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
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet