Synthesis of pyrrolo[2,1-f][1,2,4]triazine C-nucleosides. Isosteres of sangivamycin, tubercidin, and toyocamycin

Article abstract of DOI:10.1016/S0008-6215(01)00017-9

Syntheses of pyrrolo[2,1-f][1,2,4]triazine C-nucleosides are reported. Treatment of pyranulose glycoside with aminoguanidine in acetic acid gave the corresponding semicarbazone in 96% yield. The ring transformation of the semicarbazone in dioxane afforded a 51% yield of 2-amino-7-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl) pyrrolo[2,1-f][1,2,4]triazine. Vilsmeier formylation of the pyrrolotriazine gave the major product, 5-formylpyrrolo[2,1-f][1,2,4]triazine, in 69% yield. The aldehyde was treated with hydroxylamine hydrochloride in methanol to give aldoximes. Dehydration of aldoxime with trifluoromethanesulfonic anhydride and triethylamine in dichloromethane afforded 5-cyanopyrrolo[2,1-f][1,2,4]triazine in 44% yield. Conversion of the nitrile to the deprotected amide, 2-amino-7-(β-D-ribofuranosyl)pyrrolo[2,1-f][1,2,4]triazine-5- carboxamide, was accomplished in 96% yield on treatment with 30% H₂O₂ in ethanol for 1 day at room temperature. Debenzoylation with sodium hydroxide solution produced deprotected C-nucleosides.

Full text of DOI:10.1016/S0008-6215(01)00017-9

www.elsevier.nl/locate/carres
Carbohydrate Research 331 (2001) 77–82
Note
Synthesis of pyrrolo[2,1-f][1,2,4]triazine C-nucleosides.
Isosteres of sangivamycin, tubercidin, and toyocamycin
Natsu Nishimura, Ai Kato, Isamu Maeba *
Faculty of Pharmacy, Meijo Uni6ersity, Tempaku, Nagoya 468-8503, Japan
Received 22 September 2000; accepted 8 January 2001
Abstract
Syntheses of pyrrolo[2,1-f][1,2,4]triazine C-nucleosides are reported. Treatment of pyranulose glycoside with
aminoguanidine in acetic acid gave the corresponding semicarbazone in 96% yield. The ring transformation of the
semicarbazone in dioxane afforded a 51% yield of 2-amino-7-(2,3,5-tri-O-benzoyl-b-D-ribofuranosyl)pyrrolo[2,1-f]-
[1,2,4]triazine. Vilsmeier formylation of the pyrrolotriazine gave the major product, 5-formylpyrrolo[2,1-f]-
[1,2,4]triazine, in 69% yield. The aldehyde was treated with hydroxylamine hydrochloride in methanol to give
aldoximes. Dehydration of aldoxime with trifluoromethanesulfonic anhydride and triethylamine in dichloromethane
afforded 5-cyanopyrrolo[2,1-f][1,2,4]triazine in 44% yield. Conversion of the nitrile to the deprotected amide,
2-amino-7-(b-D-ribofuranosyl)pyrrolo[2,1-f][1,2,4]triazine-5-carboxamide, was accomplished in 96% yield on treat-
ment with 30% H2O2 in ethanol for 1 day at room temperature. Debenzoylation with sodium hydroxide solution
produced deprotected C-nucleosides. © 2001 Elsevier Science Ltd. All rights reserved.
Keywords: Synthesis; C-nucleoside; Pyranulose glycoside; Pyrrolo[2,1-f][1,2,4]triazine; Pyrrolo[2,1-f][1,2,4]triazine C-nucleosides;
Isostere
The pyrrolo[2,3-d]pyrimidine (7-deaza-
purine) nucleoside antibiotics, tubercidin (A),
toyocamycin (B), and sangivamycin (C), have
stimulated considerable research because of
their action against bacteria, mammalian cells
in culture, RNA and DNA viruses, and the
treatment of cutaneous neoplasms in hu-
mans.1,2 In particular, sangivamycin (C) is one
of the few nucleosides that has been selected
for clinical studies. These findings prompted
us to synthesize pyrrolo[2,1-f][1,2,4]triazine
C-nucleosides 7, 8, and 9, which are struc-
turally related to A, B, and C. During efforts
to develop a general synthetic method for
C-nucleosides, we have prepared an extremely
useful intermediate, 6-hydroxy-6-(2,3,5-tri-O-
benzoyl-b- -ribofuranosyl)pyran-3(2H,6H)-
D
one (1),3 from which some ring transfor-
mations with a variety of amines have been
reported.4 We report herein, the synthesis
of pyrrolo[2,1-f][1,2,4]triazine C-nucleosides
from 1 (Scheme 1).
