A convenient route for the synthesis of 3-deazaspongosine

Article abstract of DOI:10.1002/ejoc.201301283

The first chemical synthesis of the 3-deazaspongosine nucleoside is described, starting from commercially available 4-amino-2,6-dichloropyridine. The key step is the introduction of required functional groups at the 2 and 6 positions of the 4-amino-3-nitropyridine without any conflict in the synthesis of nucleobase. Regioselective nucleophilic substitution with allyl alkoxide at the 2 position of 4-amino-2,6-dimethoxypyridine, followed by sequential deallylation and chlorination led to the desired 2-chloro derivative. Ring closure of the 3,4-diaminopyridine and stereoselective glycosylation of the imidazo[4,5-c]pyridine with tetraacetate-protected ribofuranose gave only the N⁹-β-isomer. A final nucleophilic displacement of the 6-chloride by hydrazine followed by reduction with Raney Nickel gave the desired 3-deazaspongosine. The synthesis of 3-deazaspongosine by the stereoselective glycosylation of imidazo[4,5-c]pyridine with tetraacetate-protected ribofuranose is described. The key step is the synthesis of the nucleobase starting from 2,6-dimethoxy-3-nitropyridin-4-amine by introducing the required functional groups at the 2 and 6 positions through the regioselective addition of allyl alcohol. Copyright

Full text of DOI:10.1002/ejoc.201301283

FULL PAPER
DOI: 10.1002/ejoc.201301283
A Convenient Route for the Synthesis of 3-Deazaspongosine
Omprakash Bande[a] and Piet Herdewijn*[a]
Keywords: Ribonucleosides / Nitrogen heterocycles / Glycosylation / Nucleobases / Nucleosides / Aromatic substitution
The first chemical synthesis of the 3-deazaspongosine nucle-
oside is described, starting from commercially available 4-
amino-2,6-dichloropyridine. The key step is the introduction
of required functional groups at the 2 and 6 positions of the
4-amino-3-nitropyridine without any conflict in the synthesis
of nucleobase. Regioselective nucleophilic substitution with
allyl alkoxide at the 2 position of 4-amino-2,6-dimethoxypyr-
idine, followed by sequential deallylation and chlorination
led to the desired 2-chloro derivative. Ring closure of the 3,4-
diaminopyridine and stereoselective glycosylation of the
imidazo[4,5-c]pyridine with tetraacetate-protected ribo-
furanose gave only the N9-β-isomer. A final nucleophilic dis-
placement of the 6-chloride by hydrazine followed by re-
duction with Raney Nickel gave the desired 3-deazaspongos-
ine.
2-Alkoxyadenosine is a purine nucleoside comprising a
2-alkoxyadenine unit attached to a ribose moiety by a β-
N9-glycosidic bond. 2-Alkoxyadenosines are well known for
their biological activities, for example, as potent and selec-
tive agonists of the coronary artery A2 adenosine recep-
tor,[17] and as antibacterial adenosine LigA inhibitors.[18,19]
One such compound, 2-methoxyadenosine (1, Figure 1),
commonly known as spongosine,[20,21] which was isolated
from the Caribbean sponge Cryptotethia crypta, has been
shown to have antiviral activity[22] and antiplatelet proper-
ties.[23] It is also used in the treatment of B-cell proliferative
diseases[24] and in the treatment of pain.[25] Spongosine was
not only the first methoxy purine to be found in nature, but
also one of the first O-methyl compounds to be isolated
from animal tissues.[26]
3-Deazaspongosine (2) could be a synthon for the syn-
thesis of 3-deazaisoguanosine (3b), which could be consid-
ered to be a new nonstandard nucleoside.[27,28] Despite the
remarkable properties of spongosine as described above, to
date, no strategy for the synthesis of its 3-deaza analogues
has been reported. Only its 8-aza analogue has been synthe-
sized by Kobe et al.[29,30] As part of our continuing research
in nucleoside chemistry,[31,32] in this paper, we report the
first preparation of the hitherto unknown 3-deazaspongos-
ine nucleoside 2.
Introduction
There is much evidence in the scientific literature that
modification of the nucleobase and/or the sugar moiety of
naturally occurring purine nucleosides can result in ana-
logues that show interesting biological effects.[1–5] The nitro-
gen atoms in purine nucleosides are of particular interest,
as they are important for binding to enzymes.[6,7] 3-Deaza-
purine nucleosides deserve extra attention, because N3 of
purine nucleosides is considered to be involved in stabilizing
the syn conformation by intramolecular hydrogen bonding
(5Ј-OH–N3H).[8] A literature survey revealed that several 3-
deazapurine[9,10] nucleosides and nucleotides have been syn-
thesized, and that these compounds have been found to
have antibacterial,[11] antiviral,[12,13] immunosuppressive,[14]
anti-inflammatory,[15] and anticancer activities.[16] Thus, we
aimed to synthesize the 3-deaza analogue of spongosine nu-
cleoside 1 (Figure 1).
