Synthesis, structure and reactivity of 5-pyranosyl-1,3,4-oxathiazol-2-ones

Article abstract of DOI:10.1016/j.carres.2005.09.012

5-(1,2,3,4-Tetra-O-acetyl-α-d-xylopyranos-5S-C-yl)-1,3, 4-oxathiazol-2-one (8) has been prepared from glucuronamide in two steps and 73% overall yield by conversion to the tetra-O-acetyl derivative 7 followed by reaction with chlorocarbonylsulfenyl chloride. 5-(2,3,4-Tri-O-acetyl-β-d- xylopyranosyl)-1,3,4-oxathiazol-2-one (12) was synthesised from d-xylose by a four-step sequence involving conversion to the xylopyranosylnitromethane derivative 9, reaction with PCl₃ to afford nitrile 10, hydrolysis to amide 11, and finally treatment with ClCOSCl. d-Glucose-derived analogue 13 was prepared similarly. The structure of oxathiazolone 8 was established by X-ray crystallography. Thermolysis of the oxathiazolones 8 and 12 at 130-160°C resulted in decarboxylation and desulfuration to yield the corresponding nitriles. Attempts to trap the putative nitrile sulfide intermediates by repeating the thermolysis in the presence of dipolarophiles, such as ethyl cyanoformate, afforded only traces of the 1,3-dipolar cycloadducts; however, under microwave irradiation oxathiazolone 8 and ethyl cyanoformate afforded ethyl 3-(1,2,3,4-tetra-O-acetyl-α-d-xylopyranos-5S-C-yl)-1,2,4- thiadiazole-5-carboxylate 22 in good yield.

Full text of DOI:10.1016/j.carres.2005.09.012

Carbohydrate
RESEARCH
Carbohydrate Research 341 (2006) 41–48
Synthesis, structure and reactivity of
5-pyranosyl-1,3,4-oxathiazol-2-ones
Keith G. McMillan, Miles N. Tackett, Alice Dawson,
Euan Fordyce and R. Michael Paton*
EaStCHEM, School of Chemistry, The University of Edinburgh, The KingÕs Buildings, West Mains Road, Edinburgh EH9 3JJ, UK
Received 20 May 2005; accepted 13 September 2005
Available online 2 November 2005
Abstract—5-(1,2,3,4-Tetra-O-acetyl-a-D-xylopyranos-5S-C-yl)-1,3,4-oxathiazol-2-one (8) has been prepared from glucuronamide in
two steps and 73% overall yield by conversion to the tetra-O-acetyl derivative 7 followed by reaction with chlorocarbonylsulfenyl
chloride. 5-(2,3,4-Tri-O-acetyl-b-D-xylopyranosyl)-1,3,4-oxathiazol-2-one (12) was synthesised from D-xylose by a four-step
sequence involving conversion to the xylopyranosylnitromethane derivative 9, reaction with PCl3 to afford nitrile 10, hydrolysis
to amide 11, and finally treatment with ClCOSCl. D-Glucose-derived analogue 13 was prepared similarly. The structure of oxa-
thiazolone 8 was established by X-ray crystallography. Thermolysis of the oxathiazolones 8 and 12 at 130–160 ꢀC resulted in decar-
boxylation and desulfuration to yield the corresponding nitriles. Attempts to trap the putative nitrile sulfide intermediates by
repeating the thermolysis in the presence of dipolarophiles, such as ethyl cyanoformate, afforded only traces of the 1,3-dipolar cyclo-
adducts; however, under microwave irradiation oxathiazolone 8 and ethyl cyanoformate afforded ethyl 3-(1,2,3,4-tetra-O-acetyl-a-
D-xylopyranos-5S-C-yl)-1,2,4-thiadiazole-5-carboxylate 22 in good yield.
ꢁ 2005 Elsevier Ltd. All rights reserved.
Keywords: C-Glycosyl compounds; 1,3,4-Oxathiazol-2-ones; Nitrile sulfides; X-ray crystallography; Microwave-assisted synthesis
1. Introduction
the first syntheses of pyranosyl oxathiazolones as poten-
tial precursors of pyranosyl nitrile sulfides 5.
