Synthesis of Thiadiazolylaminoglycosides Through Ring Contraction of Triazinoglycosides Induced by [TBA-Ox]

Article abstract of DOI:10.1002/jhet.2232

A new synthetic route to thiadiazolylaminoglycosides, by a ring expansion/ring contraction sequence of glycosyl triazines, has been developed. Two potential mechanisms of this oxidative ring contraction using [TBA-Ox] are discussed. The more plausible inv

Full text of DOI:10.1002/jhet.2232

Month 2014
Synthesis of Thiadiazolylaminoglycosides Through Ring Contraction of
Triazinoglycosides Induced by [TBA-Ox]
a
a
a
a
b
a
*
Vincent Kikelj, Karine Julienne, Thibaut Chalopin, Sébastien G. Gouin, Michel Evain, and David Deniaud
aLUNAM Université, CEISAM, Chimie Et Interdisciplinarité, Synthèse, Analyse, Modélisation, UMR CNRS 6230, UFR
des Sciences et des Techniques, 2, rue de la Houssinière, BP 92208, 44322 Nantes Cedex 3, France
bLUNAM Université, Institut des Matériaux Jean Rouxel, UMR CNRS 6502, 2 rue de la Houssinière,
BP 32229, 44322 Nantes, France
*
E-mail: david.deniaud@univ-nantes.fr
Received October 1, 2013
DOI 10.1002/jhet.2232
Published online 00 Month 2014 in Wiley Online Library (wileyonlinelibrary.com).
A new synthetic route to thiadiazolylaminoglycosides, by a ring expansion/ring contraction sequence of
glycosyl triazines, has been developed. Two potential mechanisms of this oxidative ring contraction using
[TBA-Ox] are discussed. The more plausible involves formation of an oxatriazepane intermediate followed
by loss of formic acid, ring opening, and subsequent recyclization.
J. Heterocyclic Chem., 00, 00 (2014).
INTRODUCTION
triazinoglycosides by applying the optimal conditions
[TBA-Ox] (conditions c, Scheme 1).
For many years, modified N-glycosyl heterocycles such as
nucleoside analogs have been widely used in biological and
pharmaceutical fields. Considerable effort has been made to
exploit synthetic routes to these compounds. However, very
little work related to exocyclic amino nucleosides has been
carried out, despite such compounds showing interesting
activities [1–4]. For example, Clitocine, a natural ribo-
furanosylamino pyrimidine, is an inhibitor of adenosine
kinase and exhibits insecticidal activity [5–9]. Synthetic
exocyclic amino nucleosides, like ribofuranosylamino
pyrimido[5,4-d]pyrimidine, show antitumor and antiviral
properties [10]. Other glucosylamino pyrimidines [11],
triazines [12–14], thiazoles [15], and triazoles [16,17],
with various activities, have also been reported. Classi-
cally, these exocyclic amino nucleosides are prepared by
a condensation reaction of glycosylamine derivatives with
chloronucleobases [2,18] or by coupling silylated amino-
heterocycles with peracetylated glycosides [19]. On the
basis of the previous literature, it is of interest to develop
new methodologies for the synthesis of compounds con-
taining a similar structural feature. In this context, we have
previously synthesized aminothiadiazole 2 from triazi-
nethione 1 under mild oxidative reaction conditions by a
ring contraction mechanism (Scheme 1) [20].
Known β-glycosyl isothiocyanates 3a–c, easily obtained
in two steps from peracetylated glycosides, were used as
the starting material [21,22]. We recently reported that
the [4 + 2] cyclocondensation reaction between glycosyl
isothiocyanates and 1,3-diazadienium iodide is very effi-
cient, in terms of chemical yield and regioselectivity
without isomerization (β configuration 100%), for the
synthesis of nucleosides [23]. Compounds 4a–c were
synthesized within a range of 70–89% yield. The reaction
of glycosyl triazinethiones 4a–c with 1.1 eq of [TBA-Ox]
in dichloromethane at room temperature for 24 h gave the
desired ring contraction products 5a–c in good yield
(Scheme 2).
