Regarding the intramolecular cyclization of ethyl (e)- 2-cyano-3-(s- methylisothioureido)-2-propenoate

Full text of DOI:10.1007/s10593-010-0517-y

Chemistry of Heterocyclic Compounds, Vol. 46, No. 3, 2010
REGARDING THE INTRAMOLECULAR CYCLIZATION
OF ETHYL (E)- 2-CYANO-3-(S-METHYLISOTHIOUREIDO)-
2-PROPENOATE
V. Gefenas1*, Ž. Stankevičiūtė1,2, A. Malinauskas2, and S. Tumkevicius3
Keywords: ethyl 4-amino-2-methylsulfanyl-5-pyrimidine carboxylate, 5-cyano-2-methylsulfanyl-
4(3H)-pyrimidinone, ethyl (E)-2-cyano-3-(S-methylisothioureido)-2-propenoate, ethyl (E)-2-cyano-
3-ethoxy-2-propenoate, ethyl (E)- and (Z)-2-cyano-3-ureido-2-propenoates, intramolecular cyclization.
It is known that, depending on the substituent in the ureido fragment, the intramolecular cyclization of
esters of 2-cyano-3-(S-alkylisothioureido)-2-propenooic acid in basic catalysis conditions occurs by two routes to
form a mixture of the corresponding 2-alkylsulfanyl-5-cyano-4(3H)-pyrimidinone salts and ethyl 2-alkylsulfanyl-
4-amino-5-pyrimidine carboxylates [1-4]. At the same time, from our data, the cyclization reaction of 3-(S-alkyl-
isothioureido)-2-cyano-2-propenoates in acid conditions has hardly been studied.
We have found that, in contrast to the 3-benzamidino derivative [4], refluxing ethyl (E)-2-cyano-3-(S-
methylisothioureido)- 2-propenoate (2) in glacial acetic acid shows a selective formation of just the ethyl 4-amino-
2-methylsulfanyl-5-pyrimidine carboxylate (3). The interest in the synthetic method for the latter is due to its
potential use as
a
precursor of the antibiotic bacimethrin and the thiamine antimetabolites
5-hydroxymethyluracil, metioprim, and toxopyrimidine [1, 3, 5-7]. Reaction of compound 2 in aqueous alkaline
medium gives a complex mixture of cyclization and hydrolysis products, i.e. 5-cyano-2-methylsulfanyl-4(3H)-
pyrimidinone (4, the main product) and as minor products the 4-amino derivative 3 and the (E)- and (Z)-isomers
of ethyl 2-cyano-3-ureido-2-propenoate 5a,b. Compounds 4, 5 are of interest as precursors in the synthesis of
biologically active pyrimidines [8-12].
1
Elemental analysis, IR, and H and 13C NMR spectra are fully in agreement with the structure of the
cyclization and hydrolysis products. Compound 1, existing as the individual thermodynamically more stable
(E)-isomer [13], undergoes a vinyl nucleophilic substitution (SNVin) with S-methylisothiuronium sulfate to give
the 3-(S-methylisothioureido) derivative 2 with retention of configuration [14]. The 1H NMR spectra
(DMSO-d6) of the (E)-isomers 1, 2, 5a show characteristic signals for the H-3 protons at 8.42, 8.51, and 8.41
ppm respectively (8.45 ppm [10]). An analogous signal for the H-3 proton in the (Z)-isomer 5b separated by us
is seen at higher field at 8.11 ppm (8.15 ppm [10]). Additional important information in identifying the isomer
pair 5a,b comes from the position of the signals and the spin-spin coupling for the NH proton doublets. For the
_______
* To whom correspondence should be addressed, e-mail: vladasg@vpu.lt.
1Faculty of Natural Sciences, Vilnius Pedagogical University, Vilnius LT-08106, Lithuania.
2Chemistry Institute, Vilnius LT-01108, Lithuania.
3 Faculty of Chemistry, Vilnius University, Vilnius LT-03225, Lithuania.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 456-459, March, 2010. Original
article submitted January 25, 2010.
0009-3122/10/4603-0363©2010 Springer Science+Business Media, Inc.
363

