Regioselective Synthesis of Indazole N1- and N 2-(β-D-Ribonucleosides)

Article abstract of DOI:10.1081/NCN-120027830

The regioselective synthesis of 4-nitroindazole N¹- and N ²-(β-D-ribonucleosides) (8, 9, 1b and 2b) is described. The N¹-regioisomers are formed under thermodynamic control of the glycosylation reaction [fusion reaction or

Full text of DOI:10.1081/NCN-120027830

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Regioselective Synthesis of Indazole N 1‐ and N
2‐(β‐d‐Ribonucleosides)
Frank Seela a & Xiaohua Peng a
a Laboratorium für Organische und Bioorganische Chemie , Institut für Chemie ,
Universität Osnabrück , Barbarastraße 7, D‐49069, Osnabrück, Germany
Published online: 01 Jun 2007.
To cite this article: Frank Seela & Xiaohua Peng (2004) Regioselective Synthesis of Indazole N 1‐ and N
2‐(β‐d‐Ribonucleosides) , Nucleosides, Nucleotides and Nucleic Acids, 23:1-2, 227-237, DOI: 10.1081/NCN-120027830
To link to this article: http://dx.doi.org/10.1081/NCN-120027830
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NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS
Vol. 23, Nos. 1 & 2, pp. 227–237, 2004
Regioselective Synthesis of Indazole N1- and
N2-(b-D-Ribonucleosides)y
*
Frank Seela and Xiaohua Peng
Laboratorium fu¨r Organische und Bioorganische Chemie, Institut fu¨r Chemie,
Universita¨t Osnabru¨ck, Osnabru¨ck, Germany
ABSTRACT
The regioselective synthesis of 4-nitroindazole N1- and N2-(b-D-ribonucleosides) (8, 9,
1b and 2b) is described. The N1-regioisomers are formed under thermodynamic
control of the glycosylation reaction [fusion reaction or Silyl Hilbert-Johnson
glycosylation for 48 h (66%)], while the kinetic control (Silyl Hilbert-Johnson
glycosylation for 5 h) afforded only the N2-isomer (64%). The structures of the
nucleosides 1b and 2b were assigned by single crystal X-ray analyses. The 4-amino-
N1-(b-D-ribofuranosyl)-1H-indazole (3b) was obtained from the nitro nucleoside 1b
by catalytic hydrogenation. Compound 3b shows fluorescence while the 4-
nitroindazole nucleosides 1b and 2b do not possess this property.
Key Words: Glycosylation; 4-Nitroindazole; Ribonucleosides; Fluorescence;
Regioselectivity.
yIn honor and celebration of the 70th birthday of Professor Leroy B. Townsend.
*
Correspondence: Frank Seela, Laboratorium fu¨r Organische und Bioorganische Chemie, Institut
fu¨r Chemie, Universita¨t Osnabru¨ck, Barbarastraße 7, D-49069 Osnabru¨ck, Germany; E-mail:
frank.seela@uni-osnabrueck.de.
227
DOI: 10.1081/NCN-120027830
1525-7770 (Print); 1532-2335 (Online)
www.dekker.com
Copyright D 2004 by Marcel Dekker, Inc.

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Seela and Peng
INTRODUCTION
During the last years, the study of indazoles[1] has received considerable attention
because 1H-indazole is structurally related to 1H-benzimidazole,[2] and many indazoles
exhibit biological[3] or antiallergic activity[4] or function as antagonists of serotonine
receptors.[5] A series of indazole nucleosides have already been synthesized, including
indazole, 4-, 5-, 6-nitroindazole,[6–11] halogenated indazole ribonucleosides,[12] and the
2’-deoxyribonucleosides of 4-nitro and 4-aminoindazole.[13,14] In general, both N1- and
N2-isomeric nucleosides can be obtained by thermodynamic or by kinetic control of the
glycosylation reaction, respectively. However, in the case of 4-nitroindazole
ribonucleosides, only the N2-glycoside has been reported[6] while the N1-isomer is
unknown. This prompted the present investigation in an effort to study the reaction
conditions in more detail and to synthesize 4-nitro-1-(b-D-ribofuranosyl)-1H-indazole
(1b) and the corresponding amino derivative 3b.
Earlier, we have reported on the synthesis of the 4-nitroindazole 2’-deoxyribonu-
cleosides 1a and 2a, as well as the 4-aminoindazole 2’-deoxyribonucleosides 3a and 4
(Scheme 1).[13] Meanwhile, the ambiguous nature in oligonucleotide base pairing and
the influence of the glycosylation position on the duplex stability have been studied.[14]
In this paper, our work focuses on the study of the fusion method and the Silyl-Hilbert-
Johnson reaction with respect to the synthesis of the 4-nitroindazole N1-(b-D-
ribonucleoside) 1b and the N2-(b-D-ribonucleoside) 2b. The determination of the
glycosylation position and the assignment of the anomeric configuration were as-
certained by single crystal X-ray analyses. Furthermore, the fluorescence of the target
compounds was detected.
RESULTS AND DISCUSSION
From previous investigations on indazole nucleosides it has been observed that the
formation of regioisomeric glycosylation products depends on the particular reaction
conditions and on the structure of the precursors. The silyl method or the Hg(CN)2-
CH3NO2-mediated reaction afforded the N2-glycosylated indazoles, exclusively.[6–8,15]
On the other hand, the corresponding N1-glycosylated indazoles were formed under
Scheme 1. Indazole nucleosides.

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Indazole N1- and N2-( -D-Ribonucleosides)
229

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Seela and Peng
conditions of the fusion reaction using peracylated D-ribose derivatives.[9–12,16,17]
Now, the regioisomers 1b and 2b were obtained under different reaction conditions
(Scheme 2). The silylation of 4-nitro-1H-indazole (5)[18] furnished N-trimethylsilylated 4-
nitroindazole (6) in quantitative yield. At first, the glycosylation of 6 with 1-O-acetyl-
2,3,5-tri-O-benzoyl-b-D-ribofuranose (7) in dichloroethane with TMSOTf as catalyst,
was investigated at different temperatures and reaction times. The reaction performed
at room temperature within two days affording 4-nitro-1-[(2,3,5-tri-O-benzoyl)-b-D-
ribofuranosyl]-1H-indazole (8) as the major product (66%) and only traces of 4-nitro-2-
[(2,3,5-tri-O-benzoyl)-b-D-ribofuranosyl]-2H-indazole (9). If the reaction was per-
formed only for 5 hours, the nucleoside 9 was isolated (64%). The glycosylation
reaction was monitored by TLC (CH2Cl2/AcOEt, 99:1). In the initial stages of the
reaction only a slow migrating spot was observed assigned to the N2-isomer 9. When
the reaction progressed, the TLC showed two spots with a gradually diminished slow
migrating component. Later, the less polar product was formed which is the N1-isomer
8. When the coupling proceeded higher than 50°C, compound 8 was obtained exclu-
sively after one day. Compounds 8 and 9 were deprotected with methanolic ammonia
affording the indazole ribonucleosides 1b and 2b, respectively. The nitro nucleoside 1b
was hydrogenated under normal pressure (Pd/C) to give the amino nucleoside 3b.
Compound 2b could not be hydrogenated under the same conditions.
The most likely explanation for the formation of nucleosides 8 and 9 under
different conditions (reaction time and temperature) is a two step glycosylation re-
action. In the first step, the reaction of the silylated base and a sugar cation leads to
the kinetically controlled product 9. When the reaction temperature is increased or the
reaction time is prolonged, compound 9 undergoes a rearrangement to form the
thermodynamically more stable isomer 8.
Compound 1b was also synthesized by the fusion reaction (Scheme 3). The fusion
of non-silylated 5 with tetra-O-acetyl-b-D-ribofuranose (10) in vacuo at 120°C in the
presence of p-toluenesulfonic acid gave exclusively 4-nitro-1-[(2,3,5-tri-O-acetyl)-b-D-
ribofuranosyl]-1H-indazole (11), which was directly deacetylated with methanolic
ammonia furnishing the nucleoside 1b in 68% yield. The fusion of the silylated 4-
nitroindazole 6 with 10 (same conditions) resulted in a mixture of N1 and N2-isomers.
They were deprotected without isolation of the intermediates to give a mixture of
1
1b/2b (ratio = 2.6:1, determined from H-NMR spectra). A selective formation of the
Scheme 3. The synthesis of 4-nitroindazole N1-(b-D-ribonucleosides) by fusion reaction.