* Corresponding author. Tel.: +81-52-8321781; fax: +81-
52-8348090.
E-mail address: maeba@meijo-u.ac.jp (I. Maeba).
0008-6215/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0008-6215(01)00017-9

78
N. Nishimura et al. / Carbohydrate Research 331 (2001) 77–82
Treatment of pyranulose glycoside 1 with
was carried out by the dropwise addition of 3
to a solution of POCl3 in N,N-dimethylfor-
mamide (DMF) at 0 °C. After the addition of
3, the mixture was kept at 80 °C for 40 min.
The major product, 2-(N,N-dimethylamino-
methyleneamino)-5-formyl-7-(2,3,5-tri-O-ben-
aminoguanidine in acetic acid at room tem-
perature afforded the corresponding semicar-
bazone 2 in 96% yield. Semicarbazone 2 is an
inseparable mixture of diastereoisomers (dif-
fering in configuration only at C-6). The semi-
carbazone 2 in dioxane was treated with
concentrated hydrochloric acid at 60 °C to
give a 51% yield of 2-amino-7-(2,3,5-tri-O-
zoyl - b -
D
- ribofuranosyl)pyrrolo[2,1-f][1,2,4]-
triazine (4), was isolated by preparative thin-
layer chromatography (PTLC) in 69% yield.
The position of the formyl group in com-
benzoyl - b -
D
- ribofuranosyl)pyrrolo[2,1-f]-
1
[1,2,4]triazine (3) without isolation of the
pyrrole - 2 - carboxaldehyde intermediate.
Vilsmeier formylation of the aromatic nucleus
pound 4 was determined by a H–13C long-
range COSY experiment. A correlation was
observed between H-1% at l 5.95 and C-6 at l
Scheme 1. Reagents and conditions: (a) aminoguanidine bicarbonate, AcOH, rt. (b) HCl, dioxane, 60 °C. (c) Vilsmeier reagent,
DMF, 80 °C. (d) NH2OH·HCl, MeOH, reflux. (e) (CF3SO2)2O, Et3N, CH2Cl2, rt. (f) aq NH4OH, aq H2O2, aq NaOH, EtOH, rt.
(g) Aq NaOH. MeOH, 0 °C.

N. Nishimura et al. / Carbohydrate Research 331 (2001) 77–82
79
silane as an internal standard. The IR spec-
trum was measured with an FTIR-230
(JASCO) spectrometer. Optical rotations were
measured with a JASCO DIP-370 polarimeter
(10-cm cell) at 25 °C. Analytical TLC was
performed on glass plates coated with a 0.2-
mm layer of Silica Gel GF254 (E. Merck). The
compounds were detected by UV light (254
nm).
116.3. Other long-range correlations for it are
shown by arrows Scheme 1. These data indi-
cated that the formyl group was located at the
5-position.
Aldehyde 4 was treated with hydroxylamine
hydrochloride in methanol at reflux for 3 h to
give (E)- and (Z)-2-amino-5-hydroxyimi-
nomethyl-7-(2,3,5-tri-O-benzoyl-b- -ribofuran-
D
osyl)pyrrolo[2,1-f][1,2,4]triazine (5a) and (5b)
in 59 and 21% yields, respectively. The
configurational assignment of the two isomers
(6S)- and (6R)-6-hydroxy-6-(2,3,5-tri-O-
benzoyl-i- -ribofuranosyl)pyran-3-(2H,6H)-
D
1
iminosemicarbazone (2).—To a solution of 1
(1.20 g, 2.16 mmol) in AcOH (12 mL) was
added aminoguanidine bicarbonate (293.8 mg,
2.159 mmol). The mixture was stirred at rt for
2 h, and then the reaction mixture was evapo-
rated. The residue was chromatographed on a
column of silica gel with 9:1 CHCl3–MeOH
as eluent to give 1.27 g (96%) of 2 as a
5a and 5b was made based on their H NMR
spectra. The pyrrole ring proton signal of
compound 5b at l 7.13 occurs at a lower field
than that of its isomer 5a (l 6.80). This chem-
ical shift difference can be attributed to the
deshielding effect of the hydroxyl syn pyrrole
ring.5 Dehydration of aldoxime 5a with tri-
fluoromethanesulfonicanhydride6 andtriethyl-
amine in dichloromethane at room tempera-
ture afforded 2-amino-5-cyano-7-(2,3,5-tri-O-
1
pale-yellow foam. H NMR (CDCl3): l 4.34
(d, 0.5 H, J1%,2% 1.5 Hz, H-1%), 4.41 (d, 0.5 H,
J1%,2% 2.9 Hz, H-1%), 4.43–4.93 (m, 5 H, H-
2,4%,5%), 5.63–5.91 (m, 2 H, H-2%,3%), 6.23–6.48
benzoyl - b -
D
- ribofuranosyl)pyrrolo[2,1-f]-
[1,2,4]triazine (6) in 44% yield. Dehydration of
5b by the same procedure gave 6 in 32% yield.
