Transformation of methyl N-methyl-N-(6-substituted-5-nitro-4-pyrimidinyl) aminoacetates into 4-methylamino-5-nitrosopyrimidines and 9-methylpurin-8-ones

Article abstract of DOI:10.1016/j.tetlet.2005.01.119

N-Methyl-N-(6-substituted-5-nitro-4-pyrimidinyl)aminoacetic acid methyl esters under the treatment of sodium alkoxides, depending on the nature of substituents in 6 position of the pyrimidine ring, undergo ring closure and rearrangement to give 6-substituted-4-methylamino-5-nitrosopyrimidines or 9-methylpurin-8-ones.

Full text of DOI:10.1016/j.tetlet.2005.01.119

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 1841–1844
Transformation of methyl N-methyl-N-(6-substituted-
5-nitro-4-pyrimidinyl)aminoacetates into 4-methylamino-
5-nitrosopyrimidines and 9-methylpurin-8-ones
Inga Susvilo, Algirdas Brukstus and Sigitas Tumkevicius*
Department of Organic Chemistry, Faculty of Chemistry, Vilnius University, Naugarduko 24, LT-03225 Vilnius, Lithuania
Received 21 October 2004; revised 13January 2005; accepted 21 January 2005
Abstract—N-Methyl-N-(6-substituted-5-nitro-4-pyrimidinyl)aminoacetic acid methyl esters under the treatment of sodium alkox-
ides, depending on the nature of substituents in 6 position of the pyrimidine ring, undergo ring closure and rearrangement to give
6-substituted-4-methylamino-5-nitrosopyrimidines or 9-methylpurin-8-ones.
Ó 2005 Elsevier Ltd. All rights reserved.
Pyrimidines bearing formyl or cyano groups in position
5 and an active methyleneamino group in position 4 of
the pyrimidine ring, on treatment with base, undergo
Dieckmann-type cyclisations to give the corresponding
pyrrolo[2,3-d]pyrimidine derivatives.1 Some examples
of cyclisations of the nitro derivatives by nucleophilic
attack of a carbanion onto the nitro group are also
known.2 For example, 5-nitro-4-phenacylaminopyrim-
idines in aqueous sodium hydroxide solution were
shown to undergo a cyclocondensation reaction with
the formation of 9H-purine-7-oxides.3 The latter com-
pounds attract attention as possible antitumor, antimi-
crobial and antiviral agents.4 However, to the best of
our knowledge no work has been done on reactions of
N-methyl-N-(5-nitro-4-pyrimidinyl)aminoacetates under
basic non-reductive conditions for the synthesis of pur-
ine derivatives. In this context and in continuation of
our ongoing program aimed towards the synthesis of
pyrimidine-containing heterocycles of biological inter-
est,1c,5 we report herein our findings on the reaction of
the title compounds with sodium alkoxides.
N-methyl-N-(6-chloro-5-nitro-4-pyrimidinyl)aminoace-
tate with selected amines. However, compounds 1–3 and
7–9 on treatment with 1 equiv of a sodium alkoxide in
the appropriate alcohol at room temperature underwent
unexpected transformations.
Compounds 1–3 bearing a primary or secondary amino
groups in position 6 of the pyrimidine ring, in the reac-
tion with alkoxides, turned into intense blue (4) or green
(5, 6) products8 (Scheme 1). It should be mentioned that
neither the 1H nor 13C NMR spectra gave evidence
about the structure of the products 4–6 obtained. These
spectra contained two sets of all signals. For example, in
the 1H NMR spectrum of 4, four broadened singlets due
to the NH2 group and two quartets due to the NH
group were observed.9 The ratio between these signals
remained constant and did not depend on the sample
concentration or solvent (solutions in DMSO, acetone,
dichloromethane, acetonitrile have been investigated).
Fortunately, slow crystallisation of 4 from DMSO
R
N
R
N
Methyl N-methyl-N-(5-nitro-4-pyrimidinyl)aminoace-
tates (1–3 and 7–9) were synthesised from 6-substituted
4-chloro-5-nitropyrimidines6 by substitution of the chlo-
rine group with sarcosine methyl ester7 or from methyl
NH
N
NH
NO2
NO
1 equiv. NaOR'
O
R'OH, r.t., 2 h
(R' = Me, Et, Pr)
49-80%
N
N
NH
Me
Me OMe
4-6
1-3
Keywords: N-Methyl-N-(6-substituted-5-nitro-4-pyrimidinyl)aminoace-
tates; Cyclisation; Rearrangement; Purines; Nitrosopyrimidines.
R = H (1, 4), R = Ph (2, 5), R = 3-CF3C6H4 (3, 6)
Scheme 1.
*
Corresponding author. Tel.: +370 5 233 07 49; fax: +370 5 233 09
87; e-mail: sigitas.tumkevicius@chf.vu.lt
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.01.119

1842
I. Susvilo et al. / Tetrahedron Letters 46 (2005) 1841–1844
absorption of NH (3161 cmÀ1
) and CO (1736,
1720 cmÀ1) groups. The mass spectrum of 10 exhibited
a molecular ion peak with m/z = 251. The H and 13C
NMR spectra showed the expected signals for the
groups of 10–12.11
1
The results obtained suggested that the transformations
of N-methyl-N-(6-substituted-5-nitro-4-pyrimidinyl)amino-
acetic acid methyl esters (1–3 and 7–9) into products of
different structures proceeds via an intermediate 13
which is probably formed in the first step of cyclisation
of 1–3 and 7–9. N-Oxides 13 can react further in two
directions differing in the site of attack of a hydroxide
ion. The preference for the hydroxide ion to attack C8
of purine 13a is probably determined by the increased
reactivity of C8 towards nucleophiles due to the interac-
tion of the substituent in position 6 of the purine with
the oxygen of the 7-oxide group (Scheme 3).
Figure 1. ORTEP drawing of compound 4.
provided single crystals suitable for the X-ray crystallo-
graphic analysis10 (Fig. 1), which enabled the outcome
of the reaction to be elucidated. Thus, the products
formed in the reaction of compounds 1–3 with a sodium
alkoxide were the corresponding 6-substituted-4-methyl-
amino-5-nitrosopyrimidines 4–6.
Thus, addition of hydroxide to 13 with formation of the
intermediate 14 (Scheme 3) and elimination of OHC–
COOMe leads to the 5-nitroso derivative 5.
Moreover, the crystallographic data of 4 showed that in
the solid state the molecule adopted a conformation in
which the methyl C atom is directed away from the nitr-
oso group and the nitroso group is turned towards the
methylamino substituent. The distance N(7). . .O(10)
and the angle N(7)–H(7)–O(10) were found to be
When the interaction between the substituent in 6 posi-
tion and the N-oxide group by an intramolecular hydro-
gen bond is absent (intermediate 13c), attack of the
hydroxide ion takes place at the ester carbonyl group
to form intermediate 15. Rearrangement of 15 by an
abnormal addition–elimination (AEa) of water, similar
to that proposed for conversion of benzimidazole N-oxi-
des,12 proceeds to give purin-8-one 12 (Scheme 4).
˚
2.654 A and 139°, respectively, indicating that in 4 an
intramolecular hydrogen bond between the oxygen of
the nitroso group and the hydrogen of the methylamino
group had been formed. In solution, perhaps, two forms
of the nitrosopyrimidines exist (Fig. 2) and, therefore,
two sets signals were observed in the NMR spectra.9
In conclusion, the present investigation provides unex-
pected and novel results on rearrangements of (6-substi-
tuted-5-nitro-4-pyrimidinyl)aminoacetates. The reaction
Compounds 7–9 bearing dialkylamino groups in posi-
tion 6 of the pyrimidine ring on treatment with a sodium
alkoxide in an alcohol gave 9-methylpurin-8-ones 10–12,
respectively (Scheme 2). The spectral data of 10–12 were
in accordance with the proposed structures. For exam-
ple, the IR spectrum of 10 was characterised by the
H
Ph
N
H
Ph
N
-
+
-
N
N
N
N
O
N
O
N
OMe
O
OMe
O
+
N
N
Me
Me
13a
13b
R
N
H
R
N
H
N
N
N
N
O
N
N
N
HO-
O
H
H
N
Me
Ph
Ph
-
Me
O
NH
N
NH
O
OH
N
N
N
Figure 2. Conformers of 5-nitrosopyrimidines 4–6.
N
CO2Me
OH
-
CO2Me
N
N
N
Me
Me
14
NR2
NR2
H
N
NO2
N
1 equiv. NaOR'
N
N
O
Ph
N
Ph
N
R'OH, r.t., 2 h
(R' = Me, Et, Pr)
40-69%
O
NH
O
N
N
Me
NH
N
N
N
-
N
O
O
- OHC-CO2Me
CO2Me
Me OMe
7-9
10-12
N
N
NH
Me
R2N = MeNCH2CO2Me (7,10), R2N = N(CH2)6 (8,11),
R2N = PhNMe (9, 12)
Me
5
Scheme 2.
Scheme 3.