Tetrabutylammonium Oxone [TBA-Ox] was prepared
from potassium peroxomonosulfate triple salt (2KHSO5,
KHSO4, K2SO4) (Oxone) by cationic exchange using
NBu4Br and gave a soluble version of the salt mixture,
with ammonium bromide acting as a phase transfer cata-
lyst. The structures of compounds 5a–c were established
1
by ESI-MS, H NMR, 13C NMR, HSQC, and HMBC.
The anomeric configuration was confirmed by measuring
the anomeric coupling constant J1,2. Although various
crystallogenesis experiments were carried out, a monocrys-
tal suitable for X-ray analysis could not be obtained.
Nevertheless, the structure of aminothiadiazole was
confirmed by X-ray single crystal diffraction analysis for
compound 2 (Fig. 1) [24].
RESULTS AND DISCUSSION
We now report a straightforward route to the thiadiazo-
lylaminoglycosides via ring expansion/ring contraction of
A possible formation mechanism of thiadiazolylami-
noglycosides 5a–c is postulated in Scheme 3. The reaction
© 2014 HeteroCorporation

V. Kikelj, K. Julienne, T. Chalopin, S. G. Gouin, M. Evain, and D. Deniaud
Vol 000
Scheme 1. Different protocols for the synthesis of 5-amino-1,2,4-
thiadiazole 2.
(pathway A) or the C–O bond (pathway B) would break.
We showed that buffering the reaction with NaHCO3
inhibits it and leads to a mixture of compounds. This result
seems to confirm that the reaction is acid-catalyzed, with
the hydrogen sulfate (HSOÀ4 ) present in Oxone playing
the part of the Brönsted acid [25,26].
According to pathway A (Scheme 4), the opening of
oxaziridinium salt I would result, by ring expansion, in
an oxatriazepane II, which, after opening, would give an
acyclic compound III. The presence in the latter of a
nitrogen atom lacking electrons would induce a cyclization
by intramolecular substitution leading to, via the elimi-
nation of formic acid, the expected thermodynamically
favored thiadiazole.
Scheme 2. Synthesis of thiadiazolylaminoglycosides 5a–c.
Following pathway B (Scheme 4), the opening of
oxaziridinium salt I would give another acyclic com-
pound without going through an oxatriazepane. Next,
the heterocyclization could be rationalized in the same
way except that the thiadiazole intermediate IV has an
exocyclic amide function rather than an amine function.
The amide would be oxidized to give unstable carbamic
acid which, after decarboxylation, would lead to thia-
diazole. Unfortunately, all attempts to isolate the interme-
diates I–IV were unsuccessful, and the mechanism of this
unexpected ring contraction under oxidative conditions
remains under investigation. For pathway A, thiadiazole
formation is accompanied by the loss of formic acid in
stoichiometric quantity and requires an equivalent of
oxidizing agent (KHSO5) and an equivalent of water.
Pathway B, however, leads to the formation of carbon di-
oxide and requires two equivalents of oxidizing agent and
a catalytic quantity of water. With 0.55 eq of [TBA-Ox],
that is 1 eq of oxidizing agent (KHSO5), thiadiazo-
lylaminoglycosides 5a–c are obtained in similar yields
but with longer reaction times, indicating a ring
expansion followed by a ring contraction mechanism
(pathway A). In order to validate this hypothesis and
confirm this mechanism, we carried out the synthesis of
a triazine analog of compound 1 with a methyl in position
6 (compound 6) (Scheme 5). In fact, the loss of formic
acid could not be demonstrated in previous experiments,
but compound 6 should lead to the same thiadiazole 2
with the formation of acetic acid, which is easy to detect.
1,3,5-triazine 6 was obtained by cyclocondensation
between phenylisothiocyanate and diazadiene 7 under
the usual conditions [27]. Oxidation of compound 6
(TBA-Ox/dichloromethane) gave 1,2,4-thiadiazole 2 in
98% yield (Scheme 5). The presence of acetic acid was
then demonstrated by NMR analyses (1H and 13C) by car-
rying out the ring contraction in deuterated chloroform.
At the same time, we synthesized compound IV (with R =
phenyl) and reacted it with [TBA-Ox], but, whatever the
conditions, decarboxylation and formation of thiadiazole
2 was not observed.
Figure 1. ORTEP drawing of compound 2. [Color figure can be viewed
in the online issue, which is available at wileyonlinelibrary.com.]
