The specific character of the reaction of derivatives of 2-thioxo-2,3-dihydropyrimidin-4(1H)-one with iodomethane and alkyl chloromethyl sulfides

Article abstract of DOI:10.1007/s10593-010-0492-3

The alkylation of 5-alkyl-6-(2,6-dihalobenzyl)-2-thioxo-2,3- dihydropyrimidin-4(1H)-ones with MeI, AllSCH₂Cl, and MeSCH ₂Cl in the K₂CO₃-DMF, NaOMe-MeOH, and KOH-EtOH systems was investigated. A hypothetical mec

Full text of DOI:10.1007/s10593-010-0492-3

Chemistry of Heterocyclic Compounds, Vol. 46, No. 2, 2010
THE SPECIFIC CHARACTER
OF THE REACTION OF DERIVATIVES OF
2-THIOXO-2,3-DIHYDROPYRIMIDIN-4(1H)-ONE
WITH IODOMETHANE AND ALKYL
CHLOROMETHYL SULFIDES
I. A. Novakov1, B. S. Orlinson1, M. B. Nawrozkij1*, A. Mai2, M. Artico2,
D. Rotili2, A. S. Eremiychuk1, E. A. Gordeeva1, L. L. Brunilina1, and J. A. Este3
The alkylation of 5-alkyl-6-(2,6-dihalobenzyl)-2-thioxo-2,3-dihydropyrimidin-4(1H)-ones with MeI,
AllSCH2Cl, and MeSCH2Cl in the K2CO3–DMF, NaOMe–MeOH, and KOH–EtOH systems was
investigated. A hypothetical mechanism for the reaction is examined, and an explanation is proposed for
the composition of the reaction products. The presence of high anti-HIV-1 activity was established in
the obtained derivatives of 2-{[(allylsulfanyl)methyl]sulfanyl}pyrimidin-4(3H)-one.
Keywords: 5-alkyl-6-(2,6-dihalobenzyl)-2-thioxo-2,3-dihydropyrimidin-4(1H)-ones, allyl chloro-methyl
sulfide, iodomethane, methyl chloromethyl sulfide, SN1- and SN2-substitution, anti-HIV-1 agents.
Derivatives of 2-thioxo-2,3-dihydropyrimidin-4(1H)-one react ambiguously with various alkylating
agents. Thus, MeI [1], AllBr [2], EtI [2], and EtBr [2] in anhydrous DMF in the presence of K2CO3 form
mixtures of products from S-mono-, S,N(1)-di-, and S,N(3)-dialkylation. In the presence of NaOMe in MeOH
[3] and NaOEt in EtOH [4] the same alkylating agents lead exclusively to the formation of the products from
S-monoalkylation. Similar results were obtained when the reaction was carried out in DMF in the absence of a
base [5]. At the same time more active alkylating agents – alkyl chloromethyl sulfides and alkyl chloromethyl
oxides – form the products from S-monoalkylation when the reaction is carried out in DMF in the presence of
K2CO3 [6]. This effect has not found a convincing explanation in the literature.
_______
* To whom correspondence should be addressed, e-mail: kholstaedt@yandex.ru.
1Volgograd State Technical University, Volgograd 400131, Russia.
2Istituto Pasteur – Fondazione Cenci Bolognetti, Dipartimento di Studi Farmaceutici, Università degli Studidi
Roma "La Sapienza", P. le A. Moro 5, Roma 00185, Italy; e-mail: antonello.mai@uniromal.it,
marino.artico@uniromal.it, danterotili@libero.it.
3Retrovirology Laboratory IrsiCaixa, Hospital Universitari Germans Trias i Pujol, Universitat Autònoma de
Barcelona, Badalona 08916, Spain; e-mail: jaeste@irsicaixa.es.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 248-254, February, 2010. Original
article submitted April 29, 2008. Revision submitted January 11, 2009.
200
0009-3122/10/4602-0200©2010 Springer Science+Business Media, Inc.

In order to establish the reasons for these difference in reactivity and also to synthesize new probable
antiviral agents, we studied the reaction of 6-(arylmethyl)-2-thioxo-2,3-dihydropyrimidin-4(1H)-ones 1a-d with
AllSCH2Cl, MeSCH2Cl, and MeI in the K2CO3–DMF, KOH–EtOH, and NaOMe–MeOH systems.
