Unexpected reactions of 4-amino-2-methylsulfonyl-5-nitro-6- phenylethynylpyrimidine with nucleophiles

Full text of DOI:10.1007/s10593-008-0098-1

Chemistry of Heterocyclic Compounds, Vol. 44, No. 6, 2008
UNEXPECTED REACTIONS OF 4-AMINO-
2-METHYLSULFONYL-5-NITRO-6-PHENYL-
ETHYNYLPYRIMIDINE WITH NUCLEOPHILES
I. Cikotiene, E. Pudziuvelyte, and A. Brukstus
Keywords: 5-nitro-6-phenylethynylpyrimidines, nucleophiles, addition, triple bond.
Recently, we have reported that 4-amino-6-arylethynyl-5-nitropyrimidines in dry pyridine undergo
smooth intramolecular cyclization to give pyrrolo[3,2-d]-pyrimidine 5-oxides [1, 2]. The latter compounds,
being aza-analogues of isatogens, attracted our attention as potential traps for free radicals in biological milieu
[3–5]. In continuing our research aimed on the synthesis of polysubstituted pyrrolo-[3,2-d]pyrimidine 5-oxides
via cyclization of 6-arylethynyl-5-nitropyrimidines, we decided to perform modification of the 2-position of the
starting 6-arylethynyl-5-nitropyrimidines based on oxidation of methylthio moiety followed by nucleophilic
substitution reaction. Thus, reaction of 4-amino-2-methylthio-5-nitro-6-phenylethynylpyrimidine (1) with excess
of m-chloroperbenzoic acid in dihloromethane at room temperature provided the corresponding 4-amino-
2-methylsulfonyl-5-nitro-6-phenylethynylpyrimidine (2) in 70% yield. Unfortunatelly, the reaction of compound
2 with some nucleophilic reagents did not lead to formation of 2-substituted 4-amino-5-nitro-
6-phenylethynylpyrimidines 3. We observed that C≡C bond of the title compound appeared to be more reactive
towards nucleophiles than the C(2)–SO2Me moiety of the pyrimidine ring.
NH2
NH2
NH2
m-CPBA,
CH2Cl2, r.t.
NO2
NO2
NO2
N
NuH
Ph
N
N
Me
Me
Nu
N
S
N
S
N
O
O
Ph
Ph
3
2
1
PhNH2
CH2Cl2, r.t.
N
H
PhSH
CH2Cl2, r.t.
NH2
CH2Cl2, r.t.
NH2
NH2
NO2
NO2
NO2
N
N
N
Me
Ph
S
N
N
N
S
N
O
O
N
HN
Ph
Ph
Ph
S
Ph
Ph
5
6
4
__________________________________________________________________________________________
Vilnius University, Faculty of Chemistry, Department of Organic Chemistry, Vilnius LT-03225,
Lithuania; e-mail: inga.cikotiene@chf.vu.lt. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6,
pp. 944-946, May, 2008. Original article submitted January 02, 2008.
762
0009-3122/08/4406-0762©2008 Springer Science+Business Media, Inc.

