-, 4-chloro-, 2,4-dichloro-, 2,6-
dichloro-, 3,4-dichloro-, 4-hydroxy-, 3,4-dimethoxy-, and 3,4,5-trimethoxyphenylacetonitrile. The reactions
1
proceeded in a biphase system of 50% aqueous sodium hydroxide – dimethylsulfoxide. The H NMR spectra
showed that in this system the derivatives obtained had the structure of CH-acids. The reactions course is shown
in Scheme 2.
__________________________________________________________________________________________
Department of Organic Chemistry, Medical University of Gdansk, 80-416 Gdansk, Poland; e-mail:
hfoks@amg.gda.pl. Published in Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1346-1354, September,
2006. Original article submitted January 21, 2005; revision submitted June 8, 2006.
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0009-3122/06/4209-1168©2006 Springer Science+Business Media, Inc.

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TABLE 2. IR and 1H NMR Data for Compounds 1-31
Com-
pound
IR spectrum, cm-1
2
1H NMR spectrum, δ, ppm*
1
3
1
2
3
3100 (CH aromatic), 2980,
2940 (CH alkyl), 2270 (C≡N),
1590, 1540, 1480 (phenyl ring)
7.50 (5H, m, 2H pyridazine and 3H phenyl);
5.90 (1H, s, CH)
3080 (CH aromatic), 2980,
2940 (CH alkyl), 2260 (C≡N),
1600, 1540, 1480 (phenyl ring)
7.70 (4H, m, 2H pyridazine and 2H phenyl);
6.30 (1H, s, CH); 3.80 (9H, m, 3CH3)
3080 (CH aromatic), 2980,
2940 (CH alkyl), 2260 (C≡N),
1590, 1550, 1500 (phenyl ring)
7.75 (9H, m, 2H pyridazine and
7H naphthalene); 5.85 (1H, s, CH)
4
5
3100 (CH aromatic), 2220 (C≡N),
1600, 1580, 1540 (phenyl ring)
7.40 (6H, m, 2H pyridazine + 4H pyridine);
1.65 (1H, s, CH)
3070 (CH aromatic), 2990,
2950 (CH alkyl), 2252 (C≡N),
1595, 1550, 1492 (phenyl ring)
7.40 (6H, m, 2H pyridazine and 4H phenyl);
5.55 (1H, s, CH); 4.15 (3H, s, CH3)
6
7
3070 (CH aromatic), 2990,
2960 (CH alkyl), 2250 (C≡N),
1597, 1562, 1470 (phenyl ring)
7.40 (5H, m, 2H pyridazine and 3H phenyl);
5.50 (1H, s, CH); 4.15 (3H, s, CH3)
3060 (CH aromatic), 2990,
2950 (CH alkyl), 2220 (C≡N),
1600, 1570, 1500 (phenyl ring)
7.35 (5H, m, 2H pyridazine and 3H phenyl);
5.45 (1H, s, CH); 4.20 (3H, s, CH3)
8
3060 (CH aromatic), 2980,
2840 (CH alkyl), 2260 (C≡N),
1600, 1580, 1500 (phenyl ring)
7.40 (7H, m, 3H pyrimidine and 4H phenyl);
5.20 (1H, s, CH)
9
3060 (CH aromatic), 2960,
2920 (CH alkyl), 2280 (C≡N),
1580, 1500 (phenyl ring)
8.75 (3H, m, pyrimidine);
7.35 (4H, m, phenyl); 5.40 (1H, s, CH)
10
11
12
13
3100 (CH aromatic),
2940 (CH alkyl), 2280 (C≡N),
1580, 1500, 1460 (phenyl ring)
8.20 (6H, m, 3H pyrimidine and 3H phenyl);
6.36 (1H, s, CH)
3050 (CH aromatic), 2980,
2940 (CH alkyl), 2260 (C≡N),
1600, 1580, 1540 (phenyl ring)
8.60 (3H, m, pyrimidine);
6.50 (8H, m, phenyl); 5.30 (1H, s, CH);
3.65 (6H, m, 2CH3)
3060 (CH aromatic), 2980,
2940 (CH alkyl), 2260 (C≡N),
1590, 1530, 1490 (phenyl ring)
8.70 (3H, m, pyrimidine);
6.70 (2H, m, phenyl); 5.35 (1H, s, CH);
3.80 (9H, m, 3CH3)
3090 (CH aromatic), 2980,
2950 (CH alkyl), 2260 (C≡N),
1580, 1540, 1450 (phenyl ring)
8.60 (3H, m, pyrimidine);
7.65 (7H, m, nahthalene); 5.60 (1H, s, CH)
14
15
3100 (CH aromatic), 2940,
2860 (CH alkyl), 2220 (C≡N)
8.50 (3H, m, pyrimidine);
7.20 (4H, m, pyridine); 6.70 (1H, s, CH)
3090 CH aromatic), 2920,
2860 (CH alkyl), 2250 (C≡N),
1567, 1548, 1495 (phenyl ring)
8.00 (6H, m, 2H pyrimidine and 4H phenyl);
5.20 (1H, s, CH)
16
17
18
19
3100 (CH aromatic), 2920,
2850 (CH alkyl), 2200 (C≡N),
1620, 1570, 1520 (phenyl ring)
7.50 (5H, m, 2H pyrimidine and 3H phenyl);
6.40 (1H, s, CH)
3080 (CH aromatic), 2920,
2860 (CH alkyl), 2220 (C≡N),
1610, 1580, 1540 (phenyl ring)
3060 (CH aromatic), 2920,
2850 (CH alkyl), 2190 (C≡N),
1594, 1565, 1520 (phenyl ring)
7.70 (5H, m, 2H pyrimidine and 3H phenyl);
5.20 (1H, s, CH); 3.90 (3H, s, CH3);
3.65 (3H, s, CH3)
3100 (CH aromatic), 2940,
2840 (CH alkyl), 2200 (C≡N),
1600, 1580, 1530 (phenyl ring)
