Effect of the amount of sodium ethoxide on the direction of cyclization in reactions of amidines with ethoxymethylene acetoacetate

Full text of DOI:10.1007/s10593-005-0140-5

Chemistry of Heterocyclic Compounds, Vol. 41, No. 2, 2005
EFFECT OF THE AMOUNT OF SODIUM
ETHOXIDE ON THE DIRECTION OF CYCLIZATION
IN REACTIONS OF AMIDINES WITH
ETHOXYMETHYLENE ACETOACETATE
G. G. Danagulyan, A. D. Mkrtchyan, and L. G. Sahakyan
Keywords: 5-acetyl-4-hydroxypyrimidines, potassium hydroxide, 5-ethoxycarbonylpyrimidines, sodium
ethoxide, recyclization.
Recyclization of pyrimidines occurring with substitution of the endocyclic carbon atom C(4) by a non-
ring carbon atom of the 5-ethoxycarbonyl group was reported earlier in [1, 2]. Such a rearrangement was
classified as C–C recyclization of pyrimidines, in contrast to N–N recyclization (the Dimroth rearrangement) [3]
and N–C recyclization (the Kost–Sagitullin rearrangement) [4].
In studying the condensation of hydrochlorides of acetamidine (1a) and phenylacetamidine (1b) with
ethoxymethylene acetoacetate in the presence of sodium ethoxide, we noted that the amount of sodium ethoxide
has a considerable effect on the direction of heterocyclization. We found that for an equimolar ratio of the
amidines, ethoxymethylene acetoacetate, and sodium ethoxide, we obtain 5-ethoxycarbonyl-2-methyl(2-benzyl)-
4-methyl-pyrimidines 2a,b in high yield; while for a two-fold excess of sodium ethoxide relative to the amounts
of the reagents used, 5-acetyl-4-hydroxy-2-methyl(2-benzyl)pyrimidines 3a,b are formed.
We hypothesize that in the case of an excess of sodium ethoxide, as for an equimolar ratio of the
reagents, the reaction initially occurs with formation of compounds 2. However, during treatment, the base
formed in the presence of water (for excess sodium ethoxide) leads to recyclization of compounds 2 to form
pyrimidines 3.
Me
COOEt
N
1:1:1
R
N
2a,b
KOH
COOEt
CHOEt
NH
EtONa
.
.
HCl
Me
R
+
OH
NH2
O
COMe
1a,b
1:2:1
N
R
N
1–3 a R = Me, b R = Bn
3a,b
__________________________________________________________________________________________
Institute of Organic Chemistry, National Academy of Sciences of the Republic of Armenia, Yerevan
375091, Republic of Armenia; e-mail: gdanag@email.com. Translated from Khimiya Geterotsiklicheskikh
Soedinenii, No. 2, pp. 294-296, February, 2005. Original article submitted June 10, 2004.
262
0009-3122/05/4102-0262©2005 Springer Science+Business Media, Inc.

