Synthesis of triazole nucleoside derivatives

Article abstract of DOI:10.1081/NCN-120022032

5′-O-Mesyl-2′,3′-O-isopropylidene ribonucleosides (4 and 12) were converted to their 5′-substituted nucleosides in good yields by reacted with NaN₃ or KI. 2′,3′-O-Isopropylidene ribonucleosides (3 and 11) were prepared in good yields from ribonucleosides 1 and 2 with a reaction mixture of acetone and triethyl orthoformate instead of using acetone diethyl acetal. Compound 1 or 2 was treated with 2-acetoxyisobutyryl halide (Cl or Br) to give 1-[2-O-acetyl-3-halo-3-deoxy-5-O-(2,5,5-trimethyl-1,3-dioxolan-4-on-2-yl)- β-D-xylofuranosyl]-1,2,4-triazole-3-carboxamide (19, 22, and 23) in high yields. Instead of using 2-acetoxyisobutyryl bromide, the mixture of 2-acetoxyisobutyryl chloride and NaBr was employed in the synthesis of 22 and 23. Treatment of 19 with an activated Zn/Cu couple and deprotection gave 2′,3′-anhydro nucleoside (21), and treatment of 22 and 23 with an activated Zn/Cu couple and a little of HOAc and deprotection gave corresponding 2′,3′-unsaturated triazole nucleosides (24 and 25), respectively. The biological activity of the compounds (7～10, 15～18, and 24) was examined in human liver cancer cells (A-549), lung cancer cells (BEL-7402), and Flu-A cells.

Full text of DOI:10.1081/NCN-120022032

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Synthesis of Triazole Nucleoside Derivatives
Zicheng Li a , Shuhua Chen a c , Ning Jiang b & Gang Cui a
a Faculty of Chemistry , Sichuan University , Chengdu Sichuan, P. R. China
b Sichuan Industrial Institute of Antibiotics , Chengdu Sichuan, P. R. China
c Faculty of Chemistry , Sichuan University , No. 15 Road Wangjiang, Chengdu Sichuan,
610064, P. R. China
Published online: 07 Feb 2007.
To cite this article: Zicheng Li , Shuhua Chen , Ning Jiang & Gang Cui (2003) Synthesis of Triazole Nucleoside Derivatives,
Nucleosides, Nucleotides and Nucleic Acids, 22:4, 419-435, DOI: 10.1081/NCN-120022032
To link to this article: http://dx.doi.org/10.1081/NCN-120022032
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NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS
Vol. 22, No. 4, pp. 419–435, 2003
Synthesis of Triazole Nucleoside Derivatives
2
1
Zicheng Li,1 Shuhua Chen,1, Ning Jiang, and Gang Cui
*
1Faculty of Chemistry, Sichuan University, Chengdu
Sichuan, P. R. China
2Sichuan Industrial Institute of Antibiotics, Chengdu
Sichuan, P. R. China
ABSTRACT
50-O-Mesyl-20,30-O-isopropylidene ribonucleosides (4 and 12) were converted to
their 50-substituted nucleosides in good yields by reacted with NaN3 or KI. 20,30-
O-Isopropylidene ribonucleosides (3 and 11) were prepared in good yields from
ribonucleosides 1 and 2 with a reaction mixture of acetone and triethyl ortho-
formate instead of using acetone diethyl acetal. Compound 1 or 2 was treated
with 2-acetoxyisobutyryl halide (Cl or Br) to give 1-[2-O-acetyl-3-halo-3-deoxy-
5-O-(2,5,5-trimethyl-1,3-dioxolan-4-on-2-yl)-b-D-xylofuranosyl]-1,2,4-triazole-
3-carboxamide (19, 22, and 23) in high yields. Instead of using 2-acetoxyisobutyryl
bromide, the mixture of 2-acetoxyisobutyryl chloride and NaBr was employed in
the synthesis of 22 and 23. Treatment of 19 with an activated Zn=Cu couple and
deprotection gave 20,30-anhydro nucleoside (21), and treatment of 22 and 23 with
an activated Zn=Cu couple and a little of HOAc and deprotection gave correspond-
ing 20,30-unsaturated triazole nucleosides (24 and 25), respectively. The biological
activity of the compounds (7ꢀ10, 15ꢀ18, and 24) was examined in human liver
cancer cells (A-549), lung cancer cells (BEL-7402), and Flu-A cells.
Key Words: Ribavirin derivative; Triazole nucleoside derivative; Antiviral
activity; Synthesis.
*Correspondence: Shuhua Chen, Faculty of Chemistry, Sichuan University, No. 15 Road
Wangjiang, Chengdu Sichuan 610064, P. R. China; Fax: ++86-28-85412285; E-mail:
chemchensh@sina.com.