Various 1,3,4-oxathiazol-2-ones 1 have been shown to
have biological activity, for example, as fungicides.1
The principal use of these compounds, however, is as
shelf-stable precursors of nitrile sulfides (R–C„N+–
Sꢀ),2,3 which are usually generated by thermal decarbox-
ylation at 120–160 ꢀC. The cycloaddition reactions of
this rare class of 1,3-dipoles can provide access to five-
membered heterocycles incorporating the C@N–S unit,
including isothiazoles 2 and 1,2,4-thiadiazoles 3. Vari-
ous substituents can be incorporated at the 5-position,
including esters, amides and phenols in addition to sim-
ple alkyl and aryl groups. Little attention, however, has
been paid to carbohydrate analogues, the furanosyl
derivative 4 being are a rare exception.4 We now report
R'
R
R
O
S
N
S
R
O
O
R'
R'
N
N
N
S
1
2
3
BzO
BzO
R
O
_
N S
+
RO
RO
O
S
O
BzO
OR
N
4
5
2. Results and discussion
The most widely used synthetic approach to 1,3,4-oxa-
*
Corresponding author. E-mail: r.m.paton@ed.ac.uk
thiazol-2-ones 1 involves treatment of the corresponding
0008-6215/$ - see front matter ꢁ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2005.09.012

42
K. G. McMillan et al. / Carbohydrate Research 341 (2006) 41–48
S
O
O
N
O
O
OAc
OAc
O
OH
OH
O
OAc
OAc
(ii)
O
(i)
H2N
AcO
H2N
HO
AcO
OAc
OH
OAc
6
7
8
Scheme 1. Reagents: (i) Ac2O, pyridine; (ii) ClCOSCl.
carboxamide with chlorocarbonylsulfenyl chloride.1,3,5
For the present work sources of pyranosyl carbox-
amides were therefore required. For initial study glucuro-
namide 6 was selected as a readily accessible starting
material, which would afford a pyranose bearing an oxa-
thiazolone substituent at the 5-position. The glucuron-
amide was first converted to its tetra-O-acetyl
derivative 7 (92%) by treatment with acetic anhydride/
pyridine, and the product then reacted with ClCOSCl
in toluene at reflux for 6 h (Scheme 1). Work-up of the
reaction mixture afforded 5-(1,2,3,4-tetra-O-acetyl-a-D-
xylopyranos-5S-C-yl)-1,3,4-oxathiazol-2-one (8) in 79%
yield. The product was initially identified by its spectro-
1,3,4-oxathiazol-2-one (12) (74%). The overall yield for
the three steps from nitromethyl compound 9 to oxa-
thiazolone 12 was 25%. The D-glucose-derived oxa-
thiazolone 13 was prepared similarly from the
peracetylated nitromethyl-D-glucose compound 14 via
nitrile 15 and carboxamide 16 in 20% overall yield.
The 13C NMR data for the oxathiazolone ring carbons
of pyranosyl compounds 12 and 13 were very similar
to those of the pyranos-5-C-yl analogue 8, with distinc-
tive signals at ꢁ170 ppm for C-2 and ꢁ155 ppm for C-5.
The structure of the glucuronamide-derived oxa-
thiazolone 8 was determined by X-ray crystallography
(Fig. 1). The Cremer and Pople9 puckering parameters
for the glucopyranose and oxathiazolone rings are
shown in Table 1. The pyranoid ring has 91% of the
puckering of an ideal cyclohexane chair conformation
scopic properties: in addition to the expected 1H and 13
C
NMR signals for the carbohydrate moiety there were
characteristic peaks in the carbon spectrum at 170.3
and 155.4 ppm for C-2 and C-5, respectively, of the
1,3,4-oxathiazol-2-one ring. The structure was con-
firmed by X-ray crystallography (vide infra).
˚
with Q = 0.577 A and h = 4.4ꢀ, compared to
˚
Q = 0.630 A and h = 0ꢀ for the ideal chair. Such values
4
are typical of pyranoid rings in the C1 conformation.
The pyranosyl carboxamide precursors that were re-
quired for the synthesis of pyranoses with the oxathiazo-
lone linked to the anomeric position were prepared from
the readily-accessible nitromethyl compounds (Scheme
2). For example, D-xylose was converted into the per-
acetylated nitromethyl derivative 9 using the general
procedure of Ko¨ll and co-workers.6 This involves
reaction with nitromethane and sodium methoxide in
methanol, heating the resulting adduct to achieve
dehydration and cyclisation, and finally acetylation
using Ac2O/CF3SO3H. The nitromethyl compound 9
was then converted into the nitrile 10 by treatment with
phosphorus trichloride in pyridine,7 and the product
hydrolysed (TiCl4/AcOH/H2O) using the general meth-
od of BeMiller et al.8 to afford the carboxamide 11. In
the final stage the carboxamide was reacted with
ClCOSCl using the procedure that had been successfully
employed for the glucuronamide analogue described
above to yield 5-(2,3,4-tri-O-acetyl-b-D-xylopyranosyl)-
The chair arrangement is also evident from the pro-
ton–proton 1H NMR couplings for the glucose ring
[J1,2 3.6, J2,3 10.3, J3,4 9.9, J4,5 10.1 Hz], which are
characteristic of b-glucopyranosides. The H–C–C–H
torsion angles from the X-ray data are compared with
the observed and calculated10 3J values in Table 2; good
agreement is observed in all cases. The atoms of the oxa-
thiazole ring O-1, C-2, S-3, N-4, C-5 are near coplanar
˚
(maximum deviation 0.020 A) with no atom more than
˚
0.032 A from the best plane, and the plane of the oxa-
thiazole ring is near orthogonal to that involving C-10,
C-30 and C-50 of the glucopyranosyl moiety [dihedral
angle between planes = 89.62(7)ꢀ]. Selected bond lengths
and bond angles for the oxathiazolone unit are
compared in Table 3 with the corresponding values
for the non-carbohydrate oxathiazolone structures
17–20.11–14 The C@N bond length [N-4–C-5 =
˚
1.262(3) A] is somewhat shorter than the average value
˚
reported for compounds 17–20 (1.277 A), but still con-
S
O
N
O
R
O
N
R
R
O
O
R
O
NH2
NO2
OAc
O
(i)
(ii)
(iii)
AcO
OAc
AcO
AcO
OAc
AcO
OAc
OAc
OAc
OAc
OAc
9 R = H
14 R = CH2OAc
10 R = H
15 R = CH2OAc
11 R = H
16 R = CH2OAc
12 R = H
13 R = CH2OAc
Scheme 2. Reagents: (i) PCl3, pyridine; (ii) TiCl4, AcOH, H2O; (iii) ClCOSCl.

