Synthesis of C-ribosyl imidazo[2,1-f][1,2,4]triazines as inhibitors of adenosine and AMP deaminases

Article abstract of DOI:10.1039/a904065j

The 3-β-D-ribofuranoside 6 of the new imidazo[2,1-f][1,2,4]triazine 27 is isomeric and isoelectronic with the nucleoside deaminoformycin 1 which is a good inhibitor of adenosine deaminase (ADA) while its 5′-monophosphate 2 is a good inhibitor of adenosine 5′-monophosphate deaminase (AMPDA). The 6-methylsulfanyl derivative 7 of 6 is synthesized by condensation of the monocyclic 1,2,4-triazine 9 with bromo aldehyde 10, which is accompanied by cyclization to give the protected C-nucleoside 21; the 8-methylsulfanyl group of 21 is removed by replacement by hydrazine and oxidation. The 1,2,4-triazine 9 cyclizes similarly with chloroacetaldehyde or its dimethyl acetal to give 6,8-bis(methylsulfanyl)imidazo[2,1-f][1,2,4]triazine 17, which is converted into the parent heterocycle 27 by two routes, and into mono- and di-substituted derivatives (19, 20, 24, 25, 28-30) of the new ring system. Riboside 7 is an inhibitor of mammalian ADA (IC₅₀ 40 μM). The Royal Society of Chemistry 1999.

Full text of DOI:10.1039/a904065j

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Synthesis of C-ribosyl imidazo[2,1-f ][1,2,4]triazines as inhibitors
of adenosine and AMP deaminases
Philip J. Dudfield,a Van-Duc Le,b Stephen D. Lindella and Charles W. Reesb
a AgrEvo UK Limited, Chesterford Park, Saffron Walden, Essex, UK CB10 1XL
b Department of Chemistry, Imperial College of Science, Technology and Medicine, London,
UK SW7 2AY
Received (in Cambridge, UK) 20th May 1999, Accepted 29th July 1999
The 3-β--ribofuranoside 6 of the new imidazo[2,1-f ][1,2,4]triazine 27 is isomeric and isoelectronic with the
nucleoside deaminoformycin 1 which is a good inhibitor of adenosine deaminase (ADA) while its 5Ј-monophosphate
2 is a good inhibitor of adenosine 5Ј-monophosphate deaminase (AMPDA). The 6-methylsulfanyl derivative 7 of 6 is
synthesized by condensation of the monocyclic 1,2,4-triazine 9 with bromo aldehyde 10, which is accompanied by
cyclization to give the protected C-nucleoside 21; the 8-methylsulfanyl group of 21 is removed by replacement by
hydrazine and oxidation. The 1,2,4-triazine 9 cyclizes similarly with chloroacetaldehyde or its dimethyl acetal to
give 6,8-bis(methylsulfanyl)imidazo[2,1-f ][1,2,4]triazine 17, which is converted into the parent heterocycle 27 by
two routes, and into mono- and di-substituted derivatives (19, 20, 24, 25, 28–30) of the new ring system. Riboside 7
is an inhibitor of mammalian ADA (IC50 40 µM).
Inhibitors of the enzyme adenosine 5Ј-monophosphate
deaminase (AMPDA, EC 3.5.4.6) have potential for use as
herbicides1 and in the treatment of ischaemia.2 Inhibitors of
the related enzyme adenosine deaminase (ADA, EC 3.5.4.4) are
of interest as potential fungicides3 and in cancer and viral
chemotherapy.4 Deaminoformycin 1 and the corresponding 5Ј-
phosphate derivative 2 have recently been shown to be good
inhibitors of ADA and AMPDA, respectively.5 The isomeric
ADA inhibitor, purine riboside 3, binds to the enzyme as
the covalent hydrate 46 and it is believed that an analogous
hydration also occurs upon binding of 1 and 2 to ADA and
AMPDA. Calculation of the heats of formation differences
between the N7-H and N8-H tautomers of the pyrazolo-
pyrimidine ring system and their corresponding covalent
hydrates indicated that the less stable N8-H tautomer 5 formed
the more stable hydrate.5 Thus, in an effort to improve inhibi-
tory potency we have attempted to design new non-tautomeric
heterocycles possessing similar electronic properties to struc-
ture 5. Simple exchange of C-4 and N-8 of the pyrazolo-
pyrimidine ring gives the furanosyl imidazo[2,1-f ][1,2,4]triazine
6 as a new target molecule. Calculations suggested that this 10π
aromatic system would readily undergo covalent hydration as
desired for biological activity.7 This heterocyclic ring system
was unknown although various physical chemical properties of
some of its derivatives have been calculated,8 and some related
fused benzimidazo derivatives have been reported.9
We now describe the synthesis of the imidazo[2,1-f ]-
[1,2,4]triazine ring system, including the parent 27, and our
biological target, the C-nucleoside 7. The presence of the
6-methylsulfanyl group in 7 facilitated the synthesis and, based
on the results of studies with substituted purines,10 should be
compatible with achieving inhibition of ADA and AMPDA.
Disconnection of the C3–N4 bond of 7, with introduction of a
second methylsulfanyl group for synthetic convenience, leads to
the imine 8 which could be constructed from the aminotriazine
9 and the bromo aldehyde 10 (Scheme 1).
Scheme 1
Results and discussion
The bromo aldehyde 10 was synthesized from -ribose by
adapting the method used by Clingerman and Secrist in their
synthesis of the related compound 10a.11 (Scheme 2). We found
that whereas tritylation of the acetonide of -ribose afforded
the protected -ribose 11a in only modest yield (48%), silylation
with tert-butyldiphenylsilyl chloride gave 11 in good yield
(75%). Wittig reaction of the masked aldehyde 11 with the
stabilized phosphorus ylide, ethyl bromo(triphenylphosphor-
anylidene)acetate,12 followed by addition of DBU to aid
J. Chem. Soc., Perkin Trans. 1, 1999, 2929–2936
This journal is © The Royal Society of Chemistry 1999
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cyclization of the open-chain compound formed, gave a good
yield of the ester 12 (82%). Reduction of this ester with
DIBAL-H in dry toluene at low temperature gave the desired
bromo aldehyde 10 (58%) (Scheme 2).
which has been used, for example, in the removal of a phenyl-
thio group from a purine16 and a methylthio group from a
1,2,4-triazine.17 With two equiv. of hydrazine monohydrate in
refluxing ethanol for 1 h, bis-sulfide 17 gave the monohydrazine
19 in high yield; an excess of hydrazine in refluxing ethanol for
12 h still gave only the monohydrazine. Subsequent experiments
showed that conversion of 17 into 19 (89%) required only 1 h at
room temperature. The hydrazine group was readily removed
by oxidation with yellow mercuric oxide (HgO) in reflux-
ing ethanol for 5 min to give 6-(methylsulfanyl)imidazo[2,1-f ]-
[1,2,4]triazine 20 (66%) (Scheme 4).
Scheme 2 Reagents and conditions (and yields): (i) Ph3P᎐CBrCO2Et,
᎐
reflux, 7 h; then DBU (82%); (ii) DIBAL-H, PhCH3, Ϫ100 ЊC, 15 min
(58% 10).
A key feature of this synthesis of the C-nucleoside 7 is the
availability of aminotriazine 9 in gram quantities by a rapid and
reliable method (Scheme 3).13 6-Azauracil was brominated in
Scheme 4 Reagents and conditions (and yields): (i) ClCH2CHO, 4 Å
MS, RT (65%) or ClCH2CH(OCH3)2, PhCH3, PTSA, 60 ЊC, 24 h (75%);
(ii) Ra–Ni, H2O, reflux, 12 h (62%); (iii) N2H4ؒH2O, EtOH, RT, 1 h
(89%); (iv) HgO, EtOH, reflux, 5 min (66%).
We now planned to apply this removal of the 8-methyl-
sulfanyl group in the synthesis of the C-nucleoside 7, following
coupling of the amine 9 with the aldehyde 10. Condensation of
9 with 10 in toluene in a Dean–Stark apparatus for 24 h was
accompanied by spontaneous cyclization to give the protected
C-nucleoside 21 (56%) in reasonable yield (Scheme 5). The silyl
derivative gave a much cleaner reaction than the analogous
trityl derivative, but it only worked well on a small scale (up to
200 mg), the yield being much reduced on a 1 g scale. However,
with a mixture of toluene and HMPA as solvent at 100 ЊC a
reasonable yield of 21 (62%) was reinstated on the larger scale.
