Reactions of 6-benzyl-5-methyl-2-(methylsulfanyl)pyrimidin-4(3H)-one with aliphatic and aliphatic-aromatic amines

Article abstract of DOI:10.1134/S1070428009050212

The rules were investigated of the regioselective synthesis of N ²-substituted derivatives of 2-amino-6-benzyl-5-methylpyrimidin-4(3H) -one from 6-benzyl-5-methyl-2-(methylsulfanyl) pyrimidin-4(3H)-one.

Full text of DOI:10.1134/S1070428009050212

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2009, Vol. 45, No. 5, pp. 773−776. © Pleiades Publishing, Ltd., 2009.
Original Russian Text © I.A. Novakov, B.S. Orlinson, A. Mai, M. Artico, D. Rotili, M.B. Navrotskii, E.A. Gordeeva, E.N. Savel'eva, 2009, published in
Zhurnal Organicheskoi Khimii, 2009, Vol. 45, No. 5, pp. 786−789.
Reactions
of 6-Benzyl-5-methyl-2-(methylsulfanyl)pyrimidin-4(3H)-one
with Aliphatic and Aliphatic-Aromatic Amines
I. A. Novakova, B. S. Orlinsona, A. Maib, M. Articob, D. Rotilib,
M. B. Navrotskiia, E. A. Gordeevaa, and E.N. Savel'eva
aVolgograd State Technical University, Volgograd, 400131 Russia
e-mail: phanchem@vstu.ru
bInstituto Pasteur-Fondazione Cenci Bolognetti, Dipartamento di Studi Farmaceutici,
Universita degli studi di Roma “La Sapienza”
Received May 6, 2008
Abstract—The rules were investigated of the regioselective synthesis of N2-substituted derivatives of 2-amino-
6-benzyl-5-methylpyrimidin-4(3H)-one from 6-benzyl-5-methyl-2-(methylsulfanyl) pyrimidin-4(3H)-one.
DOI: 10.1134/S1070428009050212
Derivatives of 5-alkyl-2-amino-6-(arylmethyl)-
pyrimidin-4(3H)-one alkylated at the exocyclic nitrogen
atom are promising antiviral agents of high activity with
respect to a wide range of AIDS-1 strains [1–3].
Therefore the developments of new approaches to the
synthesis of these compounds is a topical problem of
organic and bioorganic chemistry. We studied the reaction
of 6-benzyl-5-methyl-2-(methylsulfanyl)pyrimidin-4(3H)-
one (I) with a series of aliphatic and aliphatic-aromatic
DABO) [4] that is now one of the most active anti-AIDS-
1 agents.
O
Me
OMe
NH
N
S
Cl
Cl
amines:
methoxyphenyl)ethylamine
2-phenethylamine
(II),
(III),
2-(4-
2-(1-
The reaction between compound I and amines II–VI
was carried out under various conditions: without solvent,
in excess amine; in ethylene glycol with 5–20-fold excess
of amine; in cellosolve (2-ethoxyethanol) with 5–20-fold
excess of amine; in carbitol [2-(2-ethoxyethoxy)ethanol]
with 2–5-fold excess of amine; at heating from 135 to
200°C.
adamantyl)ethylamine (IV), 2-(1-adamantyl)propyl-2-
amine (V), (1-adamantyl)methylamine (VI).
O
O
RNH2
Me
Bn
Me
Bn
II_VI
NH
SMe
NH
NHR
_
MeSH
N
N
VII_XI
The reaction without solvent proceeded very slowly
with considerable tarring and giving a complex mixture
of products containing the initial compound alongside
a small amount of the target compounds and a number of
impurities. Although the reaction in ethylene glycol did
not lead to strong tarring, it still resulted in a complex
mixture of products with the prevalence of initial
compound I, the target aminolysis product, and 6-benzyl-
5-methylpyrimidine-2,4(1H,3H)-dione. In reaction in
I
R = PhCH2CH2 (II, VII), 4-MeOC6H4CH2CH2 (III, VIII),
1-AdCH2CH2 (IV, IX), 1-AdCH2CH(Me) (V, X), 1-AdCH2
(VI, XI).
The choice of amines for this reaction should ensure
the formation of derivatives which would be bioisosteric
analogs of 2-{[2-(4-methoxyphenyl)ethyl]sulfanyl}-5-
methyl-6-(2,6-dichlorobenzyl)pyrimidin-4(3H)-one (S-
773