419
DOI: 10.1081/NCN-120022032
Copyright # 2003 by Marcel Dekker, Inc.
1525-7770 (Print); 1532-2335 (Online)
www.dekker.com

420
Li et al.
Virazole (1) exhibits a broad spectrum of activity against both DNA and RNA
viruses in vitro and in vivo.[1] Various derivatives modified on the triazole ring have
been widely researched, but none has exhibited better activity than the parent com-
pound. We speculated that the triazole-3-carboxamide ring was essential for the
activity of the derivatives of 1. 50-Amino-20,50-dideoxy-5-iodouridine (AIDU) has a
broad spectrum of activity against HSV-1, HSV-2, guinea-pig like virus, and murine
leukemia viruses.[2] Several 20,30-dideoxy and 20,30-unsaturated nucleosides, including
1-(2,3-dideoxy-b- D-glycero-pent-2-enofuranosyl)thymine(d4T), 1-(2,3-dideoxy-b-D-
glycero-pent-2-enofuranosyl) cytosine (d4C), 20,30-dideoxyinosine (ddI) and 20,30-
dideoxycytidine (ddC), have activity against HIV in vitro and in vivo, among them,
d4T, ddC and ddI have been approved for the treatment of AIDS. Our interest in
nucleosides as antiviral and anticancer agents prompted us to synthesize some tria-
zole nucleoside derivatives. The present study describes the synthesis of a series of
such kinds of nucleoside analogs.
RESULTS AND DISCUSSION
50-Substituted derivatives of 1-b-D-ribofuranosyl-1,2,4-triazole-3-carboxamides
(7-10) and 50-substituted derivatives of 3-nitro or amino-1-(b-D-ribofuranosyl)-
1,2,4-triazoles (15-18) were synthesized by using the following general method. Com-
pounds 1 and 2 were protected on the 20 and 30 positions with an isopropylidene
group using a reaction mixture of triethyl orthoformate and acetone with TsOHꢁ
H2O as a catalyst. Because both nucleosides have low solubility in acetone or acetone
diethyl acetal, low yields were obtained in the formation of the isopropylidene moi-
ety using only acetone or acetone diethyl acetal as reagent and solvent catalyzed by
concentrated sulfuric acid or TsOHꢁH2O (approx. 20% yield). We found that when
triethyl orthoformate was added to acetone using TsOHꢁH2O as a catalyst, and the
solution was stirred overnight, followed by addition to a suspension of virazole in a
little of DMF and stirring continued for 24 h at 50ꢂC, the yield was raised to 85%,
which was the same as or higher than that had been reported using the acetone
diethyl acetal method.[3]
50-Mesyl nucleosides were obtained by treatment of the isopropylidene-blocked
nucleosides with methanesulfonyl chloride in dry pyridine. The mesyl group was
replaced by either iodo or azido, and the isopropylidene was then removed to give
50-substituted nucleosides. The iodo, azido and nitro groups were hydrogenated to
hydrogen and amino (Sch. 1).
Compound 1 reacted with 2-acetoxyisobutyryl chloride to give 19 and 20 via an
intermediate acetoxonium ion, in the absence of participation by the triazole ring,
the intermediate acetoxonium ion will be opened by chloride ion from the b face
of the sugar at either C30 or C20 giving 19 and 20, respectively. Attack at C30 is pre-
ferred based on the steric effect.[4] Tlc and products separated by silica gel column
chromatography showed a 3:1 ratio of 19:20. Compounds 19 and 20 were treated
with an activated Zn=Cu couple in dry acetonitrile, then treated with NaOMe in
MeOH to give 20,30-anhydro compound 21.
For the synthesis of 20,30-unsaturated nucleosides, 2-acetoxyisobutyryl chloride
was prepared from 2-hydroxyisobutyric acid by reacted with acetic chloride and then

Triazole Nucleoside Derivatives
421
Scheme 1.
with SOCl2 in a 82% yield,[5] 2-acetoxyisobutyryl bromide was prepared from 2-acet-
oxyisobutyric acid and PBr3 in a low yield,[6] or prepared from 2-acetoxyisobutyryl
chloride and LiBr in 45% yield.[7] The latter method must be performed under inert
gas to avoid moisture, especially in the process of the filtration removing insoluble
salt. Herein we adopted an improved method, 2-acetoxyisobutyryl bromide was
prepared from the reaction mixture of 2-acetoxyisobutyryl chloride and NaBr in
dry acetonitrile, the product acid bromide was directly used in the next reaction with-
out further purification. It has been found that some of the chloro compounds were
also present by nucleosides reacted with 2-acetoxyisobutyryl chloride in the presence
of a large excess of bromide ions. In our case, no chloro compounds were detected
by mass spectrum.