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Indazole N1- and N2-( -D-Ribonucleosides)
Table 1. 13C-NMR chemical shifts of indazole ribonucleosides.a
231
Compound
C(3)
C(3a)
C(4)
C(5)
C(6)
C(7)
C(7a)
1b
2b
3b
5
133.1
124.0
132.9
132.5
133.5
125.9
116.6
113.5
114.0
115.3
116.6
113.5
141.5
140.3
142.4
141.5
141.5
149.8
119.0
120.8
102.2
118.4
119.4
121.4
126.5
125.1
128.2
125.7
127.1
126.3
118.1
126.5
96.2
139.7
149.1
141.7
139.6
139.9
140.4
118.2
118.0
126.5
8
9
C(1’)
C(2’)
C(3’)
C(4’)
C(5’)
3C
O
1b
2b
3b
8
90.5
95.1
89.9
88.0
91.8
73.5
75.7
73.2
71.1
71.1
70.6
69.9
70.8
74.5
75.1
85.2
85.5
84.6
79.2
79.9
62.0
61.0
62.4
62.9
63.0
165.3, 164.8, 164.6
165.3, 164.7, 164.4
9
aMeasured in DMSO.
N2-isomer was reported by Revankar and Townsend using 2,3,5-tri-O-acetyl-a-D-
ribofuranosyl bromide[19] in the fusion reaction.[6]
1
All compounds were characterized by elemental analysis as well as by H- and
13C-NMR. The 13C-NMR signals were assigned by gated-decoupled 13C-NMR spectra.
The 13C-NMR signal of the C (7) was shifted downfield about 8 ppm, while an upfield
shift of C(3) by 9 ppm was found when the glycosylation position changed from N(1)
to N(2) (Table 1).
All other 13C-NMR shifts were assigned by comparison of the NMR data shown
in Table 1 with those of 4-nitroindazole 2’-deoxyribonucleosides, which were assigned
by NOE experiments followed by 1H, 13C NMR-correlation spectra.[13] Similar to
4-nitroindazole 2’-deoxyribonucleosides, the N2-isomers 9 and 2b show a significant
downfield shift of the H-C(3) (about 0.50 ppm) compared to N1-isomer 8 and 1b.
The crystal structures of 1b (Figure 1) and 2b (Figure 2) were also determined
confirming the assignment of the anomeric configurations as well as the glycosylation
Figure 1. Perspective view of compound 1b.

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Seela and Peng
Figure 2. Perspective view of compound 2b. Type 1: S-conformation; type 2: N-conformation.
sites. Compound 2b shows two conformations in the crystalline state which differ
mainly in the sugar conformation. Type 1 adopts an S-type conformation; type 2 shows
an N-type conformation (Figure 2). Details will be published elsewhere.[20]
The photophysical properties of the compounds 1b, 2b and 3b in solution were
also studied. The UV/Vis absorption spectra are shown in Figure 3(A). At room
temperature no fluorescence could be detected for 1b and 2b due to the presence of
nitro substituents quenching the fluorescence efficiently. Nevertheless, nucleoside 3b
shows strong fluorescence. According to Figure 3(B), the emission spectrum of 3b
exhibits a broad emission band with a maximum at 400 nm. The excitation spectrum of
3b is very similar to its absorption spectrum, indicating that the sample is sufficiently
pure and that the excited singlet state is the origin of the observed emission.
CONCLUSION
The indazole N1-ribonucleoside 1b was prepared selectively via the fusion reaction,
while the Silyl Hilbert-Johnson glycosylation performed for 5 h furnished the N2-
nucleoside 2b. Both nucleoside structures were established by single crystal X-ray
analyses. The amino nucleoside 3b shows strong fluorescence.
EXPERIMENTAL PART
General. Chemicals and solvents are of laboratory grade. Flash chromatography
(FC): at 0.6 bar on silica gel 60H (VWR, Germany); Thin-layer chromatography
(TLC): aluminum sheets coated with silica gel 60 F254 (VWR, Germany). Mp.: SMP-20
apparatus (Bu¨chi, Switzerland). UV Spectra: U-3200 spectrophotometer (Hitachi,
Japan). NMR spectra: Avance-DPX-250, Brucker-AC-250 and AMX-500 spectrometer;

