A Novel and Efficient Synthesis of 6-Dialkylamino-9-benzyl-8-methoxypurines and 6-Dialkylamino-9-benzylpurin-8-ones by Reaction of Methyl N-Benzyl-N-(6-dialkylamino-5-nitropyrimidin-4-yl)glycinates with Sodium Alkoxides

Inga Susvilo; Algirdas Brukstus; Sigitas Tumkevicius

doi:10.1055/s-2006-941566

LETTER

A Novel and Efficient Synthesis of 6-Dialkylamino-9-benzyl-8-methoxypurines and 6-Dialkylamino-9-benzylpurin-8-ones by Reaction of Methyl N-Benzyl-N-(6-dialkylamino-5-nitropyrimidin-4-yl)glycinates with Sodium Alkoxides

Inga Susvilo, Algirdas Brukstus, Sigitas Tumkevicius*
Vilnius University, Faculty of Chemistry, Department of Organic Chemistry, Naugarduko 24, 03225 Vilnius, Lithuania
Fax: +370(5)23309 87; e-Mail: sigitas.tumkevicius@chf.vu.lt;

Abstract

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Abstract

A novel and simple synthesis of 6-dialkylamino-9-benzyl-8-methoxypurines and 6-dialkylamino-9-benzylpurin-8-ones by reaction of methyl N-benzyl-N-(6-dialkylamino-5-nitropyrimidin-4-yl)glycinates with sodium alkoxides is described.

Key words

methyl N-benzyl-N-(6-dialkylamino-5-nitropyrimidin-4-yl)glycinates - 8-methoxypurines - purin-8-ones - cyclisation - rearrangement

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References

References and Notes

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Typical Procedure for the Preparation of Methyl N -Benzyl- N -(6-dialkylamino-5-nitropyrimidin-4-yl)glycinates 2a-e. A solution of compound 1a-e (5 mmol), benzylamino acetic acid methyl ester (0.9 g, 5 mmol), Et₃N (0.5 g, 5 mmol) in MeOH (10 mL) was refluxed for 1 h. After cooling to r.t. the precipitate was filtered off and recrystallised to give 2a-e.
Compound 2a: yield 80%, mp 98-100 °C (from MeOH). IR (nujol): ν_max = 1748 (CO₂Me), 1563 (NO₂) cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 1.88-1.92 [4 H, m, (CH₂)₂], 3.37-3.41 [4 H, m, N(CH₂)₂], 3.76 (3 H, s, OMe), 4.23 (2 H, s, NCH₂CO), 4.96 (2 H, s, NCH₂Ph), 7.30 (5 H, s, ArH), 8.02 (1 H, s, C₂-H) ppm. Anal. Calcd for C₁₈H₂₁N₅O₄: C, 58.21; H, 5.70; N, 18.86. Found: C, 58.37; H, 5.67; N, 18.79.
Compound 2c: yield 87%, mp 140-142 °C (from MeOH). IR (nujol): ν_max = 1747 (CO₂Me), 1567 (NO₂) cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 3.30-3.34 [4 H, m, N(CH₂)₂], 3.48-3.52 [4 H, m, O(CH₂)₂], 3.71 (3 H, s, OMe), 4.51 (2 H, s, NCH₂CO), 4.96 (2 H, s, NCH₂Ph), 7.30 (5 H, s, ArH), 7.97 (1 H, s, C₂-H) ppm. Anal. Calcd for C₁₈H₂₁N₅O₅: C, 55.81; H, 5.46; N, 18.08. Found: C, 55.89; H, 5.27; N, 18.15.
Compound 2e: yield 83%, mp 125-126 °C (from i-PrOH). IR (nujol): ν_max = 1762 (CO₂Me), 1578 (NO₂) cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 1.21-1.48 [8 H, m, (CH₂)₂], 3.20-3.51 [4 H, m, N(CH₂)₂], 3.76 (3 H, s, OMe), 4.36 (2 H, s, NCH₂CO), 5.00 (2 H, s, NCH₂Ph), 7.24-7.29 (5 H, m, ArH), 7.91 (1 H, s, C₂-H) ppm. Anal. Calcd for C₂₀H₂₅N₅O₄: C, 60.14; H, 6.36; N, 17.53. Found: C, 60.29; H, 6.28; N, 17.71.