(E)-isomer 5a NH is seen at 10.34 ppm with J = 13.2 Hz (10.35 ppm, J = 13 Hz [10]) whereas for the (Z)-isomer
5b (which forms an intramolecular hydrogen bond) it is seen at 10.58 ppm with = 12.6 ppm (10.60 ppm,
J = 13 Hz [10]).
IR spectra (KBr) were taken on a Perkin-Elmer BX II FT-IR Fourier spectrophotometer and 1H and 13C
NMR spectra on a Varian INOVA spectrometer (300 and 75 MHz) respectively using DMSO-d6 and with the
1
residual DMSO signals (2.52 and 40.21 ppm for H and 13C respectively) used as the internal standard.
Monitoring of the course of the reaction and the purity of the compounds obtained was carried out by TLC on
silica gel 60 F254 glass plates (Sigma-Aldrich) and revealed using UV light.
EtO
H
CN
CO2Et
1
NH2C(O)HN
H
CN
2. MeCO2H
SMe
CO2Et
+
HN
KOH / MeOH,
0–5°C
2–
0–2°C
(A)
SO4
2
C
NH2
5a (18%)
CN
O
N
H2NC(SMe)=N
H
CN
CO2Et
1. 0.5 M NaOH
3
+
(6%) A
(8%) B
MeS
N
H
4
(64%)
2
(53%) A, (54%) B
MeCO2H,

H
CN
2. HCl
NH2
0–2°C
(B)
NH2C(O)HN
CO2Et
CO2Et
N
5b (4%)
MeS
N
3 (71%)
The starting ethyl (E)-2-cyano-3-ethoxy- and (E)-2-cyano-3-(S-methylisothioureido)- 2-propenoates (1,
2) were prepared by methods [15] and [2] respectively.
Ethyl (E)-2-cyano-3-ethoxy-2-propenoate (1). Yield 57%; mp 51-53ºC (hexane) (mp 51ºC, bp
128-132ºC (2 mm Hg) [15]), Rf 0.79 (CHCl3–ethyl acetate, 4: 1). IR spectrum, , cm-1: 2228 (CN), 1712 (CO).
1H NMR spectrum, , ppm (J, Hz): 1.25 (3H, t, J = 7.2, COOCH2CH3); 1.33 (3H, t, J = 7.2, =C–OCH2CH3);
4.21 (2H, q, J = 7.2, COOCH2CH3); 4.48 (2H, q, J = 7.2, =COCH2CH3); 8.42 (1H, s, H-3). 13C NMR spectrum,
, ppm: 14.80, 15.75, 61.77, 74.52, 84.98, 114.07, 163.32, 175.92.
Ethyl (E)-2-cyano-3-(S-methylisothioureido)- 2-propenoate (2). Yield 64%; mp 127-128ºC (128-129ºC
[2]), Rf 0.10 (CHCl3–ethyl acetate, 4:1). IR spectrum, , cm-1: 3440 (NH2), 2209 (CN), 1703 (CO), 1661 (C=N).
1H NMR spectrum, , ppm (J, Hz): 1.23 (3H, t, J = 7.2, CH3); 2.54 (3H, s, SCH3); 4.16 (2H, q, J = 7.2, CH2);
13
8.51 (1H, s, H-3); 8.75 (1H, br. s, NH); 9.16 (1H, br. s, NH). C NMR spectrum, , ppm: 14.57, 15.01, 60.90,
86.00, 117.39, 162.23, 165.57, 174.85.
Cyclization in Glacial Acetic Acid. A solution of compound 2 (1.0 g, 4.7 mmol) in glacial acetic acid
(5 ml) was refluxed for 1 h. The reaction mixture was cooled to room temperature, poured into iced water (20 ml),
and the precipitate formed was filtered off, washed with water (2×10 ml), and recrystallized to give compound 3
(0.71 g, 71%) with mp 130-132ºC (ethanol) (mp 130-131ºC [1]), Rf 0.71 (CHCl3–ethyl acetate, 4:1). IR spectrum,
364