NOVAKOV et al.
774
“addition-elimination” mechanism (Scheme 1) and the
mechanism of ipso-substitution (Scheme 2). In both cases
the reaction starts by the establishment of a dynamic
equilibrium.
cellosolve the composition of the reaction mixture (TLC
monitoring, eluent CHCl3– MeOH, 19:1) was practically
similar to the above, but the reaction time considerably
increased because of the temperature conditions
(cellosolve bp 135°C); at the same time somewhat
increased the selectivity of the process. In the general
case it should be stated that the reaction carried out above
160°C afforded a significant amount of side products.
The performance of the reaction below 150°C resulted
in a significant decrease in the aminolysis rate. It is also
important, that the formation of the side products during
the aminolysis is favored by amine excess over 5-fold.
Whereas the nonionized form of compound I exists
materially exclusively as a nonaromatic tautomer, the
anion of compound I is present as a mixture of aromatic
and nonaromatic tautomers.
In carbitol in a sealed ampoule in the presence of 2–
5-fold molar excess of amine at 150–160°C the reaction
occurred selectively leading to the formation virtually of
the target aminolysis products containing only trace
impurities. Moreover, the purity of isolated compounds
was without additional recrystallization no worse than
90%.
To get an understanding of this phenomenon we
considered two probable mechanisms of the reaction: The
The “addition-elimination” involves the nonaromatic
form, and the ipso-substitution occurs only with the
Scheme 1.
Scheme 2.
O_
N
O_
Me
Bn
Me
RNH2
SMe
N
NH
_
SMe
NH+2R
Bn
N
O_
N
O
N
OH
Me
Bn
Me
Bn
Me
Bn
NH
NHR
N
N
_
MeS
_
NH+2R
N
NHR
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 5 2009