Scheme 3 Reagents and conditions (and yields): (i) NH3(1), Cu(0),
autoclave, 80 ЊC 2 d (74%); (ii) P2S5, py, S8, reflux, 5 h; (iii) (a) MeI,
1M NaOH, EtOH, RT (43%) 9, 7% (16), (b) Hünig’s base, MeI, DCM,
RT, 16 h (52% 9 from 14).
high yield to give 13, from which the bromine was displaced by
liquid ammonia in an autoclave in the presence of copper
powder at 80 ЊC to give the amine 14 in 74% yield. Attempts to
simplify this procedure by working at atmospheric pressure or
in a Carius tube, and with ammonium acetate in place of
ammonia, all gave much lower yields of 14. Thiation was
accomplished with phosphorus pentasulfide and pyridine in the
presence of sulfur, but after extensive purification the dithione
15 was isolated in very low yield. Methylation of 15 with
iodomethane and aqueous sodium hydroxide in ethanol gave
amine 9 together with a small amount of ethoxy compound 16,
though the latter could be avoided by using Hünig’s base in
DCM for the methylation reaction. The tedious and wasteful
purification of the dithione 15 could be avoided by methylation
of the crude material before purification.
The 1,2,4-triazine 9 was first converted into the heterocyclic
aglycone of the C-nucleoside target for use in model desulfur-
ization reactions. Treatment of 9 with chloroacetaldehyde and
4 Å molecular sieves at ambient temperature gave 6,8-bis-
(methylsulfanyl)imidazo[2,1-f ][1,2,4]triazine 17 (65%); chloro-
acetaldehyde dimethyl acetal in toluene with a catalytic amount
of toluene-p-sulfonic acid at the same temperature gave a 75%
yield. Desulfurization of the bis-sulfide 17 with Raney nickel14
in boiling ethanol or with nickel boride generated in situ15 failed
to give the parent heterocycle 27. Similar reductive desulfuriz-
ation of the triazine 9 with Raney nickel in boiling water
resulted only in hydrolysis of the 5-methylsulfanyl group to give
18 (62%), presumably as a consequence of the electrophilicity
of the triazine 5-position. With the failure of reductive
desulfurization we turned to the hydrazine-oxidation method
1
The homogeneity of the H and 13C NMR spectra indicated
that the condensation reaction gave only the β-isomer of 21.
The 13C data were fully consistent with the assigned stereo-
chemistry and in particular the chemical shifts of the iso-
propylidene methyl groups and the quaternary carbon (δC 26,
28 and 115 ppm, respectively) agreed with the values reported
for 1β-substituted ribose derivatives.18 The 1H NMR signals, at
270 MHz, for the isopropylidene methyl groups appeared at
δH 1.37 and 1.62 (∆δ > 20 Hz) which also supports β-stereo-
chemistry, and J3Ј,4Ј was 3.70 Hz (usually about 0 Hz for
α-forms). This assignment was subsequently verified by X-ray
diffraction analysis of a related derivative 7 (below). Synthesis
of the protected C-nucleoside 21 was now reproducible on a 1 g
scale, and we next studied the removal of the 8-methylsulfanyl
group. Treatment of 21 with hydrazine hydrate in refluxing
ethanol for 1 h gave the monohydrazine 22 (87%), which was
oxidized with yellow mercuric oxide in refluxing ethanol to give
the 8-unsubstituted protected C-nucleoside 23 (72%). In con-
trast with the model reactions above, both of these reactions
required boiling ethanol and a longer reaction time for comple-
tion. The NMR spectra of 22 and 23 were both in agreement
with the β-configuration (Scheme 5).
Our first attempt at deprotection of 23 involved simultaneous
removal of both protecting groups with aqueous trifluoroacetic
acid,19 which proceeded only in low yield. Better was to remove
the silyl group with tetrabutylammonium fluoride (TBAF) in
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Scheme 6 Reagents and conditions (and yields): (i) (a) MCPBA, DCM,
RT, 24 h (52%) or KMnO4, AcOH, H2O, RT, 30 min (58%); (ii)
N2H4ؒH2O, EtOH, RT, 1 min (97%); (iii) HgO, EtOH, reflux, 10 min
(18%); (iv) NaBH4, EtOH, CHCl3, RT, 10 min (34%).
28 with NaBH4 under the Hitoshi conditions23 gave the
6-unsubstituted imidazotriazine 29 (79%), no reduction of
the heterocyclic ring being observed in the presence of the
8-methylsulfanyl group. This group was then removed with
hydrazine hydrate in ethanol to give the hydrazine 30 (76%),
followed by oxidation with mercuric oxide, to give the parent
imidazotriazine 27, identical with that described above, but in
slightly better yield (27%) (Scheme 7). We hope that the method
Scheme 5 Reagents and conditions (and yields): (i) PhCH3, K2CO3,
Dean–Stark 24 h (56%) or PhCH3, HMPA, 100 ЊC, 24 h (62%); (ii)
N2H4ؒH2O, EtOH, reflux, 1 h (87%); (iii) HgO, EtOH, reflux, 2 h (72%);
(iv) TBAF, THF, RT, 30 min (90%); (v) 60–80% AcOH, RT, 18 h (60%).
THF (90%) followed by hydrolysis (60%) of the acetonide with
aqueous acetic acid, both at room temperature, to give the final
target 7 (Scheme 5). Fortunately there was no sign of acid-
catalyzed addition of water (covalent hydration20) at the
free 8-position of the imidazotriazine. The β-configuration of
C-nucleoside 7 was again supported by the 1H NMR spectrum
in DMSO-d6 which showed the H-1Ј signal as a doublet at
δH 5.16 with a coupling constant of 6.23 Hz, similar to that for
the related C-nucleoside deaminoformycin 1 (δ 5.08, J 7.5
Hz).5,21 The structure and stereochemistry was subsequently
confirmed by single-crystal X-ray diffraction.22
Scheme 7 Reagents and conditions (and yields): (i) KMnO4, AcOH,
H2O, RT, 30 min (63%); (ii) NaBH4, EtOH, CHCl3, RT, 5 min (79%);
(iii) N2H4ؒH2O, EtOH, RT, 2 h (76%); (iv) HgO, EtOH, reflux, 10 min
(27%).
Imidazo[2,1-f ][1,2,4]triazine 27
Having synthesized the C-nucleoside 7 we wished to remove the
remaining methylsulfanyl group, though model studies sug-
gested that this would be difficult. In the hope of providing a
better leaving group, sulfide 20 was converted into its sulfone 24
by treatment with either m-chloroperbenzoic acid (MCPBA) in
DCM or potassium permanganate in acetic acid. Both methods
gave similar yields but oxidation with permanganate took only
30 min as opposed to 24 h for the peracid. Nucleophilic dis-
placement of methylsulfonyl by hydrazine was very fast and
virtually quantitative, and oxidation of the resulting hydrazine
25 with mercuric oxide gave the parent heterocyclic system,
imidazo[2,1-f ][1,2,4]triazine 27 as a colourless oil in low yield
(18%) (Scheme 6). Low yields are sometimes observed in the
oxidation of hydrazines which afford products susceptible to
covalent hydration since the hydrate can be oxidized by mer-
curic oxide to give the corresponding keto product, which is
sometimes isolated.
We had hoped to replace the methylsulfonyl group in 24 by
hydrogen in one step with NaBH4 following a related literature
reaction,23 but similar treatment of 24 with NaBH4 at room
temperature gave the dihydro derivative 26 (Scheme 6) with the
methylsulfonyl group intact. This parallels the ready reduction
of monocyclic 1,2,4-triazines to their dihydro derivatives.24 We
therefore returned to the bis-sulfide 17 and its oxidation with
KMnO4 in acetic acid; this gave only the monosulfone 28 (63%)
in agreement with the exclusive oxidation of 3,5-bis(methyl-
sulfanyl)-1,2,4-triazine to the 3-methylsulfone.25 With both sub-
strates the sulfur which is not oxidized is made less nucleophilic
by the electron-withdrawing heteroatoms. Reduction of sulfone
developed for the synthesis of 27 will be applied to the synthesis
of ribofuranoside 6 in the future.
In the course of this work the new ring system, imidazo[2,1-f ]-
[1,2,4]triazine 27, has been prepared, together with several of its
mono-, di- and tri-substituted derivatives including the ribo-
furanoside 7. Preliminary biochemical studies indicate that 7 is
an inhibitor of mammalian ADA (IC50 40 µM). Further details
concerning biological activity will be published elsewhere.
Experimental
Tetrahydrofuran (THF) and toluene were used freshly distilled
from sodium wire with benzophenone under nitrogen. All reac-
tions were protected from moisture by calcium chloride drying
tubes, unless carried out under a dry nitrogen atmosphere.
Anhydrous magnesium sulfate was used for drying organic
extracts, and volatiles were removed under reduced pressure.