As a result, we established that reaction with AllSCH2Cl and MeSCH2Cl in the first system leads to the
formation of the S-monoalkylation products 2a,b and 3a-c with small amounts of dialkylation products as
impurities.
When the same reaction was realized in the NaOMe–MeOH system, the corresponding 6-(arylmethyl)-
2-thioxo-2,3-dihydropyrimidin-4(1H)-ones were regenerated. In addition to them AllSCH2OMe and MeSCH2OMe
were obtained.
O
O
R
R
NH
NH
R1CH2SCH2Cl / K2CO3 / DMF
N
S
N
H
Hal
S
Cl
Hal
Cl
S
R1
1a–d
2a–e
1a,b, 2a–c R = H, 1c, 2d R = Me, 1d, 2e R = i-Pr; 2a,d,e R1 = H2C=CH, 2b,c R1 = H;
1a, 2a,b Hal = Cl, 1b,c,d, 2c,d,e Hal = F
The initial 6-(arylmethyl)-2-thioxo-2,3-dihydropyrimidin-4(1H)-ones were also regenerated when this
reaction was carried out in the presence of KOH in 96% ethanol. In addition AllSCH2OMe and MeSCH2OMe
and also small amounts of AllSCH2OCH2SAll and MeSCH2OCH2SMe were also obtained.
However, during the reaction of 6-(arylmethyl)-2-thioxo-2,3-dihydropyrimidin-4(1H)-ones 1-c, e-g with
MeI in the K2CO3–DMF system complex mixtures of polyalkylation products were obtained, and this agrees
with published data [1]. At the same time the S-monoalkylation products 3a-f were obtained almost exclusively
both in the KOH–EtOH system and in the NaOMe–MeOH system.
O
O
R
R
NH
NH
MeI / KOH / EtOH
N
H
Hal
S
N
S
Cl
Hal
Cl
Me
3a–f
1a–c, e–g
1a, 3a R = H, Hal = Cl; 1b, 3b R = H, Hal = F; 1c, 3d R = Me, Hal = F; 1e, 3c R = Me,
Hal = Cl; 1f, 3e R = Et, Hal = Cl; 1g, 3f R = Et, Hal = F
The explanation of this effect clearly involves not so much the absolute level of reactivity of the
employed alkylating agents as the dominant mechanism of their realization. It is known that alkyl chloromethyl
sulfides enter into nucleophilic substitution predominantly by the SN1 mechanism, due to the formation of a
stable (alkylsulfanyl)methyl cation [7]. At the same time the SN1 mechanism is not the main one in the case of
these compounds. The SN2 mechanism is dominant in the case of halomethanes.
201

Thus, if the reaction is carried out in a protic solvent, the 4-(arylmethyl)-6-oxo-1,6-dihydro-2-pyrimi-
dinethiolate anion is in a compact solvate shell due to the presence of a significant amount of hydrogen bonds.
Destruction of this solvate shell obviously involves significant energy expenditures. Because of this it is mainly
the most nucleophilic tautomeric form, the 4-(arylmethyl)-6-oxo-1,6-dihydro-2-pyrimidinethiolate anion, that
enters into reaction with the iodomethane. At the same time AllSCH2Cl and MeSCH2Cl enter into reaction with
the solvent molecules (a neutral nucleophile) contained in the solvate shell, reacting predominantly by the SN1
mechanism. In turn the 4-(arylmethyl)-6-oxo-1,6-dihydro-2-pyrimidinethiolate anion acts only as an acceptor of
the hydrogen chloride formed during this reaction.
When the reaction is carried out in DMF the anion is not surrounded by such a compact solvate shell
since the DMF is an aprotic solvent and is not susceptible to the formation of strong hydrogen bonds. Thus, the
solvate shell is unstable, and the MeI reacts both with the more nucleophilic 4-(arylmethyl)-6-oxo-1,6-dihydro-
2-pyrimidinethiolate anion and with other tautomeric forms of this anion, in which the negative charge is
delocalized predominantly on one of the nitrogen atoms and/or the oxygen atom. The small differences in the
activation energies of these reactions are probably balanced by the high reactivity of the MeI.