Our experiments showed that in fact, when 5-ethoxycarbonyl derivatives 2 react with KOH in alcohol, 5-
acetylpyrimidines 3a,b are rapidly (within 5-10 min) formed in high yield. By chromatographic monitoring of
the reaction mixture, we also found that in a toluene–alcohol solution of sodium ethoxide, compounds 2 are
practically unconverted to pyrimidines 3. However, adding water, i.e. forming OH– ions in solution, leads to
such a transformation. This supports our hypothesis concerning the role of water (more precisely, hydroxide
ions) in this rearrangement [2].
As in the previously described examples of the rearrangement under consideration, we did not observe
formation of the isomeric pyrimidines 3a,b of 2-substituted 5-formyl-4-hydroxy-6-methylpyrimidines either
during synthesis of compounds 2 and 3 or in recyclization of compounds 2.
OEt
O
Me
EtO
NH
Me
OEt
O
EtONa
NH
2a,b
OEt
R
N
R
N
H2O
O
OEt
O
N
Me
O
Me
OH
NH
N
3a,b
–
H
– EtO
R
N
R
2-Benzyl-5-ethoxycarbonyl-4-methylpyrimidine (2b). Phenylacetamidine hydrochloride (3.4 g,
0.02 mol) was added to a sodium ethoxide solution prepared from sodium (0.46 g, 0.02 mol) in ethanol (30 ml).
This was stirred for 30 min at ~20°C. The NaCl precipitate was filtered out and ethyl ethoxymethylene
acetoacetate (3.7 g, 0.025 mol) was added to the filtrate, which was then boiled for 6 h. The alcohol was distilled
off and the residue was extracted with hexane. The combined extracts were chromatographed on a column with
1
silica gel. Obtained 3.7 g (72%) pyrimidine 2b, an oil, Rf 0.51 (benzene–acetone, 8:1). H NMR spectrum of
compound 2b (CDCl3, 300 MHz), δ, ppm (J, Hz): 1.4 (3H, t, J = 7.1, CH3CH2O); 2.81 (3H, s, 4-CH3); 4.29 (2H,
13
s, CH2); 4.38 (2H, q, J = 7.1, OCH2); 7.19-7.40 (5H, m, Ph); 9.07 (1H, s, H-6). C NMR spectrum (CDCl3, 75
MHz), δ, ppm: 14.30 (CH3); 24.50 (4-CH3); 46.06 (CH2); 61.55 (OCH2); 121.17 (C(5)); 126.78 (p-Ph); 128.63 (o-
Ph); 129.31 (m-Ph); 137.82 (ipso-Ph); 159.22 (C(6)); 165.09 (C(4)); 169.03 (C(2)); 171.65 (CO). Found, %: N
10.58. C15H16N2O2. Calculated, %: N 10.93.
Rearrangement of 2-Substituted 5-Ethoxycarbonyl-4-methylpyrimidines 2a,b to form
2-Substituted 5-Acetyl-4-hydroxypyrimidines 3a,b when Treated with Alkali. Potassium hydroxide (0.5 g,
9 mmol) and pyrimidine 2a or 2b (3 mmol) were dissolved in ethanol (10 ml) and then stirred at 20-25°C. After
10 min, the precipitated crystals of the hydroxypyrimidine salt were filtered out, dissolved in water, and
neutralized with a 10% hydrochloric acid solution. The precipitate was filtered out and recrystallized from
aqueous alcohol. Obtained 0.35 g (76%) white crystals of 5-acetyl-4-hydroxy-2-methylpyrimidine 3a;
mp 146-148°C, Rf 0.55 (alcohol). After neutralization with hydrochloric acid (during isolation of compound 3b),
it was extracted with benzene. Then the solvent was distilled off. Obtained 0.5 g (73%) of 5-acetyl-2-benzyl-4-
1
hydroxypyrimidine 3b; mp 160-161°C, Rf 0.59 (benzene–acetone, 4:1). H NMR spectrum of compound 3a
(DMSO-d6, 300 MHz), δ, ppm: 2.53 (3H, s, 2-CH3); 2.65 (3H, s, COCH3); 8.88 (1H, s, H-6). 13C NMR spectrum
(DMSO-d6, 75 MHz), δ, ppm: 23.68 (CH3); 25.36 (2-CH3); 120.77 (5-C); 158.34 (C(6)); 165.88 (C(4)); 167.49
(C(2)); 168.80 (CO). Found, %: N 18.28. C7H8N2O2. Calculated, %: N 18.41.
263

1H NMR spectrum of compound 3b (CDCl3, 300 MHz), δ, ppm: 2.95 (3H, s, CH3); 4.46 (2H, s, CH2);
7.13-7.43 (5H, m, Ph); 9.16 (1H, s, H-6); 12.25 (1H, br. s, OH). 13C NMR spectrum (DMSO-d6, 75 MHz),
δ, ppm: 24.69 (CH3); 45.79 (CH2); 120.52 (C(5)); 127.04 (p-Ph); 128.79 (o-Ph); 129.40 (m-Ph); 137.38 (ipso-Ph);
159.85 (C(6)); 168.69 (C(4)); 170.37 (C(2)); 172.05 (CO). Mass spectrum (electron impact, 70 eV), m/z (Irel, %):
228 [M]+ (78), 227 [M–H]+ (100), 226 [M–H-1]+ (11), 213 [M–CH3]+ (4), 185 [M–COCH3]+ (5), 91 [C6H5CH2]
(20). Found, %: N 12.48. C13H12N2O2. Calculated, %: N 12.27.
This research was performed within scientific topic 0471 of the Ministry of Science and Education of the
Republic of Armenia, and also with the financial support of the National Foundation for Science and
Transitional Technologies of Armenia and the US Civilian Research and Development Fund (NFSAT RA-US
CRDF, grant No. CH 090-02/12040).
REFERENCES
1.
2.
3.
4.
R. S. Vartanyan, Zh. V. Kazaryan, and S. A. Vartanyan, Khim. Geterotsikl. Soedin., 1558 (1982).
G. G. Danagulyan and A. D. Mkrtchyan, Khim. Geterotsikl. Soedin., 1735 (2003).
D. J. Brown, Mechanisms of Molecular Migrations, Wiley, New York (1968), 1, p. 209.
G. G. Danagulyan, L. G. Sahakyan, A. R. Katritzky, and S. N. Denisenko, Heterocycles, 53, 419 (2000).
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