K. G. McMillan et al. / Carbohydrate Research 341 (2006) 41–48
43
Table 2. Selected torsion angles involving hydrogen [H(X)–C(X)–
C(Y)–H(Y)] for oxathiazolone
coupling constants
8 with observed and calculated
Hx, Hy
Angle hobs/ꢀ a
Jcalc/Hzb
Jobs/Hz
10, 20
20, 30
30, 40
40, 50
+54.9
ꢀ174.1
+170.8
ꢀ169.0
3.3
10.2
10.1
10.0
3.6
10.3
9.9
10.1
a H–C–C–H torsion angle (h) from X-ray data.
b Jcalc = 7.76 cos2h ꢀ 1.1 cosh + 1.4 (see Ref. 10).
been consumed, typically 5–60 h. Nitrile sulfides are
short-lived intermediates that are known to decompose
to sulfur and the corresponding nitrile.3 In order to
provide initial evidence for nitrile sulfide formation, a
solution of glucopyranos-5-C-yloxathiazolone
8 in
mesitylene was therefore heated at reflux (ꢁ165 ꢀC).
The oxathiazolone proved to be unusually stable and
it required 12 h for it to decompose completely. Work-
up of the reaction mixture afforded the corresponding
nitrile 21 (97%), which was identified by comparison
with an authentic sample prepared by reaction of car-
boxamide 7 with thionyl chloride. Similarly, heating a
solution xylopyranosyl oxathiazolone 12 in xylene at re-
flux for 36 h yielded the expected nitrile 10. These results
are consistent with the formation of nitrile sulfides as
intermediates. To prove their involvement, however, re-
quired trapping with a dipolarophile. Ethyl cyanofor-
mate (ECF) and dimethyl acetylenedicarboxylate
(DMAD) were selected for this purpose as both are
known to be reactive towards nitrile sulfides.3 However,
heating D-xylose-derived oxathiazolone 12 with an
excess of ECF (1:9) in xylene afforded only the nitrile
decomposition product 10 together with unreacted start-
ing material. Likewise, only the nitrile was isolated from
the corresponding reaction with DMAD. However, the
reaction of glucuronamide-derived oxathiazolone 8 with
ECF in mesitylene at reflux for 24 h afforded a mixture
of nitrile 21 (44%) and ethyl 3-(1,2,3,4-tetra-O-acetyl-a-
D-xylopyranos-5S-C-yl)-1,2,4-thiadiazole-5-carboxylate
22 (5%), from which traces (1%) of the cycloadduct were
isolated in pure form by preparative TLC (Scheme 3).
The product was identified from its analytical and spec-
troscopic properties. A full assignment of the proton
and carbon NMR spectra was achieved using from the
COSY, HMQC and HMBC techniques. There are, in
addition to the expected proton and carbon peaks for
the xylopyranos-5-C-yl unit, characteristic signals for
the ethyl 1,2,4-thiadiazole-5-carboxylate moiety [dH
Figure 1. Crystal structure of 5-(1,2,3,4-tetra-O-acetyl-a-D-xylopyr-
anos-5S-C-yl)-1,3,4-oxathiazol-2-one (8).
2
sistent with a localised C(sp )@N p-bond [1.28 A].15 The
˚
sulfur–nitrogen bond distance in compound 8 [S-3–
˚
N-4 = 1.689(2) A] is also typical for heterocycles of this
class, being slightly shorter than the accepted S–N single
15
˚
˚
bond length [1.75 A]. The average length [1.375 A] for
the two endocyclic carbon–oxygen bonds is significantly
2
˚
greater than that expected for C(sp )–O [1.34 A] and,
furthermore, O-1–C-5 is shorter than O-1–C-2 [Dd =
˚
0.017 A]. A similar effect has been reported for the 5-
11
˚
alkyl-substituted oxathiazolones 17 [Dd = 0.024 A]
