New 5,6ꢀcyclotrimethyleneuracil derivatives
Russ.Chem.Bull., Int.Ed., Vol. 61, No. 8, August, 2012
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7ꢀBromoꢀ6,7ꢀdihydroꢀ1Hꢀcyclopenta[d]pyrimidineꢀ2,4ꢀ
(3H,5H)ꢀdione (2). A solution of bromine (30 mL) in glacial
acetic acid (50 mL) was added to a suspension of uracil 1 (9 g,
0.06 mol) in glacial acetic acid (25 mL) with cooling to 5—10 C.
The reaction mixture was stirred at room temperature for 2 h.
The precipitate that formed was filtered off and successively
washed on a filter with acetic acid and diethyl ether. White crysꢀ
tals were obtained in a yield of 11 g (73%); the crystals decomꢀ
pose at 220 C. Found (%): C, 36.72; H, 3.27; N, 12.51.
C7H7BrN2O2. Calculated (%): C, 36.39; H, 3.05; N, 12.12. Rf 0.7
(CH3COOH—EtOH (3 : 0.5)). 1H NMR, : 2.34 and 2.48—2.69
(both m, 1 H, 3 H, H(5), H(6)); 5.12 (dd, 1 H, H(7), J = 6.0 Hz,
J = 2.2 Hz); 10.71 and 11.07 (both br.s, 1 H each, NH).
13C NMR, : 24.6, 33.8 (C(5), C(6)); 49.3 (C(7)); 112.1 (C(4a));
151.6, 153.0, 161.2 (NC).
Synthesis of compounds 3a—f (general procedure). The corꢀ
responding nucleophile (0.04 mol) was added to a suspension of
compound 2 (0.02 mol) in ethanol (100 mL). The reaction mixꢀ
ture was stirred at room temperature for 4—6 h (monitoring by
TLC). The crystals that precipitated were filtered off and succesꢀ
sively washed on a filter with ethanol and diethyl ethanol.
7ꢀ(Piperidinꢀ1ꢀyl)ꢀ6,7ꢀdihydroꢀ1Hꢀcyclopenta[d]pyrimidineꢀ
2,4(3H,5H)ꢀdione (3a). The reaction mixture was stirred for 5 h.
Yield 3.8 g (81%), m.p. 248—250 C (sublim.). Found (%):
C, 61.31; H, 7.24; N, 17.81. C12H17N3O2. Calculated (%): C,
61.26; H, 7.28; N, 17.86. 1H NMR, : 1.41 and 1.47—1.59
(both m, 2 H, 4 H, ,´,ꢀCH2, piperidine); 1.87 and 2.02
(both m, 1 H each, H(6)); 2.30—2.46 (m, 6 H, H(5), ,´ꢀCH2,
piperidine); 4.03 (dd, 1 H, H(7), J = 8.7 Hz, J = 4.3 Hz);
10.65 (br.s, 2 H, NH). 13C NMR, : 20.5, 24.0, 25.0 (C(5), C(6),
ꢀCH2, piperidine); 25.6 (,´ꢀCH2, piperidine); 49.0
(,´ꢀCH2, piperidine); 68.1 (C(7)); 110.9 (C(4a)); 152.2, 153.7,
161.9 (NC).
NꢀAlkylated uracil derivatives also have great practical
value and are widely used in the clinical practice (aminoꢀ
metradine, amisometradine, urapidil). These heterocyclic
derivatives often have similar therapeutic properties but
lower toxicity compared to unsubstituted analogs.7 Hence,
the alkylation of the synthesized compounds is a promisꢀ
ing method for the synthesis of new biologically active
compounds. At the same time, the spectra of Nꢀalkylated
derivatives of uracil are more informative and provide eviꢀ
dence for the direction of the substitution in product 2.
Based on the foregoing, we performed the methylation
of 3c. Due to the presence of several active centers in the
uracil ring, the alkylation usually affords a mixture of prodꢀ
ucts. However, after the heating with a twofold molar
excess of methyl iodide in a KOH aqueous solution unꢀ
der reflux, only N(1),N(3)ꢀdialkylated derivative 4 of the
starting compound was isolated as the reaction product
(Scheme 3).
Scheme 3
7ꢀ(4ꢀMethylpiperazinꢀ1ꢀyl)ꢀ6,7ꢀdihydroꢀ1Hꢀcyclopenta[d]ꢀ
pyrimidineꢀ2,4(3H,5H)ꢀdione (3b). The reaction mixture was
stirred for 6 h. Yield 3.8 g (76%), m.p. 248—250 C (sublim.).