Ether refers to diethyl ether and light petroleum had boiling
range 60–80 ЊC. All reactions and chromatography column elu-
ents were monitored by TLC using commercial aluminium-
backed thin-layer chromatography (TLC) plates (Merck
Kieselgel 60 F254). The plates were observed under UV light at
254 and 350 nm. Flash column chromatography refers to the
technique described by Still26 using medium pressure generated
by a hand bellows or a small air compressor and was used
throughout. Dry flash chromatography was carried out with
suction using a water pump according to the technique
described by Harwood.27 Mps were determined using a Reichert
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Kofler hot-stage apparatus and are uncorrected. IR spectra
were recorded on a Perkin-Elmer 1710FT spectrometer and
strong, medium and weak peaks are represented by s, m or w
respectively. 1H NMR spectra were recorded on JEOL GSX 270
(at 270 MHz) and Bruker AM300WB (at 300 MHz) machines.
13C NMR spectra were recorded on JEOL GSX 270 (at 68
MHz) and Bruker AM300WB (at 76 MHz) machines. Deuter-
ated solvents were used for homonuclear lock and the signals
are referenced to the deuterated solvent peaks. Mass spectra
were recorded on a VG Micromass 7070E or a VG Autospec
“Q” mass spectrometer. FAB spectra were obtained using a
glycerol matrix, and CI measurements were carried out using
ammonia for ionization. Microanalyses were carried out on a
Perkin-Elmer 2400 CHN Analyzer.
Ethyl 3,6-anhydro-2-bromo-7-O-tert-butyldiphenylsilyl-2-deoxy-
4,5-O-isopropylidene-D-glycero-D-allo- and -D-altro-heptonate
12
To a solution of 5-O-tert-butyldiphenylsilyl-2,3-O-isoprop-
ylidene--ribofuranose 11 (3.20 g, 7.48 mmol) in dry benzene
(10 ml) was added ethyl bromo(triphenylphosphoranylidene)-
acetate12 (4.47 g, 10.5 mmol) and the solution was heated to
reflux. After 7 h, TLC indicated the disappearance of starting
material 11 and the appearance of 3 new products. The reaction
mixture was cooled to room temperature and DBU (1 drop)
was added. After the mixture was stirred for 1 min at room
temperature, TLC indicated only 2 compounds. The solvent
was evaporated and the crude product was purified by flash
chromatography on silica gel (gradient elution; 10–15% ether in
light petroleum) to furnish a mixture of esters 12 (3.54 g, 82%)
as a colourless oil; νmax(NaCl/film)/cmϪ1 3072w, 3050w, 1746s
2,3-O-Isopropylidene-D-ribose28
A solution of -ribose (50 g, 0.33 mol) in dry acetone (800 ml)
containing conc. hydrochloric acid (0.8 ml) and copper() sul-
fate monohydrate (45 g) was stirred overnight at 37 ЊC. The
solution was neutralized by stirring with calcium hydroxide.
The inorganic salts were filtered off and washed with dry acet-
one. The combined organic phase was concentrated in vacuo to
give the crude product as pale yellow oil. Purification of the
crude product by flash chromatography on silica gel (gradient
elution; 20–30% ethyl acetate in light petroleum) gave the
acetonide (55.1 g, 87%) as a colourless oil; νmax (NaCl/film)/
cmϪ1 3391s, (OH), 1462w, 1383s, 1327s, 1274s, 1243s, 1212s,
1116s, 1068s, 997w, 925w, 871s; δH(270 MHz; CDCl3) 5.52 (1H,
d, J 6.2 Hz, H-1), 5.38 (1H, s, OH), 4.77 (1H, d, J 5.8 Hz, H-2
or H-3), 4.54 (1H, d, J 6.0 Hz, H-3 or H-2), 4.35 (1H, m, H-4),
4.19 (1H, s, OH), 3.67 (2H, m, H-5), 1.45 (3H, s, CH3), 1.29
(3H, s, CH3); δC(76 MHz; CDCl3) 112.19 (CCH3), 102.75
(C-1), 87.66 (C-4), 86.72 (C-2), 81.51 (C-3), 63.49 (C-5), 26.35
(CH3), 24.70 (CH3); m/z (CI, NH3) 208 (MNH4ϩ, 50%), 190
(MNH4ϩ Ϫ H2O, 100), 175 (Mϩ Ϫ CH3, 22), 173 (Mϩ Ϫ H2O,
20), 68 (30) (Found: MNH4ϩ, 208.1189. Calc. for C8H18NO5:
MNH4, 208.1185).
(C᎐O, ester), 1590w, 1473s, 1429s, 1382s, 1372s, 1338w, 1264s,
᎐
1213s, 1185w, 1156s, 1114s, 1080s, 1028s, 966w, 864w, 742w,
703s; δH(270 MHz; CDCl3) 7.68–7.74 (4H, m, Ar IH), 7.38–
7.47 (6H, m, ArH), 4.73–4.83 (2H, m, H-4 and H-5), 4.54, 4.50
(1H, each d, J 3.00, 3.23 Hz, H-2), 4.39–4.42 (1H, m, H-3),
4.24–4.32 (3H, m, H-6 and CO2CH2CH3), 3.64–3.81 (2H, m,
H2-7), 1.59 (3H, s, CH3, major), 1.40 (3H, s, CH3, minor), 1.57
(3H, s, CH3, major), 1.38 (3H, s, CH3, minor), 1.30 (3H, t, J
t
7.16 Hz, CO2CH2CH3), 1.11 (9H, s, Bu); δC(76 MHz; CDCl3)
168.28 (C᎐O, ester), [135.70(×3), 132.68, 130.04, 129.92,
᎐
127.94, 127.84] (Ar C), 113.59 (CCH3), 86.05 (C-6), 85.91 (C-
4), 84.29 (C-3 or C-5), 82.35 (C-5 or C-3), 64.90 (C-7), 62.12
(CO2CH2CH3), 44.59 (CHBr), 27.31 (CH3), 27.01 [C(CH3)3],
25.51 (CH3), 19.24 [C(CH3)3], 13.92 (CO2CH2CH3); m/z (CI,
NH3) 596, 594 (MNH4ϩ, 85%), 520 (Mϩ Ϫ tBu, 30), 516
(MNH4ϩ Ϫ Br, 100), 497 (Mϩ Ϫ Br, 5), 441 (42), 421 (35), 383
(8), 295 (18), 274 (16), 216 (45), 196 (28), 169 (18), 91 (18), 58
(30) (Found: C, 58.9; H, 6.1. C28H37BrO6Si requires C, 58.2; H,
6.5%; Found: MNH4ϩ, 594.1893. C28H41BrNO6Si requires
MNH4, 594.1887).
3,6-Anhydro-2-bromo-7-O-tert-butyldiphenylsilyl-2-deoxy-4,5-
O-isopropylidene-D-glycero-D-allo- and -D-altro-heptose 10
5-O-tert-Butyldiphenylsilyl-2,3-O-isopropylidene-D-ribofuranose
11
A solution of bromo ester 12 (1.14 g, 1.98 mmol) in dry toluene
(10 ml) at Ϫ100 ЊC was treated with DIBAL-H (1.5 M in tolu-
ene; 2.63 ml, 3.95 mmol) added via a cannula and stirred at
Ϫ100 ЊC for 15 min. The reaction was quenched with dry
methanol (5 ml) and the resulting mixture was allowed to warm
to 25 ЊC. A thick gelatinous mass was formed. This was filtered
off (Celite pad) and washed with ether. The resulting filtrate
was evaporated in vacuo and the residue was purified by flash
chromatography on silica gel (gradient elution; 20–30% ether in
light petroleum) to furnish the bromo aldehyde 10 (0.61 g, 58%)
as a colourless oil; νmax(NaCl/film)/cmϪ1 3072w, 3050w, 1732s
A solution of 2,3-O-isopropylidene--ribose (4.19 g, 22.1
mmol) and imidazole (1.65 g, 24.3 mmol) in DCM (40 ml) at
0 ЊC was treated with tert-butyldiphenylsilyl chloride (6.67 g,
24.3 mmol). The reaction mixture was allowed to warm to
25 ЊC and was stirred for 24 h. After dilution with ether (120
ml) the reaction mixture was washed with water (50 ml) and
brine (50 ml), dried (MgSO4), concentrated, and purified by
flash chromatography on silica gel (gradient elution; 5–10%
ethyl acetate in light petroleum) to give the epimeric alcohols 11
(7.08 g, 75%) as a colourless oily 2:1 mixture; νmax(NaCl/film)/
cmϪ1 3431br s (OH), 3072w, 3050w, 2935s, 1590s, 1568w, 1488s,
1473w, 1429w, 1383w, 1313w, 1212w, 1212w, 1075s, 990w, 872w,
798w, 742w, 703s; δH(270 MHz; CDCl3) 7.63–7.70 (4H, m,
ArH), 7.39–7.48 (6H, m, ArH), 5.36 (1H, d, J 10.2 Hz, OH),
4.65–4.80 (2H, m, H-2 and H-3), 4.61 (1H, d, J 6.01 Hz, H-1),
4.27–4.30 (1H, m, H-4, major), 4.15–4.16 (1H, m, H-4, minor),
3.79–3.89 (1H, m, H-5a), 3.61–3.69 (1H, m, H-5b), 1.57 (3H, s,
CH3, minor), 1.40 (3H, s, CH3, major), 1.48 (3H, s, CH3,
minor), 1.32 (3H, s, CH3, major), 1.10 (9H, s, tBu); δC(76 MHz;
CDCl3) [135.76, 135.58, 130.44, 130.25, 128.13, 128.07, 127.92,
127.73] (Ar C), [113.04, 112.15] (CCH3), [103.44, 98.04]
(C-1), [87.36, 87.11] (C-4), [81.99, 81.68] (C-2), [81.30, 79.54]
(C-3), [66.09, 65.53] (C-5), [26.92, 26.89] [C(CH3)3], [26.60,
24.71] (CH3), [26.50, 25.00] (CH3), [26.19, 19.16] [C(CH3)3];
m/z (CI, NH3) 446 (MNH4ϩ, 12%), 428 (MNH4ϩ Ϫ H2O, 6),
411 (MHϩ Ϫ H2O, 10), 371 (Mϩ Ϫ tBu, 2), 353 (10), 274
(Mϩ Ϫ 2Ph), 241 (8), 221 (15), 216 (25), 199 (28), 181 (13), 161
(Mϩ Ϫ OSiPh2But, 100), 91 (28), 78 (30), 58 (24) (Found: C,
67.0; H, 7.7. C24H32O5Si requires C, 67.3; H, 7.5%).