12
˚
and 18 [Dd = 0.015 A], whereas for the aryl analogues
19 and 20 these bonds are of similar length [Dd =
13,14
˚
0.004 A].
17 R = Me
18 R = adamant-1-yl
19 R = Ph
20 R = 4-MeOC6H4
R
O
O
N
S
Having established an efficient and general synthetic
route to 5-pyranosyl-1,3,4-oxathiazol-2-ones the feasi-
bility of using these compounds as sources of pyranosyl
nitrile sulfides was examined. The usual conditions for
generating nitrile sulfides is to heat the oxathiazolone
at 120–160 ꢀC in an inert solvent such as toluene, chlo-
robenzene or mesitylene until the starting material has
Table 1. Cremer and Pople puckering parametersa for oxathiazolone 8
˚
Ring
Q/A
h/ꢀ
//ꢀ
55.4
308.0
Pyranose
Oxathiazolone
C-10–C-20–C-30–C-40–C-50–O-60
O-1–C-2–S-3–N-4–C-5
0.577
0.051
4.4
—
a Ref. 9.

44
K. G. McMillan et al. / Carbohydrate Research 341 (2006) 41–48
Table 3. Selected bond lengths and bond angles for oxathiazolones 8, 17–20
Length
8
17–20
Angle
8
17–20
O-1–C-2
C-2–S-3
S-3–N-4
N-4–C-5
C-5–O-1
C-2@O-21
C-5–R
1.387(3)
1.753(3)
1.689(2)
1.262(3)
1.365(3)
1.186(3)
1.495(3)
1.380–1.392
1.744–1.768
1.677–1.687
1.267–1.289
1.367–1.380
1.184–1.198
1.457–1.491
C-5–O-1–C-2
O-1–C-2–S-3
C-2–S-3–N-4
S-3–N-4–C-5
N-4–C-5–O-1
O-1–C2@O
O-1–C5–R
110.26(18)
106.97(15)
93.23(11)
108.52(16)
120.7(2)
111.2–112.0
106.4–107.2
92.9–93.5
109.1–110.5
117.9–119.3
121.7–123.6
115.0–116.6
122.8(8)
114.69(19)
N
O
OAc
AcO
OAc
S
–
S
N
O
OAc
O
S
N
O
OAc
OAc
21
OAc
OAc
heat
O
– CO2
AcO
N
CCO2Et
AcO
S
N
OAc
N
OAc
EtO2C
O
OAc
OAc
23
8
AcO
22
OAc
Scheme 3.
1.44 (CH3), 4.51 ppm (OCH2), 3J 7.1 Hz; dC 14.0 (CH3),
63.4 (OCH2), 157.8 (C@O), 171.6 (C-3), 179.9 (C-5)]
that are very similar to those previously reported for
ethyl 1,2,4-thiadiazole-5-carboxylates.4,16 The nitrile 21
was identified by comparison with an authentic sample
prepared by dehydration of carboxamide 7 using thionyl
chloride. The formation of thiadiazole 22 provides
unequivocal evidence for the formation of pyranos-5-
C-yl nitrile sulfide 23 as an intermediate in the reaction.
The very low cycloadduct yield indicates that the
decomposition rate of pyranosyl nitrile sulfides is greater
than the rate of trapping by the dipolarophiles employed
for this purpose.
The failure to trap the pyranosyl nitrile sulfides in syn-
thetically-useful yields is attributed, not only to the unu-
sual thermal stability of the oxathiazolone precursors
and to the short lifetime of the nitrile sulfides, but also
the need to use high-boiling solvents and long reaction
times. In an attempt to overcome these problems preli-
minary studies were undertaken using microwave irradi-
ation in place of conventional thermolysis at reflux. This
technique is finding widespread application17 in organic
synthesis and has been used to promote various cycload-
dition reactions including those of nitrile imides18 and
nitrile oxides.19 Initial experiments carried out in ethyl
acetate at 160 ꢀC (300 W, 10 min) gave only unreacted
starting material. In order to perform the reactions at
higher temperatures toluene, rather than ethyl acetate,
was used in subsequent experiments. Irradiation of a
solution of xylopyranos-5-C-yl oxathiazolone 8 in tolu-
ene for 10 min at 200 ꢀC gave a mixture of the starting
material and the target 3-xylopyranos-5-C-yl-1,2,4-thi-
adiazole 22. However, after irradiation for 55 min at
the same temperature all the starting material had been
consumed and work-up of the reaction mixture afforded
the thiadiazole 22 in good yield (63%).
3. Conclusion
In conclusion, 5-pyranosyl-1,3,4-oxathiazol-2-ones can
be prepared in good yield by reaction of the correspond-
ing carboxamide with chlorocarbonylsulfenyl chloride.
