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Russian Chemical Bulletin, International Edition, Vol. 56, No. 8, pp. 1675--1678, August, 2007

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Heterocycles with the bridgehead N atom
17.* Recyclization of 2,3,5,7 tetramethyloxazolo[3,2 a]pyrimidinium perchlorate in reactions with the simplest nucleophiles
E. V. Babaev and V. L. Alifanov Department of Chemistry, M. V. Lomonosov Moscow State University, 1 Leninskie Gory, 119992 Moscow, Russian Federation. Fax: +7 (495) 939 3020. E mail: babaev@org.chem.msu.ru
2,3,5,7 Tetramethyloxazolo[3,2 a]pyrimidinium perchlorate in reactions with sodium hydroxide, sodium ethoxide, and pyrrolidine undergoes earlier unknown recyclization into 1 substituted pyrrolo[1,2 c]pyrimidines. Recyclization of the same salt under the action of ammonia gives 2,3,5,7 tetramethylimidazo[1,2 a]pyrimidine. Key words: recyclization, pyrimidine, oxazole, pyrrole, azaindolizine.

It is known2,3 that oxazolo[3,2 a]pyridinium salts 1a in reactions with secondary amines undergo opening of the pyridine ring (Scheme 1, route a). Recently,4 we have found that salts 2a (aza analogs of salts 1a) undergo analo gous opening of the six membered fragment with com plete decomposition of the pyrimidine ring (Scheme 1, route b). Compounds 1b, which are homologous to salts 1a, react with secondary amines in a different manner: the oxazole ring undergoes opening followed by recyclization into the pyrrole ring and the formation of an unknown subclass of 5 aminoindolizines 3 (Scheme 1, route c).2,5,6 Recently, this synthetic approach has been tested at pharmaceutical laboratories in the synthesis of combina torial libraries of this not easily accessible subclass of indolizines.7 In reactions of salts 1b with ammonia, the oxazole fragment becomes transformed into an imidazole fragment to give imidazo[3,2 a]pyridine derivatives 4 (Scheme 1, route d).8 (Analogous recyclization has been observed9 for salts 1a.) Thus, the direction of the transfor mation of oxazolo[3,2 a ]pyridinium ( 1) and oxazo lo[3,2 a]pyrimidinium salts (2) depends on both the na ture of the nucleophile and the presence of the methyl group in position 5. The direction of reactions of nucleo philes with salts 5, which are aza analogs of salts 1b and homologs of salts 2a, remains unclear. The solution of this problem was a subject of the present work. The pub lished10 procedure for the synthesis of salts 5a (R = Me) and 5b (R = Ph) involves condensation of 4,5 disubsti tuted 2 aminooxazoles with acetylacetone; however, their reactivities have not been studied.
* For Part 16, see Ref. 1.

Scheme 1

We synthesized perchlorate 5a according to the afore said procedure10 and studied its reactions with sodium hydroxide, sodium ethoxide, pyrrolidine, and ammonia (Scheme 2). It turned out that salt 5a reacts with aqueous NaOH at room temperature to give a novel covalent compound.

Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 8, pp. 1611--1614, August, 2007. 1066 5285/07/5608 1675 © 2007 Springer Science+Business Media, Inc.


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Scheme 2

1 ones.) Apparently, this rearrangement follows the ANRORC mechanism (Scheme 3).
Scheme 3

Reactions of perchlorate 5a with sodium ethoxide and pyrrolidine also yielded novel compounds. According to elemental analysis data and mass spectra, the molecular masses of compounds 7 and 8 correspond to the following formulas:
M(7) = M(5a) ­ M(ClO4) -- M(H2O) + M(OEt), M (8) = M (5a) ­ M (ClO4) -- M (H2O) + M(N(CH2)4)

According to elemental analysis data and mass spectra, the compound obtained is identical in composition with salt 5a minus a HClO4 molecule. In contrast to the 1H NMR spectrum of salt 5a, the spectrum of the product does not show the signal for one of the methyl groups and contains three singlets (at 5.70, 5.79 and 10.11) instead of one aromatic singlet for the pyrimidine ring (at 7.8). The signal for one of the methyl groups also disappears from the 13C NMR spectrum of the product and seven (instead of six) signals appear in the aromatic range. All these data unambiguously suggest that the oxazole ring is transformed into a pyrrole ring to give 3,6,7 tri methylpyrrolo[1,2 c]pyrimidin 1(2H ) one (6). (Note that amide type tautomerism has been proved for the sole documented11 representative of pyrrolo[1,2 c]pyrimidin