The AllCH2Cl and MeSCH2Cl are inclined to react by the SN1 mechanism, but the moderately well
defined basic character of the solvent and the weakly solvated anion favour reaction by the SN2 mechanism. In
reactions taking place by the SN2 mechanism the activity of the corresponding alkylating agents is appreciably
lower than in the case of the SN1 mechanism, and this gives rise to the relatively high selectivity of their reaction
with the most nucleophilic 4-(arylmethyl)-6-oxo-1,6-dihydro-2-pyrimidinethiolate anion.
The experiments also prove that the alkali metal cation does not have a significant effect on the
selectivity of the alkylation reaction.
Whereas the obtained derivatives of 2-(methylsulfanyl)-4(3H)-pyrimidinone are of considerable interest
as intermediate products in the synthesis of 2-amino-6-(arylmethyl)pyrimidin-4(3H)-ones having anti-HIV-1
activity, the corresponding derivatives of 2-[(alkylsulfanyl)methyl]sulfanylpyrimidin-4(3H)-one in themselves
are often highly active inhibitors of the replication of HIV-1. Here it had been shown earlier that the activity of
these derivatives increases during the transition from the 5-unsubstituted compounds to the 5-isopropyl-
substituted derivatives [8], during the insertion of 2,6-dihalobenzyl at position 6 [9], and also during the
transition from the 2-[(methylsulfanyl)methylsulfanyl]-substituted compounds to the 2-[(ethylsulfanyl)methyl-
sulfanyl]-substituted analogs [10].
Me
S
Me
S
Et
S
Me
S
O
N
R
H
N
H
H
H
HN
S
F
O
R
S
N
O
R
S
N
O
S
N
O
Me
S
S
N
N
N
N
Et
Et
R = H, Me, Et, i-Pr
Anti-HIV-1 activity increases
F
Anti-HIV-1 activity increases
Anti-HIV-1 activity increases
At the same time we took account of the fact that for 1-(alkoxymethyl)-5-alkyl-6-(arylmethyl)-
pyrimidine-2,4(1H,3H)-diones the activity increases from the 1-(methoxymethyl)- and 1-(ethoxymethyl)-
substituted compounds to the 1-[(allyloxy)methyl]-substituted analogs [11].
202

Here it had been established earlier that in the series of 5-alkyl-2-(alkylsulfanyl)-6-(arylmethyl)-4(3H)-
pyrimidinones the substituent at the sulfur atom interacts with the same section of HIV-1 revertase as the
substituent at position 1 in 1-(alkoxymethyl)-5-alkyl-6-(arylmethyl)pyrimidine-2,4-(1H,3H)-diones [12]. On the
basis of these data it seemed appropriate to insert an [(allylsulfanyl)methyl]sulfanyl group at position 2 of the
targeted derivatives and to compare their activity with the activity of the corresponding 2-[(methyl-
sulfanyl)methylsulfanyl]-substituted analogs [3]. The antiviral activity of the investigated compounds is
presented in Table 1.
O
Et
HN
O
N
R
O
Me
R = H, Me, H2C=CH
Me
Anti-HIV-1 activity increases
Thus, it was established that the activity of the allyl analogs significantly exceeds that of the methyl-
substituted compounds [3]; this confirms the proposed hypothesis and demonstrates the prospects of further
search for new highly active anti-HIV-1 agents in the investigated series of compounds.
EXPERIMENTAL
The 1H NMR spectra were recorded on a Varian-Mercury 300BB instrument (300 MHz) with HMDS as
internal standard. The melting points of the synthesized compounds were determined on a Cole-Palmer
instrument.
Allyl chloromethyl sulfide was prepared by the previously described method [13, 14]. The derivatives
1a,d [12], 1e [15], 1b [3], and 1c,f,g [16] were obtained by known methods. During the syntheses we used
reagents from Lancaster Synthesis [MeSCH2Cl (content of main substance 95%), MeI (content of main
substance 99%), K2CO3 (content of main substance 99%)], Acros [AllSH (content of main substance 70%)], and
LaChema [KOH (content of main substance 84.5%)]. The solvents were prepared, purified, and dried by
standard procedures [17].