Compounds 1 and 2 reacted with the mixture of 2-acetoxyisobutyryl chloride
and NaBr in refluxing dry acetonitrile to give 22 and 23, and the yields of 22 and
23 were the same as or higher than those reported in references. The same intermedi-
ate was produced in the formation of 22 and 23 as in the case of 19 and 20, though
the larger bromine atom more selectively attacked the 30-position, there by forming
the 30-bromoxylo isomer as the major product. Compounds 22 and 23 were treated

422
Li et al.
Scheme 2.
with an activated Zn=Cu couple, and then with NaOMe in MeOH to give the antici-
pated 20,30-unsaturated nucleosides 24 and 25, respectively[8,9] (Sch. 2).
Antitumor and antiviral activity of the compounds (7ꢀ10, 15ꢀ18, and 24) in A-
549 cells, BEL-7402 cells, and Flu-A cells revealed that only compound 9 provided a
weak level of protection against viral infection, IC25 ¼ 0.4 mmol=mL, no cytotoxicity
was evidenced at that concentration.
From the present work, the modification on sugar moiety of nucleosides with
unnatural bases does not lead to inhibition of virus and tumor multiplication, the
relation of structure and activity need further study.
EXPERIMENTAL
Melting points were determined on a capillary apparatus and are uncorrected.
TLC was performed on microscope slides coated with silica gel GF254 purchased
from Qingdao Haiyang Chemical factory, and column chromatography was per-
formed on silica gel (10–40 mM, Qingdao). Elemental analyses were performed on
a Carlo-Elmer instrument. 1H NMR spectra were recorded on a Varian A-
200 MHz or 400 MHz instrument, and tetramethylsilane was the external standard;
chemical shifts are reported in p.p.m. (d) and signals are quoted as s (singlet), d
(doublet), dd (doublet of doublet), t (triplet), m (complex multiplet), and br (broad).
Mass spectra were recorded on a PE2400-2 instrument.
1-b-D-Ribofuranosyl-1,2,4-triazole-3-carboxamide (1). According to Ref. 1,
1,2,3,5-tetra-O-acetyl-b-D-ribofuranose was fused with methyl 1,2,4-triazole-3-
carboxylate in the presence of bis (p-nitrophenyl) phosphate as a catalyst at 165–
170ꢂC, followed by treatment with NH3 in methanol to give compound 1: mp
169–170ꢂC (lit.1 mp 165–170ꢂC).

Triazole Nucleoside Derivatives
423
1-(2,3-O-Isopropylidene-b-D-ribofuranosyl)-1,2,4-triazole-3-carboxamide (3). Tri-
ethyl orthoformate (3 mL, 18 mmol) and TsOHꢁH2O (35 mg) were added to acetone
(20 mL) and the solution was stirred overnight at room temperature. The solution
was then added to 1 (2 g, 8.2 mmol) dissolved in dry DMF (5 mL), and the mixture
was stirred overnight at 50ꢂC. The solvent was evaporated under vacuum, and the
residual yellow syrup was purified by flash chromatography on silica gel (CH2Cl2-
MeOH, 8:2) to afford 3 as a colorless foam (1.63 g, yield 85%). mp: 116–118ꢂC;
1H NMR (DMSO-d6): d 8.87 (s, 1H, H-5), 7.86 and 7.66 (2s, 2H, CONH2), 6.20
(d, 1H, J ¼ 1.2 Hz, H-10), 5.18 (dd, J ¼ 1.2 Hz and 5.9 Hz, H-20), 4.97 (t, 1H,
J ¼ 5.4 Hz, H-30), 4.91(dd, 1H, J ¼ 1.8 Hz and 6 Hz, OH-50), 4.23 (dd, 1H, J ¼ 1.7 Hz
and 5.8 Hz, H-40), 3.45 (m, 2H, H-50), 1.50 (s, 3H, CH3), 1.32 (s, 3H, CH3).
1-(2,3-O-Isopropylidene-5-O-mesyl-b-D-ribofuranosyl)-1,2,4-triazole-3-carbox-
amide (4). Mesyl chloride (1.2 mL, 15.4 mmol) was slowly added to a solution of 3
(1.5 g, 5.28 mmol) dissolved in 10 mL of dry pyridine and cooled in ice-water bath,
and the mixture was stirred overnight at r.t. The solution was filtered and washed
with CH2Cl2, the filtrate was evaporated, and the residue was dissolved in CH2Cl2,
which was washed with brine and dried with anhydrous MgSO4. The solvent was
evaporated and the residue was purified by flash chromatography on silica gel
(CH2Cl2 : MeOH ¼ 95 : 5) to give 4 as a colorless foam(1.85 g, yield 87%). mp: 79–
1
81ꢂC; H NMR (DMSO-d6): d 8.84 (s, 1H, H-5), 7.89 and 7.69 (2s, 2H, CONH2),
6.39 (s, 1H, H-10), 5.18 (d, 1H, J ¼ 5.7 Hz, H-20), 5.03 (d, 1H, J ¼ 5.7 Hz, H-30),
4.25–4.49 (m, 3H, H-40, H-50), 3.14 (s, 3H, Ms), 1.52 (s, 3H, CH3), 1.34 (s, 3H,
CH3); mass spectrum (EI) m=e 361 (Mþ ꢃ 1, 65).