The IR spectrum of 6 contains an absorption
band at 2227 cm−1 due to the nitrile group on
the pyrrole ring. Conversion of the nitrile 6 to
13
(m, 2 H, H-4,5), 7.27–8.02 (m, 15 H, Ph). C
NMR (CDCl3): l 64.7 (C-5%), 67.0 (C-2), 72.4,
73.0, 73.3, 79.0, 87.4 (C-1%,2%,3%,4%), 92.7 (C-6),
127.1–133.2 (C-4,5, Ph), 147.8 (C-3), 159.7
(CꢀNH), 165.3, 165.6, 166.3, 166.5 (CꢀO).
FABMS (nitrobenzyl alcohol as matrix):
Anal. Calcd for C32H31N4O9: 615.2087 [MH].
Found: m/z 615.2091 [MH]+.
the deprotected amide, 2-amino-7-(b- -ribo-
D
furanosyl)pyrrolo[2,1-f][1,2,4]triazine - 5 - car-
boxamide (7) was accomplished in 96% yield
on treatment of 6 with basic hydrogen
peroxide7 in ethanol for 1 day at room tem-
perature. The removal of the sugar protecting
groups in compounds 3 and 6 was readily
accomplished with 5% aq sodium hydroxide
to afford compounds 8 and 9. The stereo-
chemistry of the C-1% position in compounds
7, 8, and 9 was confirmed as to be b by the
observation of an NOE between the C-1% and
C-4% protons. Examination of the biological
activities of compounds 7, 8, and 9 is now in
progress.
2-Amino-7-(2,3,5-tri-O-benzoyl-i- -ribo-
D
furanosyl)pyrrolo[2,1-f][1,2,4]triazine (3).—A
solution of 2 (906.2 mg, 1.459 mmol) in diox-
ane (90 mL) containing 0.6 mL of concd HCl
was heated at 60 °C for 40 min. After this
time, water was added, and the reaction mix-
ture was neutralized with satd aq NaHCO3
and then extracted with CHCl3 (3×150 mL).
The extracts were combined, washed with wa-
ter, dried over MgSO4, and concentrated to
dryness. The residual syrup was chro-
matographed on a column of silica gel with
CHCl3 as eluent. This afforded 434.4 mg
(51%) of 3 as a yellow foam. 1H NMR
(CDCl3): l 4.63 (dd, 1 H, J4%,5%a 4.2, J5%a,5%b 11.8
Hz, H-5%a), 4.70 (s, 2 H, NH2, exchanged with
D2O), 4.76 (m, 1 H, H-4%), 4.81 (dd, 1 H, J4%,5%b
3.7, J5%a,5%b 11.8 Hz, H-5%b), 5.77 (d, 1 H, J1%,2%
5.5 Hz, H-1%), 6.12 (dd, 1 H, J2%,3% 5.5 Hz,
H-3%), 6.23 (dd, 1 H, J1%,2%=J2%,3% 5.5 Hz, H-2%),
1. Experimental
General.—Fast-atom bombardment mass
spectra (FABMS) were run on a JMS-HX 110
1
spectrometer. The H and 13C NMR spectra
were measured with a JNM-A-400 or an A-
600 (JEOL) spectrometer, with tetramethyl-

80
N. Nishimura et al. / Carbohydrate Research 331 (2001) 77–82
6.66 (d, 1 H, J5,6 4.6 Hz, H-5), 6.76 (d, 1 H,
J5,6 4.6 Hz, H-6), 7.2–8.07 (m, 15 H, Ph), 8.63
(s, 1 H, H-4). 13C NMR (CDCl3): l 64.1
(C-5%), 72.7, 73.7, 75.5, 79.4 (C-1%,2%,3%,4%),
104.7, 112.4 (C-5,6), 122.1, 126.2 (C-4a,7),
128.4–133.4 (Ph), 152.2 (C-4), 155.9 (C-2),
165.3, 165.5, 166.3 (CꢀO). FABMS (nitroben-
zyl alcohol as matrix): Anal. Calcd for
C32H27N4O7: 579.1895 [MH]. Found: m/z
579.1880 [MH]+.