In our retrosynthetic planning, we proposed three syn-
thetic routes (Scheme 1). In proposed route A, 3-deaza-
spongosine (2) could be obtained from nucleoside 7 by am-
monolysis of the chloride at the 2 position, followed by nu-
cleophilic substitution of second chloride. Nucleoside 7
could be synthesized by coupling 2,6-dichloro-imidazo[4,5-
c]pyridine (6) with tetraacetate-protected ribofuranose in
the presence of a Lewis acid. Compound 6 could be ob-
tained from 4-amino-2,6-dichloro-3-nitropyridine (5) by re-
duction of the nitro group followed by ring closure. In pro-
Figure 1. Structures of spongosine, 3-deazaspongosine, and 3-de-
azaisoguanosine.
[a] Medicinal Chemistry, Rega Institute for Medical Research, KU
Leuven,
Minderbroedersstraat 10, 3000 Leuven, Belgium
E-mail: Piet.Herdewijn@rega.kuleuven.be
http://medchem.rega.kuleuven.ac.be/
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301283.
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O. Bande, P. Herdewijn
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posed route B, compound 2 could be prepared from nucleo- attempts to displace the second chloride of imidazo[4,5-c]-
side 13 by displacement of the methoxy group at the 4 posi- pyridine 8 using sodium methoxide or palladium-catalyzed
tion using an ammonia source. Nucleoside 13 could be syn- cross-coupling reactions[37] failed.
thesized by performing a glycosylation between intermedi-
ate 12 and tetraacetate-protected ribofuranose in the pres-
ence of a Lewis acid. Imidazo[4,5-c]pyridine 12 could be
synthesized from 4-amino-2,6-dimethoxy-3-nitropyridine
(10) by reduction of the nitro group followed by ring clo-
sure. In route C, compound 2 could be prepared from nu-
cleoside 19 by nucleophilic substitution of the 2-chloride by
an ammonia source. Nucleoside 19 could be synthesized by
coupling of 4-chloro-6-methoxyimidazo[4,5-c]pyridine (18)
with tetraacetate-protected ribofuranose in the presence of
a Lewis acid. Imidazopyridine 18 could be synthesized from
4-amino-2-chloro-6-methoxy-3-nitropyridine 17 by re-
duction of the nitro group followed by ring closure, as
shown in Scheme 1.
Scheme 2. Reagents and conditions: (a) ref.[33]; (b) (i) Fe, HCl,
EtOH; (ii) triethyl orthoformate, reflux; (iii) formic acid, reflux,
72%; (c) 9, p-toluenesulfonic acid, 160 °C, 10 min, 76%; (d) NH3
(30% aq.), 200 °C, 5 d, 80%.
As our attempts to displace the second chloride in inter-
mediate 8 were unsuccessful, we decided to perform a nucle-
ophilic substitution at an earlier stage, with a more reactive
starting material such as 5. Treatment of pyridine 5 with a
solution of sodium methoxide in methanol at 60 °C for 12 h
led to the desired disubstituted derivative (i.e., 10) in 90%
yield (Scheme 3). Reduction of the nitro group was per-
formed by treatment with sodium dithionite at room tem-
perature for 15 min to give 3,4-diamino derivative 11 in
75% yield. Subsequent ring closure with triethyl orthofor-
mate and formic acid gave 4,6-dimethoxy-imidazo[4,5-c]-
pyridine (12) in 85% yield. Glycosylation of 12 with tetra-
acetate-protected ribofuranose 9 using DBU (1,8-diazabi-
cyclo[5.4.0]undec-7-ene) and TMSOTf (trimethylsilyl tri-
fluoromethanesulfonate) gave a mixture of N9 (13a) and N7
Scheme 1. Retrosynthetic analysis of 3-deazaspongosine (2).
(13b) nucleoside isomers in a 7:3 ratio in 82% yield. The
structure of the N9 and N7 isomers was confirmed by
HMBC spectral analysis. When we attempted to displace
the methoxy group by an NH2 group, we only observed
Results and Discussion
The required 2,6-dichloro-3-nitropyridin-4-amine (5) was
prepared from commercially available 4-amino-2,6-di-
chloropyridine (4) as reported by Cosstick et al.
(Scheme 2).[33] Reduction of the nitro group of compound
5[34,35] gave 3,4-diaminopyridine, which was used without
purification in the ring closure reaction. Thus, the crude
material was heated at reflux in triethyl orthoformate and
then in formic acid to give 4,6-dichloro-imidazo[4,5-c]pyr-
idine (6) in 72% yield over three steps. Coupling of nucleo-
base 6 with tetraacetate-protected ribofuranose 9 in the
presence of p-toluenesulfonic acid gave nucleoside 7 in good
yield, as reported by Montgomery et al.[36] Treatment of
derivative 7 with ammonia (30% aq.) at 200 °C for 5 d re-
Scheme 3. Reagents and conditions: (a) NaOMe, MeOH, 12 h,
sulted in regioselective displacement of the 2-chloride and
60 °C, 90%; (b) (i) Na2S2O4, EtOH/H2O (1:1), room temp., 15 min,
concomitant deacetylation to give compound 8 (80% yield).
