A novel, simple cyclocondensation reaction towards glycosyl triazines

Article abstract of DOI:10.1055/s-0028-1083156

Sugars bearing an isothiocyanate moiety at C-1 react with diazadienium iodide to afford glycosyl triazines that represent, through an easy cyclocondensation reaction step, a flexible entry to different nucleoside analogues. We herein demonstrate that this [4+2] cycloaddition reaction occurs with total regiocontrol and good yields. Subsequent transformation of the thiocarbonyl into a carbonyl, and nucleophilic substitution of the methylsulfanyl group by ammonia, yields the 5-azacytidine analogues. All compounds were fully characterised by IR, HRMS, and ¹³C and ¹H NMR (COSY, HMBC and HMQC). Georg Thieme Verlag.

Full text of DOI:10.1055/s-0028-1083156

PAPER
3453
A Novel, Simple Cyclocondensation Reaction Towards Glycosyl Triazines
C
yclocondensation
i
R
eact
n
T
owards
c
G
lycosyl
T
e
r
iazines nt Kikelj,a,b Karine Julienne,a,b Pascal Janvier,a,b Jean-Claude Meslin,a,b David Deniaud*a,b
a
CEISAM, Chimie Et Interdisciplinarité, Synthèse, Analyse, Modélisation, UFR des Sciences et des Techniques, Université de Nantes,
2 rue de la Houssinière, BP 92208, 44322 Nantes Cedex 3, France
CNRS, UMR CNRS 6230, 2 rue de la Houssinière, BP 92208, 44322 Nantes Cedex 3, France
Fax +33(2)51125402; E-mail: david.deniaud@univ-nantes.fr
b
Received 11 June 2008; revised 3 July 2008
SMe
SMe
N
Abstract: Sugars bearing an isothiocyanate moiety at C-1 react
with diazadienium iodide to afford glycosyl triazines that represent,
through an easy cyclocondensation reaction step, a flexible entry to
different nucleoside analogues. We herein demonstrate that this
[4+2] cycloaddition reaction occurs with total regiocontrol and
good yields. Subsequent transformation of the thiocarbonyl into a
carbonyl, and nucleophilic substitution of the methylsulfanyl group
by ammonia, yields the 5-azacytidine analogues. All compounds
were fully characterised by IR, HRMS, and 13C and 1H NMR
(COSY, HMBC and HMQC).
N
N
N
O
O
N
N
S
S
OR
OR
1,2,4-triazine
nucleosides
1,3,5-triazine
nucleosides
diazabutadiene 4
diazabutadiene 2
O
NCS
Key words: nucleosides, triazines, cycloaddition, 5-azacytidine,
heterochemistry
OR
1a–f
SMe
SMe
NH⋅HI
SMe
N
For many years, studies on nucleosides with 1,3,5- or
1,2,4-triazines, like nucleobases, have received much at-
tention due to their pronounced biological activity.
Among these modified nucleosides, 5-azacytidine was re-
ported to be clinically very promising due to its cytotoxic,
antimicrobial, antiplastic and mutagenic properties.1–6 It
has been shown that Decitabine (5-aza-2¢-deoxycytidine)
interferes with the processes of DNA methylation and hi-
stone modification, and was capable of reactivating
tumour suppressor genes silenced by promoter hyper-
methylation, in association with regional DNA demeth-
ylation.7,8 The chemistry and diverse applications of
1,2,4-triazine nucleoside derivatives have received less
attention, although some of these compounds have proved
to be biologically active as potent inhibitors of orotidine
monophosphate decarboxylase (ODCase),9,10 as antiphlo-
gestic and bacteriostatic agents11 and as potential antitu-
mour agents.12–14
NH⋅HI
NH⋅HI
N
N
N
N
2
3
4
Scheme 1 Retrosynthetic route to 1,3,5- and 1,2,4-triazines. Hetero-
cyclocondensation methodology employing (poly)azadienes
and a diazabutadienic chain. We envisioned the synthesis
of 1,3,5- or 1,2,4-triazine nucleoside analogues using
either a 1,3- or 1,4-diazabutadienium salt (Scheme 1).
The hetero-cyclocondensation methodology employing
(poly)azadienes represents a straightforward and an effi-
cient approach to nitrogen-containing six-membered het-
erocycles.18,19 In the course of our ongoing research, we
first investigated the reactivity of 1,3-diazabutadienium
salt 2. This synthon proved to be a suitable, stable and ver-
satile reactant for the preparation of heterocyclic rings.20
Indeed, this reagent reacts with ketenes, sulfenes and
dialkyl acetyldicarboxylates to afford the corresponding
dihydropyrimidinones, thiadiazinedioxydes and pyrim-
idines. We also studied the behaviour of azabutadienium
iodide 3. We notably described that the cyclisation of this
salt with glycosyl isothiocyanates is a convenient method
for the preparation of pyrimidine nucleosides,21 and for
the synthesis of 1-substituted uracil ring systems and their
thio- and dithio analogues.22
Numerous methods for the synthesis of nucleoside ana-
logues involve approaches based on condensations of gly-
cosides with persilylated nucleobases. Alternative routes
to N-alkylation include heating with trimethyl
phosphate15 and alkylation of O-silylated derivatives,16
which is an important method for unambiguous N-alkyla-
tion, especially ribosylation of uracils.17 Most previous
syntheses of azacytidine analogues yield both a- and b-
anomers that are often difficult to separate. For this rea-
son, we focused on the preparation of b-glycosyl triazines
through a regioselective hetero-cyclocondensation reac-
tion from variously b-glycosylated isothiocyanates 1a–f
With the aim of extending this work to the synthesis of
1,3,5-triazine nucleosides, we have carried out an annula-
tion reaction by condensation of 2 with a range of b-gly-
cosyl isothiocyanates. Known b-glycosyl isothiocyanates
1a–e,23–27 easily obtained in two steps in good yields from
inexpensive peracetylated (perbenzoylated for 1e) glyco-
sides, were used as starting material (Scheme 2). For the
acyclic carbohydrate isothiocyanate 1f the most efficient
method involved the use of 1,3-dioxolane and acetyl chlo-
SYNTHESIS 2008, No. 21, pp 3453–3460
x
x.
x
x
.
2
0
0
8
Advanced online publication: 25.09.2008
DOI: 10.1055/s-0028-1083156; Art ID: Z13808SS
© Georg Thieme Verlag Stuttgart · New York

3454
V. Kikelj et al.
PAPER
SMe
NH2
N
O
RO
O
O
i
ii
NCS
OAc
N
N
RO
RO
i
N
O
O
X
N
N
1a–e
R = Ac and X = Br for a–d
R = Bz and X = Cl for e
O
O
OAc
OH
6a
7a
a = Glucosyl- (71%); b = Galactosyl- (70%);
c = Cellobiosyl-(72%); d = Lactosyl- (70%); e = Ribosyl- (86%)
SMe
NH2
N
N
i
OAc
OH
N
N
N
N
O
O
O
iii
iv
O
Cl
O
NCS
AcO
AcO
O
O
1f
O
6f
7f
Scheme
2
Synthetic route to glycosyl isothiocyanates 1a–f.
Scheme 4 Synthetic route to 5-azacytidine analogues 7a and 7f.
Reagents and conditions: (i) NH3 (7 M in MeOH), EtOH, r.t., 24 h.