7.40 (6H, m, 2H pyrimidine and 4H pyridine);
1.65 (1H, s, CH)
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TABLE 2 (continued)
1
2
3
20
21
22
23
3100 (CH aromatic), 2980,
2920 (CH alkyl), 2280 (C≡N),
1590, 1530, 1490 (phenyl ring)
8.45 (3H, m, pyrazine); 7.15 (4H, m, phenyl);
5.20 (1H, m, CH)
3080 (CH aromatic), 2970,
2930 (CH alkyl), 2260 (C≡N),
1560, 1500, 1440 (phenyl ring)
8.65 (3H, m, pyrazine); 7.40 (4H, m, phenyl);
5.40 (1H, s, CH)
3080 (CH aromatic), 2980,
2940 (CH alkyl), 2260 (C≡N),
1590, 1540, 1490 (phenyl ring)
8.60 (3H, m, pyrazine); 7.65 (3H, m, phenyl);
5.75 (1H, s, CH)
3080 (CH aromatic), 2980,
2940 (CH alkyl), 2260 (C≡N),
1580, 1540, 1480 (phenyl ring)
6.95(3H, m, pyrazine); 5.95 (3H, m, phenyl);
4.25 (1H, s, CH)
24
25
26
3080 (CH aromatic), 2960,
2920 (alkyl), 2260 (C≡N)
6.85 (3H, m, pyrazine); 6.10 (3H, m, phenyl);
5.40 (1H, s, CH)
3060 (CH aromatic), 2960,
2920 (CH alkyl), 2260 (C≡N)
6.90 (3H, m, pyrazine); 5.95 (4H, m, phenyl);
4.25 (1H, s, CH); 3.10 (3H, s, CH3)
3080 (CH aromatic), 2960,
2920 (CH alkyl), 2260 (C≡N),
1600, 1530, 1470 (phenyl ring)
8.50 (3H, m, pyrazine); 6.95 (3H, m, phenyl);
5.25 (1H, s, CH); 3.85 (6H, s, 2CH3)
27
28
29
30
31
3080 (CH aromatic), 2960,
2930 (CH alkyl), 2280 (C≡N),
1600, 1580, 1480 (phenyl ring)
8.60 (3H, m, pyrazine);
7.60 (7H, m, nahthalene); 3.90 (1H, s, CH)
3080 (CH aromatic), 2960,
2920 (CH alkyl), 2220 (C≡N),
1600, 1540, 1460 (phenyl ring)
8.30 (3H, m, pyrazine); 7.50 (4H, m, pyridine);
5.30 (1H, s, CH)
3030 (CH aromatic), 2980,
2960 (CH alkyl), 2260 (C≡N),
1600, 1550, 1490 (phenyl ring)
6.70 (1H, s, pyrazine); 5.90 (3H, m, phenyl);
4.30 (1H, s, CH); 2.10 (6H, m, 2CH3)
3030 (CH aromatic), 2980,
2940 (CH alkyl), 2220 (C≡N),
1620, 1580, 1530 (phenyl ring)
6.60 (1H, s, pyrazine); 5.85 (3H, m, phenyl);
4.90 (1H, s, CH); 2.10 (6H, m, 2CH3)
3060 (CH aromatic), 2930,
2830 (CH alkyl), 2250 (C≡N),
1595, 1560, 1480 (phenyl ring)
6.90 (4H, m, 1H pyrazine and 3H phenyl);
5.40 (1H, s, CH); 3.90 (6H, s, 2CH3);
2.60 (6H, s, 2CH3)
_______
* Compounds 1-9, 11-13, 15, 18-27, 29-31 in CDCl3, compounds 10, 14, 16,
28 – in DMSO-d6.
Scheme 2
R1
50% NaOH
+
R
Cl
R1CH2CN
R
CH
CN
DMSO
1–31
The foregoing syntheses gave 31 new compounds: 2-cyanomethylpyridazine derivatives 1-7,
2-cyanomethylpyrimidine derivatives 8-19, and 2-cyanomethylpyrazine derivatives 20-31. Their structures were
1
established by the analyses of IR and H NMR spectra. Spectral data, physical properties of the compounds
obtained, and reactions yields are given in Table 1.
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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 Varian Gemini 200 apparatus at
(200 MHz) with TMS as an internal standard.
Reactions of Chlorodiazines with Arylacetonitriles 1-31 (General Method). To
4-chlorophenylacetonitrile (1.5 g, 10 mmol) in DMSO (2.5 ml) 2-chloropyrazine (1.1 g, 10 mmol) and 50%
aqueous NaOH (1.5 ml) were added. The whole was heated at 70°C for 3 h with vigorous stirring. On cooling
the reaction mixture was treated with water (30 ml) and acidified with concentrated HCl to pH 3. The resulted
precipitate was crystallized from 50% aqueous ethanol. Compound 21 was obtained (1.1 g, yield 48%;
mp 103-107°C).
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1.
2.
3.
4.
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Y. Ishiguro, K. Funakoshi, S. Saehi, and M. Hamana, Heterocycles, 14, 179 (1980).
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K. Wisterowicz, H. Foks, H. Strzalkowska-Grad, E. Hac, M. Janowiec, and Z. Zwolska-Kwiek, Acta
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N. D. Pomove, J. Med. Chem., 11, 431 (1968).
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H. M. Deutsch, Q. Shi, E. Gruszecka-Kowalik, and M. M. Schweri, J. Med. Chem., 39, 1201 (1996).
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