75%; (c) (i) triethyl orthoformate, reflux, 5 h; (ii) formic acid, re-
The spectral and analytical data of 8 were found to be con-
flux, 5 h, 85%; (d) 9, TMSOTf, DBU, CH3CN, 0 °C to 65 °C, 12 h;
sistent with those reported.[36] Unfortunately, all our (e) NH2NH2, EtOH, 100 °C, 12 h, 95%.
232
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A Convenient Route for the Synthesis of 3-Deazaspongosine
cleavage of the protective groups to give derivative 14. A chlorination leading to 17. Stereoselective glycosylation of
number of attempts were made using ammonia (methanolic imidazo[4,5-c]pyridine 18 with tetraacetate-protected ribo-
or aqueous solutions) in a sealed tube, ammonia/CuI,[38] or furanose 9 yielded only the N9-β-isomer 19 in good yield.
hydrazine (85%), but none of these methods led to the de- A final nucleophilic displacement with hydrazine and re-
sired 3-deazaspongosine.
duction with Raney Nickel led to 3-deazaspongosine (2).
As an alternative synthetic route, the regioselective ad- This approach is general, as it is useful for the synthesis of
dition of allyl alcohol was achieved by treating 10 with a a series of 2-alkoxyadenosine derivatives.
solution of sodium allyl alkoxide (5 m in allyl alcohol) at
60 °C for 1.5 h to give monosubstituted derivative 15 in
Experimental Section
82% yield (Scheme 4). Deallylation of 15 was accomplished
by treatment with palladium(0) and 1,3-dimethylbarbituric
acid at room temperature in anhydrous dichloromethane to
give hydroxy derivative 16 in 98% yield.[39] Compound 16
was heated at reflux in POCl3 for 2.5 h to give chlorinated
intermediate 17 in 78% yield. The synthesis of imidazo[4,5-
c]pyridine 18 was performed in three sequential steps. First,
the nitro group was reduced by treatment with sodium di-
thionite at room temperature for 15 min, then ring closure
was achieved by refluxing successively in triethyl ortho-
formate and formic acid. Stereoselective glycosylation was
carried out using DBU and TMSOTf to give the N9-β-iso-
mer only. An attempted one-pot nucleophilic displacement
and removal of the acetate groups by treatment with ammo-
nia solution at 160 °C led to the decomposition of nucleo-
side 19. We thus envisioned that the deprotection and
nucleophilic substitution could be achieved by treatment
with hydrazine. In fact, when nucleoside 19 was treated with
an aqueous solution of hydrazine (80%) at 100 °C for 2 h,
followed by an additional step with Raney Nickel at 100 °C
for 1.5 h, 3-deazaspongosine (2) was formed. The structure
of N9 isomer 2 was confirmed by HMBC analysis (corre-
lation between C-4 and 1Ј-H).
General Remarks: 1H and 13C NMR spectra were recorded with
300 MHz (1H, 300 MHz; 13C, 75 MHz), 500 MHz (1H, 500 MHz;
13C, 125 MHz), or 600 MHz (1H, 600 MHz; 13C, 150 MHz) spec-
trometers. 2D NMR spectra (H,H-COSY, HSQC, and HMBC)
were used for the assignment of all the intermediate and final com-
pounds. Mass spectra were acquired with a quadrupole orthogonal
acceleration time-of-flight mass spectrometer. Melting points were
obtained with a melting point apparatus using open capillary tubes.
Column chromatographic separations were carried out on silica gel
(100–200 mesh or 230–400 mesh) by gradient elution with combi-
nations of two/three solvents. Solvents for reactions were distilled
before use: THF and toluene from Na/benzophenone; CH2Cl2 and
CH3CN from CaH2; Et3N and pyridine from KOH.
4,6-Dichloro-1H-imidazo[4,5-c]pyridine (6): Iron powder (1.3 g,
24.04 mmol), H2O (4.3 mL, 240 mmol), and HCl (concentrated;
1 mL, 28.85 mmol) were added to 4-amino-2,6-dichloro-3-nitropyr-
idine (5; 1 g, 4.81 mmol) in ethanol (23 mL). The mixture was
heated at reflux for 16 h. The mixture was cooled to room tempera-
ture, then it was neutralized with sodium hydrogen carbonate (satu-
rated aq.). The mixture was filtered, and the filter residue was
washed with ethyl acetate. The filtrate was concentrated. The resi-
due was dissolved in ethyl acetate and washed with water (10 mL).
The organic layer was dried (MgSO4) and evaporated. The solid
residue was used in the next step without further purification.