Scheme 3. The possible process of the formation of oxaziridinium salt.
would begin with the acid-catalyzed addition of
peroxomonosulfate ion (HSOÀ5 ) on the imine function of
the triazine leading to an oxaziridinium intermediate (I)
(with probably the formation of nitrone as a competing
process in a relatively small proportion). The attack of
water, present in the medium, on the C6 carbon would lead
to opening this intermediate. Either the C–N bond
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Scheme 4. Proposed mechanisms of formation of thiadiazole products 2, 5a–c.
Scheme 5. Synthesis of compound 6 and acetic acid elimination.
Scheme 6. Oxidation of 2 into sulfoxide or sulfone.
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V. Kikelj, K. Julienne, T. Chalopin, S. G. Gouin, M. Evain, and D. Deniaud
Vol 000
chromatography (dichloromethane/ethyl acetate: (9:1) for 5a,
ethyl acetate/petroleum spirit: (5:5) for 5b, ethyl acetate/petroleum
spirit: (6:4) for 5c) to afford compounds 5a–c as a white solid
5-[(2,3,4,6-Tetra-O-acetyl-α-D-gluconopyranosyl)amino]-3-
methylsulfanyl-1,2,4-thiadiazole (5a). This compound was
obtained as white solid (90%) mp 70–71 °C; ir (potassium bromide):
These results confirm the proposed mechanism of pathway
A for the contraction of glycosyl 1,3,5-triazinethiones into
1,2,4-thiadiazolylaminoglycosides: formation of an oxa-
ziridine intermediate by oxidation of an imine, ring
expansion by nucleophilic attack of water on the C–N bond,
opening of oxatriazepane, and then formation of a thiadiazole.
It is worth noting that, in the experimental conditions used,
no oxidation of the methylsulfanyl group was observed.
Nevertheless, the corresponding sulfoxide 8 could be iso-
lated from model thiadiazole 2 by using 0.62eq of oxone
in acetonitrile with a yield of 89% (Scheme 6). Sulfone 9
could be obtained when 1.7 eq of oxone was used in a 2/1
acetonitrile/water mixture.
3337, 3060, 1746, 1552, 1520, 1249 cmÀ1
;
1H NMR
(deuteriochloroform): δ 2.04, 2.05, 2.06, 2.09 (4 s, 12H, CH3), 2.60
(s, 3H, CH3S), 3.87 (ddd, 1H, J=9.4Hz, J=5.0Hz, J=2.1Hz, H5),
4.13 (dd, 1H, J= 12.4 Hz, J=2.1Hz, H6a), 4,30 (dd, 1H, J= 12.4 Hz,
J=5.0Hz, H6b), 4.96 (t, 1H, J=9.4Hz, H1), 5.06 (t, 1H, J=9.4Hz,
H2), 5.10 (t, 1H, J=9.4Hz, H4), 5.35 (t, 1H, J=9.4Hz, H3), 6.69
(d, 1H, J=9.4Hz, NH); 13C NMR (deuteriochloroform): δ 14.4
(CH3S), 20.5 (2×CH3), 20.7 (2×CH3), 61.6 (CH2, C6), 68.2 (CH,
C4), 70.7 (CH, C2), 72.4 (CH, C3), 73.4 (CH, C5), 84.2 (CH, C1),
168.8 (SCN, C3 thiadiazole), 169.5, 169.9, 170, 171,0 (4×CO), 182.4
(Cq, C5 thiadiazole); ms: m/z 477 (4, M+), 331 (4), 169 (31), 109
(24), 43 (100); Anal. Calcd. for C17H23N3O9S2: C, 42.76; H, 4.85;
N, 8.80. Found: C, 42.52; H, 4.97; N, 8.87.
CONCLUSION
We have thus shown that it is easy to obtain
thiadiazolylaminoglycosides from their corresponding
glycosyl triazines by oxidation and in mild conditions. The
mechanism occurs by a ring expansion/ring contraction with
loss of formic acid. This oxidative ring contraction using
[TBA-Ox] provides a convenient method to synthesize new
substituted aminoglycosides with the potential for develop-
ment to aminonucleosides and other carbohydrate mimics.