(C᎐O, aldehyde), 1590w, 1568w, 1473s, 1463s, 1429s, 1383s,
᎐
1244w, 1214s, 1157s, 1114s, 1078s, 1008w, 999w, 971w, 920w,
824w, 742s, 703s; δH(270 MHz; CDCl3) 9.50 (1H, d, J 2.77 Hz,
CHO, major), 9.41 (1H, d, J 3.69 Hz, CHO, minor), 7.68–7.75
(4H, m, ArH), 7.40–7.48 (6H, m, ArH), 4.68–4.85 (2H, m, H-4
and H-5), 4.36–4.50 (2H, m, H-3 and H-2), 4.26–4.29 (1H, m,
H-6), 3.70–3.88 (2H, m, H2-7), 1.59, 1.41 (6H, each s, CH3,
minor), 1.57, 1.39 (6H, each s, CH3, major), 1.12, 1.10 (9H,
t
each s, Bu); δC(76 MHz; CDCl3) [192.07, 190.66] (CHO),
[135.72, 135.64, 132.66, 130.10, 130.02, 129.91, 129.84, 127.99]
(Ar C), [114.73, 113.98] (CCH3), [86.19, 85.34] (C-6), [84.29,
84.22] (C-4), [82.89, 82.73] (C-3 or C-5), [82.02, 81.44] (C-5 or
C-3), [64.67, 63.95] (C-7), [55.95, 52.60] (CHBr), [27.51, 25.60]
(CH3), [27.38, 25.48] (CH3), [27.05, 26.95] [C(CH3)3], 19.29
[C(CH3)3]; m/z (CI, NH3) 552, 550 (MNH4ϩ, 3%), 472
(MNH4ϩ Ϫ Br, 12), 397 (2), 377 (2), 295 (6), 241 (2), 199 (9), 181
(6), 161 (58), 129 (22), 108 (45), 91 (100), 73 (26), 61 (50), 44 (20)
(Found: MNH4ϩ, 550.1631. C26H37BrNO5Si requires MNH4,
550.1624).
2932
J. Chem. Soc., Perkin Trans. 1, 1999, 2929–2936

View Article Online
6-Bromo-1,2,4-triazine-3,5(2H,4H)-dione 13
Method B. Crude dithione 15 (2.80 g, 17.5 mmol) was sus-
pended in absolute EtOH (400 ml) and treated with 1M NaOH
(50 ml) at 40 ЊC. The solution was allowed to cool to 25 ЊC and
iodomethane (10.90 g, 4.78 ml, 76.8 mmol) was added. The
reaction mixture was stirred at 25 ЊC for 30 min. Excess of
solvent was removed in vacuo and the residue was dissolved in
water (100 ml). The aqueous solution was extracted with ethyl
acetate (3 × 100 ml) and the combined organic extracts were
dried (MgSO4) and evaporated in vacuo to give a dark residue,
which was purified by flash chromatography on silica gel
(gradient elution; 5–15% ethyl acetate in light petroleum) to
afford the bis-sulfide 9 (1.62 g, 43%) as pale yellow crystals, mp
173–174 ЊC (lit.,12 171–173 ЊC); and 16 (260 mg, 10%) as
crystals, mp 128–130 ЊC; δH(300 MHz; CDCl3) 5.12 (2H, br s,
NH2), 4.49 (2H, q, J 7.08 Hz, OCH2CH3), 2.58 (3H, s, SCH3),
1.43 (3H, t, J 7.05 Hz, OCH2CH3); m/z (EI) 186 (Mϩ, 100%),
157 (Mϩ Ϫ Et, 35), 131 (3), 116 (10), 98 (3), 86 (6), 74 (32), 69
(25), 57 (60), 43 (26).
A mixture of 6-azauracil (25 g, 221 mmol), bromine (25 ml) and
water (400 ml) was stirred at 25 ЊC for 27 h. The colourless
crystalline precipitate was collected by filtration. More product
was obtained by concentrating the filtrate. Recrystallization of
the combined product from water gave 6-bromo-1,2,4-triazine-
3,5(2H,4H)-dione 13 (35 g, 82%) as crystals, mp 235–236 ЊC
(lit.,13 232–234 ЊC); νmax(NaCl/Nujol)/cmϪ1 3262br w, 3162br w
(NH), 1694s (C᎐O, amide), 1566s, 1464s, 1269w, 1136w, 1087w,
᎐
994w, 845w, 753w, 721w; δH(270 MHz; DMSO-d6) 12.58 (1H, br
s, NH), 12.32 (1H, br s, NH); δC(76 MHz; DMSO-d6) 154.19
(C-5), 149.58 (C-3), 129.62 (C-6); m/z (EI) 192, 191 (Mϩ, 100%),
[150, 148] (Mϩ Ϫ NCO, 49), [122, 120] (47), 103 (9), 94 (13), 69
(24), 57 (12), 44 (51) (Found: Mϩ, 190.9312. Calc. for
C3H2BrN3O2: M, 190.9330).
6-Amino-1,2,4-triazine-3,5(2H,4H)-dione 14
6-Bromo-1,2,4-triazine-3,5-dione 13 (3.75 g, 19.5 mmol), cop-
per powder (2 mg) and liquid ammonia (30 ml) were heated in
an autoclave at 80 ЊC for 48 h. After the mixture was cooled,
excess of ammonia was vented off and the residual solid was
dissolved in hot water (30 ml). The cool, blue solution was
carefully acidified to pH 4 with conc. HCl and the resulting
precipitate collected by filtration. The crude product was sus-
pended in distilled water (35 ml) and dissolved by the dropwise
addition of conc. NH4OH. The solution was filtered and the
colourless filtrate was acidified to pH 4 with conc. HCl. The
white precipitate formed was collected by filtration, washed
with distilled water (2 × 5 ml) and air-dried to furnish 6-amino-
1,2,4-triazine-3,5(2H,4H)-dione 14 (1.85 g, 74%), mp >300 ЊC
(lit.,12 310–315 ЊC) (from water); δH(270 MHz; DMSO-d6) 11.60
(1H, br s, NH), 10.91 (1H, br s, NH), 5.98 (2H, br s, NH2);
δC(76 MHz; DMSO-d6) 155.04 (C-5), 149.51 (C-3), 144.22
(C-6); m/z (EI) 128 (Mϩ, 100%), 85 (8), 70 (6), 57 (80), 43 (30)
(Found: Mϩ, 128.0329. Calc. for C3H4N4O2: M, 128.0334).