A mixture of 3,4-diaminopyridine (500 mg, 22.81 mmol) and tri-
ethyl orthoformate (6.5 mL, 39.32 mmol) was heated at reflux at
145 °C for 5 h. The solution was then evaporated to dryness using
a rotary evaporator. The residue was dissolved in formic acid (99%;
6.3 mL), and the solution was heated at reflux at 110 °C for 5 h.
When the reaction was complete, the excess formic acid was re-
moved with the rotary evaporator. The residue was purified by col-
umn chromatography (dichloromethane/methanol, 97:3) to give 6
(390 mg, 72%) as a yellow solid. Rf = 0.65 (dichloromethane/meth-
anol, 9:1). m.p. 252–254 °C. 1H NMR (300 MHz, [D6]DMSO): δ =
8.54 (s, 1 H, 2-H), 7.75 (s, 1 H, 7-H) ppm. 13C NMR (75 MHz,
[D6]DMSO): δ = 146.3 (C-2), 143.4, 139.6, 137.6, 135.5 (C-6, C-4,
C-3a, C-7a), 108.3 (C-7) ppm. HRMS (ESI+): calcd. for C6H3Cl2N3
[M + H]+ 187.9776; found 187.9771.
Scheme 4. Reagents and conditions: (a) sodium allylate, allyl
alcohol, 60 °C, 1.5 h, 82%; (b) Pd(PPh3)4, 1,3-dimethylbarbituric
acid, CH2Cl2, room temp., 2.5 h, 98%; (c) POCl3, reflux, 2.5 h,
78%; (d) (i) Na2S2O4, EtOH/H2O (1:1), room temp., 15 min. (ii) tri-
ethyl orthoformate, reflux, 5 h; (iii) formic acid, reflux, 5 h, 68%;
(e) 9, TMSOTf, DBU, CH3CN, 65 °C, 12 h, 74%; (f) (i) 80%
NH2NH2, EtOH, 100 °C, 2 h; (ii) Raney Ni (50% aq.), EtOH,
100 °C, 1.5 h, 65%.
4,6-Dichloro-9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-3-deazapurine
(7): Reaction of nucleobase 6 with tetraacetate-protected ribofur-
anose 9 in the presence of p-toluenesulfonic acid gave nucleoside 7,
as reported by Montgomery et al.[36] Spectral and analytical data
were in agreement with previous reports. Rf = 0.3 (n-hexane/ethyl
1
acetate, 1:1). m.p. 240–242 °C. H NMR (500 MHz, [D6]DMSO):
δ = 8.79 (s, 1 H, 8-H), 8.03 (s, 1 H, 3-H), 6.40 (d, J = 5.70 Hz, 1
H, 1Ј-H), 5.62 (t, J = 5.70 Hz, 1 H, 2Ј-H), 5.41–5.45 (m, 1 H, 3Ј-
H), 4.31–4.50 (m, 3 H, 4Ј-H, 5aЈ-H, 5bЈ-H), 2.13 (s, 3 H, CH3),
2.09 (s, 3 H, CH3), 2.04 (s, 3 H, CH3) ppm. 13C NMR (125 MHz,
[D6]DMSO): δ = 170.1, 169.5, 169.4 (3 C=O), 146.0 (C-6), 141.8,
140.8, 139.6, 137.3 (C-2, C-4, C-8, C-5), 107.3 (C-3), 86.8 (C-1Ј),
Conclusions
In conclusion, we have developed an efficient route for
the synthesis of 3-deazaspongosine (2) starting from 2,6-
dichloro-4-amino-pyridine (4). The key steps were the selec-
tive introduction/removal of allyl alkoxide group, and the 79.9 (C-4Ј), 72.2 (C-2Ј), 69.4 (C-3Ј), 62.9 (C-5Ј), 20.6, 20.4, 20.2 (3
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O. Bande, P. Herdewijn
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CH3) ppm. HRMS (ESI+): calcd. for C17H17Cl2N3O7 [M + H]+
4,6-Dimethoxy-9-(2,3,5-tri-O-acetyl-β-
D-ribofuranosyl)-3-deazapur-
446.0503; found 446.0504.