2-{[(Allylsulfanyl)methyl]sulfanyl}-6-(2,6-dichlorobenzyl)pyrimidin-4(3H)-one (2a). To a solution
of 6-(2,6-dichlorobenzyl)-2-thioxo-2,3-dihydropyrimidin-4(1H)-one (1a) (287 mg, 1 mmol) in absolute DMF
(2 ml) we added anhydrous K2CO3 (145 mg, 1.05 mmol). The mixture was stirred at 90-100°C for 1 h, and
cooled to room temperature, AllSCH2Cl (135 mg, 1.1 mmol) was added, and the mixture was stirred until the
initial compound had been completely converted (TLC, 3% MeOH in CHCl3). The solution was diluted with
water (50 ml), neutralized with 1 N acetic acid, and filtered. The precipitate was washed with water (20 ml),
1
dried, and crystallized. The yield was 217 mg (58%); mp 162.5-163.5°C (PhMe). H NMR spectrum (CCl4), δ,
ppm (J, Hz): 13.34 (1H, s, NH); 7.25 (2H, d, J = 7.9, H-3,5 Ar); 7.09 (1H, d, J = 7.6, H-4 Ar); 5.70 (1H, s, H-5
pyrimidine); 5.67-5.59 (1H, m, CH2CHCH2S); 5.12-4.95 (2H, m, CH2CHCH2S); 4.11 (2H, s, ArCH2); 4.09 (2H,
s, SCH2S); 3.12 (2H, d, J = 7.3, CH2CHCH2S). Found, %: C 48.66; H 4.01. C15H14Cl2N2OS2. Calculated, %:
C 48.26; H 3.78.
2-{[(Allylsulfanyl)methyl]sulfanyl}-6-(6-chloro-2-fluorobenzyl)-5-methylpyrimidin-4(3H)-one (2d).
The compound was obtained similarly to compound 2a with a yield of 40%; mp 152-154.5°C (cyclo-
203

TABLE 1. Antiviral Activity of Compounds 3a-c
Effective concentration, EC50
Compound
cmax, mol
Noninfected
colony of cells, CC50*
NL4-3 wt K103N
Y181C
Y188L
Nevirapine*2
8
0.026
0.0025
0.75
1.92
0.108
8.68
4.31
8.70
2.78
0.0041
>13
>8
>8
Ifavirenz*2
0.3
13
13
13
>0.3
>13
>13
>13
>0.3
>13
>13
>13
3a
3b
3c
0.051
0.075
1.78
1.62
_______
* CC50 is the cytotoxic concentration.
*2 Reference standard.
1
C6H12). H NMR spectrum (CCl4), δ, ppm (J, Hz): 13.52 (1H, s, NH); 7.19-7.04 (2H, m, H-3,5 Ar); 6.96-6.85
(1H, m, H-4 Ar); 5.68-5.52 (1H, m, CH2CHCH2S); 5.03-4.89 (2H, m, CH2CHCH2S); 3.99 (2H, s, ArCH2); 3.81
(2H, s, SCH2S); 3.04 (2H, d, J = 7.3, CH2CHCH2S); 2.13 (3H, s, CH3). Found, %: C 51.97; H 4.00.
C16H16ClFN2OS2. Calculated, %: C 51.81; H 4.35.
2-{[(Allylsulfanyl)methyl]sulfanyl}-6-(6-chloro-2-fluorobenzyl)-5-isopropylpyrimidin-4(3H)-one
(2e). The compound was obtained similarly to compound 2a with a yield of 36%; mp 162-165°C (C6H14–cyclo-
1
C6H12). H NMR spectrum (CCl4), δ, ppm (J, Hz): 13.47 (1H, s, NH); 7.20-7.04 (2H, m, H-3,5 Ar); 6.99-6.83
(1H, m, H-4 Ar); 5.67–5.51 (1H, m, CH2CHCH2S); 5.10-4.94 (2H, m, CH2CHCH2S); 4.05 (2H, s, ArCH2);
3.84-3.68 (2H, m, SCH2S); 3.19-3.08 (1H, m, (CH3)2CH); 1.43-1.26 (6H, m, (CH3)2CH). Found, %: C 53.97;
H 5.25. C18H20ClFN2OS2. Calculated, %: C 54.19; H 5.05.
6-(6-Chloro-2-fluorobenzyl)-2-{[(methylsulfanyl)methyl]sulfanyl}pyrimidin-4(3H)-one (2c). The
compound was obtained similarly to compound 2a with a yield of 54%; mp 154.5-156.5°C (EtOH) (corresponds
to data in [3]).
6-(2,6-Dichlorobenzyl)-2-{[(methylsulfanyl)methyl]sulfanyl}pyrimidin-4(3H)-one (2b). The com-
pound was obtained similarly to compound 2a with a yield of 55%; mp 180.5-182°C (EtOH) (corresponds to
data in [3]).
6-(6-Chloro-2-fluorobenzyl)-5-ethyl-2-(methylsulfanyl)pyrimidin-4(3H)-one (3f). To a solution of
500 mg (7.53 mmol) of 84.5% KOH in 100 ml of 96% EtOH we added 6-(6-chloro-2-fluorobenzyl)-5-ethyl-
2-thioxo-2,3-dihydropyrimidin-4(1H)-one (1g) (2 g, 7.39 mmol). The mixture was stirred at 40-50°C until
dissolved and cooled to room temperature, and MeI (2.3 ml, 5.24 g, 36.91 mmol) was added. The reaction mass
was stirred at room temperature for 2 h, diluted with an equal volume of water, neutralized with acetic acid, and
filtered. The precipitate was washed with water (50 ml) and dried. The yield of the product was practically
quantitative. The yield (after recrystallization) was 2.1 g (75%); mp 209-211°C (MeCN). 1H NMR spectrum, δ,
ppm (J, Hz): 12.49 (1H, br. s, NH); 7.32-7.25 (2H, m, H-3,5 Ar); 7.17-7.11 (1H, m, H-4 Ar); 3.98 (2H, s,
ArCH2); 1.99 (2H, s, SCH3); 1.03-0.98 (3H, m, CH2CH3). The signal of the protons of the CH2 group in Et is
overlapped by the signal of the DMSO impurity in the DMSO-d6. Found, %: C 54.10; H 4.11. C14H14ClFN2OS.
Calculated, %: C 53.76; H 4.51.
6-(6-Chloro-2-fluorobenzyl)-2-(methylsulfanyl)pyrimidin-4(3H)-one (3b). The compound was
obtained similarly to compound 3f with a yield of 60%; mp 217-219.5 °C (MeCN). 1H NMR spectrum (DMSO-
d6), δ, ppm (J, Hz): 7.33-7.26 (2H, m, H-3,5 Ar); 7.22-7.19 (1H, m, H-4 Ar); 5.70 (1H, s, H-5 pyrimidine); 3.90
(2H, s, ArCH2); 2.30 (3H, s, CH3). The proton of the pyrimidine ring NH group has the form of a broad singlet
with extremely low intensity, which does not make it possible to make an appropriate assignment. Found, %:
C 50.20; H 3.96. C12H10ClFN2OS. Calculated, %: C 50.62; H 3.54.
204

6-(6-Chloro-2-fluorobenzyl)-5-methyl-2-(methylsulfanyl)pyrimidin-4(3H)-one (3d). The compound
was obtained similarly to compound 3f with a yield of 62%; mp 241-241.5°C (MeCN). 1H NMR spectrum
(CDCl3), δ, ppm (J, Hz): 11.68 (1H, br. s, NH); 7.10-7.06 (2H, m, H-3,5 Ar); 6.93-6.89 (1H, m, H-4 Ar); 3.99
(2H, s, ArCH2); 2.13 (3H, s, SCH3); 2.12 (3H, s, CH3). Found, %: C 52.27; H 4.11. C13H12ClFN2OS. Calculated,
%: C 52.26; H 4.05.
6-(2,6-Dichlorobenzyl)-2-(methylsulfanyl)pyrimidin-4(3H)-one (3a). The compound was obtained
similarly to compound 3f with a yield of 65%; mp 238-241°C (MeCN) (corresponds to data in [12]).
6-(2,6-Dichlorobenzyl)-5-methyl-2-(methylsulfanyl)pyrimidin-4(3H-one (3c). The compound was
obtained similarly to compound 3f with a yield of 65%; mp 262-264°C (MeCN) (corresponds to data in [12]).