6,8-Bis(methylsulfanyl)imidazo[2,1-f ][1,2,4]triazine 17
Method A. A mixture of amine 9 (1.20 g, 6.38 mmol), chlo-
roacetaldehyde (12 ml; ≈50 wt.-% solution in water) and 4 Å
molecular sieves was stirred at 25 ЊC for 2 days. The molecular
sieves were removed (Celite pad), and washed with DCM. The
filtrate was washed successively with water and brine, dried
(MgSO4) and evaporated in vacuo. Purification of the residue by
flash chromatography on silica gel (gradient elution; 20–30%
ether in light petroleum) gave the title compound 17 (0.88 g,
65%) as a white solid, mp 120–122 ЊC (from DCM–light petrol-
eum); νmax(NaCl/film)/cmϪ1 3442w, 3304w, 3051w, 1693, 1628w,
1560w, 1519w, 1451s, 1428s, 1355s, 1316s, 1292s, 1266s, 1169s,
1156s, 1145s, 1063w, 1019w, 968w, 928w, 880s, 759s, 739s;
δH(300 MHz; CDCl3) 7.74 (1H, d, J 0.97 Hz, H-2 or H-3),
7.60 (1H, d, J 0.96 Hz, H-3 or H-2), 2.65 (3H, s, SCH3),
2.56 (3H, s, SCH3); δC(76 MHz; CDCl3) [163.36, 161.41,
132.66(×2), 117.24] (Het C), 14.15 (SCH3), 11.88 (SCH3); m/z
(EI) 212 (Mϩ, 100%), 197 (15), 165 (35), 152 (10), 139 (20),
103 (25), 93 (60), 84 (35), 57 (39), 47 (14), 43 (38) (Found: C,
39.7; H, 3.6; N, 26.7. C7H8N4S2 requires C, 39.6; H, 3.8; N,
26.4%).
6-Amino-1,2,4-triazine-3,5(2H,4H)-dithione 15
Phosphorus pentasulfide (8.89 g, 40 mmol) was added to a
stirred, warm solution of the amino compound 14 (2.56 g, 20
mmol) and elemental sulfur (1.28 g, 5 mmol) in dry pyridine
(180 ml). The mixture was heated to reflux for 5 h. The reaction
mixture was allowed to cool and to stand at 25 ЊC for 16 h. The
clear, reddish-brown supernatant liquid was decanted and the
pyridine removed in vacuo. The resulting residue was covered
with water (50 ml), boiled for 10 min and allowed to stand at
4 ЊC for 18 h. The precipitate was collected, washed with water
and air-dried to give the crude dithione 15 (3.2 g); m/z (CI, NH3)
161 (MHϩ, 100%) (Found: MHϩ, 160.9983. Calc. for C3H5N4S2:
MH, 160.9956).
Method B. To a stirred solution of amine 9 (500 mg, 2.66
mmol) in dry toluene (6 ml) were added chloroacetaldehyde
dimethyl acetal (8 ml) and toluene-p-sulfonic acid (PTSA,
80 mg). The reaction mixture was stirred at 60 ЊC for 24 h and
then allowed to cool to 25 ЊC. Excess of solvent was removed in
vacuo and the residue was diluted with chloroform. The organic
solvent was washed successively with water and brine, dried
(MgSO4) and concentrated in vacuo to give a dark residue. This
was purified by flash chromatography on silica gel (gradient
elution; 20–30% ether in light petroleum) to give the title com-
pound 17 (423 mg, 75%) which was identical to that described
above.
6-Amino-3,5-bis(methylsulfanyl)-1,2,4-triazine 9
Method A. A solution of the above crude dithione 15 (3.2 g,
20 mmol) was suspended in DCM (150 ml) and treated with
Hünig’s base (20.9 ml, 120 mmol) and iodomethane (6.25 g,
2.73 ml, 44 mmol). The mixture was stirred at 25 ЊC for 24 h.
Excess of solvent was removed in vacuo and the residue was
purified by flash chromatography on silica gel (gradient elution;
5–15% ethyl acetate in light petroleum) to give the triazine 9
(1.96 g, 52%) as pale yellow crystals, mp 173–174 ЊC (lit.,12 171–
173 ЊC) (from DCM–light petroleum); νmax(NaCl/film)/cmϪ1
[3424br w, 3275br w, 3115br w] (NH), 1693w, 1636s, 1579w,
1523s, 1489s, 1462s, 1420s, 1325s, 1244s, 1202w, 1121s, 1074s,
972w, 891s, 720w; δH(270 MHz; CDCl3) 4.79 (2H, br s, NH2),
2.61 (3H, s, SCH3), 2.59 (3H, s, SCH3); δC(76 MHz; DMSO-d6)
[159.18, 153.99, 153.36] (Het C), 13.87 (SCH3), 12.04 (SCH3);
m/z (EI) 188 (Mϩ, 68%), 173 (Mϩ Ϫ CH3, 30), 150 (2), 136 (4),
102 (12), 87 (98), 72 (100), 69 (52), 45 (50) (Found: Mϩ,
188.0197. Calc. for C5H8N4S2: M, 188.0190).
Attempted desulfurization of triazine 9: 6-amino-3-methyl-
sulfanyl-1,2,4-triazine-5(4H)-one 18
To a stirred solution of aminotriazine 9 (100 mg, 0.53 mmol) in
water (8 ml) was added Raney nickel (≈80 mg). The reaction
mixture was stirred vigorously at 40 ЊC for 12 h and the Raney
nickel was then removed (Celite pad). The mixture was concen-
trated in vacuo and the crude product was purified by recrystal-
lization from ethanol to afford the aminotriazinone 18 (52 mg,
62%) as a solid, mp >280 ЊC (from ethanol); νmax(NaCl/Nujol)/
cmϪ1 3326s (NH), 1675s (C᎐O, amide), 1651s, 1588s, 1568s,
᎐
1539s, 1521s, 1249w, 1214w, 1079w, 991w, 949w, 794w, 722w;
δH(300 MHz; DMSO-d6) 6.48 (2H, br s, NH2), 2.50 (3H, s,
SCH3); δC(76 MHz; DMSO-d6) [157.66, 157.62, 150.24] (Het
C), 13.25 (SCH3); m/z (EI) 158 (Mϩ, 100%), 116 (Mϩ Ϫ NCO,
10), 111 (Mϩ Ϫ SCH3, 8), 91 (3), 86 (5), 74 (17), 69 (90), 57 (12),
J. Chem. Soc., Perkin Trans. 1, 1999, 2929–2936
2933

View Article Online
48 (30), 43 (54) (Found: Mϩ, 158.0280. C4H6N4OS requires M,
requires C, 59.8; H, 6.15; N, 9.0%. Found: MHϩ, 623.2182.
158.0262).
C31H39N4O4S2Si requires MH, 623.2111).
Method B. To a stirred solution of amine 9 (1.20 g, 6.38
mmol) in HMPA (6 ml) was added a solution of aldehyde 10
(3.40 g, 6.38 mmol) in dry toluene (16 ml). The reaction mixture
was stirred at 100 ЊC for 18 h under nitrogen and then allowed
cool to 25 ЊC. Excess of solvent was removed in vacuo to give a
dark residue. This was dissolved in water and the aqueous solu-
tion was extracted with ethyl acetate (3 × 40 ml). The combined
organic extract was washed successively with water and brine,
dried (MgSO4), and concentrated in vacuo to give the crude
product. The residue was purified by flash chromatography on
silica gel (gradient elution; 10–15% ether in light petroleum) to
afford the title compound 21 (2.46 g, 62%) which was identical
to that described above.
8-Hydrazino-6-(methylsulfanyl)imidazo[2,1-f ][1,2,4]triazine 19
To a solution of bis-sulfide 17 (100 mg, 0.47 mmol) in ethanol
(4 ml) was added hydrazine monohydrate (47.2 mg, 0.046 ml,
0.94 mmol) and the mixture was stirred at 25 ЊC for 1 h. A white
precipitate was collected, and washed with ethyl acetate. The
precipitate was recrystallized from ethanol to give the title com-
pound 19 (82 mg, 89%) as white crystals, mp 225–226 ЊC (from
EtOH); νmax(NaCl/Nujol)/cmϪ1 3442br w (NH), 3328w (NH),
3134w, 1694w, 1627w, 1604s, 1568w, 1498w, 1451s, 1404s, 1347s,
1314w, 1279w, 1215s, 1179w, 1142w, 1124w, 1098w, 971w, 922s,
867w, 754s, 739s, 722w; δH(300 MHz; CDCl3) 10.26 (1H, br s,
NH), 7.94 (1H, s, H-2 or H-3), 7.46 (1H, s, H-3 or H-2), 4.88
(2H, br s, NH2), 2.50 (3H, s, SCH3); δC(76 MHz; CDCl3)
[162.06, 149.94, 130.62, 126.49, 117.90] (Het C), 13.84 (SCH3);
m/z (EI) 196 (Mϩ, 46%), 181 (12), 150 (2), 133 (5), 119 (2), 109
(8), 103 (2), 94 (40), 89 (26), 84 (7), 73 (25), 68 (7), 45 (100)
(Found: C, 37.6; H, 3.8; N, 42.2%; Mϩ, 196.0536. C6H8N6S
requires C, 36.7; H, 4.1; N, 42.8%; M, 196.0531).