ine (13a) and 4,6-Dimethoxy-7-(2,3,5-tri-O-acetyl-β-D-ribofurano-
syl)-3-deazapurine (13b): TMSOTf (1.22 mL, 6.70 mmol) was
added to a stirred solution of compound 12 (600 mg, 3.35 mmol),
sugar 9 (1.1 g, 3.68 mmol), and DBU (0.56 mL, 3.68 mmol) in
CH3CN (15 mL) at 0 °C. The mixture was stirred at 60 °C for 12 h,
then it was poured into NaHCO3 (aq. solution). The mixture was
extracted with ethyl acetate. The organic phase was washed with
brine, dried (MgSO4), and filtered, and the solvents were evapo-
rated. The residue was purified by silica gel column chromatog-
raphy (dichloromethane/methanol, 98:2) to give compound 13a
(740 mg, 50%) as a pale yellow foam. Rf = 0.3 (n-hexane/ethyl acet-
ate, 1:1). 1H NMR (500 MHz, CDCl3): δ = 7.89 (s, 1 H, 8-H), 6.48
(s, 1 H, 3-H), 5.94 (d, J = 5.70 Hz, 1 H, 1Ј-H), 5.52 (t, J = 5.70 Hz,
1 H, 2Ј-H), 5.40 (dd, J = 4.20, 5.70 Hz, 1 H, 3Ј-H), 4.11–4.46 (m,
3 H, 4Ј-H, 5aЈ-H, 5bЈ-H), 4.11 (s, 3 H, OCH3), 3.94 (s, 3 H, OCH3),
2,6-Dichloro-9-(β-D-ribofuranosyl)-3-deazapurine (8): A solution of
13a (300 mg, 672 μmol) in ammonia (30% aq.) was heated at
200 °C for 5 d. The reaction mixture was concentrated, and the
residue was purified by column chromatography (dichloromethane/
methanol, 9:1) to give 14 (180 mg, 93%) as a solid. Rf = 0.5 (di-
chloromethane/methanol, 9:1). m.p. 224–226 °C. 1H NMR
(600 MHz, CD3OD): δ = 8.33 (s, 1 H, 8-H), 7.07 (s, 1 H, 3-H), 5.82
(d, J = 5.80 Hz, 1 H, 1Ј-H), 4.38 (t, J = 5.80 Hz, 1 H, 2Ј-H), 4.25
(dd, J = 3.60, 5.80 Hz, 1 H, 3Ј-H), 4.11 (dt, J = 3.60, 6.0 Hz, 1 H,
4Ј-H), 3.84 (dd, J = 6.0, 12.0 Hz, 1 H, 5aЈ-H), 3.77 (dd, J = 3.60,
12.0 Hz, 1 H, 5bЈ-H) ppm. 13C NMR (125 MHz, CD3OD): δ =
152.5 (C-6), 143.2 (C-2), 142.1 (C-8), 141.1 (C-4), 126.8 (C-5), 97.8
(C-3), 91.0 (C-1Ј), 87.3 (C-4Ј), 76.1 (C-2Ј), 71.7 (C-3Ј), 62.5 (C-5Ј)
ppm. HRMS (ESI+): calcd. for C11H13ClN4O4 [M + H]+ 301.0698;
found 301.0693.
2.21 (s, 3 H, CH3), 2.15 (s, 3 H, CH3), 2.08 (s, 3 H, CH3) ppm. 13
C
NMR (125 MHz, CDCl3): δ = 170.5, 169.7, 169.3 (3 C=O), 159.3
(C-6), 154.1 (C-2), 142.1 (C-4), 139.3 (C-8), 124.2 (C-5), 87.2 (C-
1Ј), 82.6 (C-3), 80.4 (C-4Ј), 72.9 (C-2Ј), 70.2 (C-3Ј), 62.9 (C-5Ј),
54.3, 53.7 (2 OCH3), 20.9, 20.6, 20.4 (3 CH3) ppm. HRMS (ESI+):
calcd. for C19H23N3O9 [M + H]+ 438.1506; found 438.1506.
2,6-Dimethoxy-3-nitropyridin-4-amine (10): Sodium methoxide (5 m
in MeOH; 2.8 mL) was added to a solution of 5 (500 mg, 2.4 mmol)
in methanol (14 mL), and the mixture was heated at 60 °C for 12 h.
The mixture was concentrated, then the residue was dissolved in
ethyl acetate and washed with water (5 mL). The solution was dried
(MgSO4) and concentrated, and the residue was purified by column
chromatography (n-hexane/ethyl acetate, 9:1) to give 12 (430 mg,
90%) as a yellow solid. Rf = 0.25 (n-hexane/ethyl acetate, 8:2). m.p.
136–138 °C. 1H NMR (500 MHz, [D6]DMSO): δ = 7.35 (br. s, 2
H, NH2), 5.78 (s, 1 H, 5-H), 3.89 (s, 3 H, OCH3), 3.81 (s, 3 H,
OCH3) ppm. 13C NMR (125 MHz, [D6]DMSO): δ = 162.8 (C-6),
158.6 (C-2), 153.9 (C-4), 115.8 (C-3), 86.2 (C-5), 54.0, 53.7, (2
OCH3) ppm. HRMS (ESI+): calcd. for C7H9N3O4 [M + H]+
200.0665; found 200.0670.
Further elution (dichloromethane/MeOH, 97:3) gave 13b (310 mg,
32%) as a pale yellow foam. Rf = 0.31 (n-hexane/ethyl acetate, 1:1).