(0.427 mmol) of hydroxylamine hydrochlo-
ride. The mixture was stirred at reflux for 3 h.
After this time, TLC (97:3 CHCl3–MeOH)
showed that the reaction mixture contained
two major components (Rf 0.23 and 0.16). The
mixture was allowed to cool to rt, and the
solvent was evaporated. The residue was sepa-
rated by PTLC with 49:1 CHCl3 –MeOH as
eluent after two elutions.
Compound 5a. Yellow oil; yield 65.3 mg
1
2-(N,N-Dimethylaminomethyleneamino)-5-
(59%); Rf 0.23. H NMR (CDCl3): l 4.61 (dd,
formyl-7-(2,3,5-tri-O-benzoyl-i-
osyl)pyrrolo[2,1-f][1,2,4]triazine (4).—To
D
-ribofuran-
1 H, J4%,5%a 4.0, J5%a,5%b 12.1 Hz, H-5%a), 4.76 (m,
1 H, H-4%), 4.79 (br, 2 H, NH2, exchanged
with D2O), 4.86 (dd, 1 H, J4%,5%b 3.3, J5%a,5%b 12.1
Hz, H-5%b), 5.72 (d, 1 H, J1%,2% 5.4 Hz, H-1%),
6.08 (dd, 1 H, J2%,3%=J3%,4% 5.4 Hz, H-3%), 6.20
(dd, 1 H, J1%,2%=J2%,3% 5.4 Hz, H-2%), 6.80 (s, 1
H, H-6), 7.34–8.14 (m, 16 H, CHꢀNOH, Ph),
a
mixture of 0.5 mL of DMF and 1 mL of
phosphorus oxychloride, which was kept at
0–5 °C for 20 min, was added 101.9 mg (0.176
mmol) of 2 in 0.8 mL of DMF under stirring
at such a rate that the temperature of reaction
mixture did not rise above 20 °C. After the
addition of 2, the mixture was kept at 80 °C
for 40 min. The reaction mixture was poured
into 30 mL of cracked ice and water and
neutralized with satd aq NaHCO3, and the
mixture was extracted with EtOAc (3×50
mL). The extracts were combined, washed
with water, dried over MgSO4, and evapo-
rated in vacuo to a brown syrup. The residue
was purified by PTLC with 98.5:1.5 CHCl3–
MeOH as eluent. This afforded 80.2 mg (69%)
13
9.26 (s, 1 H, H-4). C NMR (CDCl3): l 63.6
(C-5%), 72.4, 73.6, 75.4, 79.3 (C-1%,2%,3%,4%),
112.7 (C-5), 113.3 (C-6), 119.1, 126.8 (C-4a,
7), 128.4–133.4 (Ph), 143.9 (CHꢀNOH), 153.5
(C-4), 155.8 (C-2), 165.2, 165.5, 166.2 (CꢀO).
FABMS (nitrobenzyl alcohol as matrix):
Anal. Calcd for C33H28N5O8: 622.1934 [MH].
Found: m/z 622.1938 [MH]+.