They show unusual thermal stability and require tem-
peratures in excess of 150 ꢀC before they undergo decar-
boxylation to the nitrile sulfide. The latter either
fragment to the corresponding nitrile or can be trapped
by cycloaddition with ethyl cyanoformate to afford the
3-pyranosyl-1,2,4-thiadiazole. Only trace amounts of
cycloadduct were isolated by conventional thermolysis;
however, using microwave irradiation the thiadiazole
is formed in good yield.
4. Experimental
4.1. General methods and materials
The analytical methods, instrumentation and procedures
for preparative chromatography were as previously de-
scribed.20 Microwave experiments were conducted in
closed vessels using a CEM Discoverer microwave with

K. G. McMillan et al. / Carbohydrate Research 341 (2006) 41–48
45
ramp times of between 5 and 15 min and 20 min cooling.
2,3,4-Tri-O-acetyl-b-D-xylopyranosylnitromethane (9)
and 2,3,4,6-tetra-O-acetyl-b-D-glucopyranosylnitrome-
thane (14) were prepared from D-xylose and D-glucose,
respectively, by reaction with MeNO2/NaOMe/MeOH
and acetylation of the resulting b-D-pyranosylnitrome-
thane as previously reported.8
and cooled in an ice bath. To this PCl3 (0.05 mL,
0.52 mmol) was added and the mixture stirred overnight
at room temperature. Ice-cold aq 1 M HCl (20 mL) was
added and the solution stirred for 20 min. The product
was extracted into chloroform (3 · 10 mL) and the com-
bined organic layers were washed with satd aq NaHCO3
(2 · 10 mL) and with water (10 mL). The organic layer
was dried (MgSO4) and the solvent was removed in va-
cuo, to give the title compound 10 as a white solid
4.2. 5-(1,2,3,4-Tetra-O-acetyl-a-D-xylopyranos-5S-C-yl)-
1,3,4-oxathiazol-2-one (8)
18
(113 mg, 84%); mp 128–129 ꢀC (lit.7 131–132 ꢀC); ½aꢂD
ꢀ36.7 (c 0.90, CHCl3); Rf 0.54 (Et2O); 1H NMR
(250 MHz, CDCl3): d 2.03, 2.06, 2.07 (3 · s, 9H, CH3),
3.56 (dd, 1H, H-5e), 4.18 (dd, 1H, H-5a), 4.46 (d, 1H,
H-1), 4.83–4.90 (m, 1H, H-4), 5.04–5.07 (m, 2H, H-2,
H-3); J(x–y)/Hz 1–2 6.9, 2–3 nd, 3–4 nd, 4–5a 4.0, 4–
5e 6.8, 5a–5e 12.4; 13C NMR (63 MHz, CDCl3): d
20.3, 20.5 (COCH3), 65.1 (C-5), 65.3, 66.8, 67.6, 68.7
(C-1, C-2, C-3, C-4), 114.3 (CN), 168.8, 169.2, 169.4
(3 · COCH3). HRFABMS: (m/z): [M+H]+ calcd for
C12H16NO7, 286.0927; found, 286.0921.
4.2.1. 1,2,3,4-Tetra-O-acetyl-a-D-glucuronamide (7).
Ac2O (20 mL) was added to a suspension of glucurona-
mide (2.00 g, 10.4 mmol) in pyridine (20 mL) and stirred
overnight under nitrogen at room temperature. The
mixture was concentrated, azeotroped with toluene fol-
lowed by Et2O and the residue recrystallised from EtOH
to afford the title compound 7 as colourless needles
(3.43 g, 92%); mp 155–156 ꢀC (lit.21 147–149 ꢀC; lit.22
18
145–148 ꢀC); ½aꢂD +10.4 (c 1.0, CHCl3). 1H NMR
(250 MHz, CDCl3): d 2.04, 2.05, 2.08, 2.15 (4 · s, 12H,
COCH3), 4.27 (d, 1H, H-5), 5.06 (dd, 1H, H-2), 5.21
(dd, 1H, H-4), 5.51 (t, 1H, H-3), 6.35 (d, 1H, H-1),
6.41 (br s, 2H, CONH2); J(x–y)/Hz 1–2 3.6, 2–3 10.1,
3–4 9.5, 4–5 10.1. 13C NMR (63 MHz, CDCl3): d 20.3,
20.5, 20.6 (4 · COCH3), 68.8, 70.1 (C-2, C-3, C-4,
C-5), 88.1 (C-1), 168.7, 168.9, 169.6, 169.7 (4 · COCH3,
CONH2). HRFABMS: (m/z): [M+H]+ calcd for
C14H20NO10, 362.1087; found, 362.1086.
4.3.2.
2,3,4-Tri-O-acetyl-b-D-xylopyranosylformamide
(11). Titanium tetrachloride (0.13 mL, 1.19 mmol)
was added to a solution of 2,3,4-tri-O-acetyl-b-D-xylo-
pyranosyl cyanide (1.71 g, 5.96 mmol) in glacial acetic
acid (5 mL) at 0 ꢀC. After addition of H2O (0.11 mL),
the mixture was stirred at room temperature for 5 h.