1-(5-Azido-5-deoxy-2,3-O-isopropylidene-b-D-ribofuranosyl)-1,2,4-triazole-3-car-
boxamide (5). To a solution of 4 (1 g, 2.76 mmol) dissolved in 5 mL of dry DMF
was added sodium azide (350 mg, 5.4 mmol), and the suspension was then heated
at 120ꢂC for 0.75 h until tlc showed that the reaction had been completed. The reac-
tion solution was poured into 10 g of crushed ice and extracted with CH2Cl2
(3 ꢄ 20 mL). The organic phases were washed with water, dried with anhydrous
NaSO4, evaporated, and purified by silica gel column chromatography (CH2Cl2-
1
MeOH, 95:5) to afford 5 as a colorless foam (0.82 g, 96% yield). mp: 97–99ꢂC; H
NMR (DMSO-d6): d 8.85 (s, 1H, H-5), 7.90 and 7.68 (2s, 2H, CONH2), 6.37
(s, 1H, H-10), 5.22 (d, 1H, J ¼ 5.5 Hz, H-20), 4.94 (d, 1H, J ¼ 5.6 Hz, H-30), 4.38
(m, 1H, H-40), 3.65 (pseudo t, 2H, H-50), 1.52 (s, 3H, CH3), 1.33 (s, 3H, CH3).
1-(5-Azido-5-deoxy-b-D-ribofuranosyl)-1,2,4-triazole-3-carboxamide (7). To a
solution of 5 (800 mg, 2.59 mmol) in 10 mL of methanol was added 0.5 mL of concen-
trated HCl at r. t. and the solution was stirred for 5 h. Solid NaHCO3 was used to
adjust the solution to pH 7 and the solvent was removed under reduced pressure.
The residual solid was purified by silica gel column chromatography (CH2Cl2:
1
MeOH ¼ 8 : 2) to give a colorless solid (660 mg, 95%). mp: 124–125ꢂC; H NMR
(DMSO-d6) : d 8.86 (s, 1H, H-5), 7.84 and 7.64 (2s, 2H, CONH2), 5.92 (d, 1H,
J ¼ 2.7 Hz, H-10), 5.70 (d, 1H, J ¼ 5.2 Hz, OH-20), 5.38 (d, 1H, J ¼ 5.7 Hz, OH-30),
4.39 (dd, 1H, J ¼ 2.8 Hz and 5.3 Hz, H-20), 4.20 (dd, 1H, J ¼ 5.4 Hz and 5.6 Hz,
H-30), 4.06 (dd, 1H, J ¼ 5.8 Hz and 9.3 Hz, H-40), 3.54 (m, 2H, H-50); mass spectrum

424
Li et al.
(EI) m=e 270 (Mþ þ 1, 87); Anal. for C8H11N7O4: C, 35.69; H, 4.12; N, 36.42; found:
C, 35.66; H, 4.00; N, 36.52.
1-(5-Amino-5-deoxy-b-D-ribofuranosyl)-1,2,4-triazole-3-carboxamide
(8).
A
solution of 7 (500 mg, 1.86 mmol) in 25 mL of methanol was hydrogenated in the pre-
sence of 0.5 g of 10% Pd=C for 6 h at 1 atmosphere, the mixture was filtered through
a celite pad, and the filtrate was concentrated and purified by silica gel column chro-
1
matography to afford a pale-yellow solid (370 mg, 82%). mp: 142–143ꢂC; H NMR
(DMSO-d6): d 8.88 (s, 1H, 5-H), 7.84 and 7.64 (2s, 2H, CONH2), 5.96 (s, 1H, H-10),
5.85 (d, 2H, J ¼ 3.6 Hz, OH-20, OH-30), 4.34 (br s, 1H, H-20), 4.20 (br s, 1H, H-30),
3.95 (dd, 1H, J ¼ 5.4 Hz and 11.5 Hz, H-40), 3.2–3.4 (m, 2H, H-50); mass spectrum
(EI) m=e 266 (Mþ þ Na, 10); Anal. for C8H13N5O4: C, 39.51; H, 5.39; N, 28.79;
found: C, 39.60; H, 5.41; N, 28.65.