Reagents and conditions: (i) HBr in AcOH, CH2Cl2, 2 h, 0 °C [or
HCl(g), AcOCl, 2 h, r.t. for 1e]; (ii) KSCN, 4 Å MS, TBAB, MeCN,
2 h, 82 °C; (iii) AcCl, 8 h, 70 °C; (iv) KSCN, toluene, 6 h, 110 °C.
equivalent of isothiocyanate to give glycosyl thioureas as
side products. Compounds 5a–f proved to be slightly un-
stable (except 5f) and degraded after four hours at room
temperature, though, they were stable under an inert atmo-
sphere for several weeks at –25 °C. This problem of room
temperature instability has been circumvented by trans-
formation of the thiocarbonyl into a carbonyl. The most
efficient method for synthesising 6a–f involved the use of
trifluoroacetic anhydride in acetonitrile at reflux for two
hours.29 Naturally these compounds could be obtained
from glycosyl isocyanates but isothiocyanates are more
accessible, more stable and less toxic.
H2N+
SMe
I–
H
N
S
C
N
S
SMe
i
+
N
N
N
Sugar
Sugar
N
N
1a–f
2
SMe
SMe
SMe
N
N
5a 77%
5b 70%
5c 89%
5d 62%
5e 92%
5f 91%
OAc
OAc
N
N
N
or
O
N
N
O
O
S
S
OR
With a view to expanding the scope of this investigation
to potential 5-azacytidine derivatives, we examined the
possibilities of introducing an amino group onto the triaz-
ine ring at the 4-position. It is known that a sulfanyl sub-
stituent in this position can act as a good leaving
group.22b,30,31 Thus, nucleophilic displacement of the
methylsulfanyl group of 6a and 6f was carried out with al-
coholic solution of ammonia at room temperature, to af-
ford 4-amino-1,3,5-triazine glycosides 7a and 7f. The
long duration of reaction required (24 hours) was due to
the decomposition of 6a and 6f at elevated temperature.
The formation of aminotriazines was confirmed by the
disappearance of the peak due to the thiomethyl group
(SMe) of the starting material in the NMR spectrum and
the appearance of the signal arising from NH2 around
3300 cm–1 in the IR spectrum (Scheme 4). It is worth not-
ing that during this reaction, complete deacetylation of
peracetylated glycosyl 6a, and deprotection of compound
6f, took place quantitatively.
5a–e
5f
SMe
ii
N
N
6a 95%
6b 96%
6c 88%
6d 77%
6e 71%
6f 91%
or
N
O
N
N
O
O
OR
6a–e
6f
Scheme 3 Synthetic route to 1,3,5-triazine nucleosides 5a–f and
6a–f. Reagents and conditions: (i) CH2Cl2, 5 min, r.t. then Et3N,
0 °C → r.t., 2 h (1 h for 5f); (ii) TFAA, MeCN, 2 h, 82 °C.
ride. The chloromethoxyethyl acetate was converted into
its isothiocyanate through reaction with potassium thiocy-
anate and used directly without purification (Scheme 2).
This method proved to be more suitable than that de-
scribed by Foye and coworkers, which provided yields of
no more than 41%.28
The formation of triazinethiones 5a–f is based on a [4+2]
cycloaddition reaction of 1,3-diazadienium iodide (2)
with appropriate b-glycosyl isothiocyanates, in basic me-
dium, followed by a deamination of the formed cycload-
duct (Scheme 3). These compounds were synthesised in
good yields and in a regiocontrolled manner. The b-ano-
meric configuration was fully preserved, and we observed
only 1,2-trans glycosidic linkage.
With a view to extending this work to the preparation of
1,2,4-triazine nucleosides, we decided to investigate the
behaviour of 1,4-diazabutadienium salt 4, which presents
an original heteroatomic chain, towards glycosyl isothio-
cyanates 1a–f. Compound 4 was synthesised in four steps
starting from inexpensive thiophosgene, which reacts
with 1-trimethylsilyl-1,2,4-triazole to give 1,1¢-thiocarbo-
nyldibenzimidazole (8; Scheme 5).
The structures of compounds 5a–f were determined un-
The unstable, unisolated thiocarbonyl transfer reagent 8
was treated with an equimolar amount of formaldehyde
N,N-dimethylhydrazone32 in dichloromethane, to afford
the thiazadiene 9 in 84% yield, according to the method
1
equivocally by complementary H/13C-2D NMR tech-
niques (COSY, HMQC and HMBC). In this reaction, the
dimethylamine generated in situ reacts with a second
Synthesis 2008, No. 21, 3453–3460 © Thieme Stuttgart · New York

PAPER
Cyclocondensation Reaction Towards Glycosyl Triazines
3455
Table 1 Calculated Frontier Orbital Energies, HOMO and LUMO Coefficients
Compd
HOMO
(eV)
LUMO
(eV)
N
C
N
C
p-Tol-NCS
Ph-NCS
Me-NCS
2a
–8.731
–8.904
–8.893
–8.668
–0.396
–0.412
0.430
0.315
–0.040
–0.019
–0.042
0
–0.765
–0.892
–0.155
0
0.187
0.180
–0.003
–0.406
–0.445
–0.449
0.005
–0.639
a Neutral form.
N
N
N
Table 2 Calculated Net Atomic Charges
Cl
N
Cl
i
N
N
ii
N
Compd
Net atomic charge
S
S
8
NH
C
N
N
iii
H2N
N
p-Tol-NCS
0.351
0.358
0.333
0.241
0.140
–0.299
N
N
N
N
S
Ph-NCS
–0.314
–0.281
S
10
9
Me-NCS
iv
v
MeS
N
MeS
I–
N
2a
–0.555
–0.507
–0.486
N
N
+ NH2
NH
3a
11
4
4a
–0.112
Scheme 5 Synthetic route to S-methyl salt 4: Reagents and condi-
tions: (i) 1-trimethylsilyl-1,2,4-triazole, CH2Cl2, 18 h, r.t.; (ii) form-
aldehyde dimethylhydrazone, CH2Cl2, 2 h, r.t.; (iii) NH3 (7 M in
MeOH), EtOH, 5 min, 65 °C; (iv) MeI, THF, 18 h, r.t.; (v) Et3N,
CH2Cl2, 5 min, 0 °C.
a Neutral form.
nyl- or methyl- isothiocyanates as models (aryl- and alkyl-
isothiocyanates have experimentally shown the same de-
gree of reactivity as glycosyl-isothiocyanates). The results
obtained from these competitive experiments are incon-
sistent with a simple FMO (Frontier Molecular Orbitals)
analysis. Some calculated properties concerning the most
reactive species are given in Table 1.
described by Larsen et al.33 Reaction of compound 9 in
methanolic solution of ammonia gave thioamide 10,
which was alkylated to provide the S-methyl salt 4 as the
sole product due to the preferential alkylation of the more
nucleophilic sulfur atom. Unfortunately, in contrast to
methods described in the literature,34 and irrespective of
the operating conditions, we never observed cyclisation of
iodide 4 with isothiocyanates to afford 1,2,4-triazines.
The dienic chain does not allow the [4+2] cycloaddition
reaction. Similarly, interaction of acrylic dienophiles or
acid chlorides, with S-methyl salt 4 did not give rise to
pyrazines. To investigate the reactivity of the neutral
form, we dehydrohalogenated iodide 4 to afford 1,4-di-
azabutadiene 11. In the same way, all attempts at cyclo-
condensation of this diazadiene chain in the presence of
dienophiles were unsuccessful and none of the desired
heterocycles were detected.
A more complete inspection of the FMO involving
NHOMO (next HOMO) or NLUMO (next LUMO), con-
sidering coefficients, symmetry (vide infra), normal or in-
verse electron demand, leads to the same conclusion. The
simple analysis of the calculated net atomic charges is in
agreement with the experimental results as shown in
Table 2. The nucleophilic character of the nitrogen in the
case of 4, and the more pronounced nucleophilic character
of the NH and electrophilic character for the carbon in the
case of 2 can explain the experimental observed reactivi-
ty.
In summary, we have achieved the synthesis of interesting
nucleoside analogues with 1,3,5-triazine moieties by a
heterocyclocondensation reaction of isothiocyanate sug-
ars 1a–f and a 1,3-diazabutadienium salt 2. The sulfanyl
group was successfully removed by transformation of the
thiocarbonyl into a carbonyl and subsequent substitution
by ammonia, affording 5-azacytidine analogues. Regret-
tably, we were not able to develop the synthesis of nucle-
oside-1,2,4-triazines according to the same strategy, the
iodide 4 having shown itself to be non-reactive towards
In order to rationalise the large difference of behaviour
between the two diazabutadienes 2 and 4, calculations
were carried out by means of the semiempirical PM635
method implemented on MOPAC 2007.36 We wished to
compare the 1,3-diazabutadienic chain of 2, which was
very reactive, with the 1,4-diazabutadienic chain of 4,
which was unreactive, and the 1-azabutadienic chain 3
which showed a medium reactivity towards [4+2] cy-
cloaddition reactions. Calculations were recorded on the
neutral forms of butadienic chains, and with p-tolyl-, phe-
Synthesis 2008, No. 21, 3453–3460 © Thieme Stuttgart · New York

3456
V. Kikelj et al.
PAPER
13C NMR (CDCl3): d = 14.4 (CH3S), 20.4 and 20.6 (4 × COCH3),
61.4 (glu C-6), 67.6 and 71.1 (glu C-2 and C-4), 72.0 (glu C-3), 75.4
(glu C-5), 84.3 (glu C-1), 152.1 (C-6 triaz), 169.4, 169.5, 170.1 and
170.4 (4 × COCH3), 178.1 (C=N), 180.8 (C=S).
[4+2] cycloaddition reactions. The pharmacological ac-
tivities of new compounds are investigated and will be re-
ported in due course.
MS (EI, 70 eV): m/z (%) = 489 (2) [M+], 330 (28), 288 (54), 169
All reagents were purchased either from Acros Organics or Sigma–
Aldrich. Column chromatography was conducted on silica gel 60
(40–63 mm), obtained from E. Merck. Melting points were mea-
sured using a Reichert microscope. 13C and 1H NMR spectra were
recorded at r.t. using a Bruker Avance 300 spectrometer at 75.5 and
300 MHz, respectively. Chemical shifts (d) are given relative to
TMS as internal standard. Mass spectra were determined with a
Hewlett–Packard 5989 spectrometer. IR spectra were obtained us-
ing a Bruker Vector 22 spectrometer. All chemicals were reagent
grade and used without further purification. THF was freshly dis-
tilled from Na/benzophenone, while CH2Cl2 was distilled over
CaH2. Petroleum ether (PE), where used, had a boiling range of 40–
60 °C.
(59), 43 (100).
HRMS (ESI): m/z [M + Na]+ calcd for C18H23N3NaO9S2: 512.0773;
found: 512.0775.
1-(2,3,4,6-Tetra-O-acetyl-b-D-galactopyranosyl)-4-methylsulfa-
nyl-1,3,5-triazine-2(1H)-thione (5b)
Purified by column chromatography (EtOAc–PE, 1:1).
Yield: 342 mg (70%); yellow solid; mp 82–83 °C.
IR (KBr): 1751, 1588, 1459, 1244 cm–1.
1H NMR (CDCl3): d = 2.02 (s, 3 H, COCH3), 2.04 (s, 3 H, COCH3),
2.07 (s, 3 H, COCH3), 2.20 (s, 3 H, COCH3), 2.58 (s, 3 H, CH3S),
4.10–4.22 (m, 3 H, gal H-5, H-6a and H-6b), 5.29 (t, J = 9.8 Hz,
1 H, gal H-2), 5.31 (dd, J = 9.8, 2.6 Hz, 1 H, gal H-3), 5.54 (d,
J = 2.6 Hz, 1 H, gal H-4), 6.96 (d, J = 7.3 Hz, 1 H, H-1), 8.16 (s,
1 H, H-6 triaz).
13C NMR (CDCl3): d = 14.4 (CH3S), 20.4 and 20.5 (4 × COCH3),
61.1 (gal C-6), 66.8 (gal C-4), 69.9 (gal C-2), 70.3 (gal C-3), 74.3
(gal C-5), 84.7 (gal C-1), 152.4 (C-6 triaz), 169.5, 169.6, 170.2 and
170.5 (4 × COCH3), 178.1 (C=N), 180.8 (C=S).
4-(Dimethylamino)-2-methylsulfanyl-1,3-diazabuta-1,3-dieni-
um Iodide (2)
N,N-Dimethyl formamide dimethyl acetal (1.55 g, 13 mmol) was
added to a suspension of thiourea (0.76 g, 10 mmol) in MeOH (10
mL). The mixture was heated under reflux for 4 h, then the solvent
was removed under reduced pressure and the residue was crystal-
lised from MeOH. A suspension of this thiazadiene (655 mg, 5
mmol) in MeI (4 mL) and THF (4 mL) was stirred at r.t. for 18 h.
The mixture was evaporated under reduced pressure and Et2O (40
mL) was added to precipitate the product compound 2, which was
collected by filtration.
MS (EI, 70 eV): m/z (%) = 489 (1) [M+], 330 (8), 288 (22), 169 (43),
43 (100).
HRMS (ESI): m/z [M + Na]+ calcd for C18H23N3NaO9S2: 512.0773;
found: 512.0777.
Yield: 1.34 g (98%); white solid; mp 148–149 °C.
IR (KBr): 3232, 3070, 1624, 1521 cm–1.
1H NMR (DMSO-d6): d = 2.55 (s, 3 H, SCH3), 3.11 and 3.27 [2 × s,
6 H, N(CH3)2], 8.39 (s, 1 H, CH), 9.53 (br s, 2 H, NH2).
1-(2,3,6,2¢,3¢,4¢,6¢-Hepta-O-acetyl-b-cellobiosyl)-4-methylsulfa-
nyl-1,3,5-triazine-2(1H)-thione (5c)
Purified by column chromatography (EtOAc–PE, 6:4).
13C NMR (DMSO-d6): d = 14.4 (SCH3), 35.9 and 41.9 [N(CH3)2],
Yield: 691 mg (89%); yellow solid; mp 110–111 °C.
IR (KBr): 1753, 1589, 1460, 1233 cm–1.
158.7 (CH), 178.2 (C=N).
MS (CI+): m/z (%) = 146 (100) [M – I]+.
HRMS (CI+): m/z [M – I]+ calcd for C5H12N3S: 146.0752; found:
1H NMR (CDCl3): d = 1.96 (s, 3 H, COCH3), 1.98 (s, 3 H, COCH3),
1.99 (s, 3 H, COCH3), 2.02 (s, 3 H, COCH3), 2.03 (s, 3 H, COCH3),
2.07 (s, 3 H, COCH3), 2.11 (s, 3 H, COCH3), 2.54 (s, 3 H, CH3S),
3.68 (dd, J = 8.9, 4.2 Hz, 1 H, glu H-5¢), 3.84 (t, J = 9.0 Hz, 1 H, glu
H-4), 3.91 (dd, J = 9.0, 4.1 Hz, 1 H, glu H-5), 4.03 (d, J = 12.8 Hz,
1 H, glu H-6¢a), 4.13 (dd, J = 11.8, 4.1 Hz, 1 H, glu H-6a), 4.35 (dd,
J = 12.8, 4.2 Hz, 1 H, glu H-6¢b), 4.49 (d, J = 11.8 Hz, 1 H, glu
H-6b), 4.55 (d, J = 8.9 Hz, 1 H, glu H-1¢), 4.91 (t, J = 8.9 Hz, 1 H,
glu H-2¢), 5.05 (t, J = 8.9 Hz, 1 H, glu H-4), 5.08 (t, J = 9.0 Hz, 1 H,
glu H-2), 5.14 (t, J = 8.9 Hz, 1 H, glu H-3¢), 5.46 (t, J = 9.0 Hz, 1 H,
glu H-3), 6.86 (d, J = 9.0 Hz, 1 H, glu H-1), 8.04 (s, 1 H, H-6 triaz).
13C NMR (CDCl3): d = 14.4 (CH3S), 20.4, 20.6 and 20.7 (7 ×
COCH3), 61.5 (glu C-6¢ and C-6), 67.6 (glu C-4¢), 70.9 (glu C-2),
71.2 (glu C-3), 71.4 (glu C-2¢), 72.0 (glu C-5¢), 72.7 (glu C-3¢), 75.8
and 76.0 (glu C-4 and C-5), 84.5 (glu C-1), 100.6 (glu C-1¢), 151.9
(C-6 triaz), 168.9, 169.1, 169.2, 170.0, 170.1 and 170.4 (7 ×
COCH3), 177.9 (C=N), 180.6 (C=S).
146.0752.
Triazinethione Nucleosides (5a–f); General Procedure
Diazabutadienium iodide 2 (1 mmol) was added to a solution of gly-
cosyl isothiocyanate 1a–f (2.2 mmol) in CH2Cl2 (20 mL). After stir-
ring at r.t. for 5 min, the reaction mixture was cooled to 0 °C and
Et3N (2.2 mmol) was added. The mixture was stirred at r.t. under ar-
gon for 1 h (for 5f), or 2 h (for 5a–e). The solution was washed with
H2O (2 × 20 mL), dried (MgSO4), and evaporated under reduced
pressure. The resulting residue was purified by flash chromatogra-
phy on silica gel to give compounds 5a–f.
1-(2,3,4,6-Tetra-O-acetyl-b-D-glucopyranosyl)-4-methylsulfa-
nyl-1,3,5-triazine-2(1H)-thione (5a)
Purified by column chromatography (EtOAc–PE, 1:1).
MS (EI, 70 eV): m/z (%) = 777 (1) [M+], 331 (10), 43 (100).
HRMS (ESI): m/z [M + Na]+ calcd for C30H39N3NaO17S2: 800.1619;
Yield: 377 mg (77%); yellow solid; mp 88–89 °C.
IR (KBr): 1753, 1590, 1459, 1242 cm–1.
1H NMR (CDCl3): d = 2.00 (s, 3 H, COCH3), 2.02 (s, 3 H, COCH3),
2.05 (s, 3 H, COCH3), 2.08 (s, 3 H, COCH3), 2.55 (s, 3 H, CH3S),
3.89 (ddd, J = 9.6, 4.9, 1.7 Hz, 1 H, glu H-5), 4.13 (dd, J = 12.5, 1.7
Hz, 1 H, glu H-6b), 4.27 (dd, J = 12.5, 4.9 Hz, 1 H, glu H-6a), 5.16
and 5.17 (2 × t, J = 9.6 Hz, 2 H, glu H-2 and H-4), 5.48 (t, J = 9.6
Hz, 1 H, glu H-3), 6.95 (t, J = 9.6 Hz, 1 H, H-1), 8.13 (s, 1 H, H-6
triaz).
found: 800.1619.
1-(2,3,6,2¢,3¢,4¢,6¢-Hepta-O-acetyl-b-lactosyl)-4-methylsulfanyl-
1,3,5-triazine-2(1H)-thione (5d)
Purified by column chromatography (EtOAc–PE, 6:4).
Yield: 482 mg (62%); yellow solid; mp 101–102 °C.
IR (KBr): 1752, 1589, 1460, 1370 cm–1.
Synthesis 2008, No. 21, 3453–3460 © Thieme Stuttgart · New York

PAPER
Cyclocondensation Reaction Towards Glycosyl Triazines
3457
1H NMR (acetone-d6): d = 1.97 (s, 3 H, COCH3), 2.01 (s, 3 H,
COCH3), 2.04 (s, 3 H, COCH3), 2.06 (s, 3 H, COCH3), 2.07 (s, 3 H,
COCH3), 2.13 (s, 3 H, COCH3), 2.16 (s, 3 H, COCH3), 2.56 (s, 3 H,
CH3S), 3.83–3.97 (m, 3 H, glu H-4, H-5 and gal H-5), 4.04–4.20 (m,
3 H, glu H-6a, H-6b and gal H-6a), 4.48 (m, 1 H, gal H-6b), 4.52 (d,
J = 9.8 Hz, 1 H, gal H-1), 4.97 (dd, J = 9.8, 3.3 Hz, 1 H, gal H-3),
5.09 (t, J = 8.7 Hz, 1 H, glu H-2), 5.12 (t, J = 9.8 Hz, 1 H, gal H-2),
5.36 (d, J = 3.3 Hz, 1 H, gal H-4), 5.49 (t, J = 8.7 Hz, 1 H, glu H-3),
6.88 (d, J = 8.7 Hz, 1 H, glu H-1), 8.05 (s, 1 H, H-6 triaz).
13C NMR (acetone-d6): d = 14.4 (CH3S), 20.4 and 20.6 (7 ×
COCH3), 60.8 (glu C-6), 61.6 (gal C-6), 65.6 (gal C-4), 68.9 (gal C-
2), 70.8 (gal C-3 and glu C-4), 71.0 (glu C-2), 71.4 (glu C-3), 75.5
and 76.1 (glu C-5 and gal C-5), 77.4 (glu C-1), 100.9 (gal C-1),
151.9 (C-6 triaz), 168.9, 169.0, 170.0, 170.1 and 170.3 (7 ×
COCH3), 178.0 (C=N), 180.7 (C=S).
1-(2,3,4,6-Tetra-O-acetyl-b-D-glucopyranosyl)-4-methylsulfa-
nyl-1,3,5-triazine-2(1H)-one (6a)
Purified by column chromatography (CH2Cl2–EtOAc, 8:2).
Yield: 90 mg (95%); white solid; mp 269–270 °C.
IR (KBr): 1748, 1695, 1606, 1475, 1230 cm–1.
1H NMR (CDCl3): d = 2.01 (s, 3 H, COCH3), 2.04 (s, 3 H, COCH3),
2.07 (s, 3 H, COCH3), 2.10 (s, 3 H, COCH3), 2.53 (s, 3 H, CH3S),
3.95 (ddd, J = 9.8, 4.8, 1.9 Hz, 1 H, glu H-5), 4.15 (dd, J = 12.6, 1.9
Hz, 1 H, glu H-6a), 4.28 (dd, J = 12.6, 4.8 Hz, 1 H, glu H-6b), 5.18
(t, J = 9.8 Hz, 2 H, glu H-2 and H-4), 5.42 (t, J = 9.8 Hz, 1 H, glu
H-3), 5.96 (d, J = 9.5 Hz, 1 H, glu H-1), 8.15 (s, 1 H, H-6 triaz).
13C NMR (CDCl3): d = 14.4 (CH3S), 20.3, 20.5 and 20.7 (4 ×
COCH3), 61.4 (glu C-6), 67.6 and 70.6 (glu C-2 and C-4), 72.3 (glu
C-3), 75.4 (glu C-5), 80.6 (glu C-1), 150.4 (C=O), 153.2 (C-6 triaz),
169.4, 169.6, 169.9 and 170.4 (4 × COCH3), 184.9 (C=N).
MS (ESI): m/z (%) = 800 (100) [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C30H39N3NaO17S2: 800.1619;
MS (CI+): m/z (%) = 474 (100) [M + H]+.