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233

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Seela and Peng
d values in ppm rel. to internal Me4Si, J values in Hz. Fluorescence spectra: F-4500
spectrometer (Hitachi, Japan). Elemental analyses were performed by Mikroanaly-
tisches Laboratorium Beller, Go¨ttingen, Germany.
4-Nitro-1-[(2,3,5-tri-O-benzoyl)- -D-ribofuranosyl]-1H-indazole (8). A mixture
of dry 4-nitro-1H-indazole[18] (5) (652 mg, 4.0 mmol) and a catalytic amount of ammo-
nium sulfate (15 mg) was refluxed in hexamethyldisilazane (15.0 mL, 72.76 mmol)
with the exclusion of moisture for 20 h. After removal of the solvent, the result-
ing semi-solid trimethylsilyl 4-nitro-1H-indazole (6) was suspended in dry dichloro-
ethane (20.0 mL). Into this mixture, 1-O-acetyl-2,3,5-tri-O-benzoyl-b-D-ribofuranose
(7) (2.27 g, 4.5 mmol)[21] and TMSOTf (0.95 mL, 5.46 mmol) were added, yielding a
clear solution which was stirred at room temperature for 48 h. It was diluted with
dichloromethane (50 mL), washed with aq. saturated sodium bicarbonate (20 mL);
and the organic phase was washed with water. The solution was dried over anhydrous
sodium sulfate and filtered. The solvent was evaporated under reduced pressure to
give a syrup, which was applied to FC on a silica gel (column 4 ꢀ 12 cm, solvent
CH2Cl2). The main zone afforded compound 8 as yellowish foam (1.60 g, 66%). Rf
0.35 (CH2Cl2/AcOEt, 99:1); UV (MeOH) lmax = 229 nm (e 48600), 282 nm (e 6100),
1
340 nm (e 6600); H NMR (DMSO-d6) d 4.49–4.52 (dd, J = 3.5, 12.3, 1 H, H-5’),
4.68–4.71 (dd, J = 2.8, 12.2, 1 H, H-5’), 4.95 (m, 1 H, H-4’), 6.27 (t, J = 6.1, 1 H,
H-3’), 6.41 (t, J = 3.7, 1 H, H-2’), 7.13 (s, 1 H, H-1’), 7.47–7.54 (m, 6 H, arom),
7.64–7.69 (m, 3 H, arom), 7.74 (t, J = 7.7, 8.5, 1 H, H-6), 7.8 (m, 2 H, arom), 7.95–
7.99 (m, 4 H, arom), 8.22 (d, J = 7.7, 1 H, H-5), 8.48 (d, J = 8.5, 1 H, H-7), 8.66 (s, 1
H, H-3); Anal. Calc. for C33H25N3O9 (607.6): C 65.24, H 4.15, N 6.92, found C 65.28,
H 4.21, N 7.02.
4-Nitro-2-[(2,3,5-tri-O-benzoyl)- -D-ribofuranosyl]-2H-indazole (9). A mixture
of 5 (128 mg, 0.79 mmol) and a catalytic amount of ammonium sulfate (10 mg,
0.76 mmol) in hexamethyldisilazane (4.0 mL, 19.40 mmol) was refluxed under the
protection of Ar for 20 h. After evaporation of the solvent, the resulting semi-solid
material was suspended in dry dichloroethane (5.0 mL). Into this reaction mixture, 7
(395 mg, 0.78 mmol) and TMSOTf (0.2 mL, 1.15 mmol) were added, giving a clear
solution which was stirred at room temperature for 5 h. The reaction mixture was
diluted with dichloromethane (5 mL), washed with aq. saturated sodium bicarbonate
(5 mL) and then with water. The organic layer was dried over anhydrous sodium
sulfate and the solvent was evaporated to give a syrup, which was applied to FC on
silica gel (column: 4 ꢀ 9 cm, CH2Cl2). The main zone afforded compound 9 as a
yellowish foam (306 mg, 64%). Rf 0.31 (CH2Cl2/AcOEt, 99:1); UV (MeOH) lmax
1
229 nm (e 48600), 273 nm (e 4300), 282 nm (e 4400), 312 (e 5600), 355 (e 6500); H
NMR (DMSO-d6) d 4.57–4.64 (dd, J = 4.1, 12.4, 1 H, H-5’), 4.76–4.82 (dd, J = 3.1,
12.3, 1 H, H-5’), 5.03 (m, 1 H, H-4’), 6.31 (m, 2 H, H-2’, H-3’), 6.99 (s, 1 H, H-1’),
7.44–7.68 (m, 10 H, H-6, arom), 7.69–7.98 (m, 6 H, arom), 8.15 (t, J = 7.7, 8.5, 1 H,
H-5), 8.25 (d, J = 8.3, 1 H, H-7), 9.20 (s, 1 H, H-3); Anal. Calc. for C33H25N3O9
(607.6): C 65.24, H 4.15, N 6.92, found C 65.28, H 4.20, N 6.88.
4-Nitro-1-( -D-ribofuranosyl)-1H-indazole (1b). Compound 8 (1.0 g, 1.65
mmol) was dissolved in methanolic ammonia (methanol saturated with ammonia at