1-(5-Iodo-5-deoxy-2,3-O-isopropylidene-b-D-ribofuranosyl)-1,2,4-triazole-3-car-
boxamide (6). Dry potassium iodide (730 mg, 4.4 mmol) was added into a solution
of 4 (800 mg, 2.21 mmol) in 5 mL of dry DMF and the suspension was heated for
0.5 h at 125ꢂC. The reaction mixture was then poured into 20 g of crushed ice, which
was extracted with CH2Cl2 (3 ꢄ 20 mL). The combined organic phase was washed
with 10% aqueous Na2S2O3 (2 ꢄ 10 mL) and brine, dried with anhydrous Na2SO4,
filtered, and evaporated to give a brown oil that was purified by silica gel column
chromatography (CH2Cl2 : MeOH ¼ 95 : 5) to give a colorless solid (810 mg, yield
1
93%). mp: 136–138ꢂC; H NMR (DMSO-d6): d 8.89 (s, 1H, H-5), 7.84 and 7.64
(2s, 2H, CONH2), 6.27 (d, 1H, J ¼ 2.8 Hz, H-10), 5.36 (d, 1H, J ¼ 5.4 Hz, H-20),
4.95 (d, 1H, J ¼ 5.5 Hz, H-30), 4.34 (dd, 1H, J ¼ 5.8 Hz and 9.3 Hz, H-40), 3.54
(m, 2H, H-50). 1.53 (s, 3H, CH3), 1.34 (s, 3H, CH3).
1-(5-Iodo-5-deoxy-b-D-ribofuranosyl)-1,2,4-triazole-3-carboxamide (9). Com-
pound 9 was prepared from 6 using the procedure of the synthesis of 7 in 83% yield.
1
mp: 164–165ꢂC; H NMR (DMSO-d6): d 8.87 (s, 1H, 5-H), 7.87 and 7.64 (2s, 2H,
CONH2), 5.88 (d, 1H, J ¼ 3.7 Hz, H-10), 5.70 (d, 1H, J ¼ 5.1 Hz, OH-20), 5.47
(d, 1H, J ¼ 4.9 Hz, OH-30), 4.48 (d, 1H, J ¼ 3.9 Hz, H-20), 4.19 (d, 1H, J ¼ 4.4 Hz,
H-30), 4.04 (dd, 1H, J ¼ 5.2 Hz and 11.5 Hz, H-40), 3.3–3.57 (m, 2H, H-50); Anal.
for C8H11IN4O4, C, 27.14; H, 3.13; N, 15.82; found: C, 27.10; H, 3.17; N, 15.64.
1-(5-Deoxy-b-D-ribofuranosyl)-1,2,4-triazole-3-carboxamide (10). Compound 9
1
was hydrogenated according to the procedure for 7 to give 10, mp: 126–127ꢂC; H
NMR (DMSO-d6): d 8.89 (s, 1H, 5-H), 7.86 and 7.66 (2s, 2H, CONH2), 5.91
(d, 1H, J ¼ 2.8 Hz, H-10), 5.68 (d, 1H, J ¼ 5.3 Hz, OH-20), 5.37 (d, 1H, J ¼ 5.6 Hz,
OH-30), 4.38 (dd, 1H, J ¼ 2.8 Hz and 5.3 Hz, H-20), 4.21 (dd, 1H, J ¼ 5.4 Hz and
5.6 Hz, H-30), 4.01 (dd, 1H, J ¼ 5.8 Hz and 9.3 Hz, H-40), 1.33 (m, 3H, H-50); mass
spectrum (EI) m=e 229 (Mþ þ 1, 100); Anal. for C8H12N4O4: C, 42.10; H, 5.30; N,
24.55; found: C, 42.25; H, 5.25; N, 24.38.
3-Nitro-1-(b-D-ribofuranosyl)-1,2,4-triazole (2). Compound 2 was prepared
according to a previously reported procedure.[10] mp: 138.5–140ꢂC (lit.10 138–
140ꢂC).

Triazole Nucleoside Derivatives
425
3-Nitro-1-(2,3-O-isopropylidene-b-D-ribofuranosyl)-1,2,4-triazole (11). Com-
pound 11 was prepared from 2 according to the procedure for 3 in 82% yield,
1
mp 105–106ꢂC; H NMR (DMSO-d6): d 9.01 (s, 1H, H-5), 6.25 (s, 1H, H-10), 5.21
(d, 1H, J ¼ 4.4 Hz, H-20), 4.99 (dd, 1H, J ¼ 4.4 Hz and 7.8 Hz, H-30), 4.90 (t, 1H,
J ¼ 5.2 Hz, OH-50), 4.36 (dd, 1H, J ¼ 5.2 Hz and 5.2 Hz, H-40), 3.5 (m, 2H, H-50),
1.50 (s, 3H, CH3), 1.34 (s, 3H, CH3); mass spectrum (EI) m=e 287 (Mþ þ 1, 100).