6-(2,6-Dichlorobenzyl)-5-ethyl-2-(methylsulfanyl)pyrimidin-4(3H)-one (3e). The compound was
obtained similarly to compound 3f with a yield of 66%; mp 246-249°C (MeCN). 1H NMR spectrum (DMSO-d6), δ,
ppm (J, Hz): 7.41–7.35 (2H, m, H-3,5 Ar); 7.27–7.21 (1H, m, H-4 Ar); 4.14 (2H, s, ArCH2); 1.94 (3H, s, SCH3);
1.09-1.00 (3H, m, CH2CH3). The proton of the NH group of the pyrimidine ring has the form of a broad singlet
with extremely low intensity, which does not make it possible to make an appropriate assignment. The signal of
the protons of the CH2 group in Et is overlapped by the signal of the DMSO impurity in the DMSO-d6. Found,
%: C 51.10; H 4.30. C14H14Cl2N2OS. Calculated, %: C 51.07; H 4.29.
REFERENCES
1.
2.
3.
4.
5.
K. Danel, E. B. Pedersen, and C. Nielsen, J. Med. Chem., 41, 191 (1998).
O. S. Pedersen, L. Petersen, and M. Brandt, Monatsh. Chem., 130, 1499 (1999).
M. B. Navrotskii, Thesis for Cand. Pharm. Sci. [in Russian], Pyatigorsk (2002).
O. G. Sim, Thesis for Cand. Pharm. Sci. [in Russian], (2006).
A. Mai, M. Artico, G. Sbardella, S. Massa, A. G. Loi, E. Tramontano, P. Scano, and P. La Colla, J. Med.
Chem., 38, 3258 (1995).
6.
7.
M. B. Nawrozkij, Khim. Farm. Zh., 37, No. 9, 22 (2003).
Yu. A. Pokonova, Halogen Sulfides. Methods of Production, Properties, Application of Thioether
Halides [in Russian], Izd. LGU, Leningrad (1977).
8.
9.
E. A. Sudbeck, C. Mao, R. Vig, T. K. Venkatachalam, L. Tuel-Ahlgren, and F. M. Uckun, Antimicrob.
Agents Chemother., 42, 3225 (1998).
G. Sbardella, A. Mai, M. Artico, S. Massa, T. Marceddu, L. Vargiu, M. E. Maron-giu, and P. La Colla,
Med. Chem. Res., 10, 30 (2000).
10.
11.
K. Danel, C. Nielsen and E. B. Pedersen, Acta Chem. Scand., 51, 426 (1997).
N. R. El-Brollosy, P. T. Jorgensen, B. Dahan, A. M. Boel, E. B. Pedersen, and C. Nielsen, J. Med.
Chem., 45, 5721 (2002).
12.
A. Mai, M. Artico, G. Sbardella, S. Massa, E. Novellino, G. Greco, A. G. Loi, E. Tramontano,
M. E. Marongiu, and P. La Colla, J. Med. Chem., 42, 619 (1999).
13.
14.
15.
H. Bohme, Ber., 69, 1612 (1936).
L. A. Walter, L. H. Goodson, and R. J. Fosbinder, J. Am. Chem. Soc., 67, 655 (1945).
A. Mai, G. Sbardella, M. Artico, R. Ragno, S. Massa, E. Novellino, G. Greco, A. Lavecchia, C. Musiu,
M. La Colla, C. Murgioni, P. La Colla, and R. Loddo, J. Med. Chem., 44, 2544 (2001).
M. B. Nawrozkij, D. Rotili, D. Tarantino, G. Botta, A. S. Eremiychuk, I. Musmuca, R. Ragno,
A. Samuele, S. Zanoli, M. Armand-Ugon, I. Clotet-Codina, I. A. Novakov, B. S. Orlinson, G. Maga,
J. A. Este, M. Artico, and A. Mai, J. Med. Chem., 51, 4641 (2008).
16.
17.
L. Titze and T. Eicher, Preparative Organic Chemistry: Reactions and Syntheses in Practical Organic
Chemistry and Scientific Research Laboratory [Russian translation], Mir, Moscow (1999).
205