I. Susvilo et al. / Tetrahedron Letters 46 (2005) 1841–1844
1843
Kaminskas, A.; Urbelis, G.; Zevaco, T. A.; Walter, O.
Tetrahedron Lett. 2002, 43, 695–697; (c) Tumkevicius, S.;
Sarakauskaite, Z. Pol. J. Chem. 2003, 77, 1275–1282.
6. (a) Boon, W. R.; Jones, G. M.; Ramage, G. R. J. Chem.
Soc. 1951, 96–99; (b) Clark, J. J. Chem. Soc., Perkin.
Trans. 1 1974, 1611–1614.
Me
Ph
N
Ph
N
Me
-
+
N
N
-
+
O
N
N
N
O
OH
OMe
O
-
HO
OMe
O
N
-
N
N
Me
Me
7. Representative procedure for the synthesis of compounds 1–
3 and 7–9. To a suspension of 4-amino-6-chloro-5-nitro-
pyrimidine (0.86 g, 5 mmol) and sarcosine methyl ester
hydrochloride13 (0.7 g, 5 mmol) in methanol (5 mL) a
solution of triethylamine (1.01 g, 10 mmol) in methanol
(3mL) was added dropwise. The reaction mixture was
refluxed for 30 min. The solution was cooled to room
temperature, the precipitate was filtered off, washed with
water and recrystallised to give 0.95 g (80%) of compound
1, mp 149–150 °C (from methanol). IR (Nujol) mmax/cmÀ1
3325, 3187 (NH2), 1758 (CO); dH (300 MHz, CDCl3): 2.97
(3H, s, NCH3); 3.78 (3H, s, OCH3); 4.34 (2H, s, NCH2);
7.00 (2H, br s, NH2), 7.97 (1H, s, C2-H); (found: C, 39.90;
H, 4.46; N, 29.19. C8H11N5O4 requires C, 39.84; H, 4.60;
N, 29.04).
8. General procedure for the synthesis of compounds 4–6 and
10–12. To a suspension of compounds 1–3 and 7–9
(5 mmol) in the corresponding alcohol (5 mL) a solution
of the appropriate sodium alkoxide in alcohol, prepared
from sodium (0.115 g, 5 mmol) and alcohol (3mL), was
added dropwise with stirring. The reaction mixture
was stirred at room temperature for 2 h. The precipitate
was filtered off, washed with water and recrystallised to
give compounds 4–6 and 10–12.
13c
- CO2,
- MeOH
Ph
N
Me
-
Me
Ph
N
N
N
O
N
N
OH
+
H2O
N
N
OH
H
N
N
Me
Me
-
15
OR'
-H2O
Ph
Me
N
H
N
N
O
N
Me
N
12
Scheme 4.
9. Spectral data of selected 4-methylamino-5-nitrosopyrim-
idines. Compound 4: yield 60% (using sodium methoxide
in methanol), 55% (using sodium ethoxide in ethanol),
49% (using sodium propoxide in 1-propanol), mp 256 °C
(dec) (from DMSO), IR (Nujol) mmax/cmÀ1 3320, 3329,
3331 (NH2, NH); dH (300 MHz, DMSO-d6): 2.91, 3.05
(3H, d, J = 4.8 Hz, NCH3); 8.07 (1H, s, C2-H); 8.62, 8.51,
9.11, 10.23(2H, br s, NH 2); 9.59, 11.11 (1H, q, J = 4.8 Hz,
NHCH3); dc (75 MHz, DMSO-d6): 26.3, 27.7 (NCH3),
139.99, 140.7 (C5), 145.5, 146.0 (C4 or C6), 163.05, 164.5
(C6 or C4), 164.7, 165.9 (C2); (found: C, 39.49; H, 4.56; N,
45.43. C5H7N5O requires C, 39.21; H, 4.61; N, 45.73).
Compound 5: yield 65% (using sodium methoxide in
methanol), 58% (using sodium ethoxide in ethanol), 49%
(using sodium propoxide in 1-propanol), mp 162–164 °C
(from 2-PrOH), IR (Nujol) mmax/cmÀ1 3340, 3338 (NH);
dH (300 MHz, CD2Cl2): 3.11, 3.30 (3H, d, J = 4.8 Hz,
NCH3); 7.29–7.89 (5H, m, ArH); 8.28, 8.34 (1H, s, C2-H);
9.93, 11.12 (1H, q, J = 4.8 Hz, NHCH3); 11.46, 13.41 (1H,
br s, NHC6H5); dc (75 MHz, CD2Cl2): 26.6, 28.1 (NCH3),
122.6, 122.7 (C5), 125.3, 126.2, 129.2, 129.2 (Ar), 136.6,
137.8, (C4 or C6), 139.6, 139.7 (C6 or C4), 165.4, 165.7
(C2); (found: C, 57.59; H, 4.76; N, 30.39. C11H11N5O
requires C, 57.63; H, 4.84; N, 30.55).
outcomes mainly depend on the substituent in the 6
position of the pyrimidine ring.
Acknowledgements
We are grateful to M. Kreneviciene and A. Karosiene
for recording NMR and IR spectra and to E. Kersuliene
and M. Gavrilova for the elemental analyses.
References and notes
1. (a) Ried, W.; Beller, G. Liebigs Ann. 1988, 633–642; (b)
Hirota, K.; Shirahashi, M.; Senda, S.; Yogo, M. J.
Heterocycl. Chem. 1990, 27, 717–721; (c) Tumkevicius,
S.; Sarakauskaite, Z.; Masevicius, V. Synthesis 2003,
1377–1382; (d) Clark, J.; Shahhet, M. S.; Korakas, D.;
Varvounis, G. J. Heterocycl. Chem. 1993, 30, 1065–1072.
2. Preston, P. N.; Tennant, G. Chem. Rev. 1972, 72, 627–677.
3. (a) Nohara, F.; Nishii, M.; Ogawa, K.; Isono, K.;
Ubukata, M.; Fujii, T.; Itaya, T.; Saito, T. Tetrahedron
Lett. 1987, 28, 1287–1290; (b) Ogawa, K.; Nishii, M.;
Inagaki, J.; Nohara, F.; Saito, T.; Itaya, T.; Fujii, T.
Chem. Pharm. Bull. 1992, 40, 343–350; (c) Ogawa, K.;
Itaya, T.; Fujii, T. Heterocycles 1994, 38, 1225–1228; (d)
Fujii, T.; Itaya, T.; Ogawa, K. Heterocycles 1997, 44, 573–
592.
4. (a) Kern, D. L.; Hokanson, G. C.; French, J. C.; Dalley,
N. K. J. Antibiot. 1985, 38, 572–574; (b) Nishii, M.;
Inagaki, J.; Nohara, F.; Isono, K.; Kusakabe, H.;
Kobayashi, K.; Sakurai, T.; Koshimura, S.; Sethi, S. K.;
McCloskey, J. A. J. Antibiot. 1985, 38, 1440–1443; (c)
Hasobe, M.; Saneyoshi, M.; Isono, K. J. Antibiot. 1985,
38, 1581–1587.
10. Crystal data for compound 4: C5H7N5O, Mw 153.16,
orthorhombic, space group Pca21; Z = 4, a = 16.4247(4),
˚
b = 4.7518(2), c = 8.3893(8) A, a = b = c = 90°; V =
3
3
˚
654.8(3) A , F(000) = 320, Dx = 1.554 g/cm . Crystallo-
graphic data for structure 4 have been deposited at the
Cambridge Crystallographic Data Centre (CCDC number
252806).
11. Spectral data for the selected 9-methylpurin-8-ones. Com-
pound 11: yield 52% (using sodium methoxide in metha-
nol), mp 189 °C (from H2O), IR (Nujol) mmax/cmÀ1 3155
(NH), 1717 (CO); dH (300 MHz, DMSO-d6): 1.62 (8H, m,
(CH2CH2)2); 3.41 (3H, s, NCH3), 3.81 (4H, m, N(CH2)2),
8.23(1H, s, C2-H), 11.00 (1H, br s, NH). dC (75 MHz,
DMSO-d6): 24.6 (NCH3), 25.5 (CH2CH2), 27.1
(CH2CH2), 47.1 (N(CH2)2), 102.0 (C5), 145.55 (C4 or
5. (a) Susvilo, I.; Brukstus, A.; Tumkevicius, S. Synlett 2003,
1151–1152; (b) Tumkevicius, S.; Agrofoglio, L. A.;