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235
0°C, 30 mL) and stirred at room temperature for 24 h. After removal of the solvent, the
residue was dissolved in MeOH and adsorbed on a small amount (4.0 g) of silica gel.
This material was loaded on the top of a silica gel column (4 ꢀ 15cm), and the
product was eluted stepwise with CH2Cl2/MeOH (98:2, 300 mL) and CH2Cl2/MeOH
(9:1, 600 mL). The product-containing fractions were combined and evaporated to give a
semi-solid, which was crystallized from MeOH furnishing yellowish needles (433 mg,
89%). Mp. 176–177°C; Rf 0.35 (CH2Cl2/MeOH, 9:1); UV (MeOH) lmax 235 nm (e
1
11000) 340 nm (e 6800); H NMR (DMSO-d6) d 3.43–3.47 (m, 1 H, H-5’); 3.54–3.61
(m, 1 H, H-5’); 3.94–4.00 (q, J = 4.8, 1 H, H-4’); 4.23–4.29 (q, J = 5.1, 1 H, H-3’); 4.65–
4.71 (q, J = 5.0, 1 H, H-2’); 4.82–4.86 (t, J = 5.5, 1 H, OH-5’); 5.24 (d, J = 5.4, 1 H, OH-
2’); 5.48 (d, J = 5.8, 1 H, OH-3’); 6.25 (d, J = 4.5, 1 H, H-1’); 7.68 (t, J = 8.1, 1 H, H-6);
8.21 (d, J = 7.7, 1 H, H-5); 8.42 (d, J = 8.5, 1 H, H-7); 8.63 (s, 1 H, H-3); Anal. Calc. for
C12H13N3O6 (295.25): C 48.82, H 4.44, N 14.23, found C 49.15, H 4.51, N 14.02.
4-Nitro-2-( -D-ribofuranosyl)-2H-indazole (2b). Compound 9 (280 mg,
0.46 mmol) was dissolved in methanolic ammonia (20 mL) and stirred at room
temperature overnight. After removal of the solvent, the residue was dissolved in
MeOH and adsorbed on a small amount (2.0 g) of silica gel. This material was loaded
on the top of a silica gel column (3 ꢀ 9 cm), and the product was eluted stepwise with
CH2Cl2/MeOH (98:2, 100 mL) and CH2Cl2/MeOH (9:1, 200 mL). The product-
containing fractions were combined and evaporated to give a semi-solid, which was
crystallized from MeOH. Yellowish needles (125 mg, 92%). Mp. 172–173°C; Rf 0.35
(CH2Cl2:MeOH, 9:1); UV(MeOH) lmax 230 nm (e 8600), 314 nm (e 5500), 359 nm
1
(e 6400); H NMR (DMSO-d6) d 3.59–3.64 (m, 1 H, H-5’), 3.70–3.74 (m, 1 H, H-5’),
4.05 (q, J = 4.8, 1 H, H-4’), 4.24 (q, J = 5.1, 1 H, H-3’), 4.42 (q, J = 3.6, 1 H, H-2’),
5.11 (t, J = 5.3, 1 H, OH-5’), 5.24 (d, J = 5.7, 1 H, OH-3’), 5.66 (d, J = 5.6, 1 H, OH-
2’), 6.12 (d, J = 3.5, 1 H, H-1’), 7.54 (t, J = 8.1, 1 H, H-6), 8.21 (d, J = 7.7, 1 H, H-5,
H-7), 9.21 (s, 1 H, H-3); Anal. Calc. for C12H13N3O6 (295.25): C 48.82, H 4.44, N
14.23, found C 48.79, H 4.31, N 14.15.
4-Nitro-1-( -D-ribofuranosyl)-1H-indazole (1b) (Fusion reaction, one step
procedure). A mixture of compound 5 (652 mg, 4.0 mmol), 1,2,3,5-tetra-O-acetyl-
b-D-ribofuranose (10, 1.53 g, 4.8 mmol)[22,23] and p-toluenesulfonic acid monohydrate
(15.0 mg, 0.079 mmol) was heated to 100–130°C for 30 min under vacuo. The dark
melt was dissolved in methanolic ammonia (30 mL), and stirred at r.t. overnight. The
solution was evaporated to dryness, redissolved in MeOH (10 mL) and adsorbed on a
small amount (5.0 g) of silica gel. This material was loaded on the top of a silica gel
column (4 ꢀ 15 cm), and the product was eluted with a stepwise gradient CH2Cl2/
MeOH (98:2, 300 mL) and CH2Cl2/MeOH (9:1, 600 mL). The product-containing
fractions were combined and evaporated to give a semi-solid, which was crystallized
from MeOH. Yellowish needles (800 mg, 68%). The NMR data are identical to those
obtained from the compound synthesized by the Silyl-Hilbert-Johnson glycosylation
followed by deprotection.
4-Amino-2-( -D-ribofuranosyl)-2H-indazole (3b). Compound 1b (200 mg, 0.68
mmol), dissolved in EtOH (20 mL), was hydrogenated for 4h in the presence of 10%
Pd/C (200 mg) at r.t./1 atm. The catalyst was filtered off and washed with EtOH. The

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Seela and Peng
solvent was evaporated, the residue was dissolved in MeOH and adsorbed on a small
amount (3.0 g) of silica gel. This material was loaded on the top of a silica gel column
(2.0 ꢀ 6 cm), and the product was eluted stepwise with CH2Cl2/MeOH (95:5, 100 mL)
and CH2Cl2/MeOH (9:1, 100 mL). The product-containing fractions were combined
and evaporated to give a foam, which was crystallized from MeOH. Yellowish needles
(129 mg, 72%). Mp. 151–152°C; Rf 0.25 (CH2Cl2/MeOH, 9:1); UV (MeOH) lmax
1
264 nm (e 4900), 312 (e 8300); H NMR (DMSO-d6) d 3.42 (m, 1 H, H-5’), 3.54 (m, 1
H, H-5’), 3.88 (m, 1 H, H-4’), 4.20 (m, 1 H, H-3’), 4.60 (m, 1 H, H-2’), 4.77 (t, J = 5.6,
1 H, OH-5’), 5.12 (d, J = 5.6, 1 H, OH-2’), 5.32 (d, J = 5.8, OH-3’), 5.76 (s, 2 H, NH2),
5.92 (d, J = 4.2, 1 H, H-1’), 6.20 (d, J = 7.5, 1 H, H-5), 6.75 (d, J = 8.2, 1 H, H-7),
7.05 (t, J = 8.2, 1 H, H-6), 8.18 (s, 1 H, H-3); Anal. Calc. for C12H15N3O4 (265.3): C
54.33, H 5.70, N 15.84, found C 54.32, H 5.56, N 15.78.
ACKNOWLEDGMENTS
The authors thank Dr. H. Rosemeyer and Dr. Y. He for the measurement of
1
the H- and 13C-NMR spectra. We gratefully acknowledge financial support by the
European Community (grant no.: QLRT-2001-00506, ‘‘Flavitherapeutics’’).
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Received August 22, 2003
Accepted October 6, 2003

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