A convenient, highly selective and eco-friendly N-Boc protection of pyrimidines under microwave irradiation

Abstract

Protected pyrimidine nucleobases are of major importance as intermediates in the synthesis of nucleoside analogues and molecules with biological interests. We describe herein a novel practical microwaveassisted N-Boc protection of pyrimidine nucleobases under mild conditions using silica gel, avoiding treatment steps, and in increased yield.Pyrimidine systems are found in many drugs which interact with the synthesis and functions of nucleic acids such as the antitumor drug uorouridine 1 (1), the anti-HIV drug lamivudine 2 (2) or the anti-HBV drug telbivudine 3 (3), or the antimalarial drug pyrimethamine 4 (4), (Fig. 1), to only quote some of them.As chemical modications of nucleobases are of paramount importance in the development of new drugs, 5 their syntheses have been largely described. 6 Focusing on the base moiety, a key step is the choice of the appropriate protecting groups for the N1 and N3 atoms of pyrimidines which have to meet several requirements such as: a differential protection at N1 and N3, a selective deprotection, and a removal under mild reaction conditions. There is an abundant literature relating to the protection of amino groups, such as by 9-uorenyl-methoxycarbonyl (FMOC), 7 tert-butyl carbamates (Boc), benzyl carbamate, benzamide, acetamide, 8 phtalimides, 9 triphenyl methyl amide 10 and tosylamide. 11Among these groups, one of the most used is the Boc; it's stable towards most nucleophiles and bases 12 and it can be removed cleanly and selectively under neutral conditions. 13 This is of particular interest when working with biolabile groups such as found in nucleoside prodrugs. 14 Surprisingly, only two teams have reported the synthesis of N-Boc-protected pyrimidines under basic conditions and in two steps. Gothelf et al. 15 have prepared the N3-Boc-protected thymine (6) through the formation of N1,N3-di-Boc protected derivative and subsequent selective deprotection of N1-Boc group with K 2 CO 3 in dioxane, in only 31% overall yield (Fig. 2). Porcheddhu et al. 16 have described the synthesis of N4,N4-di-Boc cytosine (7) in two steps in moderate 60% yield, via the fully Boc protected cytosine which was then treated with aq. NaHCO 3 in MeOH at reux. However, in spite of their potential utility, these methods suffer from some drawbacks such (a) a long reaction time implied by the rst step, (b) unsatisfactory yields of the deprotection step and (c) cumbersome product isolation procedures. Thus, we present herein, a greener practical protocol to selectively synthesize N1-free, N3-Boc protected pyrimidine nucleobases (5-7, 8a-c) under milder conditions, shorter reaction time and in moderate to quantitatively yields.The general strategy involves two steps: (1) the use of microwave irradiation to reach quantitatively the fully protected pyrimidines (10a, b) and (2) the subsequent selective N1-deprotection by treatment with SiO 2 (ref. 17) in diethoxymethane/ethanol (9 : 1) as an eco-friendly surrogate to CH 2 Cl 2 /MeOH, to desired compounds 5 and 6, respectively Fig. 1 Chemotherapeutics c...

Highly convergent synthesis and antiviral activity of (E)-but-2-enyl nucleoside phosphonoamidates

“…This reaction is performed under ultrasonic activation to afford after seven hours the desired compound 16 in quantitative yield. 16 was then converted to the N3-Boc thymine derivative 17 in quantitative yield, (Scheme 3) [35].…”

Synthesis of 5,5-difluoro-5-phosphono-pent-2-en-1-yl nucleosides as potential antiviral agents

“…Then uracil 6a was converted to its N 3 -benzoyl derivative 7a through a two steps procedure involving rst the formation of N 1 ,N 3 -dibenzoyl derivative in presence of an excess of benzoyl chloride in CH 3 CN/pyridine mixture, then its selective N 1deprotection by treatment with potassium carbonate in 1,4dioxane, (Scheme 3). 17 Similarly, thymine 6b was converted to its N 3 -protected derivative bromide their 7b. Finally, the successful N 1 -alkylation of 7a and 7b on 5 in the presence of cesium carbonate in DMF proceeded in good yields and excellent regioselectivities and afforded 8a and 8b, in 86% and 75% yields, respectively.…”

Sonication-Assisted Synthesis of(E)-2-Methyl-but-2-enyl Nucleoside Phosphonate Prodrugs

“…This protection step used to obtain respectively 8 or 9 , can be performed either following the conventional procedure (Method A) or under microwave irradiation (Method B). The later method required (1) the per‐protection of nitrogens with an excess of Boc 2 O followed by (2) a selective deprotection of N 7 position with SiO 2 in a CH 2 Cl 2 /MeOH mixture at 60 °C . It should be emphasized that the microwave irradiation remarkably reduced the reaction times from 8 h to 10 minutes when compared to the classical method while maintaining comparable yields (Scheme ).…”