3-Nitro-1-(2,3-O-isopropylidene-5-O-mesyl-b-D-ribofuranosyl)-1,2,4-triazole (12).
Compound 12 was prepared from 11 according to the procedure for 4 in 88% yield,
1
mp: 87–88ꢂC; H NMR (DMSO-d6): d 9.04 (s, 1H, H-5), 6.43 (s, 1H, H-10), 5.28
(dd, 1H, J ¼ 1.4 Hz and 5.8 Hz, H-20), 4.99 (dd, 1H, J ¼ 1.6 Hz and 6.0 Hz, H-30),
4.59 (m, 1H, H-40), 4.39 (dd, 1H, J ¼ 4.8Hz and 10.5 Hz, H-50a), 4.32 (dd, 1H,
J ¼ 7.0 Hz and 10.5 Hz, H-50b), 3.13 (s, 3H, MsO), 1.52 (s, 3H, CH3), 1.35 (s, 1H,
CH3); mass spectrum (EI) m=e 365 (Mþ þ 1, 20).
3-Nitro-1-(5-azido-5-deoxy-b-D-ribofuranosyl)-1,2,4-triazole (15). Compound
15 was prepared from 12 according to the procedure for 7 in 92% yield. mp:
1
136.5–138ꢂC; H NMR (DMSO-d6): d 9.10 (s, 1H, H-5), 6.02 (d, 1H, J ¼ 2.8 Hz,
H-10), 5.84 (d, 1H, J ¼ 2.8 Hz, OH-20), 5.50 (d, 1H, J ¼ 6 Hz, OH-30), 4.40 (m, 1H,
H-20), 4.27 (dd, 1H, H-30), 4.12 (ddd, 1H, J ¼ 3.2 Hz, 6 Hz and 3 Hz, H-40), 3.62
(dd, 1H, J ¼ 3.2 Hz and 13.6 Hz, H-50a), 3.45 (dd, 1H, J ¼ 6 Hz and 13.6 Hz,
H-50b); mass spectrum (EI) m=e 272 (Mþ þ 1, 25); Anal. for C7H9N7O5: C, 31.00;
H, 3.35; N, 36.15; found: C, 30.85; H, 3.36; N, 35.96.
3-Amino-1-(5-amino-5-deoxy-b-D-ribofuranosyl)-1,2,4-triazole (16). Compound
16 was prepared from 13 according to the procedure for 8 in 87% yield as a pale yel-
1
low oil. H NMR (DMSO-d6): d 8.2 (s, 1H, H-5), 5.50 (d, 1H, J ¼ 4 Hz, H-10), 5.37
(s, 2H, OH-20, OH-30), 4.28 (m, 1H, H-20), 4.08 (m, 1H, H-30), 3.80 (m, 1H, H-40),
3.50 (m, 2H, NH2), 2.75 (dd, 1H, J ¼ 4.4 Hz and 13.2 Hz, H-50a), 2.66 (dd, 1H,
J ¼ 6 Hz and 13.2 Hz, H-50b); mass spectrum (EI) m=e 216 (Mþ þ 1, 10); Anal. for
C7H13N5O3: C, 39.07; H, 6.09; N, 32.54; found: C, 39.13; H, 6.15; N, 32.42.
3-Nitro-1-(5-iodo-5-deoxy-b-D-ribofuranosyl)-1,2,4-triazole (17). Compound 17
was prepared from 12 according to the procedure for 9 in 89% yield as a colorless
solid, mp: 107–109ꢂC; 1H NMR (DMSO-d6): 9.10 (s, 1H, H-5), 5.99 (d, 1H,
J ¼ 3.2 Hz, H-10), 5.79 (br s, 1H, OH-20), 5.53 (br s, 1H, OH-30), 4.48 (s, 1H,
H-20), 4.22–4.03 (m, 2H, H-30, H-40), 3.56–3.33 (m, 2H, H-50); mass spectrum (EI)
m=e 357 (Mþ þ 1, 20); Anal. for C7H9IN4O5: C, 23.61; H, 2.55; N, 15.73; found:
C, 23.50; H, 2.43; N, 15.45.