Compound 5b. Yellow oil; yield 22.7 mg
1
(21%); Rf 0.16. H NMR (CDCl3): l 4.63 (dd,
1 H, J4%,5%a 4.0, J5%a,5%b 12.1 Hz, H-5%a), 4.79 (m,
1 H, H-4%), 4.87 (dd, 1 H, J4%,5%b 3.7, J5%a,5%b 12.1
Hz, H-5%b), 5.53 (br, 2 H, NH2, exchanged
with D2O), 5.75 (d, 1 H, J1%,2% 53 Hz, H-1%),
6.13 (dd, 1 H, J2%,3%=J3%,4% 5.3 Hz, H-3%), 6.23
(dd, 1 H, J1%,2%=J2%,3% 5.3 Hz, H-2%), 7.13 (s, 1
H, H-6), 7.34–8.07 (m, 16 H, CHꢀNOH, Ph),
1
of 4 as a yellow oil. H NMR (CDCl3): l 3.13,
3.14 (each s, each 3 H, CH3), 4.61 (dd, 1 H,
J4%,5%a 3.8, J5%a,5%b 12.3 Hz, H-5%a), 4.77 (m, 1 H,
H-4%), 4.87 (dd, 1 H, J4%,5%b 3.1, J5%a,5%b 12.3 Hz,
H-5%b), 5.95 (m, 2 H, H-1%,3%), 6.21 (dd, 1 H,
J1%,2%=J2%,3% 5.3 Hz, H-2%), 7.25 (s, 1 H, H-6),
735–8.08 (m, 15 H, Ph), 8.65 (s, 1 H,
ꢁNꢀCH), 9.46 (s, 1 H, H-4), 9.78 (s, 1 H,
CHO). 13C NMR (CDCl3): l 35.0, 40.9
(ꢁNꢁCH3), 63.3, (C-5%), 72.0, 73.6, 74.8, 79.3
(C-1%,2%,3%,4%), 115.9 (C-5), 1163 (C-6), 122.5
(C-4a), 127.9–133.3 (C-7, Ph), 152.4
(ꢁNꢀCHꢁN), 158.0 (C-4), 160.8 (C-2), 165.1,
165.3, 165.9 (CꢀO), 184.5 (CHO). FABMS
(nitrobenzyl alcohol as matrix): Anal Calcd
for C36H32N5O8: 662.2256 [MH]. Found: m/z
662.2251 [MH]+.
13
9.51 (s, 1 H, H-4). C NMR (CDCl3): l 63.7
(C-5%), 72.5 (C-3%), 73.7 (C-2%), 75.7 (C-1%), 79.3
(C-4%), 110.2 (C-5), 116.0 (C-6), 120.2, 127.0
(C-4a,7), 128.4–133.4 (Ph), 138.9 (CHꢀNOH),
154.4 (C-4), 155.7 (C-2), 165.2, 165.5, 1663
(CꢀO). FABMS (nitrobenzyl alcohol as ma-
trix): Anal. Calcd for C33H28N5O8: 622.1938
[MH]. Found: m/z 622.1938 [MH]+.
2-Amino-5-cyano-7-(2,3,5-tri-O-benzoyl-i-
-ribofuranosyl)pyrrolo[2,1-f][1,2,4]triazine (6).
D
—To a solution of 5a (122.1 mg, 0.197 mmol)
and triethylamine (45.2 mg, 0.447 mmol) in
CH2Cl2 (12 mL) at 0 °C was added CH2C12 (3
mL) containing trifluoromethanesulfonic an-
hydride (56.4 mg, 0.200 mmol). The mixture
was stirred at rt for 1 h. Water was added,
(E)- and (Z)-2-amino-5-hydroxyimino-
methyl-7-(2,3,5-tri-O-benzoyl-i-
osyl)pyrrolo[2,1-f][1,2,4]triazine
D
-ribofuran-
(5a) and
(5b).—To a solution of 4 (117.7 mg, 0.178
mmol) in MeOH (10 mL) was added 29.7 mg

N. Nishimura et al. / Carbohydrate Research 331 (2001) 77–82
81
6), 111.8 (C-5), 120.7 (C-4a), 128.3 (C-7),
152.7 (C-4), 156.9 (C-2), 164.6 (CONH2).
FABMS (nitrobenzyl alcohol as matrix):
Anal. Calcd for C12H16N5O5: 310.1151 [MH].
Found: m/z 310.1147 [MH]+. Anal. Calcd for
C12H15N5O5: C, 46.60; H, 4.89; N, 22.64.
Found: C, 46.45; H, 4.95; N, 22.40.
and the mixture was neutralized with satd aq
NaHCO3 and extracted with CHCl3 (3×30
mL). The extracts were combined, washed
with water, dried over MgSO4, and concen-
trated in vacuo to a yellow oil. The residue
was purified by PTLC (99:1 CHCl3–MeOH)
as eluent. This afforded 51.9 mg (44%) of 6 as
a pale-yellow oil. IR (KBr) 2227 (CN) cm−1
.