1844
I. Susvilo et al. / Tetrahedron Letters 46 (2005) 1841–1844
C6), 147.8 (C6 or C4), 149.5 (C2), 152.3(CO); (found: C,
127.8, 129.1, 130.1 (Ar), 143.8 (C4 or C6), 145.5 (C6 or
C4), 149.1 (C2), 152.1 (C8); (found: C, 61.49; H, 5.05; N,
27.55. C13H13N5O requires C, 61.16; H, 5.13; N,
27.43).
58.42; H, 6.86; N, 28.45. C12H17N5O requires C, 58.28; H,
6.93; N, 28.32). Compound 12: yield 55% (using sodium
methoxide in methanol), 42% (using sodium ethoxide in
ethanol), mp 195–197 °C (from 2-PrOH), IR (Nujol) mmax
/
12. Benzimidazoles and Congeneric Tricyclic Compounds; Pres-
ton, P. N., Smith, D. M., Gettennant, G., Eds.; Wiley
Interscience: New York, 1981, pp 313–316.
13. Arshody, R.; Atherton, E.; Cleve, D. L. J.; Sheppard, R.
C. J. Chem. Soc., Perkin. Trans. 1 1981, 529–537.
cmÀ1 3393 (NH); dH (300 MHz, CDCl3): 3.39, (3H, s,
NCH3); 3.59, (3H, s, NCH3); 5.86 (1H, br s NH); 7.29–
7.51 (5H, m, ArH); 8.41 (1H, s, C2-H); dc (75 MHz,
CDCl3): 25.9 (NCH3), 38.2 (NCH3), 104.6 (C5), 126.4,