3-Amino-1-(5-deoxy-b-D-ribofuranosyl)-1,2,4-triazole (18). Compound 18 was
prepared from 17 according to the procedure for 10 in 85% yield as a colorless solid,
1
mp: 101–103ꢂC; H NMR (DMSO-d6): d 8.22 (s, 1H, H-5), 5.65 (d, 1H, J ¼ 3.8 Hz,
H-10), 5.67 (d, 1H, J ¼ 3.2 Hz, OH-20), 5.49 (d, 1H, J ¼ 3.3 Hz, OH-30), 4.38 (d, 1H,
J ¼ 4.0 Hz, H-20), 4.14 (t, 1H, J ¼ 5 Hz, H-30), 3.9 (m, 1H, H-40), 1.21(dd, 3H,
J ¼ 3.2 Hz and 5.8 Hz, H-50); mass spectrum (EI) m=e 199 (Mþ ꢃ 1, 14); Anal. for
C7H12N4O3: C, 42.00; H, 6.04; N, 27.99; found: C, 41.92; H, 6.15; N, 27.75.

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1-[2-O-Acetyl-3-chloro-3-deoxy-5-O-(2,5,5-trimethyl-1,3-dioxolan-4-on-2-yl)-b-
D-xylofuranosyl]-1,2,4-triazole-3-carboxamide (19) and 1-[3-O-acetyl-2-chloro-2-
deoxy-5-O-(2,5,5-trimethyl-1,3- dioxolan-4-on-2-yl)-b-D-arabinofuranosyl]-1,2,4-tria-
zole-3-carboxamide (20). Compound 1 (230 mg, 0.9 mmol) was suspended in dry
acetonitrile (20 mL). To this solution was slowly added 2-acetoxyisobutyryl chloride
(540 mg, 2.7 mmol) in 10 mL of anhydrous acetonitrile with stirring at r.t.. After a
clear solution was attained for about 20 min, stirring was continued for 4 h
at 60ꢂC. The solution was then cooled to room temperature, and the solvent was
removed under reduced pressure. The residue was dissolved in ethyl acetate
(100 mL), washed with satur. aqueous NaHCO3 (2 ꢄ 30 mL), water (50 mL) and
dried with anhydrous MgSO4. The solvent was removed giving a pale yellow oily
product (387 mg, 94% yield). The oily product was purified by silica gel column chro-
matography (CH2Cl2:MeOH ¼ 97:3), a colorless foam was obtained (292 mg), which
1
showed a 3 : 1 mixture of compounds 19: 20. H NMR (DMSO-d6) of 19: d 8.82
(s, 1H, H-5), 7.82 and 7.68 (2s, 2H, CONH2), 6.20 (d, 1H, J ¼ 3.9 Hz, H-10), 5.76
(dd, 1H, J ¼ 4.2 Hz and 3.3 Hz, H-20), 4.86 (dd, 1H, J ¼ 3.3 Hz and 6.6 Hz,
H-30), 4.38 (m, 1H, H-40), 3.88 (dd, 1H, J ¼ 4.8 Hz and 12.9 Hz, H-50a), 3.59
(dd, 1H, J ¼ 6.2 Hz and 12.9 Hz, H-50b), 2.08 (s, 3H, OAc), 1.73 (s, 3H, CH3CO3),
1.49, 1.45 (2s, 6H, (CH3)2C); mass spectrum (EI) m=e 433 (Mþ, 100).
1-(2,3-Anhydro-b-D-ribofuranosyl)-1,2,4-triazole-3-carboxamide
(21). Com-
pound 19 (156 mg, 0.33 mmol) was dissolved in 15 mL of anhydrous MeCN, Zn=Cu
(0.8 g) was added, the mixture was stirred overnight at r. t., the mixture was filtered
through a celite pad, and the filtrate was evaporated under vacuum. The residue was
dissolved in 0.5 g NaOMe in 20 mL of dry methanol, and the solution was stirred
overnight at r. t. The solvent was removed, and the residue was purified by silica col-
1
umn chromatography (CH2Cl2:MeOH ¼ 20:1) to give a colorless foam. H NMR
(DMSO-d6): d 8.77 (s, 1H, H-5), 7.91 and 7.69 (2s, 2H, CONH2), 5.82 (d, 1H,
J ¼ 2.6 Hz, H-10), 4.70 (s, 1H, H-20), 4.48 (d, 1H, J ¼ 4.3 Hz, H-30), 3.73 (m, 1H,
H-40), 3.5 (m, 2H, H-50); mass spectrum (EI) m=e 227 (Mþ þ 1, 100); Anal. for
C8H10N4O4: C, 42.48; H, 4.46; N, 24.77; found: C, 42.79; H, 4.76; N, 24.39.