HRMS (ESI): m/z [M + Na]+ calcd for C18H23N3NaO10S: 496.1002;
found: 800.1620.
found: 496.1000.
1-(2,3,5-Tri-O-benzoyl-b-D-ribofuranosyl)-4-methylsulfanyl-
1,3,5-triazine-2(1H)-thione (5e)
Purified by column chromatography (EtOAc–PE, 8:2).
1-(2,3,4,6-Tetra-O-acetyl-b-D-galactopyranosyl)-4-methylsulfa-
nyl-1,3,5-triazine-2(1H)-one (6b)
Purified by column chromatography (EtOAc–PE, 1:1).
Yield: 495 mg (92%); yellow solid; mp 84–85 °C.
IR (KBr): 1729, 1601, 1451, 1266 cm–1.
MS (CI+): m/z (%) = 604 (100) [M + H]+.
Yield: 91 mg (96%); white solid; mp 80–81 °C.
IR (KBr): 1745, 1710, 1602, 1483, 1225 cm–1.
1H NMR (CDCl3): d = 2.01 (s, 3 H, COCH3), 2.02 (s, 3 H, COCH3),
2.06 (s, 3 H, COCH3), 2.20 (s, 3 H, COCH3), 2.53 (s, 3 H, CH3S),
4.09–4.21 (m, 3 H, gal H-5, H-6a and H-6b), 5.23 (dd, J = 9.5, 2.9
Hz, 1 H, gal H-3), 5.31 (d, J = 9.5 Hz, 1 H, gal H-2), 5.53 (d, J = 2.9
Hz, 1 H, gal H-4), 5.93 (d, J = 9.5 Hz, 1 H, gal H-1), 8.20 (s, 1 H,
H-6 triaz).
13C NMR (CDCl3): d = 14.4 (CH3S), 20.4 and 20.5 (4 × COCH3),
61.2 (gal C-6), 66.8 (gal C-4), 68.3 (gal C-3), 70.4 (gal C-2), 74.2
(gal C-5), 80.8 (gal C-1), 150.4 (C=O), 153.4 (C-6 triaz), 169.5,
169.7 and 170.2 (4 × COCH3), 184.7 (C=N).
1H NMR (CDCl3): d = 2.57 (s, 3 H, CH3S), 4.79 (br s, 2 H, rib H-5a
and H-5b), 4.86 (dt, J = 6.7, 2.8 Hz, 1 H, rib H-4), 5.80 (dd, J = 6.7,
5.3 Hz, 1 H, rib H-3), 5.99 (dd, J = 5.3, 3.1 Hz, 1 H, rib H-2), 7.04
(d, J = 3.1 Hz, 1 H, rib H-1), 7.30–7.66 (m, 9 H, Ar-H), 7.87, 8.03
and 8.06 (3 × d, J = 7.4 Hz, 6 H, Ar-H), 8.59 (s, 1 H, H-6 triaz).
13C NMR (CDCl3): d = 14.4 (CH3S), 62.6 (rib C-5), 69.4 (rib C-3),
74.7 (rib C-2), 80.4 (rib C-4), 91.4 (rib C-1), 128.4, 128.5, 128.8,
129.7, 129.8 and 130.0 (15 × Ar), 133.7 (3 × Ar), 151.1 (C-6 triaz),
164.7, 165.0 and 166.0 (3 × COC6H5), 178.4 (C=N), 180.1 (C=S).
MS (CI+): m/z (%) = 604 (100) [M + H]+.
HRMS (ESI): m/z [M + Na]+ calcd for C30H25N3NaO7S2: 626.1032;
MS (ESI): m/z (%) = 496 (100) [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C18H23N3NaO10S: 496.1002;
found: 626.1032.
found: 496.1001.
1-(2-O-Acetylethoxy)methyl-4-methylsulfanyl-1,3,5-triazine-
2(1H)-thione (5f)
Purified by column chromatography (EtOAc–PE, 1:1).
1-(2,3,6,2¢,3¢,4¢,6¢-Hepta-O-acetyl-b-cellobiosyl)-4-methylsulfa-
nyl-1,3,5-triazine-2(1H)-one (6c)
Purified by column chromatography (EtOAc–PE, 6:4).
Yield: 250 mg (91%); yellow oil.
IR (KBr): 1739, 1582, 1525, 1456, 874 cm–1.
Yield: 134 mg (88%); white solid; mp 107–108 °C.
IR (KBr): 1754, 1603, 1484, 1232 cm–1.
1H NMR (CDCl3): d = 2.08 (s, 3 H, CH3), 2.57 (s, 3 H, CH3S), 3.91–
3.95 (m, 2 H, H-2), 4.22–4.26 (m, 2 H, H-1), 5.70 (s, 2 H, CH2N),
8.19 (s, 1 H, H-6 triaz).
13C NMR (CDCl3): d = 14.4 (CH3S), 20.7 (CH3), 62.8 (C-1), 69.2
(C-2), 81.3 (CH2N), 153.2 (C-6 triaz), 170.6 (C=O), 178.6 (C=N),
181.3 (C=S).
MS (EI, 70 eV): m/z (%) = 275 (3) [M+], 87 (53), 43 (100).
HRMS (ESI): m/z [M + Na]+ calcd for C9H13N3NaO3S2: 298.0296;
1H NMR (CDCl3): d = 1.98 (s, 3 H, COCH3), 1.99 (s, 3 H, COCH3),
2.01 (s, 3 H, COCH3), 2.03 (s, 3 H, COCH3), 2.07 (s, 3 H, COCH3),
2.09 (s, 3 H, COCH3), 2.11 (s, 3 H, COCH3), 2.51 (s, 3 H, CH3S),
3.68 (ddd, J = 9.1, 4.2, 2.0 Hz, 1 H, glu H-5¢), 3.82–3.92 (m, 2 H,
glu H-4 and H-5), 4.05 (dd, J = 12.3, 2.0 Hz, 1 H, glu H-6¢a), 4.13
(dd, J = 12.2, 3.2 Hz, 1 H, glu H-6a), 4.37 (dd, J = 12.3, 4.2 Hz,
1 H, glu H-6¢b), 4.51 (d, J = 12.2 Hz, 1 H, glu H-6b), 4.55 (d,
J = 9.1 Hz, 1 H, glu H-1¢), 4.93 (t, J = 9.1 Hz, 1 H, glu H-2¢), 5.07
(t, J = 9.1 Hz, 1 H, glu H-4), 5.11 (t, J = 9.3 Hz, 1 H, glu H-2), 5.15
(t, J = 9.1 Hz, 1 H, glu H-3¢), 5.39 (t, J = 9.3 Hz, 1 H, glu H-3), 5.88
(d, J = 9.3 Hz, 1 H, glu H-1), 8.06 (s, 1 H, H-6 triaz).
found: 298.0297.
Triazinone Glycosides 6a–f; General Procedure
TFAA (0.8 mmol) was added at r.t. to a solution of triazinethione
glycosides 5a–f (0.2 mmol) in freshly distilled MeCN (10 mL). The
resulting solution was stirred at reflux under argon for 2 h. The sol-
vent was evaporated under reduced pressure and the resulting resi-
due was purified by flash chromatography on silica gel to give
compounds 6a–f.
13C NMR (CDCl3): d = 14.4 (CH3S), 20.4, 20.5, 20.6 and 20.7 (7 ×
COCH3), 61.5 (glu C-6¢ and C-6), 67.7 (glu C-4¢), 70.6 (glu C-2),
71.5 (glu C-2¢), 71.6 (glu C-3), 72.1 (glu C-5¢), 72.8 (glu C-3¢), 75.7
and 76.2 (glu C-4 and C-5), 80.7 (glu C-1), 100.6 (glu C-1¢), 150.2
(C=O), 153.0 (C-6 triaz), 168.9, 169.2, 169.3, 170.1, 170.2 and
170.4 (7 × COCH3), 184.6 (C=N).