3-(5Ј-O-tert-Butyldiphenylsilyl-2Ј,3Ј-O-isopropylidene-ꢀ-D-
ribofuranosyl)-8-hydrazino-6-(methylsulfanyl)imidazo[2,1-f ]-
[1,2,4]triazine 22
To a solution of bis-sulfide 21 (50.9 mg, 0.08 mmol) in ethanol
(2 ml) was added hydrazine monohydrate (0.02 ml, 0.70 mmol).
The solution was stirred and heated under reflux for 1 h. The
reaction mixture was allowed to cool to 25 ЊC and concentrated
in vacuo. The residue was dissolved in DCM (6 ml), washed
with water, dried (MgSO4), concentrated in vacuo and purified
by flash chromatography on silica gel (ether as eluent) to
furnish the title compound 22 (43.1 mg, 87%) as a colourless
foam; νmax(NaCl/film)/cmϪ1 3442br s (NH), 2931w, 2858w,
1694s, 1631s, 1603s, 1443s, 1428s, 1353s, 1265s, 1113s, 1079s,
863w, 703s; δH(270 MHz; CDCl3) 7.63–7.69 (4H, m, ArH), 7.54
(1H, s, H-2), 7.31–7.40 (6H, m, ArH), 5.35 (1H, d, J 4.85 Hz,
H-1Ј), 5.02 (1H, dd, J 6.47, 4.85 Hz, H-2Ј), 4.82 (1H, dd, J 6.47,
3.69 Hz, H-3Ј), 4.24–4.25 (1H, m, H-4Ј), 3.84–3.86 (2H, m,
H2-5Ј), 2.48 (3H, s, SCH3), 1.62 (3H, s, CH3), 1.37 (3H, s, CH3),
6-(Methylsulfanyl)imidazo[2,1-f ][1,2,4]triazine 20]
To a stirred solution of the hydrazine 19 (36 mg, 0.18 mmol) in
ethanol (4 ml) was added yellow mercury() oxide (120 mg, 0.55
mmol) at 25 ЊC. The reaction mixture was heated to reflux for 5
min, cooled and the inorganic residue was removed (Celite
pad), washed with ethanol and the filtrate was evaporated in
vacuo to give a pale yellow solid. Purification of the solid by
flash chromatography on silica gel (gradient elution; 30–40%
ether in light petroleum) afforded the title compound 20 (20 mg,
66%) as crystals, mp 129–130 ЊC (from DCM–light petroleum);
νmax(NaCl/Nujol)/cmϪ1 1694w, 1629w, 1584w, 1316w, 1290w,
1116w, 910w, 755w, 740w, 662w; δH(300 MHz; CDCl3) 9.02
(1H, s, H-8), 7.93 (1H, s, H-2 or H-3), 7.84 (1H, s, H-3 or H-2),
2.61 (1H, s, SCH3); δC(76 MHz; CDCl3) [163.42, 149.38, 135.41,
134.19, 117.52] (Het C), 14.22 (SCH3); m/z (CI, NH3) 184
(MNH4ϩ, 3%), 167 (MHϩ, 100), 153 (2), 138 (3), 121 (6), 96 (7),
69 (4), 45 (2) (Found: C, 43.7; H, 3.3; N, 33.6. C6H6N4S requires
C, 43.4; H, 3.6; N, 33.7%).
t
1.05 (9H, s, Bu); δC(76 MHz; CDCl3) [162.60, 151.39, 135.59,
133.23, 129.70] (Het C), [135.59, 133.23, 127.65, 126.75] (Ar C),
114.46 (CCH3), 84.75 (C-4Ј), 83.83 (C-3Ј), 82.20 (C-2Ј), 77.24
(C-1Ј), 64.11 (C-5Ј), 27.57 (CH3), 26.81 [C(CH3)3], 25.59 (CH3),
19.23 [C(CH3)3], 13.99 (SCH3); m/z (FAB, NBA) 607 (MHϩ,
100%), 577 (4), 491 (4), 279 (15), 264 (4), 197 (22), 183 (4), 163
(12), 135 (54), 121 (12), 95 (18), 57 (58) (Found: MHϩ,
607.2537. C30H39N6O4SSi requires MH, 607.2523).
3-(5Ј-O-tert-Butyldiphenylsilyl-2Ј,3Ј-O-isopropylidene-ꢀ-D-
ribofuranosyl)-6,8-bis(methylsulfanyl)imidazo[2,1-f ][1,2,4]-
triazine 21
3-(5Ј-O-tert-Butyldiphenylsilyl-2Ј,3Ј-O-isopropylidene-ꢀ-D-
ribofuranosyl)-6-(methylsulfanyl)imidazo[2,1-f ][1,2,4]triazine
23
Method A. A mixture of bromo aldehyde 10 (664 mg, 1.25
mmol), amine 9 (234 mg, 1.25 mmol) and anhydrous K2CO3
(208 mg, 1.50 mmol) in dry toluene (80 ml) was stirred at reflux
with azeotropic removal of water (Dean–Stark trap) for 24 h.
After the solution was cooled to 25 ЊC, excess of solvent was
removed in vacuo to give a dark residue. This was purified by
flash chromatography on silica gel (gradient elution; 10–15%
ether in light petroleum) to furnish the title compound 21 (434
mg, 56%) as pale yellow foam; νmax(NaCl/film)/cmϪ1 3071w,
1694w, 1631w, 1574w, 1516w, 1441s, 1372w, 1352w, 1214w,
1154s, 1114s, 1080s, 952w, 863w, 704s; δH(270 MHz; CDCl3)
7.63–7.69 (4H, m, ArH), 7.60 (1H, s, H-2), 7.32–7.43 (6H, m,
ArH), 5.39 (1H, d, J 4.9 Hz, H-1Ј), 4.97 (1H, dd, J 6.58, 4.85
Hz, H-2Ј), 4.82 (1H, dd, J 6.47, 3.70 Hz, H-3Ј), 4.24–4.27 (1H,
m, H-4Ј), 3.84–3.86 (2H, m, H2-5Ј), 2.67 (3H, s, SCH3), 2.52
(3H, s, SCH3), 1.62 (3H, s, CH3), 1.37 (3H, s, CH3), 1.05 (9H, s,
tBu); δC(76 MHz; CDCl3) [163.47, 161.46, 135.63, 129.79
127.74] (Het C), [135.63, 133.15, 131.42, 127.70] (Ar C), 114.58
(CCH3), 84.87 (C-4Ј), 83.97 (C-3Ј), 82.14 (C-2Ј), 77.27
(C-1Ј), 64.07 (C-5Ј), 27.62 (CH3), 26.86 [C(CH3)3], 25.62
(CH3), 19.28 [C(CH3)3], 14.20 (SCH3), 11.83 (SCH3); m/z
(FAB, NBA) 623 (MHϩ, 100%), 507 (7), 295 (25), 267 (4),
237 (6), 225 (12), 197 (19), 135 (42), 120 (6), 105 (7), 91 (14), 69
(17), 57 (29) (Found: C, 58.6; H, 5.5; N, 8.05. C31H38N4O4S2Si
A solution of the hydrazine 22 (1.04 g, 1.72 mmol) in eth-
anol (60 ml) at room temperature was treated with yellow
mercury() oxide (1.12 g, 5.15 mmol). The dark solution was
heated to reflux for 2 h. After being cooled to 25 ЊC, the
inorganic residue was removed through a pad of Celite and
washed with ethanol, and the combined solution concentrated
in vacuo to give the crude product as a yellow foam. This was
purified by flash chromatography on silica gel (gradient elution;
5–10% ether in light petroleum) to furnish the title compound
23 (712 mg, 72%) as a colourless foam; δH(300 MHz; CDCl3)
9.00 (1H, s, H-8), 7.80 (1H, s, H-2), 7.64–7.70 (4H, m, ArH),
7.33–7.44 (6H, m, ArH), 5.46 (1H, d, J 4.99 Hz, H-1Ј), 4.98
(1H, dd, J 6.38, 5.10 Hz, H-2Ј), 4.86 (1H, dd, J 6.10, 3.59 Hz,
H-3Ј), 4.30–4.31 (1H, m, H-4Ј), 3.87–3.89 (2H, m, H2-5Ј), 2.56
(3H, s, SCH3), 1.65 (3H, s, CH3), 1.39 (3H, s, CH3), 1.07 (9H, s,
tBu); δC(76 MHz; CDCl3) [163.56, 149.36, 135.62, 129.85,
127.73] (Het C), [134.67, 134.13, 132.89, 128.00] (Ar C), 114.67
(CCH3), 84.92 (C-4Ј), 83.94 (C-3Ј), 82.12 (C-2Ј), 77.25 (C-1Ј),
64.08 (C-5Ј), 27.62 (CH3), 26.86 [C(CH3)3], 25.60 (CH3), 19.29
[C(CH3)3], 14.27 (SCH3); m/z (FAB, NBA) 577 (MHϩ, 100%),
549 (3), 519 (4), 461 (7), 369 (6), 313 (2), 290 (5), 273 (4), 249
(25), 221 (4), 197 (17), 150 (18), 135 (52), 120 (20), 105 (18),
2934
J. Chem. Soc., Perkin Trans. 1, 1999, 2929–2936

View Article Online
91 (36), 77 (40), 69 (74), 55 (68) (Found: MHϩ, 577.2321.