, cm-1: 3415, 3270, 3136 (NH2), 1692 (CO). 1H NMR spectrum, , ppm (J, Hz): 1.31 (3H, t, J = 7.2, CH3); 2.48
(3H, s, SCH3); 4.29 (2H, q, J = 7.2, CH2); 7.67 (1H, br. s, NH); 8.04 (1H, br. s, NH); 8.59 (1H, s, H-6).
13C NMR spectrum, , ppm: 14.13, 14.78, 61.29, 101.12, 159.18, 162.05, 166.34, 175.50.
Cyclization in aqueous alkaline medium. A. Compound 2 (1.0 g, 4.7 mmol) was added to an aqueous
solution of NaOH (0.5 M, 10 ml) and stirred at room temperature for 1 h. The reaction mixture was then cooled
to 10ºC, the insoluble precipitate filtered off and washed with water (2×30 ml) to give compound 3 (0.04 g, 6%);
mp 129-131ºC, Rf 0.71 (CHCl3–ethyl acetate, 4:1). The filtrate cooled to 0-2ºC was acidified with glacial acetic
acid to pH 2-3 and the precipitate formed was filtered off and recrystallized from 2-propanol to give the
pyrimidinone 4 (0.29 g, 53%); mp 220-224ºC (mp 220-222ºC [2]) and Rf 0.16 (CHCl3–ethyl acetate, 4:1). IR
1
spectrum, , cm-1: 2229 (CN), 1666 (CO). H NMR spectrum, , ppm (J, Hz): 2.56 (3H, s, SCH3); 8.53 (1H, s,
H-6); 13.80 (1H, br. s, NH). 13C NMR spectrum, , ppm: 14.00, 97.46, 115.81, 160.37, 160.80, 169.19. The
filtrate was held for 96 h at 0ºC and the precipitate formed was filtered off to give the (E)-isomer 5a (0.11 g,
18%); mp 198-203ºC (2-propanol), Rf 0.08 (CHCl3–ethyl acetate, 4:1). IR spectrum, , cm-1: 3432, 3338, 3256,
3183 (NH2), 2222 (CN), 1740 (sh, CO ester), 1699 (CO amide). 1H NMR spectrum, , ppm (J, Hz): 1.24 (3H, t,
J = 7.2, CH3); 4.20 (2H, q, J = 7.2, CH2); 6.67 (1H, br. s, NH); 7.47 (1H, br. s, NH), 8.41 (1H, d, J = 13.2, H-3);
13
10.34 (1H, d, J = 13.2, NH). C NMR spectrum, , ppm: 14.85, 61.67, 79.12, 115.48, 151.80, 152.84, 164.08.
Found, %: C 46.04; H 4.97. C7H9N3O3. Calculated, %: C 45.90; H 4.95.
B. Compound 2 (21.3 g, 100 mmol) was added to an aqueous solution of NaOH (0.5 M, 213 ml) and
stirred for 10 min at 50ºC. The reaction mixture was cooled to 15ºC and the insoluble precipitate was filtered off
and washed with water (2×30 ml) to give compound 3 (1.66 g, 8%); mp 130-132ºC, Rf 0.71 (CHCl3–ethyl
acetate, 4:1). The filtrate cooled to 0-2ºC was acidified with 1M HCl to pH 2 and the precipitate formed was
filtered off and washed with water (2×30 ml) to give the pyrimidinone 4 (9.14 g, 54%); mp 222-224ºC
(2-propanol). The filtrate was held for 12 h at 0ºC and the insoluble precipitate was filtered off to give the
(Z)-isomer 5b (0.9 g, 4%); mp 213-216ºC (2-propanol), Rf 0.18 (CHCl3–ethyl acetate, 4:1). IR spectrum, , cm-1:
1
3366, 3312, 3236, 3196 (NH2), 2233 (CN), 1755 (CO ester), 1687 (CO amide). H NMR spectrum, , ppm (J,
Hz): 1.28 (3H, t, J = 7.2, CH3); 4.25 (2H, q, J = 7.2, CH2); 7.40 (1H, br. s, NH); 7.63 (1H, br. s, NH); 8.11 (1H,
d, J = 12.6, H-3); 10.58 (1H, d, J = 12.6, NH). 13C NMR Spectrum, , ppm: 14.78, 61.71, 78.24, 117.83, 152.46,
152.58, 165.44. Found, %: C 46.10; H 4.80. C7H9N3O3. Calculated, %: C 45.90; H 4.95.
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