Found (%): C, 57.62; H, 7.29; N, 22.31. C12H18N4O2. Calculatꢀ
An analysis of the chemical shifts of methyl groups in
1
the H and 13C NMR spectra of compound 4 shows that
the methylation occurs at both nitrogen atoms. The presꢀ
ence of the NOE signal between the protons H(7) and
N(1)Me in the 2D NOESY spectrum indicates that the
morpholine group is bound to C(7). For the N(3)Me group,
no NOE signals are observed because this group is far
remote from the other protons. Hence, the bromination of
uracil 1 also occurs at the C(7) atom.
1
ed (%): C, 57.58; H, 7.25; N, 22.38. H NMR, : 1.90 and 2.02
(both m, 1 H each, H(6)); 2.17 (s, 3 H, NMe); 2.27—2.48 (m, 10 H,
H(5), NCH2); 4.06 (dd, 1 H, H(7), J = 8.5 Hz, J = 4.0 Hz);
10.60 (br.s, 1 H, NH); 10.70 (br.s, 1 H, NH). 13C NMR, : 20.8,
25.0 (C(5), C(6)); 45.6 (NMe); 47.4, 54.6 (NCH2); 67.2 (C(7));
111.1 (C(4a)); 152.2, 153.2, 161.9 (NC).
7ꢀMorpholinoꢀ6,7ꢀdihydroꢀ1Hꢀcyclopenta[d]pyrimidineꢀ2,4ꢀ
(3H,5H)ꢀdione (3c). The reaction mixture was stirred for 5 h.
Yield 3.7 g (78%), m.p. 250 C (sublim.). Found (%): C, 55.73;
H, 6.25; N, 17.75. C11H15N3O3. Calculated (%): C, 55.69;
H, 6.37; N, 17.71. 1H NMR, : 1.94 and 2.06 (both m, 1 H each,
H(6)); 2.36—2.52 (m, 6 H, H(5), NCH2); 3.59 (m, 4 H, OCH2);
4.03 (dd, 1 H, H(7), J = 8.5 Hz, J = 4.3 Hz); 10.54 (br.s, 1 H,
NH); 10.62 (br.s, 1 H, NH). 13C NMR, : 20.9, 24.9 (C(5),
C(6)); 48.2 (NCH2); 66.1 (OCH2); 67.6 (C(7)); 111.2 (C(4a));
152.1, 152.5, 161.5 (NC).
7ꢀ(Pyrrolidinꢀ1ꢀyl)ꢀ6,7ꢀdihydroꢀ1Hꢀcyclopenta[d]pyrimidꢀ
ineꢀ2,4(3H,5H)ꢀdione (3d). The reaction mixture was stirred for
3 h. Yield 3.6 g (81%), m.p. 260 C (sublim.). Found (%): C, 59.66;
H, 6.83; N, 19.06. C11H15N3O2. Calculated (%): C, 59.71;
H, 6.83; N, 18.99. 1H NMR, : 1.72 (m, 4 H, ,´ꢀCH2, pyrrolꢀ
idine); 1.93—2.01 (m, 2 H, H(6)); 2.36—2.51 (m, 2 H, H(5));
2.55 (m, 4 H, ,´ꢀCH2, pyrrolidine); 4.16 (br.s, 1 H, H(7));
10.57 (br.s, 2 H, NH). 13C NMR, : 22.5, 24.9 (C(5), C(6)); 23.0
The structures of the synthesized compounds were conꢀ
1
firmed by H and 13C NMR spectroscopy. The assignꢀ
ment of the signals in the NMR spectra was made using
the HMQC and DEPT methods.
Experimental
The NMR spectra were measured on a Varian Mercuryꢀ
300Vx spectrometer (300.08 and 75.46 MHz for 1H and 13C,
respectively) in a 1 : 3 DMSOꢀd6—CCl4 solution at 30 C. The
chemical shifts are given with respect to SiMe4 as the internal
standard. The individuality and purity of the synthesized comꢀ
pounds were confirmed by TLC on Silufol UVꢀ254 plates; the
spots were visualized with iodine vapor. Elemental analyses of
solid samples were carried out on a EuroVector EA 3000ꢀSingle
analyzer.
Papoyan