Hz, H-3 or H-2), 3.45 (3H, s, SO2CH3); δC(76 MHz; CDCl3)
C30H37N4O4SSi requires MH, 577.2305).
[157.78, 151.07, 139.69, 135.11, 119.35] (Het C), 40.26
(SO2CH3); m/z (CI, NH3) 216 (MNH4ϩ, 100%), 199 (MHϩ,
98), 183 (Mϩ Ϫ CH3, 2), 138 (10), 130 (15), 121 (48), 96 (4), 88
(6), 69 (4) (Found: MHϩ, 199.0296. C6H7N4O2S requires
MH,199.0290).
3-(2Ј,3Ј-O-Isopropylidene-ꢀ-D-ribofuranosyl)-6-(methyl-
sulfanyl)-imidazo[2,1-f ][1,2,4]triazine
A solution of silyloxy compound 23 (211 mg, 0.37 mmol) in
dry THF (12 ml) was treated with n-Bu4NF (TBAF; 0.73 ml of
a 1 M solution in THF, 0.73 mmol) and stirred at 25 ЊC for 30
min. After dilution of the mixture with ether (20 ml), water (20
ml) was added. The organic layer was separated, washed with
brine (10 ml), dried (MgSO4), concentrated, and purified by
flash chromatography on silica gel (gradient elution; 60–70%
ether in light petroleum) to give the title compound (111 mg,
90%) as a white solid, mp 92–93 ЊC (from DCM–light petrol-
eum); νmax(NaCl/film)/cmϪ1 3441w (OH), 2935w, 2876w, 1694w,
1628w, 1591s, 1531s, 1471s, 1422s, 1382s, 1342s, 1304s, 1274w,
1214s, 1157w, 1122s, 1078s, 921w, 862w, 763w, 735w, 662w;
δH(270 MHz; CDCl3) 8.99 (1H, s, H-8), 7.82 (1H, s, H-2), 5.31
(1H, d, J 5.54 Hz, H-1Ј), 5.16 (1H, dd, J 6.58, 5.54 Hz, H-2Ј),
4.96 (1H, dd, J 6.59, 3.70 Hz, H-3Ј), 4.25–4.27 (1H, m, H-4Ј),
3.89–3.90 (2H, m, H2-5Ј), 2.91–3.22 (1H, m, OH), 2.62 (3H, s,
SCH3), 1.62 (3H, s, CH3), 1.37 (3H, s, CH3); δC(68 MHz;
CDCl3) [163.89, 149.65, 135.13, 135.05, 126.73] (Het C), 114.95
(CCH3), 84.78 (C-4Ј), 82.51 (C-3Ј), 81.68 (C-2Ј), 77.72 (C-1Ј),
62.61 (C-5Ј), 27.54 (CH3), 25.43 (CH3), 14.25 (SCH3); m/z
(FAB, NBA) 339 (MHϩ, 20%), 282 (24), 242 (100), 197 (6), 135
(22), 121 (15), 91 (50), 69 (42), 55 (48) (Found: MHϩ, 339.1144.
C14H19N4O4S requires MH, 339.1127).
Method B. A solution of the sulfide 20 (36 mg, 0.22 mmol) in
DCM (1 ml) was added to a stirred suspension of MCPBA (172
mg of a 50% mixture with m-chlorobenzoic acid, 0.5 mmol)
in DCM (2 ml) at 0 ЊC. The resulting mixture was allowed
to warm to 25 ЊC and stirred vigorously for 24 h. The organic
mixture was evaporated in vacuo and the residue was purified by
flash chromatography on silica gel (gradient elution; 20–30%
ethyl acetate in light petroleum) to give the sulfone 24 (22 mg,
52%) which was identical to that described above.
6-Hydrazinoimidazo[2,1-f ][1,2,4]triazine 25
To a stirred solution of sulfone 24 (20 mg, 0.10 mmol) in eth-
anol (0.5 ml) was added hydrazine monohydrate (6 mg, 0.10
mmol) at 25 ЊC. The reaction mixture was stirred for 1 min
and excess of solvent was removed in vacuo. The residue was
purified by flash chromatography on silica gel (gradient elution;
2–5% MeOH in DCM) followed by recrystallization from
EtOH to afford the hydrazine 25 (52 mg, 97%) as a white solid;
νmax(NaCl/film)/cmϪ1 3303br s (NH2), 1667s, 1652s, 1623s,
1538w, 1481w, 1376w, 1142w, 993w, 761w; m/z (EI) 150 (Mϩ,
100%), 135 (40), 121 (40), 93 (38), 80 (30), 67 (42), 43 (22)
(Found: Mϩ, 150.0647. C5H6N6 requires M, 150.0654).
6-Methylsulfanyl-3-ꢀ-D-ribofuranosylimidazo[2,1-f ][1,2,4]-
triazine 7
6-Methylsulfonyl-7,8-dihydroimidazo[2,1-f ][1,2,4]triazine 26
A solution of 3-(2Ј,3Ј-O-isopropylidene-β--ribofuranosyl)-6-
(methylsulfanyl)imidazo[2,1-f ][1,2,4]triazine (50.9 mg, 0.15
mmol) in a mixture of glacial acetic acid (2 ml) and water
(1 ml) was stirred at 25 ЊC for 18 h. The solvent was removed
in vacuo to dryness. The residue was recrystallized from ethanol
to yield the title compound 7 (27 mg, 60%) as white crystals,
mp 227–228 ЊC (from EtOH); νmax(NaCl/Nujol)/cmϪ1 3441
(OH), 3202 (OH), 1693w, 1630w, 1595s, 1529w, 1311s, 1225s,
1172w, 1116s, 1069w, 1040w, 985w, 957w, 931w, 774w; δH(270
MHz; DMSO-d6 ϩ D2O) 9.14 (1H, s, H-8), 7.97 (1H, s, H-2),
5.16 (1H, d, J 6.23 Hz, H-1Ј), 4.42 (1H, dd, J 6.00, 5.55 Hz,
H-2Ј), 4.00–4.08 (1H, m, H-3Ј), 3.90–3.91 (1H, m, H-4Ј), 3.52–
3.58 (2H, m, H2-5Ј), 2.60 (3H, s, SCH3); δC(76 MHz; DMSO-d6)
[163.29, 150.31, 135.37, 135.03, 129.26] (Het C), 85.20 (C-4Ј),
74.95 (C-1Ј), 73.79 (C-2Ј), 71.68 (C-3Ј), 62.19 (C-5Ј), 14.45
(SCH3); m/z (FAB, NBA) 299 (MHϩ, 40%), 273 (5), 242 (6), 192
(22), 165 (18), 150 (40), 133 (65), 124 (28), 120 (45), 105 (32), 89
(90), 77 (100), 69 (20), 63 (52), 51 (55) (Found: C, 44.3; H, 4.5;
N, 18.7. C11H14N4O4S requires C, 44.3; H, 4.7; N, 18.8%.
Found: MHϩ, 299.0809. C11H15N4O4S requires MH, 299.0814).
A solution of sulfone 24 (30 mg, 0.15 mmol) in a mixture of
chloroform (0.5 ml) and EtOH (0.5 ml) at 25 ЊC was treated
with NaBH4 (8.63 mg, 0.23 mmol) in small portions. The reac-
tion mixture was stirred for 10 min and then quenched with
water (0.1 ml). Excess of solvent was removed in vacuo and the
residue was purified by flash chromatography on silica gel
(gradient elution; 2–5% MeOH in DCM) to afford the dihydro
sulfone 26 (10 mg, 34%) as a white solid, δH(270 MHz; CDCl3)
7.25 (1H, d, J 1.62 Hz, H-2 or H-3), 7.01 (1H, d, J 1.61 Hz, H-3
or H-2), 4.79 (2H, s, H2-8), 3.31 (3H, s, SO2CH3); m/z 200 (Mϩ,
76%), 165 (8), 151 (8), 121 (Mϩ Ϫ SO2CH3, 20), 111 (35), 97
(52), 81 (95), 69 (78), 57 (100), 43 (82) (Found: Mϩ, 200.0383.