1-[2-O-Acetyl-3-bromo-3-deoxy-5-O-(2,5,5-trimethyl-1,3-dioxolan-4-on-2-yl)-b-
D-xylofuranosyl]-1,2,4-triazole-3-carboxamide (22). 2-Acetoxyisobutyryl chloride
(10.29 g, 62.5 mmol) was added in a suspension solution of NaBr (24.4 g, 237 mmol)
in 100 mL of anhydrous MeCN, and the mixture was stirred for 0.5 h at room tem-
perature under N2. Compound 1 (5 g, 20.5 mmol) was then added, and the resulting
mixture was heated for 3 h at 70ꢂC. The reaction solution was cooled to r. t., filtered,
and most of the solvent was removed under vacuum with maintaining the tempera-
ture at lower than 40ꢂC. Water (50 mL) was added into the residue, it was extracted
with ethyl acetate (2 ꢄ 50 mL). The organic phases were washed with satur. aqueous
NaHCO3 (2 ꢄ 30 mL), water (2 ꢄ 30 mL), and dried with anhydrous MgSO4. The
1
solvent was removed to give a brown oily product (7.3 g, 74.8% yield). H NMR
(DMSO-d6): d 8.82 (s, 1H, H-5), 7.82 and 7.66 (2s, 2H, CONH2), 6.20 (d, 1H, J ¼
3.9 Hz, H-10), 5.16 (dd, 1H, J ¼ 4.2 Hz, H-20), 4.86 (dd, 1H, J ¼ 3.3 Hz and 6.6 Hz,
H-30), 4.38 (m, 1H, H-40), 3.88 (dd, 1H, J ¼ 4.8 Hz and 12.9 Hz, H-50a), 3.61(dd,
1H, J ¼ 5.6 Hz and 12.8 Hz, H-50b), 2.09 (s, 3H, OAc), 1.73 (s, 3H, CH3CO3), 1.49

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Li et al.
and 1.45 (2s, 6H, (CH3)2C); mass spectrum (EI) m=e 477 (Mþ þ 1, 95), 479 (Mþ þ 3,
100%).
1-(2,3-Dideoxy-b-D-glycero-pent-2-enofuranosyl)-1,2,4-triazole-3-carboxamide (24).
Compound 22 (7.2 g) was dissolved in 30 mL of anhydrous MeCN, to which was added
3.5 g of Zn=Cu and 1.5 mL of HOAc. The mixture was stirred for 5 h at r. t. filtered
through a celite pad, and the filtrate was removed under vacuum. The residue was dis-
solved in 100 mL of ethyl acetate, organic phase was washed with 5% aqueous EDTA
(2 ꢄ 50mL), water (2 ꢄ 50 mL), and dried with anhydrous MgSO4. The solvent was
removed, and the residue was dissolved in 20mL of methanol containing 0.3 g of
NaOMe. The solution was stirred for 4 h at r. t., the solvent was removed, and the resi-
due was purified by silica column chromatography to give a colorless foam (350 mg,
16% yield). 1H NMR (acetone-d6): d 8.86 (s, 1H, H-5), 7.87 and 7.64 (2s, 2H, CONH2),
7.29 (br s, 1H, H-10), 6.67 (br s, 1H, H-30), 5.91 (d, 1H, J ¼ 3.3 Hz, H-20), 4.18 (m, 1H,
H-40), 3.3–3.6 (m, 2H, H-50); mass spectrum (EI) m=e 211 (Mþ þ 1, 24%); Anal. for
C8H10N4O3: C, 45.71; H, 4.80; N, 26.66; found: C, 45.92; H, 4.65; N, 26.79.
3-Nitro-1-[2-O-acetyl-3-bromo-3-deoxy-5-O-(2,5,5-trimethyl-1,3-dioxolan-4-on-2-
yl)-b-D-xylofuranosyl]-1,2,4-triazole (23). Compound 23 was prepared according
to procedure for 22 in 89% yield. mass spectrum (EI) m=e 481 (Mþ þ 1, 5), 365
(Mþ ꢃ 114, 100).
3-Nitro-1-(2,3-dideoxy-b-D-glycero-pent-2-enofuranosyl)-1,2,4-triazole
(25).
Compound 25 was prepared from 23 according to the procedures for 24 to give a pale
yellow foam in 21% yield. 1H NMR (acetone-d6): d 8.99 (s, 1H, H-5), 7.21 (s, 1H, H-
10), 6.78 (s, 1H, H-30), 5.94 (s, 1H, H-20), 4.96 (m, 1H, H-40), 3.52 (m, 2H, H-50); mass
spectrum (EI) m=e 212 (Mþ, 7); Anal. for C7H8N4O4: C, 39.63; H, 3.80; N, 26.41;
found: C, 39.51; H, 3.66; N, 26.75.
ACKNOWLEDGMENTS
This paper was supported by funding from Chengdu Molecule Laboratory,
Hengdian Group, Zhejiang, P. R. China. The authors also thank the National
Center for Drug Screening of China for biological activity test.
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Received May 22, 2002
Accepted February 10, 2003