2-Amino-7-(i- -ribofuranosyl)pyrrolo[2,1-f]-
D
1H NMR (CDCl3): l 4.62 (dd, 1 H, J4%,5%a 4.8,
J5%a,5%b 12.1 Hz, H-5%a), 4.77 (m, 1 H, H-4%),
4.87 (dd, 1 H, J4%,5%b 3.7, J5%a,5%b 12.1 Hz, H-5%b),
4.92 (s, 2 H, NH2, exchanged with D2O), 5.65
(d, 1 H, J1%,2% 5.6 Hz, H-1%), 6.05 (dd, 1 H,
[1,2,4]triazine (8).—To a solution of 3 (18.0
mg, 0.031 mmol) in MeOH (2 mL) at 0 °C
was added 5% aq NaOH (0.35 mL). The
mixture was kept at 0 °C for 2 h. After this
time, the mixture was neutralized with AcOH,
and the solvent was evaporated under reduced
pressure. The residue was purified by PTLC
(3:1 CHCl3–MeOH) as eluent to afford 8.0
mg (97%) of 8 as a yellow solid. The yellow
solid was recrystallized from MeOH to a give
pale-yellow solid; mp 110–112 °C. [h]2D5 −7.3°
J2%,3%=J3%,4% 5.6 Hz, H-3%), 6.18 (dd, 1 H, J1%,2%
=
J2%,3% 5.6 Hz, H-2%), 7.06 (s, 1 H, H-6), 7.37–
8.06 (m, 15 H, Ph), 8.88 (s, 1 H, H-4). 13C
NMR (CDCl3): l 63.5 (C-5%), 72.3 (C-3%), 73.1
(C-2%), 75.4 (C-1%), 79.6 (C-4%), 86.5 (C-5),
113.9 (CN), 116.7 (C-6), 124.3 (C-4a), 127.2
(C-7), 128.5–133.6 (Ph), 151.4 (C-4), 156.8
(C-2), 165.1, 165.5, 166.2 (CꢀO). FABMS (ni-
trobenzyl alcohol as matrix): Anal. Calcd for
C33H26N5O7: 604.1832 [MH]. Found: m/z
604.1824 [MH]+.
1
(c 1.8, CH3OH). H NMR (CD3OD): l 3.69
(dd, 1 H, J4%,5%a 4.0, J5%a,5%b 11.8 Hz, H-5%a), 3.81
(dd, 1 H, J4%,5%b 3.4, J5%a,5%b 11.8 Hz, H-5%b), 4.02
(m, 1 H, H-4%), 4.17 (dd, 1 H, J2%,3%=J3%,4% 5.6
Hz, H-3%), 4.46 (dd, 1 H, J1%,2%=J2%,3% 5.6 Hz,
H-2%), 5.26 (d, 1 H, J1%,2% 5.6 Hz, H-1%), 6.77 (s,
2 H, H-5,6), 8.65 (s, 1 H, H-4). 13C NMR
(CD3OD): l 63.7 (C-5%), 73.2, 74.9, 78.3, 86.1
(C-1%,2%,3%,4%), 106.2, 113.5 (C-5,6), 123.1, 130.2
(C-4a,7), 153.0 (C-4), 157.6 (C-2). FABMS
(glycerol as matrix): Anal. Calcd for
C11H15N4O4; 267.1093 [MH]. Found: m/z
267.1093 [MH]+. Anal. Calcd for C11H14N4O4·
0.2 H2O: C, 48.96; H, 5.38; N, 20.76. Found:
C, 48.86; H, 5.42; N, 20.56.
2-Amino-7-(i- -ribofuranosyl)pyrrolo[2,1-f]-
D
[1,2,4]triazine-5-carboxamide (7).—To a solu-
tion of 6 (79.3 mg, 0.132 mmol) and 28% aq
NH4OH (2.6 mL) in EtOH (17 mL) was
added dropwise 30% aq H2O2 (0.7 mL). The
mixture was stirred at rt for 1 day, then 5% aq
NaOH (1.2 mL) was added at 0 °C, and the
mixture was stirred at rt for 3 h. After this
time, the reaction mixture was neutralized
with AcOH, and the solvents were evaporated
under reduced pressure. The residue was chro-
matographed on a column of silica gel with
4:1 CHCl3 –MeOH as eluent to afford 39.2 mg
(96%) of 7 as a yellow oil. The oil was recrys-
tallized from 2-propanol–hexane to give a
pale-yellow solid; mp 209–211 °C. [h]D25
2 - Amino - 5 - cyano - 7 - (i - - ribofuranosyl)-
D
pyrrolo[2,1-f][1,2,4]triazine (9).—The same
procedure was used as for the debenzoylation
of 3 with 5% aq NaOH.