C6H8N4O2S requires M, 200.0368).
8-Methylsulfanyl-6-(methylsulfonyl)imidazo[2,1-f ][1,2,4]-
triazine 28
A solution of bis-sulfide 17 (166 mg, 0.78 mmol) in glacial ace-
tic acid (1 ml) was added to a stirred solution of KMnO4 (248
mg, 1.57 mmol) in a mixture of glacial acetic acid (1 ml) and
water (8 ml) at 0 ЊC. The resulting mixture was allowed to warm
to 25 ЊC and stirred vigorously for 30 min. The dark solution
was extracted with ethyl acetate (3 × 20 ml) and the combined
organic extract was washed successively with 1M NaOH
and brine. After drying (MgSO4) and evaporation of solvent
in vacuo, the residue was purified by flash chromatography on
silica gel (gradient elution; 30–40% ethyl acetate in light petrol-
eum) to give the sulfone 28 (120 mg, 63%) as pale yellow
crystals, mp 202–203 ЊC (from DCM–light petroleum);
νmax(NaCl/Nujol)/cmϪ1 3020w, 2927w, 1693s, 1607w, 1566w,
1538w, 1467w, 1427s, 1406s, 1354w, 1315s, 1268w, 1190w, 1133s
(SO2), 1070w, 1041w, 967w, 883w, 665w; δH(270 MHz; CDCl3)
8.04 (1H, d, J 1.15 Hz, H-2 or H-3), 7.90 (1H, d, J 0.92 Hz,
H-3 or H-2), 3.39 (3H, s, SO2CH3), 2.80 (3H, s, SCH3); δC(76
MHz; CDCl3) [165.02, 153.78, 133.29, 131.11, 116.46] (Het C),
37.52 (SO2CH3), 9.99 (SCH3); m/z (EI) 244 (Mϩ, 45%), 165
(Mϩ Ϫ SO2CH3, 100), 151 (2), 138 (7), 123 (60), 119 (25), 94
(30), 93 (45), 69 (15), 47 (8) (Found: C, 34.75; H, 3.0; N, 22.6%;
6-(Methylsulfonyl)imidazo[2,1-f ][1,2,4]triazine 24
Method A. A solution of sulfide 20 (50 mg, 0.30 mmol) in
glacial acetic acid (1 ml) was added to a stirred solution of
KMnO4 (95 mg, 0.60 mmol) in a mixture of glacial acetic acid
(0.5 ml) and water (0.5 ml) at 0 ЊC. The resulting mixture was
allowed to warm to 25 ЊC and stirred vigorously for 30 min. The
dark solution was extracted with ethyl acetate (3 × 10 ml)
and the combined organic extract was washed successively with
1 M NaOH and brine. After drying (MgSO4) and evaporation
of volatiles in vacuo, the residue was purified by flash chrom-
atography on silica gel (gradient elution; 30–40% ethyl acetate
in light petroleum) to give the sulfone 24 (35 mg, 58%) as pale
yellow crystals, mp 185–190 ЊC (from DCM–light petroleum);
νmax(NaCl/Nujol)/cmϪ1 1695s, 1591w, 1307s, 1264w, 1139s
(SO2), 1113w, 1074w, 899s, 779s, 750w; δH(300 MHz; CDCl3)
9.41 (1H, s, H-8), 8.31 (1H, s, H-2 or H-3), 8.25 (1H, d, J 0.91
J. Chem. Soc., Perkin Trans. 1, 1999, 2929–2936
2935

View Article Online
Mϩ, 244.0086. C7H8N4O2S2 requires C, 34.4; H, 3.3; N, 22.9%;
to furnish the title compound 27 (8 mg, 27%) as an oil which was
M, 244.0089).
identical with that described above.
8-(Methylsulfanyl)imidazo[2,1-f ][1,2,4]triazine 29
Acknowledgements
A solution of sulfone 28 (36 mg, 0.15 mmol) in a mixture of
chloroform (0.6 ml) and EtOH (0.6 ml) at room temperature
was treated with NaBH4 (11 mg, 0.30 mmol) in small portions.
The reaction mixture was stirred for 5 min and then quenched
with water (0.2 ml). Excess of solvent was removed in vacuo and
the residue was purified by flash chromatography on silica gel
(gradient elution; 5–15% ethyl acetate in light petroleum) to
afford the sulfide 29 (19.5 mg, 79%) as a pale yellow solid, mp
114–116 ЊC (from DCM–light petroleum); νmax(NaCl/Nujol)/
cmϪ1 1692s, 1607w, 1579w, 1538w, 1482w, 1430s, 1410s, 1370s,
1340w, 1314w, 1142w, 908w, 864w, 748w; δH(270 MHz; CDCl3)
8.45 (1H, s, H-6), 7.88 (1H, d, J 1.15 Hz, H-2 or H-3), 7.74 (1H,
d, J 0.93 Hz, H-3 or H-2), 2.70 (3H, s, SCH3); δC(76 MHz,
CDCl3) [164.90, 146.92, 133.35, 132.69, 117.49] (Het C), 11.83
(SCH3); m/z (EI) 166 (Mϩ, 85%), 139 (10), 112 (10), 95 (30), 94
(60), 93 (100), 70 (55), 65 (20 ), 45 (22) (Found: Mϩ, 166.0317.
C6H6N4S requires M, 166.0313).
We thank AgrEvo UK Limited for a research studentship
(to V.-D. Le), Ms T. Monk for performing the ADA assay and
the Wolfson Foundation for establishing the Wolfson Centre
for Organic Chemistry in Medical Science at Imperial College.
References
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8-Hydrazinoimidazo[2,1-f ][1,2,4]triazine 30
To a stirred solution of sulfide 29 (60 mg, 0.36 mmol) in ethanol
(1 ml) was added hydrazine monohydrate (22 mg, 0.43 mmol) at
25 ЊC. The reaction was stirred for 2 h and excess of solvent was
removed in vacuo. The residue was purified by flash chroma-
tography on silica gel (gradient elution; 2–5% MeOH in DCM)
followed by recrystallization from EtOH to afford the hydrazine
30 (41 mg, 76%) as a white solid, mp 205–210 ЊC (decomp);
νmax(NaCl/Nujol)/cmϪ1 3289w, 3116w, 3103 (NH), 1682w,
1682w, 1661w, 1608w, 1505w, 1417w, 1349s, 1274w, 1140w,
1089w, 1041w, 920w, 773w, 646s; δH(270 MHz; DMSO-d6) 10.08
(1H, br s, NH), 8.12 (1H, s, H-6), 8.02 (1H, s, H-2 or H-3), 7.53
(1H, d, J 0.70 Hz, H-3 or H-2), 4.95 (2H, br s, NH2); δC(76
MHz; DMSO-d6) [151.56, 149.23, 130.92, 128.09, 118.07] (Het
C); m/z (EI) 150 (Mϩ, 70%), 121 (65), 105 (35), 94 (100), 77 (20),
67 (40), 53 (50), 43 (45).
Imidazo[2,1-f ][1,2,4]triazine 27
Method A. A solution of the hydrazine 25 (50 mg, 0.33
mmol) in ethanol (1 ml) at room temperature was treated with
yellow mercury() oxide (214 mg, 0.99 mmol). The dark solu-
tion was heated gently for 10 min. After being cooled to 25 ЊC,
the inorganic residue was removed through a pad of Celite,
washed with ethanol and the combined solution concen-
trated in vacuo to give the crude product as a yellow oil. This
was purified by flash chromatography on silica gel (ether as
eluent) to furnish the title compound 27 (7 mg, 18%) as an oil;
νmax(NaCl/film)/cmϪ1 1691s, 1608w, 1580w, 1482w, 1370s,
1314w, 1142w, 863w, 752w; δH(270 MHz; CDCl3) 9.10 (1H, s,
H-8), 8.52 (1H, s, H-6), 7.80 (1H, d, J 1.10 Hz, H-2 or H-3),
7.73 (1H, d, J 0.96 Hz, H-3 or H-2); m/z (EI) 120 (Mϩ, 25%), 93
(100), 70 (32), 45 (22) (Found: Mϩ, 120.1608. C5H4N4 requires
M, 120.1616).
Method B. A solution of the hydrazine 30 (35 mg, 0.23 mmol)
in ethanol (1 ml) at room temperature was treated with yellow
mercury() oxide (150 mg, 0.69 mmol). The dark solution was
heated gently for 10 min. After being cooled to 25 ЊC, the
inorganic residue was removed through a pad of Celite and
washed with ethanol, and the combined solution concentrated
in vacuo to give the crude product as a yellow oil. This was
purified by flash chromatography on silica gel (ether as eluent)
Paper 9/04065J
2936
J. Chem. Soc., Perkin Trans. 1, 1999, 2929–2936