The mixture was then poured into ice-water (50 mL)
and extracted with CHCl3 (3 · 50 mL). The combined
organic layers were washed with H2O (50 mL) and dried
(MgSO4). After removal of the solvent in vacuo the
resulting solid was recrystallised from CHCl3/Et2O to
afford the title compound (722 mg, 40%); mp 175 ꢀC;
4.2.2. 5-(1,2,3,4-Tetra-O-acetyl-a-D-xylopyranos-5S-C-
yl)-1,3,4-oxathiazol-2-one (8). Chlorocarbonylsulfenyl
chloride (0.1 mL, 1.2 mmol) was added to a solution of
carboxamide 7 (100 mg, 0.28 mmol) in Na-dried toluene
(3 mL) and the mixture heated at reflux for 6 h. After
concentration the residue was azeotroped with toluene
and the residue recrystallised from EtOAc to afford the
title compound as colourless crystals (92 mg, 79%); mp
18
½aꢂD ꢀ38.0 (c 1.00, CHCl3). 1H NMR (250 MHz,
CDCl3): d 2.13, 2.14, 2.16 (3 · s, 9H, COCH3), 3.48 (d,
1H, H-5a), 3.93 (dd, 1H, H-1), 4.30 (dd, 1H, H-5e),
5.08 (ddd, 1H, H-4), 5.22 (t, 1H, H-2), 5.36 (t, 1H, H-
3), 6.28 (br s, 1H, CONH2), 6.54 (br s, 1H, CONH2);
J(x–y)/Hz 1–2 9.6, 2–3 9.4, 3–4 9.2, 4–5a 10.3, 4–5e
5.5, 5a-5e 11.2. 13C NMR (63 MHz, CDCl3): d 21.0
(3 · COCH3), 66.5 (C-5), 69.1, 69.7 72.9, 76.9 (C-1, C-
2, C-3, C-4), 170.2, 170.3, 170.4 (3 · COCH3, CONH2).
HRFABMS: (m/z): [M+H]+ calcd for C12H18NO8,
304.1032; found, 304.1027. Anal. Calcd for
C12H17NO8: C, 47.5; H, 5.6; N, 4.6; found: C, 47.4; H,
5.6; N, 4.3.
18
212–214 ꢀC; ½aꢂD +12.7 (c 1.0, CHCl3). 1H NMR
(250 MHz, CDCl3): d 2.03, 2.04, 2.07, 2.23 (4 · s, 12H,
COCH3), 4.75 (d, 1H, H-50), 5.16 (dd, 1H, H-20), 5.30
(dd, 1H, H-40), 5.58 (t, 1H, H-30), 6.42 (d, 1H, H-10);
J(x–y)/Hz 10–20 3.6, 20–30 10.3, 30–40 9.5, 40–50 10.1. 13C
NMR (63 MHz, CDCl3): d 20.8 (4 · COCH3), 68.9,
69.1, 69.2, 69.6 (C-10, C-20, C-30, C-40), 89.1 (C-50),
155.4 (C-5), 168.8, 169.8, 169.9 (4 · COCH3), 170.3 (C-
2). HRFABMS: (m/z): [M+H]+ calcd for C15H18NO11S,
420.0601; found, 420.0600. The structure of compound 8
was established by X-ray crystallography (vide infra).
4.3.3.
5-(2,3,4-Tri-O-acetyl-b-D-xylopyranosyl)-1,3,4-
oxathiazol-2-one (12). Chlorocarbonylsulfenyl chloride
(0.08 mL, 0.94 mmol) was added to a solution of car-
boxamide 11 (117 mg, 0.39 mmol) in dry CHCl3
(10 mL) and the mixture heated at reflux for 48 h. After
concentration the residue was azeotroped with toluene
(3 · 20 mL) and the resulting solid dissolved in CH2Cl2.
The solution was passed through a silcica pad (ꢁ5 mm)
and the eluant concentrated to afford the title compound
4.3. 5-(2,3,4-Tri-O-acetyl-b-D-xylopyranosyl)-1,3,4-oxa-
thiazol-2-one (12)
4.3.1. 2,3,4-Tri-O-acetyl-b-D-xylopyranosyl cyanide
(10). Percetylated nitromethyl-xylose derivative
9
(150 mg, 0.47 mmol) was dissolved in pyridine (3 mL)

46
K. G. McMillan et al. / Carbohydrate Research 341 (2006) 41–48
18
as white crystals (104 mg, 74%); mp 134–137 ꢀC; ½aꢂD
organic layer was dried (MgSO4) and concentrated in
vacuo. The resulting solid was recrystallised from
CHCl3/Et2O to afford the title compound as fine white
crystals (478 mg, 46%); mp partially 112–114 ꢀC, totally
146–147 ꢀC (lit.7 partially 112–114 ꢀC, totally 146–
1
ꢀ41.7 (c 0.48, CHCl3). H NMR (250 MHz, CDCl3): d
1.95, 1.98, 1.99 (3 · s, 9H, COCH3), 3.36 (dd, 1H, H-
5a0), 4.20 (dd, 1H, H-5e0), 4.25 (d, 1H, H-10), 5.00
(ddd, 1H, H-40), 5.16 (t, 1H, H-20), 5.22 (t, 1H, H-30);
J(x–y)/Hz 10–20 9.3, 20-30 9.3, 30–40 9.1, 40–50a 10.7, 40–
50e 5.5, 50a–50e 11.4. 13C NMR (63 MHz, CDCl3): d
20.3, 20.5 (3 · COCH3), 66.8 (C-5), 68.1, 69.1 72.0 (C-
20, C-30, C-40), 74.5 (C-10), 155.4 (C-5), 169.3, 169.5,
169.9 (3 · COCH3), 172.2 (C-2). HRFABMS: (m/z):
[M+H]+ calcd for C12H16NO9S, 362.0547; found,
362.0546.
25
147 ꢀC); ½aꢂD +103.1 (c 0.98, CHCl3). 1H NMR
(250 MHz, CDCl3): d 1.81, 1.85, 1.88, 1.93 (4 · s, 9H,
COCH3), 3.57–3.59 (m, 1H, H-5), 3.69 (d, 1H, H-1),
4.00 (m, 2H, H-6a, H-6b), 5.10 (t, 1H, H-2), 5.28 (t,
1H, H-4), 5.42 (t, 1H, H-3), 5.49 (br s, 1H, CONH2);
J(x–y)/Hz 1–2 9.6, 2–3 9.7, 3–4 9.7, 4–5 10.3, 5–5a 7.0,
5–6b 2.2, 6a–b 13.0. 13C NMR (63 MHz, CDCl3): d
20.2, 20.4, 20.5 (4 · COCH3), 61.8 (C-7), 66.4, 68.1
73.6, 75.0. 75.9 (C-1, C-2, C-3, C-4, C-5), 169.1, 169.8,
170.4, 170.5 (4 · COCH3, CONH2). HRFABMS: (m/
z): [M+H]+ calcd for C15H22NO10, 376.1244; found,
376.1244.
4.4. 5-(2,3,4,6-Tetra-O-acetyl-b-D-glucopyranosyl)-1,3,4-
oxathiazol-2-one (13)
4.4.1. 2,3,4,6-Tetra-O-acetyl-b-D-glucopyranosyl cyanide
(15). Phosphorus trichloride (0.4 mL, 4.58 mmol) was
added to an ice-cold solution of nitromethyl-glucose
derivative 14 (1.50 g, 3.84 mmol) in pyridine under
nitrogen; the reaction mixture was allowed to warm to
room temperature and left stirring for 72 h. The result-
ing dark-brown mixture was quenched with ice-cold aq
HCl (1 M, ca. 150 mL) and left stirring for 1 h then
extracted with chloroform (3 · 150 mL). The organic
extracts were combined, washed with satd aq NaHCO3
(100 mL), H2O (50 mL) and satd aq NaCl (50 mL).
The organic layers were then dried (MgSO4) and the sol-
vent removed in vacuo to give an orange-brown oil. This
was dissolved in CH2Cl2 (ca. 100 mL), passed through a
silica pad and concentrated in vacuo to give the title
compound as a white solid (812 mg, 59%); mp 110–
111 ꢀC (lit.23 114–115 ꢀC); Rf 0.33 (petroleum ether/
ethyl acetate, 1:1); 1H NMR (250 MHz, CDCl3): d
2.03, 2.04, 2.11 (4 · s, 12H, COCH3), 3.73 (m, 1H, 5-
H), 4.20 (m, 2H, 6a-H, 6b-H), 4.33 (d, 1H, 1-H), 5.07–
5.22 (m, 2H, 2-H, 4-H), 5.32 (t, 1H, 3-H); J(x–y)/Hz
1–2 10.1, 2–3 9.8, 3–4 9.8, 4–5 9.4, 5–6a 4.8, 5–6b 2.3,
6a–e 12.7; 13C NMR (63 MHz, CDCl3): d 20.3
(4 · COCH3), 61.3 (C-6), 66.3, 67.1, 68.8, 72.7, 76.7
(C-1. C-2, C-3, C-4, C-5), 114.0 (CN), 168.6, 169.0,
169.9, 170.4 (4 · COCH3); HRFABMS: (m/z):
[M+H]+ calcd for C15H20NO9, 358.1138; found,
358.1137.
4.4.3.
1,3,4-oxathiazol-2-one
5-(2,3,4,6-Tetra-O-acetyl-b-D-glucopyranosyl)-
(13). Chlorocarbonylsulfenyl
chloride (0.1ml, 1.2 mmol) was added to a solution of
carboxamide 16 (100 mg, 0.27 mmol) in Na-dried tolu-
ene (3 mL), and the mixture heated at reflux for 4 h.