The 1H and 13C NMR spectra of the products ob tained do not contain, in contrast to the spectra of the starting salt 5a, the signal for one of the methyl groups but show signals for the coming ethoxy group or the pyrrolidine fragment. The 1H NMR spectra contain a new singlet at 5.9 and the sole low field singlet for the pyrimidine ring of salt 5a is shifted upfield to 6.4--6.5. Therefore, like the reaction of salt 5a with NaOH, its reactions with sodium alkoxide and the secondary amine involve opening of the oxazole ring followed by re cyclization into a pyrrole ring. The reaction is accompa nied by introduction of the ethanol (amine) residue and loss of a water molecule during cyclocondensation. There fore, the recyclization products are 1 ethoxy(pyrrolidi no)pyrrolo[1,2 c]pyrimidines 7 and 8 (Scheme 4).

Scheme 4

i. NR2H or RO­. X = NR2, RO
­


Recyclization of oxazolo[3,2 a]pyrimidinium

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Scheme 5

The compounds obtained demonstrate a positive Ehrlich color probe typical of fused pyrroles.12 A reaction of salt 5a with ammonia gives a product in the 1H and 13C NMR spectra of which all the characteris tic signals of the starting salt 5a are retained with a general upfield shift. The physical properties of the product are identical with the literature13 data for 2,3,5,7 tetra methylimidazo[1,2 a]pyrimidine (9). In this case, re cyclization probably involves the coming amino group (Scheme 5). In conclusion, we discovered with salt 5a as examples that 5 methyloxazolo[3,2 a]pyrimidinium cations 5 react with nucleophiles with opening and transformation of the oxazole rather than pyrimidine ring to give, via earlier unknown recyclization, not easily accessible azaindolizi nes 6--8. Such a type of the reactivity of fused pyrim idines 5 differs from the behavior of lower homologs 2a and resembles the conversion of salts 1b of the pyridine series. Experimental
and 13C NMR spectra were recorded on a Bruker AC 400 instrument (350 (1H) and 100 MHz (13C)) in DMSO d6. Chemi cal shifts were measured using the scale with SiMe4 as the internal standard. Mass spectra were recorded on a Kratos MS 30 instrument (EI, 70 eV). Thin layer chromatography was car ried out on Silufol F254 plates (Merck); spots were visualized under UV light ( = 254 and 365 nm). 2 Amino 4,5 dimethyloxazole was prepared from cyanamide and acetoin according to a known procedure.14 2,3,5,7 Tetra methyloxazolo[3,2 a]pyrimidinium perchlorate (5a) was pre pared by condensation of 2 amino 4,5 dimethyloxazole with acetylacetone as described earlier.10 The yield was 60%, m.p. 227--228 °C (ethanol) (cf. Ref. 10: 227--228 °C). 1H NMR, : 2.59 (s, 3 H, C(7)H3); 2.72 (s, 3 H, C(3)H3); 2.77 (s, 3 H, C(2)H3); 3.06 (s, 3 H, C(5)H3); 7.80 (s, 1 H, H(6)). 13C NMR, : 9.8; 10.0; 18.6; 24.3; 118.9; 121.3; 146.7; 153.1; 153.9; 172.4. 3,6,7 Trimethylpyrrolo[1,2 c ]pyrimidin 1(2 H ) one (6). A 20% solution of NaOH (100 mL) was added to salt 5a (2.765 g, 0.01 mol). The reaction mixture was stirred at room temperature for 5 h and then kept for 16 h. The precipitate that formed was filtered off, washed with water, and recrystallized from ethanol. The yield of compound 6 was 1.58 g (90%), m.p. 179--181 °C. Found (%): C, 67.93; H, 6.88; N, 15.68. C10H12N2O. Calcu lated (%): C, 68.16; H, 6.86; N, 15.90. 1H NMR, : 1.99, 2.02 (both s, 3 H each, C(6)Me, C(7)Me); 2.55 (s, 3 H, C(3)H3); 5.70 (s, 1 H, H(5)); 5.79 (s, 1 H, H(4)); 10.11 (br.s, 1 H, NH).
1H