REACTIONS OF 6-BENZYL-5-METHYL-2-(METHYLSULFANYL)PYRIMIDIN-4(3H)-ONE
775
6-Benzyl-5-methyl-2-[(2-phenylethyl)amino]-
pyrimidin-4(3H)-one (VII). Amixture of 2 g (8.12 mmol)
of reagent I, 5 ml (4.82 g, 39.78 mmol) of 2-phenethyl-
amine (II), and 20 ml of carbitol was heated for 50 h at
150–160°C in a sealed ampoule, cooled to room tempera-
ture, and evaporated in a vacuum. The residue was
dissolved in 150 ml of toluene and the solution was
washed with 250 ml of 10% aqueous citric acid. Then
the organic layer was washed with water and dried by
aseotropic distillation of water. The solvent was distilled
off in a vacuum, the residue was recrystallized from
acetonitrile. Yield after recrystallization 2.3 g (89%), mp
146–148°C (MeCN), Rf 0.21 (A), 0.16 (B). IR spectrum,
ν, cm–1: 3416, 3026, 2630 (NH), 1667 (C=O), 1609
(C6H5, C=N, NH), 1538 (NH), 1494 (C6H5, C=N),
1473 (CH2), 1322, 1454, 1392, 1375, 1240 (C6H5, CH2),
1178, 1101, 1027, 929 (C–O), 779 (NH), 758 (NH),
744 (NH), 696, 614, 591, 566 (NH). 1H NMR spectrum,
δ, ppm: 1.77 s (3H, CH3), 2.78 t (2H, CH2, J 7.33 Hz),
3.52 m (2H, CH2), 3.76 s (2H, CH2), 6.33 br.s (1H,
NH), 7.15 m (10H, 2C6H5), 11.55 br.s (1H, NH). Found,
%: C 75.61; H 6.23; N 13.56. M+ 319. C20H21N3O.
Calculated, %: C 75.21; H 6.63; N 13.16. M 319.40.
aromatic tautomer. The proceeding of the “addition-
elimination” is favored for the nonionized form. This is
due to the occurrence of the first reaction stage as
a nucleophilic attack by the amine on the electron-
deficient C2 atom of the pyrimidine ring, and the
nucleophilic attack on the same atom in the anionic form
of compound I is hampered (Scheme 1).
In the anionic form of compound I the sequence of
the transformations is retained.
We presume that the reason of the catalytic effect of
carbitol and of its ability to increase the regioselectivity
of this reaction is caused by the fact of carbitol being
a shortened analog of podandes (open-chain analogs of
crown ethers). Therefore it apparently is able to
coordinate with the small cationic sites of the molecule
thus stabilizing the transition state of the reaction.
All target compounds were obtained in nearly
quantitative yields. At the same time the yield of some
products was decreased by the high solubility and large
losses at the recrystallization.
The homogeneity of all compounds obtained was
confirmed by TLC, and their structure, by IR, NMR, and
mass spectra..
Likewise were obtained compounds VIII–XI.
Hence we investigated the aminolysis of 6-benzyl-5-
methyl-2-(methylsulfanyl)pyrimidin-4(3H)-one and
established that the preferred solvent for this reaction
was carbitol ensuring the high level of the reaction
regioselectivity. The hypothetic mechanism was assumed
to provide an understanding of this phenomenon.
6-Benzyl-5-methyl-2-{[2-(4-methoxyphenyl)-
ethyl]amino}pyrimidin-4(3H)-one (VIII). Yield 63%,
mp 156–157°C (MeCN), Rf 0.28 (A), 0.17 (B). IR
spectrum, ν, cm–1: 3418, 2687 (NH), 1670 (C=O), 1610
(C6H5, CN, NH), 1513 (CN, NH), 1494 (C6H5, CN),
1472, 1393, 1325, 1299, 1250 (CH2), 1174 (C–O), 1101,
1029, 918 (CH in 1,4-C6H4), 814 (CH in 1,4-C6H4), 761
1
EXPERIMENTAL
(NH), 778 (NH), 702, 609, 568, 522 (NH), . H NMR
spectrum, δ, ppm: 1.79 s (3H, CH3), 2.72 m (2H, CH2),
3.49 m (2H, CH2), 3.69 s (3H, CH3), 3.77 s (2H, CH2),
6.20 s (1H, NH), 6.73 d (2H, C6H4, J 8.79 Hz), 7.01 d
(2H, C6H4, J 8.79 Hz), 7.15 m (1H, C6H5), 7.21 m (4H,
C6H5), 11.56 s (1H, NH). Found, %: C 72.58; H 6.33; N
12.43. M+ 349. C21H23N3O2. Calculated, %: C 72.18;
H 6.63; N 12.03. M 349.43.
1H NMR spectra were registered on a spectrometer
Varian Mercury 300BB from solutions in CDCl3, internal
reference HMDS. IR spectra were recorded on a Fourier
IR spectrophotometer Nicolet-6700. Mass spectra were
obtained on an instrument Varian MAT 111, electron
impact 70 eV, the direct sample admission into the ion
source. The product homogeneity was checked and the
reactions progress was monitored by TLC on high-
efficiency plates Alugram NanoSil G/UV254 in the
systems chloroform–methanol, 19:1 (A), and petroleum
ether of bp 40–70°C –ethyl acetate– methanol, 12:3:1
(B). The melting points were measured on a Cole-Palmer
instrument and are reported with correction.
2-{[2-(1-Adamantyl)ethyl]amino}-6-benzyl-5-
methylpyrimidin-4(3H)-one (IX). Yield 69%. 182–
184°C (MeCN), Rf 0.30 (A), 0.24(Α). IR spectrum, ν,
cm–1: 3319, 2897, 2844 (NH), 1612, 1575 (C6H5, CN,
NH), 1495, 1451, 1395, 1328, 1302, 1236, 1093, 901
(C6H5, CN), 763 (NH), 701, 597, 567 (NH). 1H NMR
spectrum, δ, ppm: 1.23 q (J1,2 8.79 Hz, J2,3 7.32 Hz),
1.43 s, 1.59 q (15 H, 1-Ad, J1,2 11.72 Hz, J2,3 13.19 Hz),
1.87 br.s (2H, CH2), 1.90 s (3H, CH3), 3.29 m (2H, CH2),
3.77 s (2H, CH2), 5.92 s (1H, NH), 7.14 m (1H, C6H5),
6-Benzyl-5-methyl-2-(methylsulfanyl)pyrimidin-
4(3H)-one (I) was obtained by procedure [5]. Yield
84%, mp 205–206°C (MeCN) (mp 199–200°C [6]).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 5 2009