The reaction of compound 2 with 2 equivalents of piperidine or thiophenol in dichloromethane at room
temperature furnished products 4 and 5. However, when compound 2 was treated with a weaker nucleophile
(aniline) only addition reaction to the triple bond was observed. It should be noted that addition reactions of
nucleophiles to the C≡C bond of the title compounds are regio- and stereoselective, as we have shown recently
[6]. So these reactions lead to the formation of syn-addition (in the case of secondary amine) or anti-addition (in
the case of thiophenol or primary amine) products 4–6, respectively.
The IR spectra were obtained on a Spectrum BX II FT-IR spectrophotometer (Perkin–Elmer) in KBr
1
disks. The H and 13C NMR spectra were recorded on a Varian Unity Inova (300 and 75 MHz respectively)
internal standard TMS.
The starting 4-amino-2-methylthio-5-nitro-6-phenylethynylpyrimidine (1) was synthesized according to
the method described in [6].
4-Amino-2-methylsulfonyl-5-nitro-6-phenylethynylpyrimidine (2). To a solution of compound 1
(0.5 g, 1.7 mmol) in dichloromethane (25 ml) m-chloroperbenzoic acid (0.83 g, 4.8 mmol) was added portion-
wise. The resulting solution was stirred for 6 h at room temperature The precipitate was filtered off, washed with
NaHCO3 (sat.), and dried. The obtained compound 2 was pure and used in the next steps without further
1
purification. Yield 70%; mp 202-205°C. IR spectrum, δ, cm-1: 3447, 3288 (NH2), 2205 (C≡C). H NMR
spectrum (DMSO-d6), δ, ppm: 3.35 (3H, s, SO2CH3); 7.58-7.63 (3H, m, ArH); 7.73-7.79 (2H, m, ArH); 8.44
13
(2H, br. s, NH2). С NMR spectrum (DMSO-d6), δ, ppm: 43.8, 83.9, 100.3, 119.8, 128.4, 130.5, 132.2, 144.5,
156.6, 164.7, 175.7. Found, %: C 49.49; H 3.34; N 17.39. C13H10N4O4S. Calculated, %: C 49.05; H 3.17;
N 17.60.
Reaction of 4-Amino-2-methylsulfonyl-5-nitro-6-phenylethynylpyrimidine (2) with Nucleophiles.
To a solution of compound 2 (0.32 g, 1 mmol) in dichloromethane (5 ml), the corresponding nucleophile
(2 mmol) was added. The reaction mixture was kept at room temperature for 2 h. The solvent was evaporated
under reduced pressure, the residue was recrystallized from 2-propanol to give compounds 4, 5 or 6.
4-Amino-5-nitro-6-[(E)-2-phenyl-2-(1-piperidinyl)ethenyl]-2-piperidinylpyrimidine (4). Yield 85%;
1
mp 155-157°C. IR spectrum, δ, cm-1: 3468, 3360 (NH2). H NMR spectrum (CDCl3), δ, ppm: 1.29 (4H, br. s,
2(CH2)2); 1.47 (4H, br. s, (CH2)2); 1.65 (4H, br. s, (CH2)2); 2.65 (2H, br. s, NCH2); 3.19 (4H, br. s, N(CH2)2);
3.53 (2H, br. s, NCH2); 6.51 (1H, s, CH); 7.32-7.36 (5H, m, ArH); 8.49 (2H, br. s, NH2). 13С NMR spectrum
(CDCl3), δ, ppm: 24.7, 24.8, 26.2, 26.3, 49.8, 50.2, 100.9, 117.9, 128.4, 128.6, 129.5, 138.6, 156.9, 159.8,
162.4, 163.8. Found, %: C 64.98; H 7.03; N 20.28. C22H28N6O2. Calculated, %: C 64.68; H 6.91; N 20.57.
4-Amino-5-nitro-6-[(Z)-2-phenyl-2-(phenylthio)ethenyl]-2-phenylthiopyrimidine (5). Yield 52%;
mp 145-147 °C. IR spectrum, δ, cm-1: 3450, 3368 (NH2). 1H NMR spectrum (CDCl3), δ, ppm: 7.00-7.04 (5H, m,
ArH); 7.09-7.12 (3H, m, ArH); 7.30-7.35 (2H, m, ArH); 7.31 (1H, s, CH); 7.40-7.44 (3H, m, ArH); 7.67-7.69
(2H, m, ArH); 8.69 (2H, br. s, NH2). Found, %: C 62.91; H 4.01; N 12.44. C24H18N4O2S2. Calculated, %:
C 62.86; H 3.96; N 12.22.
4-Amino-2-methylsulfonyl-5-nitro-6-[(Z)-2-phenyl-2-(phenylamino)ethenyl]pyrimidine (6). Yield
1
80%; mp 225-227°C. IR spectrum, δ, cm-1: 3446, 3360, 3161 (NH2, NH). H NMR spectrum (DMSO-d6), δ,
ppm (J, Hz): 3.28 (3H, s, SO2CH3); 6.30 (1H, s, CH); 6.77 (2H, d, J = 7.8, ArH); 6.98 (1H, t, J = 7.8, ArH); 7.13
(2H, d, J = 7.8, ArH); 7.42 (5H, s, ArH); 8.49 (2H, br. s, NH2); 12.80 (1H, br. s, NH). 13С NMR spectrum
(DMSO-d6), δ, ppm.: 43.8, 120.2, 121.6, 123.3, 127.7, 128.2, 128.3, 129.4, 136.4, 138.9, 157.9, 159.2, 162.1,
174.9. Found, %: C 56.58; H 4.53; N 16.16. C20H20N5O4S. Calculated, %: C 56.33; H 4.73; N 16.42.
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