MS (ESI): m/z (%) = 784 (100) [M + Na]+.
Synthesis 2008, No. 21, 3453–3460 © Thieme Stuttgart · New York

3458
V. Kikelj et al.
PAPER
Aminotriazinone Glycosides 7a and 7f; General Procedure
HRMS (ESI): m/z [M + Na]+ calcd for C30H39N3NaO18S: 784.1847;
found: 784.1848.
Compounds 6a and 6f (0.5 mmol) were dissolved in EtOH (20 mL)
and a solution of NH3 in MeOH (7 M, 1.07 mL, 7.5 mmol) was add-
ed. The solution was stirred at r.t. for 24 h under argon. The solvent
was evaporated to dryness and the residue was purified by chroma-
tography on silica gel (CH2Cl2–MeOH, 1:1) to afford compounds
7a and 7f.
1-(2,3,6,2¢,3¢,4¢,6¢-Hepta-O-acetyl-b-lactosyl)-4-methylsulfanyl-
1,3,5-triazine-2(1H)-one (6d)
Purified by column chromatography (EtOAc–PE, 1:1).
Yield: 117 mg (77%); white solid; mp 96–97 °C.
IR (KBr): 1755, 1610, 1480, 1232 cm–1.
4-Amino-1-(b-D-glucopyranosyl)-1,3,5-triazine-2(1H)-one (7a)
Yield: 108 mg (79%); white solid; mp 215–216 °C.
IR (KBr): 3402, 1644, 1481, 1074 cm–1.
1H NMR (CDCl3): d = 1.98 (s, 3 H, COCH3), 2.01 (s, 3 H, COCH3),
2.06 (s, 3 H, COCH3), 2.07 (s, 3 H, COCH3), 2.09 (s, 3 H, COCH3),
2.13 (s, 3 H, COCH3), 2.17 (s, 3 H, COCH3), 2.53 (s, 3 H, CH3S),
3.83–3.99 (m, 3 H, glu H-4, H-5 and gal H-5), 4.08–4.20 (m, 3 H,
glu H-6a, glu H-6b and gal H-6a), 4.49 (d, J = 10.0 Hz, 1 H, gal
H-1), 4.50–4.55 (m, 1 H, gal H-6b), 4.98 (dd, J = 10.0, 3.3 Hz, 1 H,
gal H-3), 5.08–5.18 (m, 2 H, gal H-2 and glu H-2), 5.37 (d, J = 3.3
Hz, 1 H, gal H-4), 5.42 (t, J = 9.0 Hz, 1 H, glu H-3), 5.91 (d, J = 9.0
Hz, 1 H, glu H-1), 8.08 (s, 1 H, H-6 triaz).
13C NMR (CDCl3): d = 14.6 (CH3S), 20.4, 20.6 and 21.0 (7 ×
COCH3), 61.0 (glu C-6), 62.3 (gal C-6), 66.8 (gal C-4), 69.3 and
70.8 (glu C-2 and gal C-2), 70.9 (glu C-4), 71.2 (gal C-3), 72.1 (glu
C-3), 75.4 and 76.7 (glu C-5 and gal C-5), 80.9 (glu C-1), 101.1 (gal
C-1), 149.7 (C=O), 163.9 (C-6 triaz), 168.9, 169.1, 169.3, 170.2 and
170.3 (7 × COCH3), 184.5 (C=N).
1H NMR (CDCl3): d = 3.16 (t, J = 9.1 Hz, 1 H, glu H-4), 3.22–3.46
(m, 3 H, glu H-3, H-5¢ and H-6a), 3.55 (t, J = 9.1 Hz, 1 H, glu H-2),
3.67 (d, J = 11.2 Hz, 1 H, glu H-6b), 4.56 (br s, 1 H, OH), 5.00–5.55
(m, 3 H, OH), 5.34 (d, J = 9.1 Hz, 1 H, glu H-1), 7.56 (br s, 2 H,
NH2), 8.35 (s, 1 H, H-6 triaz).
13C NMR (CDCl3): d = 60.9 (glu C-6), 69.7 (glu C-4), 71.0 (glu
C-2), 77.0 (glu C-3), 80.1 (glu C-5), 82.3 (glu C-1), 153.2 (C=O),
157.0 (C-6 pyr), 165.5 (C=N).
MS (CI+): m/z (%) = 275 (100) [M + H]+.
HRMS (EI): m/z [M]+ calcd for C9H14N4NaO6: 297.0811; found:
297.0809.
MS (ESI): m/z (%) = 784 (100) [M + Na]+.
4-Amino-1-(2-hydroxyethoxy)ethyl-1,3,5-triazine-2(1H)-one
(7f)
HRMS (ESI): m/z [M + Na]+ calcd for C30H39N3NaO18S: 784.1847;
Yield: 92 mg (98%); white solid; mp 160–161 °C.
IR (KBr): 3381, 3247, 2956, 1708, 1675, 1627, 1480 cm–1.
found: 784.1849.
1-(2,3,5-Tri-O-benzoyl-b-D-ribofuranosyl)-4-methylsulfanyl-
1,3,5-triazine-2(1H)-one (6e)
Purified by column chromatography (CH2Cl2–EtOAc, 98:2).
1H NMR (DMSO-d6): d = 3.42–3.55 (m, 4 H, H-1 and H-2), 4.68 (t,
J = 5.0 Hz, 1 H, OH), 5.10 (s, 2 H, CH2N), 7.56 (br s, 2 H, NH2),
8.35 (s, 1 H, H-6 triaz).
Yield: 83 mg (71%); white solid; mp 179–180 °C.
IR (KBr): 1723, 1602, 1478, 1268 cm–1.
13C NMR (DMSO-d6): d = 60.1 (C-2), 70.8 (C-1), 75.8 (CH2N),
153.7 (C=O), 159.3 (C-6 triaz), 166.3 (C=N).
1H NMR (CDCl3): d = 2.54 (s, 3 H, CH3S), 4.74 (dd, J = 12.7, 5.8
Hz, 1 H, rib H-5b), 4.82 (dd, J = 12.7, 2.8 Hz, 1 H, rib H-5b), 4.83
(dt, J = 5.8, 2.8 Hz, 1 H, rib H-4), 5.88 (dd, J = 5.8, 4.2 Hz, 1 H, rib
H-2), 5.97 (t, J = 5.8 Hz, 1 H, rib H-3), 6.13 (d, J = 4.2 Hz, 1 H, rib
H-1), 7.32–7.63 (m, 9 H, Ar-H), 7.94, 7.99 and 8.08 (3 × d, J = 1.4
Hz, 6 H, Ar-H), 8.24 (s, 1 H, H-6 triaz).
13C NMR (CDCl3): d = 14.4 (CH3S), 63.8 (rib C-5), 71.3 (rib C-3),
74.7 (rib C-2), 81.0 (rib C-4), 90.7 (rib C-1), 128.3 (2 × Ar-C), 128.5
and 128.6 (6 × Ar-C), 129.1 (Ar-C), 129.7, 129.8, 129.9, 133.5,
133.7 and 133.8 (9 × Ar-C), 150.6 (C=O), 153.8 (C-6 triaz), 165.2,
165.4 and 166.0 (3 × COCH3), 184.8 (C=N).
MS (CI+): m/z (%) = 187 (100) [M + H]+.
HRMS (ESI): m/z [M + Na]+ calcd for C6H10N4NaO3: 209.0651;
found: 209.0653.
Thioxo(1H-1,2,4-triazol-1-yl)acetaldehyde Dimethylhydrazone
(9)
To a solution of 1-trimethylsilyl-1,2,4-triazole (5 mL, 4.94 g, 35
mmol) in CH2Cl2 (35 mL) was added, dropwise at r.t., thiophosgene
(1.33 mL, 17.5 mmol). After stirring the mixture at r.t. for 18 h,
formaldehyde dimethylhydrazone monohydrate (3.15 g, 35 mmol)
was added under argon and the resulting solution was stirred for 2 h
at the same temperature. The solution was evaporated under re-
duced pressure and the residue was purified by chromatography on
silica gel (CH2Cl2–PE–Et3N, 50:47:3) to afford compound 9.
MS (ESI): m/z (%) = 610 (100) [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C30H25N3NaO8S: 610.1260;
found: 610.1262.
Yield: 2.69 g (84%); red solid; mp 129–130 °C.
IR (KBr): 3121, 1505, 1467, 1442, 916 cm–1.
1H NMR (acetone-d6): d = 3.45 [br s, 6 H, N(CH3)2], 8.13 (s, 1 H,
H-5 triaz), 8.14 (s, 1 H, H hydra), 9.26 (s, 1 H, H-3 triaz).
1-(2-O-Acetylethoxy)methyl-4-methylsulfanyl-1,3,5-triazine-
2(1H)-one (6f)
Purified by column chromatography (PE–EtOAc, 6:4).
Yield: 41 mg (91%); white solid: mp 79–81 °C.
IR (KBr): 1739, 1694, 1605, 1450, 1223, 799 cm–1.
13C NMR (acetone-d6): d = 119.7 (CH hydra), 136.5 (C-5 triaz),
144.5 (C-3 triaz), 179.1 (C=S). Signal from N(CH3)2 undetected.
1H NMR (CDCl3): d = 2.05 (s, 3 H, CH3), 2.52 (s, 3 H, CH3S), 3.85–
3.89 (m, 2 H, H-2), 4.17–4.21 (m, 2 H, H-1), 5.32 (s, 2 H, CH2N),
8.12 (s, 1 H, H-6 triaz).
13C NMR (CDCl3): d = 14.3 (CH3S), 20.7 (CH3), 62.9 (C-1), 68.7
(C-2), 76.7 (CH2N), 151.8 (C=O), 155.9 (C-6 triaz), 184.9 (C=N).
MS (EI, 70 eV): m/z (%) = 183 (53) [M+], 114 (32), 86 (73), 42
(100).
HRMS (CI+): m/z [M + H]+ calcd for C6H10N5S: 184.0657; found:
184.0655.
2-(Dimethylhydrazono)ethanethioamide (10)
MS (ESI): m/z (%) = 282 [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C9H13N3NaO4S: 282.0524;
Compound 9 (916 mg, 5 mmol) was dissolved in EtOH (20 mL) and
a solution of NH3 in MeOH (7M, 7.1 mL, 50 mmol) was added. The
solution was stirred at reflux for 5 min under argon then the solvent
found: 282.0525.
Synthesis 2008, No. 21, 3453–3460 © Thieme Stuttgart · New York

PAPER
Cyclocondensation Reaction Towards Glycosyl Triazines
3459
was evaporated to dryness and the residue was purified by chroma-
tography on silica gel (CH2Cl2–PE–Et3N, 50:47:3) to afford com-
pound 10.
(2) Townsend, A.; Leclerc, J. M.; Dutschman, G.; Cooney, D.;
Cheng, Y. C. Cancer Res. 1985, 45, 3522.
(3) Revankar, G. R.; Gupta, P. K.; Adams, A. D.; Dalley, N. K.;
McKernan, P. A.; Cook, P. D.; Canonico, P. G.; Robins,
R. K. J. Med. Chem. 1984, 27, 1389.
(4) (a) Hrdlicka, P. J.; Jepsen, J. S.; Nielsen, C.; Wengel, J.
Bioorg. Med. Chem. 2005, 13, 1249. (b) Hrdlicka, P. J.;
Jepsen, J. S.; Wengel, J. Nucleosides, Nucleotides Nucleic
Acids 2005, 24, 397.
(5) Gaubert, G.; Mathé, C.; Imbach, J. L.; Eriksson, S.;
Vincenzetti, S.; Salvatori, D.; Vita, A.; Maury, G. Eur. J.
Med. Chem. 2000, 35, 1011.
Yield: 630 mg (96%); yellow solid; mp 145–146 °C.
IR (KBr): 3245, 3154, 1611, 1517, 1418 cm–1.
1H NMR (acetone-d6): d = 3.08 [s, 6 H, N(CH3)2], 6.74 (s, 1 H, CH),
7.94 (br s, 1 H, NH), 8.25 (br s, 1 H, NH).
13C NMR (acetone-d6): d = 42.5 [N(CH3)2], 127.7 (CH), 195.2
(C=S).
MS (EI, 70 eV): m/z (%) = 131 (49) [M+], 61 (45), 60 (57), 44
(100).
(6) Gama, Y.; Shibuya, I.; Shimizu, M.; Goto, M. J. Carbohydr.
Chem. 2001, 20, 459.
(7) Galm, O.; Herman, J. G.; Baylin, S. B. Blood Rev. 2006, 20,
1.
HRMS (CI+): m/z [M + H]+ calcd for C4H9N3S: 132.0595; found:
132.0596.
(8) Chang, H. C.; Cho, C. Y.; Hung, W. C. Cancer Res. 2006,
66, 8413.
(9) Levine, H. L.; Brody, R. S.; Westheimer, F. H. Biochemistry
4-(Dimethylamino)-2-methylsulfanyl-1,4-diazabuta-1,3-dieni-
um Iodide (4)
A suspension of thiazabutadiene 10 (262 mg, 2 mmol) in MeI (2
mL) and THF (6 mL) was stirred at r.t. for 18 h. The mixture was
evaporated under reduced pressure and Et2O (40 mL) was added in
order to precipitate the product, which was collected by filtration
and dried under vacuum.
1980, 19, 4993.
(10) Poduch, E.; Bello, A. M.; Tang, S.; Fujihashi, M.; Pai, E. F.;
Kotra, L. P. J. Med. Chem. 2006, 49, 4937.
(11) Al-Etaibi, A.; Makhseed, S.; Al-Awadi, N. A.; Ibrahim,
Y. A. Tetrahedron Lett. 2005, 46, 31.
Yield: 540 mg (99%); white solid; mp 155–156 °C.
IR (KBr): 3238, 3146, 2978, 1615, 1474 cm–1.
1H NMR (DMSO-d6): d = 2.58 (s, 3 H, CH3S), 3.35 [s, 6 H,
N(CH3)2], 6.96 (s, 1 H, CH), 10.40 (br s, 2 H, NH2).
13C NMR (DMSO-d6): d =12.9 (CH3S), 44.0 [N(CH3)2], 117.1
(CH), 179.9 (C=N).
(12) Chun, M. W.; Kim, M. J.; Kim, H. O.; Kim, H. D.; Kim,
J. H.; Moon, H. R.; Jeong, L. S. Nucleosides, Nucleotides
Nucleic Acids 2003, 22, 915.
(13) El-Barbary, A. A.; Sakran, M. A.; El-Madani, A. M.
J. Heterocycl. Chem. 2005, 42, 935.
(14) Mansour, A. K.; Eid, M. M.; Khalil, N. S. A. Nucleosides,
Nucleotides Nucleic Acids 2003, 22, 21.
MS (CI+): m/z (%) = 146 (100) [M – I]+.
HRMS (CI+): m/z [M – I]+ calcd for C5H12N3S: 146.0752; found:
(15) Yamauchi, M.; Kinoshita, M. J. Chem. Soc., Perkin Trans. 1
1973, 8, 391.
(16) Müller, C. E. Tetrahedron Lett. 1991, 32, 6539.
(17) Matsuda, A.; Kurasawa, Y.; Watanabe, K. Synthesis 1981,
748.
(18) (a) Jayakumar, S.; Ishar, M. P. S.; Mahajan, M. P.
Tetrahedron 2002, 58, 379. (b) Abbiati, G.;
Cirrincione de Carvalho, A.; Rossi, E. Tetrahedron 2003,
59, 7397. (c) Mohan, C.; Kumar, V.; Mahajan, M. P.
Tetrahedron Lett. 2004, 45, 6075. (d) Jayakumar, S.; Singh,
P.; Mahajan, M. P. Tetrahedron 2004, 60, 4315.
(19) (a) Landreau, C.; Deniaud, D.; Meslin, J. C. J. Org. Chem.
2003, 68, 4912. (b) Landreau, C.; Deniaud, D.; Reliquet, A.;
Meslin, J. C. Eur. J. Org. Chem. 2003, 3, 421. (c) Robin,
A.; Meslin, J. C.; Deniaud, D. Synthesis 2004, 1633.
(d) Robin, A.; Julienne, K.; Meslin, J. C.; Deniaud, D.
Tetrahedron Lett. 2004, 45, 9557. (e) Landreau, C.; Janvier,
P.; Julienne, K.; Meslin, J. C.; Deniaud, D. Tetrahedron
2006, 62, 9226.
146.0753.
4-(Dimethylamino)-2-methylsulfanyl-1,4-diazabuta-1,3-diene
(11)
Et3N (139 mL, 1 mmol) was added to a solution of 4 (136 mg, 0.5
mmol) in freshly distilled CH2Cl2 (5 mL) at 0 °C. The mixture was
stirred for 5 min at this temperature under argon, then washed with
H2O (2 × 20 mL), dried (MgSO4), and evaporated under reduced
pressure to afford compound 11.
Yield: 68 mg (94%); orange oil.
IR (KBr): 3396, 1652, 1596, 1511 cm–1.
1H NMR (CDCl3): d = 2.30 (s, 3 H, CH3S), 3.06 [s, 6 H, N(CH3)2],
6.88 (s, 1 H, CH).
13C NMR (CDCl3): d = 11.2 (CH3S), 42.2 [N(CH3)2], 126.9 (CH),
171.3 (C=N).
(20) Landreau, C.; Deniaud, D.; Reliquet, A.; Meslin, J. C.
Phosphorus, Sulfur Silicon Relat. Elem. 2002, 177, 2651.
(21) Pearson, M. S. M.; Robin, A.; Bourgougnon, N.; Meslin, J.
C.; Deniaud, D. J. Org. Chem. 2003, 68, 8583.
(22) (a) Robin, A.; Julienne, K.; Raimbault, S.; Meslin, J. C.;
Deniaud, D. Synlett 2005, 18, 2805. (b) Robin, A.; Julienne,
K.; Meslin, J. C.; Deniaud, D. Eur. J. Org. Chem. 2006, 41,
634.
(23) (a) Lindhorst, T. K.; Kieburg, C. Synthesis 1995, 1228.
(b) Kuehne, M.; Gyoergydeak, Z.; Lindhorst, T. K. Synthesis
2006, 949. (c) Witczak, Z. J. Adv. Carbohydr. Chem.
Biochem. 1986, 44, 91.
MS (EI, 70 eV): m/z (%) = 145 (5) [M+], 98 (48), 71 (60), 42 (100).
HRMS (EI): m/z [M+] calcd for C5H11N3S: 145.0674; found:
145.0672.
Acknowledgment
The French Ministry of Education and CNRS are gratefully
acknowledged for financial support.
References
(24) Koch, A.; Lamberth, C.; Wetterich, F.; Giese, B. J. Org.
(1) Pramod, G.; Prasanthkumar, K. P.; Mohan, H.; Manoj,
V. M.; Manoj, P.; Suresh, C. H.; Aravindakumar, C. T.
J. Phys. Chem. A 2006, 110, 11517.
Chem. 1993, 58, 1083.
(25) Camarasa, M. J.; Fernandez-Resa, P.; Garcia-Lopez, M. T.;
de las Heras, F. G.; Mendez-Castrillon, P. P.; San Felix, A.
Synthesis 1984, 509.
Synthesis 2008, No. 21, 3453–3460 © Thieme Stuttgart · New York

3460
V. Kikelj et al.
PAPER
(26) (a) Garcia-Fernandez, J. M.; Ortiz-Mellet, C. Adv.
Carbohydr. Chem. Biochem. 2000, 55, 35. (b) Jiménez-
Blanco, J. L.; Sylla, B.; Ortiz-Mellet, C.; Garcia-Fernandez,
J. M. J. Org. Chem. 2007, 72, 4547.
(27) (a) Bundle, D. R.; Lemieux, R. U. Method. Carbohydr.
Chem. 1976, 7, 79. (b) Marino, C.; Varela, O.; de
Lederkremer, R. M. Carbohydr. Res. 1989, 190, 65. (c) de
Lederkremer, R. M.; Nahmad, V. B.; Varela, O. J. Org.
Chem. 1994, 59, 690. (d) Menuel, S.; Porwanski, S.;
Marsura, A. New J. Chem. 2006, 30, 603.
(31) (a) Elgemeie, G. H.; Sood, S. A. J. Chem. Res., Synop. 2001,
439. (b) Chen, N.; Murata, S.; Yoshikawa, K. Chem. Eur. J.
2005, 11, 4835. (c) Dalai, S.; Belov, V. N.; Nizamov, S.;
Rauch, K.; Finsinger, D.; de Meijere, A. Eur. J. Org. Chem.
2006, 41, 2753.
(32) Kamitori, Y.; Hojo, M.; Masuda, R.; Fujitani, T.; Ohara, S.;
Yokoyama, T. J. Org. Chem. 1988, 53, 129.
(33) (a) Larsen, C.; Steliou, K.; Harpp, D. N. J. Org. Chem. 1978,
43, 337. (b) Larsen, C.; Harpp, D. N. J. Org. Chem. 1981,
46, 2465.
(28) (a) Banijamali, A. R.; Foye, W. O. J. Heterocycl. Chem.
1986, 23, 1613. (b) Foye, W. O.; Banijamali, A. R.;
Patarapanich, C. J. Pharm. Sci. 1986, 75, 1180.
(29) Masuda, R.; Hojo, M.; Ichi, T.; Sasano, S.; Kobayashi, T.;
Kuroda, C. Tetrahedron Lett. 1991, 32, 1195.
(34) (a) Reliquet, A.; Besbes, R.; Reliquet, F.; Meslin, J. C.
Synthesis 1991, 543. (b) Gil, M. J.; Reliquet, A.; Meslin,
J. C. Phosphorus, Sulfur Silicon Relat. Elem. 1997, 128,
105. (c) Charrier, J. D.; Reliquet, A.; Meslin, J. C.
Tetrahedron: Asymmetry 1998, 9, 1531.
(30) (a) Hori, M.; Kataoka, T.; Shimizu, H.; Imai, E.; Yokomoto,
M.; Ando, Y. Synthesis 1987, 278. (b) Nikiforov, T. T.;
Connolly, B. A. Tetrahedron Lett. 1991, 32, 2505.
(35) MOPAC2007, J. J. P. Stewart, Stewart Computational
Chemistry, Version 7.334W.
(36) Stewart, J. J. P. J. Mol. Mod. 2007, 13, 1173.
Synthesis 2008, No. 21, 3453–3460 © Thieme Stuttgart · New York