C NMR, : 10.9; 12.2; 17.6; 96.2; 102.5; 120.7; 121.4; 130.1; 130.7; 148.3. MS, m/z (Irel (%)): 176 [M]+ (100%). 1 Ethoxy 3,6,7 trimethylpyrrolo[1,2 c]pyrimidine (7). Me tallic Na (0.05 mol) was dissolved with cooling in anhydrous ethanol (100 mL). The resulting solution of sodium ethoxide was heated to 50 °C and oxazolo[3,2 a]pyrimidinium perchlorate 5a (2.765 g, 0.01 mol) was added. The reaction mixture was refluxed for 3 h. On cooling, the solvent was removed and the residue was poured into water. The precipitate that formed was washed with water, dried, and recrystallized from ether. The yield of compound 7 was 1.63 g (80%), m.p. 38--40 ° C. Found (%): C, 70.04; H, 7.60; N, 13.39. C10H12N2O. Calcu lated (%): C, 70.56; H, 7.89; N, 13.71. 1H NMR, : 1.45 (q, 3 H, C(3)H3, J = 7.1 Hz); 2.10 (s, 3 H, C(7)H3); 2.17 (s, 3 H, C(6)H3); 2.56 (s, 3 H, C(3)H3); 4.49 (t, 2 H, OCH2, J = 7.1 Hz); 5.85 (s, 1 H, H(5)); 6.42 (s, 1 H, H(4)). 13C NMR, : 11.5; 12.5; 14.0; 22.5; 63.2; 99.6; 103.7; 116.5; 122.5; 133.2; 138.0; 147.6. MS, m/z (Irel (%)): 204 [M]+ (54%), 175 (100). 3,6,7 Trimethyl 1 (pyrrolidino)pyrrolo[1,2 c]pyrimidine (8). Perchlorate 5a (2.765 g, 0.01 mol) was suspended in anhydrous acetonitrile (50 mL). The solution was heated to 50 °C and refluxed with pyrrolidine (0.05 mol) for 4 h. On cooling, the solvent was removed and the resulting brown oil was dissolved in water. The product was extracted with chloroform (3в20 mL). The extract was dried over Na2SO4 and concentrated; the resi due was dissolved in chloroform and chromatographed on silica gel with chloroform as an eluent. The first fraction was col lected. The yield of compound 8 was 0.92 g (40%), a yellow oil. Found (%): C, 73.22; H, 8.37; N, 18.51. C14H19N3. Calcu lated (%): C, 73.33; H, 8.35; N, 18.32. 1H NMR, : 1.91 (m, 4 H, (CH2)2); 2.13 (s, 3 H, C(7)H3); 2.18 (s, 3 H, C(6)H3); 2.59 (s, 3 H, C(3)H3); 3.29 (m, 4 H, N(CH2)2); 5.91 (s, 1 H, H(5)); 6.50 (s, 1 H, H(4)). 13C NMR, : 11.5; 11.7; 22.4; 23.4; 50.2; 99.2; 104.9; 116.5; 123.8; 134.0; 137.4; 148.2. MS, m/z (Irel (%)): 229 [M]+ (100%). 2,3,5,7 Tetramethylimidazo[1,2 a]pyrimidine (9). Perchlo rate 5a (2.765 g, 0.01 mol) was added to a 4 M solution of NH3 in methanol (100 mL). The mixture was stirred for 12 h and then refluxed for 2 h. The solvent was removed and the residue was treated with water. The precipitate that formed was filtered off and recrystallized from ethanol. The yield of compound 9 was 1.5 g (86%), m.p. 201--202 °C (ethanol) (cf. Ref. 14: 202 °C). 1H NMR, : 2.23 (s, 3 H, C(7)H ); 2.38 (s, 3 H, C(3)H ); 2.61 3 3 (s, 3 H, C(2)H3); 2.80 (s, 3 H, C(5)H3); 6.58 (s, 1 H, H(6)). 13C NMR, : 11.4; 13.1; 18.9; 23.7; 109.2; 115.1; 139.6; 144.8; 147.5; 157.1.
13

This work was financially supported by the Russian Foundation for Basic Research (Project Nos 07 03 00921 a and 05 03 39022 GFEN_a).


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