5-[(2,3,4,6-Tetra-O-acetyl-α-D-galactopyranosyl)amino]-3-
methylsulfanyl-1,2,4-thiadiazole (5b).
This compound was
obtained as white solid (92%) mp 74–75°C; ir (potassium
bromide): 3353, 2931, 1751, 1555, 1227,cmÀ1 1H NMR
;
(deuteriochloroform): δ 2.00, 2.04, 2.05, 2,16 (4 s, 12H, CH3),
2.59 (s, 3H, CH3S), 4.04–4.17 (m, 3H, H5, H6a and H6b), 4.92
(t, 1H, J = 9.2 Hz, H1), 5.16 (dd, 1H, J = 9.2Hz, J = 3.3Hz, H3),
5.26 (t, 1H, J = 9.2 Hz, H2), 5.46 (d, 1H, J = 3.3Hz, H4), 7.03
(d, 1H, J =9.2 Hz, NH); 13C NMR (deuteriochloroform): δ 14.3
(CH3S), 20.4, 20.5 (2×CH3), 20.6 (2×CH3), 61.2 (CH2, C6), 67.0
(CH, C4), 68.0 (CH, C2), 70.0 (CH, C3), 72.4 (CH, C5), 84.4
(CH, C1), 168.4 (SCN, C3 thiadiazole), 169.7, 170.0, 170.4, 171.0
(4×CO), 182.3 (Cq, C5 thiadiazole); ms: m/z 500 (M+ Na+), 478
(M+ H+); Anal. Calcd. for C17H23N3O9S2: C, 42.76; H, 4.85; N,
8.80. Found: C, 42.65; H, 4.77; N, 8.81.
5-[(2,3,6,2′,3′,4′,6′-Hepta-O-acetyl-α-D-cellobiopyranosyl)
amino]-3-methylsulfanyl-1,2,4-thiadiazole (5c). This compound
was obtained as white solid (91%) mp 110–111 °C; ir (potassium
bromide): 3459, 2942, 1756, 1630, 1556, 1232; 1H NMR
(deuteriochloroform): δ 1.99, 2.01, 2.04 (3 s, 9H, CH3), 2.05
(1 s, 6H, CH3), 2.09, 2.12 (2 s, 6H, CH3), 2.59 (s, 3H, CH3S), 3.67
(dm, 1H, J=8.8Hz, H5′), 3.72–3.85 (m, 2H, H4 and H5), 4.05
(d, 1H, J= 12.3 Hz, H6′a); 4,15 (dd, 1H, J= 11.6 Hz, J=4.2Hz,
H6a), 4.38 (dd, 1H, J= 12.3 Hz, J=4.0Hz, H6′b), 4.49 (d, 1H,
J= 11.6 Hz, H6b), 4.84 (t, 1H, J=8.6Hz, H1), 4.94 (t, 1H,
J=8.8Hz, H2′), 4.97 (t, 1H, J=8.6Hz, H2), 5.07 (t, 1H, J=8.8Hz,
H4′); 5,15 (t, 1H, J=8.8Hz, H3′), 5,31 (t, 1H, J=8.6Hz, H3), 6.61
(d, 1H, J= 8.6 Hz, NH); 13C NMR (deuteriochloroform): δ 14.4
(CH3S), 20.5, 20.6, 20.8 (7×CH3), 61.6 (CH2, C6′), 61.7 (CH2, C6),
67.8 (CH, C4′), 70.9 (CH, C2), 71.5 (CH, C2′), 72.0 (2×CH, C3 et
C5′), 72.9 (CH, C3′), 74.4 (CH, C4), 76.3 (CH, C5), 84.2 (CH, C1),
100.7 (CH, C1′), 168.8 (SCN, C3 thiadiazole), 169.0, 169.3, 169.4,
170.2, 170.3, 170.4, 171.1 (7×CO), 182.4 (Cq, C5 thiadiazole); ms:
m/z 788 (M + Na+); Anal. Calcd. for C29H39N3O17S2: C, 45.49; H,
5.13; N, 5.49. Found: C, 45.65; H, 5.27; N, 5.81.
EXPERIMENTAL
General. The NMR spectra were recorded at room temperature
with a Bruker Avance 300 Ultra Shield (Wissembourg, France).