NOVAKOV et al.
776
spectrum, δ, ppm: 1.38 s, 1.56 q (J1,2 13.19, J2,3 17.33 Hz),
1.84 s (15H, 1-Ad), 1.88 s (3H, CH3), 3.01 d (2H, CH2,
J 6.00 Hz), 3.75 s (2H, CH2), 6.14 s (1H, NH), 7.12 m
(1H, C6H5), 7.20 m (4H, C6H5), 11.48 s (1H, NH). Found,
%: C 76.23; H 8.17; N 11.21. M+ 363. C23H29N3O.
Calculated, %: C 76.00; H 8.04; N 11.56. M 363.50.
7.21 m (4H, C6H5), 11.52 s (1H, NH). Found, %: C 76.00;
H 8.00; N 11.13. M+ 377. C24H31N3O. Calculated, %:
C 76.35; H 8.28; N 11.13. M 377.52.
2-{[1-(1-Adamantyl)prop-2-yl]amino}-6-benzyl-5-
methylpyrimidin-4(3H)-one (X). Yield 38%, mp 167–
168°C (petroleum ether bp 40–70°C). Rf 0.37 (A), 0.38
(B). IR spectrum, ν, cm–1: 3273, 2895 (NH), 2846 (CH2,
CH3), 1618 (C=O), 1569 (C=N, NH), 1493 (C=N,
C6H5), 1449, 1391(CH3), 1373, 1344, 1311, 1235, 1183,
1128, 1097, 1082, 1049, 1031, (CH3), 855, 783 (NH),
758, 750 (NH), 706, 694, 597, 569, 517, 491, 478,
468, 461, 456 (NH). 1H NMR spectrum, δ, ppm: 1.06 d
(3H, CH3, J 6.84 Hz), 1.12 d (J 3.42 Hz), 1.24 d.d
(J1,2 8.55 Hz, J2,3 5.13 Hz), 1.35 br.s, 1.40 s, 1.52 q
(J1,2 11.97 Hz, J2,3 17.10 Hz) (15H, 1-Ad), 1.80 br.s (3H,
CH3), 1.93 s (2H, CH2), 3.78 q (2H, CH2, J1,2 13.68 Hz,
J2,3 3.42 Hz), 4.23 m (1H, CH), 5.87 d (1H, NH,
J 8.55 Hz), 7.12 d (J 6.84 Hz), 7.16 s (1H, C6H5),
7.20 d (2H, C6H5, J 6.84 Hz), 7.25 d (2H, C6H5,
J 6.84 Hz), 11.23 s (NH). Found, %: C 76.29; H 8.89;
N 10.73. M+ 391. C25H33N3O. Calculated, %: C 76.69;
H 8.49; N 10.73. M 391.55.
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methylpyrimidin-4(3H)-one (XI). Yield 78%, mp 228–
229°C (MeCN). Rf 0.26 (A). IR spectrum, ν, cm–1: 3322,
2898 (NH), 2846 (CH2, CH3), 1638 (C=N, C=O), 1609
(C=N, NH, C6H5), 1493 (C=N, C6H5), 1451 (CH2),
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1
(CH3), 700, 595, 569, 517, 489, 453 (NH). H NMR
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 5 2009