Compound 9. Yield: 95%; pale yellow solid
(2-propanol–hexane); mp 196–198 °C. [h]D25
1
1
3.0° (c 0.7, CH3OH). H NMR [(CD3)2SO]: l
−66.5° (c 0.6, CH3OH). H NMR [(CD3)2-
3.45 (dd, 1 H, J4%,5%a 4.4, J5%a,5%b 12.2 Hz, H-5%a),
3.54 (dd, 1 H, J4%,5% 3.9, J5%a,5%b 12.2 Hz, H-5%b),
3.78 (m, 1 H, H-4%), 3.97, 4.19 (each dd, each
1 H, J1%,2%=J2%,3%=J3%,4% 5.3 Hz, H-2%,3%),4.85
(br, 1 H, OH, exchanged with D2O), 5.12 (d, 1
H, J1%,2% 5.3 Hz, H-1%), 5.34 (br, 2 H, OH,
exchanged with D2O), 6.89 (s, 2 H, NH2,
exchanged with D2O), 7.34 (s, 1 H, H-6), 9.06
(s, 1 H, H-4). 13C NMR [(CD3)2SO]: l 61.6
(C-5%), 70.9, 73.9, 74.0, 84.6 (C-1%,2%,3%,4%), 84.1
SO]: l 3.46 (dd, 1 H, J4%,5%a 5.1, J5%a,5%b 11.5 Hz,
H-5%a), 3.52 (dd, 1 H, J4%,5%a 11.5 Hz, H-5%b),
3.79 (m, 1 H, H-4%), 3.95 (dd,1 H, J2%,3%=J3%,4%
5.7 Hz, H-3%), 4.17 (dd, 1 H, J1%,2%=J2%,3% 5.7
Hz, H-2%), 5.12 (d, 1 H, J1%,2% 5.7 Hz, H-1%),
6.57 (s, 2 H, NH2, exchanged with D2O), 7.10,
7.73 (br, 1 H×2, CONH2, exchanged with
D2O), 7.29 (s, 1 H, H-6), 9.23 (s, 1 H, H-4).
13C NMR [(CD3)2SO]: l 62.1 (C-5%), 71.2 (C-
3%), 73.8, 73.9 (C-1%,2%), 84.7 (C-4%), 110.9 (C-

82
N. Nishimura et al. / Carbohydrate Research 331 (2001) 77–82
(C-5), 114.9 (CN), 115.6 (C-6), 123.0 (C-4a),
130.4 (C-7), 151.4 (C-4), 157.6 (C-2). FABMS
(nitrobenzyl alcohol as matrix): Anal. Calcd
for C12H14N5O4: 292.1046 [MH]. Found: m/z
292.1045 [MH]+. Anal. Calcd for C12H13N5O4:
C, 49.48; H, 4.50; N, 24.04. Found: C, 49.31;
H, 4.53; N, 23.84.
References
1. Suhandolnik, R. J. Nucleoside Antibiotics; Wiley-Inter-
science: New York, 1970; p. 226, 231.
2. Revankar, G. R.; Robins, R. K. Chemistry of Nucleosides
and Nucleotides; Plenum: New York, 1991; Vol. 2, pp.
200–246.
3. Maeba, I.; Takeuchi, T.; Iijima, T.; Furukawa, H. J. Org.
Chem. 1988, 53, 1401–1405.
4. (a) Hayashi, M.; Araki, A.; Maeba, I. Heterocycles 1992,
34, 569–574. (b) Nishimura, N.; Hasegawa, Y.; Mizuno,
S.; Yuasa, M.; Maeba, I. Heterocycles 1998, 48, 2339–
2345.
Acknowledgements
5. Tyson, Jr., B. C.; Poviomek, E. J.; Danielson, E. R. J.
Org. Chem. 1969, 34, 3635–3638.
6. Hendrickson, J. B.; Bair, K. W.; Keehe, P. M. Tetrahedron
Lett. 1976, 603–604.
7. Tolman, R. L.; Robins, R. K.; Townsend, L. B. J. Am.
Chem. Soc. 1969, 91, 2102.
This work was partly supported by the
Ministry of Education Science, Sports and
Culture of Japan (High-Tech Research Center
Project).
.