Chemical shifts are reported in parts per million (ppm); coupling
constant are reported in units of Hertz [Hz]. Infrared (IR) spectra
were recorded with a Bruker Vector 22 FTIR using KBr films
or KBr pellets. Low-resolution mass spectra were recorded
with a Thermo electron DSQ spectrometer (Illkirch, France).
High-resolution mass spectra were recorded with a Thermofisher
hybrid LTQ-orbitrap spectrometer (ESI+) (Illkirch, France) and
with a Bruker Autoflex III SmartBeam spectrometer (MALDI)
(Wissembourg, France). Microanalyses were performed on a
Thermo Scientific FLASH 2000 Series CHNS/O Analyzers.
Melting points were determined in open capillary tubes and are
uncorrected. All reagents were purchased from Acros Organics
(Geel, Belgium) or Aldrich (Lyon, France) and were used without
further purification. Column chromatographies were conducted on
silica gel Kieselgel SI60 (40–63μm) from Merck (Darmstadt,
Germany). Reactions requiring anhydrous conditions were
performed under argon. Dichloromethane was distilled from
calcium hydride under nitrogen prior to use. Toluene and
tetrahydrofuran were distilled from sodium/benzophenone under
argon prior to use.
General procedure for thiadiazolylaminoglycosides 5a–c.
Oxone® (DuPont, Puteaux, France) (676 mg; 1.1 mmol) and
tetrabutylammonium bromide (355 mg; 1.1 mmol) were added
to a solution of compounds 4a–c (1 mmol) in 20 mL of dry
dichloromethane. The mixture was stirred at room temperature
24h under nitrogen. The reaction mixture was filtered, and the
filtrate was washed two times with 10mL of water and dried over
magnesium sulfate. The solution was filtered and evaporated
under reduced pressure. The residue was purified by
6-Methyl-4-methylsulfanyl-1-phenyl-1,3,5-triazine-2(1H)-thione
(6).
solution of 4-methyl-4-(dimethylamino)-2-methylsulfanyl-1,3-
diazabuta-1,3-dienium iodide (574 mg, 2 mmol) in dry
Phenyl isothiocyanate (595mg, 4.4mmol) was added to
a
7
dichloromethane (10 mL). After 5 min of stirring at room
temperature, the reaction mixture was cooled to 0 °C and
triethylamine (446 mg, 4.4 mmol) was added. The mixture was
stirred at room temperature under argon for an additive 4 h. The
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Ring Contraction
solution was washed with water (2 × 20 mL), dried (MgSO4), and
evaporated under reduced pressure. The resulting residue was
purified by flash chromatography on silica gel column with
dichloromethane as eluent to give 6 as a yellow solid (413 mg,
83%), mp 137 °C; ir (potassium bromide): 1569, 1558, 1469, 1450,
1260; 1H NMR (deuteriochloroform): δ 2.15 (s, 3H, CH3), 2.61
(s, 3H, CH3S), 7.19–7.58 (m, 5H, CHar.); 13C NMR
(deuteriochloroform): δ 14.3 (CH3S), 24.2 (CCH3), 126.9 (2×CHar.),
129.8 (CHar.), 130.5 (2×CHar.), 140.0 (Cq ar.), 164.6 (CCH3, C6),
177.5 (SCN, C4), 184.1 (CS, C2); ms: m/z 249 (88, M+); 234 (43);
202 (34); 118 (71); 77 (100); Anal. Calcd. for C11H11N3S2: C,
52.98; H, 4.45; N, 16.85. Found: C, 53.11; H, 4.53; N, 16.58.
Acknowledgment. The authors are grateful to the French Ministry
of Education, and to the Centre National de la Recherche
Scientifique (CNRS) for financial support.
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3–Methylsulfinyl-5-(phenylamino)-1,2,4-thiadiazole (8). Oxone®
(381 mg; 0.62 mmol) was added to a solution of 1,2,4-thiadiazole 2
(223 mg; 1 mmol) in 10mL of dry acetonitrile. After stirring for 24h
at room temperature, mixture was filtered, and solvent was removed
under reduced pressure to give a colorless oil, which was dissolved
in dichloromethane (10 mL), washed two times with water
(2 × 10 mL). The organic layer was separated, dried over
anhydrous Na2SO4, filtered, and concentrated under reduced
pressure. The residue was purified by chromatography on silica gel
(dichloromethane/ethyl acetate: (9:1)) to afford 8 as a white solid
(213 mg, 89%), mp 131–132 °C; ir (potassium bromide): 3265,
1
2963, 1602, 1553, 1501, 1446; H NMR (deuteriochloroform): δ
3.04 (s, 3H, CH3SO), 7.21 (t, 1H, J=7.6Hz, Hp ar.), 7.25–7.32 (m,
2H, Ho ar.), 7.43 (t, 2H, J=7.6Hz, Hm ar.), 8.77 (s-e, 1H, NH); 13
C
NMR (deuteriochloroform): δ 39.9 (CH3SO), 119.1 (2×CHo ar.),
125.0 (CHp ar.), 129.8 (2×CHm ar.), 138.7 (Cq ar.), 172.1 (SCN, C3),
182.4 (Cq, C5); ms: m/z 239 (34, M+), 194 (25), 176 (7), 145
(100), 77 (33); Anal. Calcd. for C9H9N3OS2: C, 45.17; H, 3.79; N,
17.56. Found: C, 45.55; H, 3.56; N, 17.81.
3-Méthylsulfonyl-5-(phénylamino)-1,2,4-thiadiazole (9). Oxone®
(1.05 g; 1.7 mmol) was added to a solution of 1,2,4-thiadiazole 2
(223 mg; 1 mmol) in solution of acetonitrile/water (2/1) (10mL).
After stirring for 48 h at room temperature, solution was
evaporated under reduced pressure to give a colorless oil, which
was dissolved in dichloromethane (10 mL), and washed two times
with water (2 × 10mL). The organic layer was separated, dried
over anhydrous Na2SO4, filtered, and concentrated under reduced
pressure. The residue was purified by chromatography on silica
gel (dichloromethane/ethyl acetate: (9:1)) to afford 9 as a white
solid (243 mg, 95%), mp 44–145 °C; ir (potassium bromide): 3264,
3089, 2853, 1601, 1554, 1501, 1456; 1H NMR (deuteriochloroform):
δ 3.34 (s, 3H, CH3SO2), 7.24–7.29 (m, 3H, Har.), 7.47 (t, 2H,
J=7.9Hz, Har.), 8.51 (s-e, 1H, NH); 13C NMR (deuteriochloroform):
δ 41.1 (CH3SO2), 119.8 (2×CHar.), 126.1 (CHar.), 130.2 (2×CHar.),
138.1 (Cq ar.), 166.9 (SCN, C3), 183.4 (Cq, C5); ms: m/z 255
(100, M+), 176 (67), 149 (23), 118 (50), 77 (46); Anal. Calcd. for
C9H9N3O2S2: C, 42.34; H, 3.55; N, 16.46. Found: C, 42.78; H,
3.61; N, 16.49.
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[24] CCDC reference number: 945704
[25] Mohajer, D.; Iranpoor, N.; Rezaeifard, A. Tetrahedron Lett
2004, 45, 631.
[26] Travis, B. R.; Ciaramitaro, B. P.; Borhan, B. Eur J Org Chem
2002, 2002, 3429.
[27] Landreau, C.; Deniaud, D.; Reliquet, A.; Reliquet, F.; Meslin,
J. C. J Heterocycl Chem 2001, 38, 93.
Crystal data for compound 2.
C9H9N3S2, M = 223.3,
monoclinic, a = 10.1834(18) Å, b = 5.1482(6) Å, c = 10.260(2) Å,
α = 90°, β = 113.92(3)°, γ = 90°, V = 491.72(18) Å3, T = 110K,
space group P1211, Z = 2, μ(Mo Kα) = 0.501mmÀ1
, 5431
reflections measured, 2071 independent reflections (Rint = 0.0985).
The final R1 values were 0.0512 (I > 2σ(I)). The final wR(F2)
values were 0.1051 (I > 2σ(I)). The final R1 values were 0.0654
(all data). The final wR(F2) values were 0.1099 (all data). The
goodness of fit on F2 was 1.53. CCDC number CCDC.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet