N(1)-, N(3)-, and O-alkylation of 5-cyano- 2-methylsulfanyl-4(3h)- pyrimidinone by 4-substituted ω-Bromoacetophenones in the system acetonitrile-K2CO3

Full text of DOI:10.1007/s10593-010-0444-y

Chemistry of Heterocyclic Compounds, Vol. 45, No. 11, 2009
N(1)-, N(3)-, AND O-ALKYLATION OF 5-CYANO-
2-METHYLSULFANYL-4(3H)-PYRIMIDINONE BY
4-SUBSTITUTED ω-BROMOACETOPHENONES
IN THE SYSTEM ACETONITRILE-K2CO3
V. Gefenas1*, Z. Stankeviciute1,2, and A. Malinauskas2
Keywords: ω-Bromoacetophenones, potassium carbonate, 5-cyano-2-methylsulfanyl-4(3H)-pyrimidi-
none, N(1)-, N(3)-, and O-alkylation, acetonitrile.
Alkylation of 4(3H)-pyrimidinones occurs to give a mixture of N(1)-, N(3)-, and O-alkylation products [1].
Analysis of literature data shows that alkylation with haloacetic esters, chloroacetonitrile, N-benzyl-
haloacylamides, 3-bromopropan-1-ol, or ω-bromoacetophenone generally gives just the O- and N(3)-alkylation
products. According to our results N(1)-alkylation products have hardly been studied and only discovered and
separated with the use of haloalkanes and benzyl halides as alkylating agent [1-4].
R
O
O
NC
N
3a,b
N
O
SMe
R
R
R
Br
O
NC
N
N
O
NC
2a,b
O
SMe
NH
N
N
MeCN / K2CO3 [KI]
SMe
N
4a,b
1
NC
O
O
SMe
2–5 a R = OMe, b R = Cl
5a,b
_______
* To whom correspondence should be addressed, e-mail: vladasg@vpu.lt.
1Faculty of Natural Sciences, Vilnius Pedagogical University, Vilnius LT-08106, Lithuania.
2Institute of Chemistry, Vilnius LT-01108, Lithuania.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp. 1754-1756, November, 2009.
Original article submitted October 12, 2009.
0009-3122/09/4511-1413©2009 Springer Science+Business Media, Inc.
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We have found that treatment of 5-cyano-2-methylsulfanyl-4(3H)-pyrimidinone (1) with the
4-substituted ω-bromoacetophenones 2a,b in the presence of potassium carbonate and a catalytic amount of
potassium iodide in anhydrous acetonitrile medium readily gives all three O-, N(3)-, and N(1)-alkylation
products 3a-b to 5a-b. According to 1H NMR spectroscopic data for the reaction mixtures side products are not
formed under these conditions.
The main reaction product is the O-alkylated isomer 3a,b with the N(3)- and N(1)-alkylation products
4a,b and 5a,b respectively separated as minor components by fractional crystallization or by column
chromatography. (the overall alkylation yield being 70-74%). Elemental analysis, IR , 1H and 13C NMR spectra
for the compounds prepared were fully in agreement with their structures as alkylated derivatives of the
5-cyano-2-methylsulfanyl-4(3H)-pyrimidinone.
IR spectra were taken on a Perkin-Elmer BX II FT-IR spectrophotometer for KBr tablets and 1H and 13C
NMR spectra on a Varian INOVA spectrometer (300 and 75 MHz respectively) using DMSO-d6 and with TMS
as internal standard. Monitoring of the reaction course and the purity of the compounds prepared was carried out
by TLC on Sigma-Aldrich Silica Gel 60 F254 glass plates using the system chloroform-ethyl acetate (4: 1) and
were revealed using UV light.
Starting 5-Cyano-2-methylsulfanyl-4(3H)-pyrimidinone (1) was prepared by method [5].
Compounds 3a,b-5a,b (General Method). A mixture of compound 1 (2 g, 12.0 mmol) and anhydrous
K2CO3 (0.84 g, 6.0 mmol) was refluxed with stirring in anhydrous MeCN (30 ml) for 1 h. Potassium iodide
(0.2 g, 1.2 mmol) was then added to the refluxing reaction mixture followed by dropwise addition over 1 h of a
solution of the ω-bromoacetophenone 2a,b (2.38 g, 12.0 mmol) in anhydrous acetonitrile (30 ml) and further
refluxing for 2 h. The hot reaction mixture was filtered, the inorganic residue was washed with refluxing
acetonitrile, and the filtrate obtained crystallized successfully at -15 and 0ºC. The filtrate was evaporated to a
dry residue which was treated successively with benzene and acetonitrile. The obtained fractions were
recrystallized or separated by column chromatography (Silica Gel S, chloroform-ethyl acetate, 4:1).
4-(4'-Methoxyphenacyloxy)-2-methylsulfanylpyrimidine-5-carbonitrile (3a). Yield 50%; mp
140-142ºC (benzene), Rf 0.74. IR spectrum, ν, cm-1: 1686 (ketone C=O), 2226 (CN). 1H NMR spectrum, δ, ppm
(J, Hz): 2.31 (3H, s, SCH3); 3.89 (3H, s, OCH3); 5.99 (2H, s, OCH2); 7.12 (2H, d, J = 9.0, H-3',5'); 8.01 (2H, d,
J = 9.0, H-2',6'); 8.93 (1H, s, H-6). 13C NMR spectrum, δ, ppm: 14.41 (SCH3); 56.38 (OCH3); 70.00 (OCH2);
90.91 (C-5); 114.56 (CN); 114.98 (C-3',5'); 127.24 (C-1'); 130.92 (C-2',6'); 162.84 (C-6); 164.56 (C-4'); 167.57
(C-4); 176.50 (C-2); 191.26 (CO). Found, %: C 57.15; H 4.23; N 13.61. C15H13N3O3S. Calculated, %: C 57.13;
H 4.15; N 13.32.
3-(4'-Methoxyphenacyl)-2-methylsulfanyl-4-oxo-3,4-dihydropyrimidine-5-carbonitrile (4a). Yield
3%, mp 183-185ºC (from 2-propanol); Rf 0.54. IR Spectrum, ν, cm-1: 1680 (lactam and ketone C=O), 2232
1
(CN). H NMR Spectrum, δ, ppm (J, Hz): 2.63 (3H, s, SCH3); 3.90 (3H, s, OCH3); 5.66 (2H, s, NCH2); 7.15
(2H, d, J = 9.0, H-3',5'); 8.11 (2H, d, J = 9.0, H-2',6'); 8.67 (1H, s, H-6). 13C NMR Spectrum, δ, ppm: 16.00
(SCH3); 51.45 (NCH2); 56.47 (OCH3); 96.60 (C-5); 115.08 (C-3',5'); 115.40 (CN); 127.44 (C-1'); 131.50
(C-2',6'); 158.91 (C-6); 160.38 (C-2); 164.97 (C-4'); 170.72 (C-4); 189.28 (CO). Found, %: C 57.29; H 4.23;
N 13.26. C15H13N3O3S. Calculated, %: C 57.13; H 4.15; N 13.32.
1-(4'-Methoxyphenacyl)-2-methylsulfanyl-4-oxo-1,4-dihydropyrimidine-5-carbonitrile (5a). Yield
11%; mp 242-245ºC (acetonitrile); Rf 0.23. IR spectrum, ν, cm-1: 1651 (C=O ring), 1684 (C=O ketone), 2225
(CN). 1H NMR spectrum, δ, ppm (J, Hz): 2.50 (3H, s, SCH3); 3.91 (3H, s, OCH3); 5.68 (2H, s, NCH2); 7.16 (2H,
d, J = 9.0, H-3',5'); 8.08 (2H, d, J = 9.0, H-2',6'); 8.61 (1H, s, H-6). 13C NMR spectrum, δ, ppm: 15.09 (SCH3);
56.51 (OCH3); 58.89 (NCH2); 94.93 (C-5); 115.14 (C-3',5'); 115.40 (CN); 127.08 (C-1'); 131.45 (C-2',6');
154.81 (C-2); 163.12 (C-4); 165.06 (C-4'); 166.65 (C-6); 190.09 (CO). Found, %: C 57.42; H 4.31; N 13.10.
C15H13N3O3S. Calculated, %: C 57.13; H 4.15; N 13.32
4-(4'-Chlorophenacyloxy)-2-methylsulfanylpyrimidine-5-carbonitrile (3b). Yield 37%; mp 173-175ºC
1
(benzene); Rf 0.81. IR spectrum, ν, cm-1: 1699 (C=O ketone), 2229 (CN). H NMR spectrum, δ, ppm (J, Hz):
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2.33 (3H, s, SCH3); 6.04 (2Н, s, OCH2); 7.69 (2H, d, J = 8.7, H-3',5'); 8.05 (2H, d, J = 8.7, H-2',6'); 8.95 (1H, s,
H-6). 13C NMR spectrum, δ, ppm: 14.42 (SCH3); 70.19 (OCH2); 90.94 (C-5); 114.48 (CN); 129.92 (C-3',5'); 130.51
(C-2',6'); 133.11 (C-1'); 139.84 (C-4'); 162.91 (C-6); 167.43 (C-4); 176.53 (C-2); 192.28 (CO). Found, %: C 52.61;
H 3.23; N 13.21. C14H10ClN3O2S. Calculated, %: C 52.59; H 3.15; N 13.14.
3-(4'-Chlorophenacyl)-2-methylsulfanyl-4-oxo--3,4-dihydropyrimidine-5-carbonitrile (4b). Yield
1.6%; mp 186-188ºC (2-propanol); Rf 0.61. IR spectrum, ν, cm-1: 1683 (C=O lactam), 1690 (C=O ketone), 2224
(CN). 1H NMR spectrum, δ, ppm (J, Hz): 2.64 (3H, s, SCH3); 5.73 (2H, s, NCH2); 7.72 (2H, d, J = 9.0, H-3',5');
8.16 (2H, d, J = 8.7, H-2',6'); 8.68 (1H, s, H-6). 13C NMR spectrum, δ, ppm: 16.03 (SCH3); 51.79 (NCH2); 96.66
(C-5); 115.30 (CN); 129.98 (C-3',5'); 131.01 (C-2',6'); 133.23 (C-1'); 140.40 (C-4'); 158.84 (C-6); 160.45 (C-2);
170.65 (C-4); 190.56 (CO). Found, %: C 52.72; H 3.20; N 13.28. C14H10ClN3O2S. Calculated, %: C 52.59;
H 3.15; N 13.14.
1-(4'-Chlorophenacyl)-2-methylsulfanyl-4-oxo--1,4-dihydropyrimidin-5-carbonitrile (5b). Yield
12%; mp 244-247ºC (acetonitrile); Rf 0.23. IR spectrum, ν, cm-1: 1651 (C=O ring), 1689 (C=O ketone), 2227
(CN). 1H NMR spectrum, δ, ppm (J, Hz): 2.51 (3H, s, SCH3); 5.76 (2H, s, NCH2); 7.74 (2H, d, J = 8.4, H-3',5');
8.12 (2H, d, J = 8.7, H-2',6'); 8.59 (1H, s, H-6). 13C NMR spectrum, δ, ppm: 15.12 (SCH3); 59.19 (NCH2); 95.02
(C-5); 115.34 (CN); 130.06 (C-3',5'); 130.92 (C-2',6'); 132.91 (C-1'); 140.48 (C-4'); 154.73 (C-2); 163.04 (C-4);
166.65 (C-6); 191.22 (CO). Found, %: C 52.19; H 3.58; N 13.00. C14H10ClN3O2S . Calculated, %: C 52.59;
H 3.15; N 13.14.
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