1H NMR (600 MHz, CDCl3): δ = 8.04 (s, 1 H, 8-H), 6.17 (s, 1 H,
3-H), 5.53 (d, J = 5.80 Hz, 1 H, 1Ј-H), 5.52 (t, J = 5.80 Hz, 1 H,
2Ј-H), 5.40 (t, J = 5.80 Hz, 1 H, 3Ј-H), 4.16–4.26 (m, 3 H, 4Ј-H,
5aЈ-H, 5bЈ-H), 3.89 (s, 3 H, OCH3), 3.73 (s, 3 H, OCH3), 1.97 (s,
3 H, CH3), 1.96 (s, 3 H, CH3), 1.92 (s, 3 H, CH3) ppm. 13C NMR
(150 MHz, CDCl3): δ = 169.9, 169.1, 168.7 (3 C=O), 158.2 (C-6),
154.6 (C-2), 148.1 (C-4), 143.1 (C-8), 112.7 (C-5), 89.5 (C-3), 88.5
(C-1Ј), 78.8 (C-4Ј), 74.0 (C-2Ј), 68.7 (C-3Ј), 62.1 (C-5Ј), 53.9, 53.2
(2 OCH3), 20.3, 20.0, 20.0 (3 CH3) ppm. HRMS (ESI+): calcd. for
C19H23N3O9 [M + H]+ 438.1506; found 438.1505.
2,6-Dimethoxypyridine-3,4-diamine (11): A solution of sodium di-
thionite (1.2 g, 7.53 mmol) in water (12.5 mL) was added to a solu-
tion of 10 (500 mg, 2.51 mmol) in ethanol (12.5 mL), and the mix-
ture was stirred at room temperature for 15 min. The ethanol was
evaporated at 20 °C. The residue was dissolved in ethyl acetate and
washed with water (6 mL). The organic layer was dried (MgSO4),
and concentrated. The residue was purified by column chromatog-
raphy (n-hexane/ethyl acetate, 1:1) to give 11 (320 mg, 75%) as a
yellow solid. Rf = 0.3 (n-hexane/ethyl acetate, 1:1). m.p. 70–72 °C.
1H NMR (300 MHz, [D6]DMSO): δ = 5.64 (s, 1 H, 5-H), 5.35 (br.
s, 2 H, NH2), 3.51 (br. s, 2 H, NH2), 3.79 (s, 3 H, OCH3), 3.67 (s,
3 H, OCH3) ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 154.7,
150.0 (C-6, C-2), 146.0 (C-4), 109.0 (C-3), 86.9 (C-5), 52.5, 52.4 (2
OCH3) ppm. HRMS (ESI+): calcd. for C7H11N3O2 [M + H]+
170.0923; found 170.0927.
2,6-Dimethoxy-9-(β-D-ribofuranosyl)-3-deazapurine (14): Hydrazine
(80%; 7 mL) was added to a solution of 13a (200 mg, 457 μmol) in
ethanol (1 mL), and the mixture was heated at 100 °C for 12 h. The
reaction mixture was concentrated, and the residue was purified by
column chromatography (dichloromethane/methanol, 9:1) to give
14 (136 mg, 95%) as a solid. Rf = 0.5 (dichloromethane/methanol,
9:1). 1H NMR (500 MHz, CD3OD): δ = 8.26 (s, 1 H, 8-H), 6.74 (s,
1 H, 3-H), 5.77 (d, J = 6.20 Hz, 1 H, 1Ј-H), 5.51 (s, 1 H, OH), 5.25
(s, 1 H, OH), 5.16 (s, 1 H, OH), 4.32 (br. s, 1 H, 2Ј-H), 4.11 (br. s,
1 H, 3Ј-H), 3.96–3.80 (m, 4 H, OCH3, 4Ј-H), 3.85 (s, 3 H, OCH3),
3.50–3.68 (m, 2 H, 5aЈ-H, 5bЈ-H) ppm. 13C NMR (125 MHz,
CD3OD): δ = 158.0 (C-6), 153.0 (C-2), 142.7 (C-4), 141.5 (C-8),
123.5 (C-5), 88.8 (C-1Ј), 85.7 (C-3), 83.0 (C-4Ј), 73.6 (C-2Ј), 70.1
(C-3Ј), 61.2 (C-5Ј), 53.9, 53.0 (2 OCH3) ppm. HRMS (ESI+): calcd.
for C13H17N3O6 [M + H]+ 312.1190; found 312.1194.