Typical Procedure for the Preparation of 6-Dialkyl-amino-9-benzyl-8-methoxypurines (3a-e) and 6-Dialkylamino-9-benzylpurin-8-ones (4a-e). To a suspension of the corresponding compound 2a-e
(5 mmol) in an alcohol (5 mL) a solution of the sodium alkoxide, prepared from sodium (0.115 g, 5 mmol) and appropriate alcohol (3 mL), was added dropwise under stirring. The reaction mixture was stirred at r.t. for 2 h. The precipitate was filtered off and recrystallised to give 3a-e or 4a-e.
Compound 3a: yield 80%, mp 139-140 °C (from EtOH). [8]
Compound 3b: yield 79%, mp 143-145 °C (from i-PrOH). [8]
Compound 3c: yield 91%, mp 142-144 °C (from MeOH). ¹H NMR (300 MHz, CDCl₃): δ = 3.79-3.81 [4 H, m, N(CH₂)₂], 4.12 (3 H, s, OMe), 4.17-4.20 [4 H, m, O(CH₂)₂], 5.17 (2 H, s, NCH₂Ph), 7.29 (5 H, s, ArH), 8.30 (1 H, s, C₂-H) ppm. ¹³C NMR (CDCl₃): δ = 43.6, 45.1, 57.0, 66.0, 115.0, 127.0, 127.4, 128.4, 136.3, 150.2, 150.3, 151.2, 153.4 ppm. MS (%): m/z = 325 (30) [M⁺]. Anal. Calcd for C₁₇H₁₉N₅O₂: C, 62.75; H, 5.89; N, 21.52. Found: C, 62.86; H, 5.74; N, 21.17.
Compound 3d: yield 85%, mp 150-151 °C (from hexane). [8]
Compound 3e: yield 76%, mp 127-128 °C (from i-PrOH). [8]
Compound 4a: yield 82% (using NaOEt in EtOH). Yield 62% (using NaOPr in PrOH), mp 254-255 °C (from MeOH). [8]
Compound 4b: yield 80% (using NaOEt in EtOH), mp 215-216 °C (from MeOH). [8]
Compound 4c: yield 81% (using NaOEt in EtOH), mp 259-260 °C (from MeOH). IR (nujol): ν_max = 3116 (NH), 1715 (CO) cm^-1. ¹H NMR (300 MHz, DMSO-d ₆): δ = 3.52-3.56 [4 H, m, N(CH₂)₂], 3.68-3.71 [4 H, m, O(CH₂)₂], 4.98 (2 H, s, NCH₂Ph), 7.32 (5 H, s, ArH), 8.19 (1 H, s, C₂-H), 11.16 (1 H, br s, NH) ppm. ¹³C NMR (75 MHz, DMSO-d ₆): δ = 43.1, 46.6, 66.7, 105.9, 128.1, 128.2, 129.2, 137.7, 147.7, 149.7, 150.9, 153.5 ppm. MS (%): m/z = 311 (40) [M⁺]. Anal. Calcd for C₁₆H₁₇N₅O₂: C, 61.72; H, 5.50; N, 22.49. Found: C, 61.87; H, 5.47; N, 22.52.
Compound 4d: yield 82% (using NaOEt in EtOH), mp 222-223 °C (from MeOH). [8]
Compound 4e: yield 77% (using NaOEt in EtOH), yield 59% (using NaOPr in PrOH), mp 249-250 °C (from
i-PrOH). [8]
Compound 5: yield 93%, mp 128-129 °C (from MeOH). ¹H NMR (300 MHz, CDCl₃): δ = 3.78-3.80 [4 H, m, N(CH₂)₂], 4.19-4.21 [4 H, m, O(CH₂)₂], 5.17 (2 H, s, NCH₂Ph), 7.28 (5 H, s, ArH), 8.29 (1 H, s, C₂-H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 44.7, 45.9, 56.2, 67.3, 116.3, 127.8, 127.9, 128.9, 136.5, 150.9, 151.2, 152.3, 154.2 ppm. Anal. Calcd for C₁₇H₁₆D₃N₅O₂: C, 62.18; H/D, 6.75; N, 21.33. Found: C, 62.05; H/D, 6.74; N, 21.52.

Compounds 2b,d, 3a,b,d,e and 4a,b,d,e were also fully characterised by IR, ¹H NMR, ¹³C NMR spectroscopic and microanalytical data.

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