4,6-Dimethoxy-1H-imidazo[4,5-c]pyridine (12): A mixture of 3,4-di-
aminopyridine 11 (600 mg, 3.55 mmol) and triethyl orthoformate
(8.2 mL, 49.65 mmol) was heated at reflux for 5 h at 145 °C. The
solution was evaporated to dryness using a rotary evaporator. The
residue was dissolved in formic acid (99%; 27 mL), and the solu-
tion was heated at reflux at 110 °C for 5 h. When the reaction was
complete, the excess formic acid was removed using the rotary
evaporator, and the residue was purified by column chromatog-
2-(Allyloxy)-6-methoxy-3-nitropyridin-4-amine (15): Sodium allyl
alkoxide (5 m in allyl alcohol; 5 mL, 25.1 mmol) was added to a
solution of 10 (1.0 g, 5.2 mmol) in allyl alcohol (25 mL), and the
mixture was heated at 60 °C for 1.5 h. The mixture was concen-
trated, the residue was dissolved in ethyl acetate and washed with
raphy (dichloromethane/methanol, 97:3) to give 12 (540 mg, 85%) water (10 mL). The organic layer was was dried (MgSO4) and con-
as a yellow solid. Rf = 0.6 (dichloromethane/methanol, 9:1). m.p. centrated. The residue was purified by column chromatography (n-
232–234 °C. 1H NMR (300 MHz, [D6]DMSO): δ = 8.06 (s, 1 H, 2- hexane/ethyl acetate, 9:1) to give 15 (805 mg, 82%) as a yellow so-
H), 6.43 (s, 1 H, 7-H), 3.99 (s, 3 H, OCH3), 3.85 (s, 3 H, OCH3)
ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 157.7 (s, C-4, C-6),
152.1 (C-7a), 141.6 (C-2), 121.9 (C-3a), 83.7 (C-7), 52.5, 52.4 (2
OCH3) ppm. HRMS (ESI+): calcd. for C8H9N3O2 [M + H]+
180.0767; found 180.0777.
lid. Rf = 0.3 (n-hexane/ethyl acetate, 8:2). m.p. 68–70 °C. 1H NMR
(500 MHz, CDCl3): δ = 6.29 (br. s, 2 H, NH2), 5.95–6.01 (m, 1 H,
CH=C), 5.63 (s, 1 H, 5-H), 5.43 (dd, J = 1.52, 17.2 Hz, 1 H,
CH2=C), 5.22 (dd, J = 1.52, 10.30 Hz, 1 H, CH2=C), 4.85–4.93 (m,
2 H, CH2), 3.83 (s, 3 H, OCH3) ppm. 13C NMR (125 MHz,
234
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 231–236

A Convenient Route for the Synthesis of 3-Deazaspongosine
CDCl3): δ = 162.6 (C-6), 157.9 (C-4), 152.8 (C-2), 131.4 (CH=C),
116.8 (s, C=CH, C-3), 86.3 (C-5), 66.8 (CH2), 53.0 (OCH3) ppm.
HRMS (ESI+): calcd. for C9H11N3O4 [M + H]+ 226.0822; found
226.0818.
umn chromatography (n-hexane/ethyl acetate, 6:4) to give com-
pound 19 (783 mg, 74%) as a thick yellow liquid. Rf = 0.27 (n-
hexane/ethyl acetate, 1:1). 1H NMR (600 MHz, CDCl3): δ = 8.05
(s, 1 H, 8-H), 6.89 (s, 1 H, 3-H), 5.96 (d, J = 5.80 Hz, 1 H, 1Ј-H),
5.50 (d, J = 5.80 Hz, 1 H, 2Ј-H), 5.40 (dd, J = 3.93, 5.80 Hz, 1 H,
3Ј-H), 4.31–4.49 (m, 3 H, 4Ј-H, 5aЈ-H, 5bЈ-H), 3.98 (s, 3 H, OCH3),
4-Amino-6-methoxy-3-nitropyridin-2-ol (16): Compound 15
(800 mg, 3.55 mmol) was dissolved in dry dichloromethane
(25 mL), and tetrakis(triphenylphosphine)palladium(0) (40 mg,
35 μmol) and 1,3-dimethylbarbituric acid (832 mg, 5.33 mmol)
were added simultaneously. The reaction mixture was stirred at
room temp for 2.5 h. The resulting precipitate was obtained by fil-
tration, and it was washed with cold dichloromethane to give 16
(540 mg, 98%) as a yellow solid. Rf = 0.21 (ethyl acetate). m.p.
2.23 (s, 3 H, CH3), 2.16 (s, 3 H, CH3), 2.09 (s, 3 H, CH3) ppm. 13
C
NMR (150 MHz, CDCl3): δ = 170.4, 169.7, 169.4 (3 C=O), 159.7
(C-2), 142.3 (C-8), 141.6 (C-6), 139.0 (C-4), 134.4 (C-5), 90.1 (C-
3), 87.4 (C-1Ј), 80.6 (C-4Ј), 72.7 (C-2Ј), 70.0 (C-3Ј), 62.8 (C-5Ј),
54.8 (OCH3), 20.9, 20.6, 20.4 (3 CH3) ppm. HRMS (ESI+): calcd.
for C18H20ClN3O8 [M + H]+ 442.1011; found 442.1012.
1
241–243 °C. H NMR (600 MHz, [D6]DMSO): δ = 11.40 (s, 1 H,
6-Amino-2-methoxy-9-(β-D-ribofuranosyl)-3-deazapurine (2): Hy-
OH), 8.24 (br. s, 2 H, NH2), 5.34 (s, 1 H, 5-H), 3.79 (s, 3 H, OCH3)
drazine (80%; 10 mL) was added to a solution of 19 (340 mg,
769 μmol) in ethanol (1 mL), and the mixture was heated at 100 °C
ppm. 13C NMR (150 MHz, [D6]DMSO): δ = 158.6, 157.1, 156.6
(C-4, C-2, C-6), 115.6 (C-3), 75.4 (C-5), 56.2 (OCH3) ppm. HRMS for 2 h. The reaction mixture was concentrated, Raney Ni (50%;
(ESI+): calcd. for C6H7N3O4 [M + H]+ 186.0509; found 186.0507.
10 mL) was added, and the mixture was heated at 100 °C for 2 h.
The reaction mixture was filtered through Celite, the filtrate was
concentrated, and the residue was purified by column chromatog-
raphy (dichloromethane/methanol, 9:1) to give 2 (149 mg, 65%) as
a thick liquid. Rf = 0.25 (ethyl acetate/methanol, 6:1). 1H NMR
(500 MHz, CD3OD): δ = 8.19 (s, 1 H, 8-H), 6.38 (s, 1 H, 3-H), 5.80
(d, J = 5.80 Hz, 1 H, 1Ј-H), 4.44 (dd, J = 4.11, 5.80 Hz, 1 H, 2Ј-
H), 4.26 (dd, J = 4.11, 5.80 Hz, 1 H, 3Ј-H), 4.11 (d, J = 4.11 Hz,
1 H, 4Ј-H), 3.70–3.90 (m, 5 H, OCH3, 5aЈ-H, 5bЈ-H) ppm. 13C
NMR (125 MHz, CD3OD): δ = 161.9 (C-2), 150.8 (C-6), 142.7 (C-
4), 140.8 (C-8), 123.3 (C-5), 90.8 (C-1Ј), 87.0 (C-4Ј), 78.9 (C-3),
75.6 (C-2Ј), 71.7 (C-3Ј), 62.6 (C-5Ј), 55.0 (OCH3) ppm. HRMS
(ESI+): calcd. for C12H16N4O5 [M + H]+ 297.1193; found 297.1194.
2-Chloro-6-methoxy-3-nitropyridin-4-amine (17): A solution of 16
(400 mg, 2.16 mmol) in POCl3 (2.5 mL) was heated at 95 °C for
4 h. Then the reaction mixture was allowed to cool down to room
temperature, and the POCl3 was evaporated. The residue was dis-
solved in ethyl acetate, and this solution was washed with NaHCO3
(saturated aq.; 2ϫ 5 mL). The organic phase was dried with
MgSO4 and concentrated. The oily residue was purified by silica
gel column chromatography (dichloromethane) to give 17 (290 mg,
78%) as a yellow solid. Rf = 0.35 (n-hexane/ethyl acetate, 7:3). m.p.
140–142 °C. 1H NMR (500 MHz, [D6]DMSO): δ = 6.11 (s, 1 H, 5-
H), 3.81 (s, 3 H, OCH3) ppm. 13C NMR (125 MHz, [D6]DMSO):
δ = 162.5, 151.7, 141.8 (C-4, C-2, C-6), 127.8 (C-3), 92.1 (C-5), 54.3
(OCH3) ppm. HRMS (ESI+): calcd. for C6H6ClN3O3 [M + H]+
204.0170; found 204.0172.
Supporting Information (see footnote on the first page of this arti-
1
cle): H and 13C NMR spectra.
4-Chloro-6-methoxy-1H-imidazo[4,5-c]pyridine (18): A solution of
sodium dithionite in water (10 mL) was added to a solution of 17
(400 mg, 1.96 mmol) in ethanol (10 mL), and the mixture was
stirred at room temperature for 15 min. The mixture was concen-
trated, the residue was dissolved in ethyl acetate and washed with
water (5 mL). The organic layer was dried with MgSO4 and concen-
trated. The crude oily 3,4-diaminopyridine was used in the next
step without further purification. A mixture of crude 3,4-di-
aminopyridine (300 mg, 1.73 mmol) and triethyl orthoformate
(4 mL, 24.19 mmol) was heated at reflux at 145 °C for 5 h. The
solution was evaporated to dryness using a rotary evaporator. The
residue was dissolved in formic acid (99%; 4 mL) and the solution
was heated at reflux at 110 °C for 5 h. When the reaction was com-
plete, the excess formic acid was removed using a rotary evaporator.
The residue was purified by column chromatography to give 18
(216 mg, 68%) as a yellow solid. Rf = 0.15 (n-hexane/ethyl acetate,
Acknowledgments
We are grateful to Prof. Jef Rozenski for recording HRMS spectra,
Luc Baudemprez for NMR experiments, and Mrs. Chantal Bier-
naux for excellent editorial help. We are indebted to Dr. Jang and
Dr. Bel Abed for helpful discussions.
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