The reaction mixture was concentrated in vacuo, azeo-
troped with toluene and then passed through a silica
pad [cyclohexane/ethyl acetate, 1:1 (50 mL)] and con-
centrated in vacuo to give the title compound as a white
25
solid (88 mg, 75%); mp 112–113 ꢀC; ½aꢂD +1.8 (c 1.64,
CHCl3); Rf 0.43 (petroleum ether/ethyl acetate, 1:1);
1H NMR (250 MHz, CDCl3): d 2.02, 2.03, 2.07, 2.09
(4 · s, 12H, COCH3), 3.70 (m, 1H, 50-H), 4.18 (m, 2H,
60a-H, 6b0-H), 4.48 (d, 1H, 10-H), 5.17 (t, 1H, 20-H),
5.30 (t, 1H, 40-H), 5.52 (t, 1H, 30-H); J(x–y)/Hz 10–20
10.0, 20–30 9.6, 30–40 9.6, 40–50 9.4, 50–60a nd, 50–60b
nd, 60a–60b nd; 13C NMR (63 MHz, CDCl3): d 20.3,
20.4 (4 · COCH3), 61.5 (C-60), 66.3, 67.9, 70.2, 72.8,
73.8 (C-10, C-20, C-30, C-40, C-50), 156.1 (C-5), 168.9,
169.3, 169.7 (4 · COCH3) 170.0 (C-2); HRFABMS:
(m/z): [M+H]+ calcd for C16H20NO11S, 434.0757; found
434.0752.
4.5. 1,2,3,4-Tetra-O-acetyl-a-D-glucuronic acid nitrile
(21)
A solution of 1,2,3,4-tetra-O-acetyl-a-D-glucuronamide
(7) (220 mg, 0.61 mmol) in thionyl chloride (1.0 mL)
was heated at reflux for 72 h, then passed through a sil-
ica pad (eluting with 1:1 cyclohexane/EtOAc, 50 mL)
and concentrated in vacuo to afford the title compound
4.4.2.
amide
2,3,4,6-Tetra-O-acetyl-b-D-glucopyranosylform-
(16). Titanium tetrachloride (0.05 mL,
0.46 mmol) and water (0.06 mL) were added to an ice-
cold solution of 2,3,4,6-tetra-O-acetyl-b-D-glucpyran-
osyl cyanide (1.00 g, 2.80 mmol) in glacial acetic acid
(5 mL) and the mixture stirred at 0 ꢀC for 30 min. The
mixture was allowed to warm to room temperature
and then stirred for 5 days. It was then poured into
ice-water (50 mL) and extracted with CHCl3
(3 · 50 mL). The combined organic layers were washed
with satd aq NaHCO3 (50 mL) and satd aq NaCl. The
25
as a white (155 mg, 74%); mp 212–215 ꢀC; ½aꢂD +83.9 (c
0.62, CHCl3); Rf 0.65 (petroleum ether/ethyl acetate,
1
1:1); H NMR (250 MHz, CDCl3): d 2.28, 2.30, 2.37,
2.47 (4 · s, 12H, COCH3), 4.98 (d, 1H, 5-H), 5.35 (dd,
1H, 2-H), 5.54–5.70 (m, 2H, 3-H, 4-H), 6.62 (d, 1H, 1-
H); J(x–y)/Hz 1–2 3.7, 2–3 9.5, 3–4 nd, 4–5 10.0; 13C
NMR (63 MHz, CDCl3): d 20.2, 20.6 (4 · COCH3),

K. G. McMillan et al. / Carbohydrate Research 341 (2006) 41–48
47
61.0, 68.1, 68.5, 68.6 (C-1, C-2, C-3, C-4), 88.3 (C-5),
114.0 (C-6), 167.9, 168.6, 169.2, 169.8 (4 · COCH3);
HRFABMS: (m/z): [M+H]+ calcd for C14H18NO9,
344.0982; found 344.0979. Anal. Calcd for
C14H17NO9: C, 48.98; H, 4.99; N, 4.08; found: C,
48.97; H, 5.38; N, 3.68.
NMR (360 MHz, CDCl3): d 1.44 (t, 3H, CH3), 1.91,
2.03, 2.04, 2.22 (4 · s, 12H, COCH3), 4.51 (q, 2H,
OCH2), 5.28 (dd, 1H, 20-H), 5.35 (d, 1H, 50-H), 5.50
(t, 1H, 40-H), 5.65 (t, 1H, 30-H), 6.47 (d, 1H, 10-H);
J(x–y)/Hz CH3–CH2 7.1, 10–20 3.6, 20–30 10.2, 30–40
9.4, 40–50 10.1; 13C NMR (90 MHz, CDCl3): d 14.0
(CH3), 20.2, 20.3, 20.6, 20.8 (4 · COCH3), 63.4
(OCH2), 68.9 (C-40), 69.1 (C-50), 70.1 (C-30), 70.7
(C-20), 88.9 (C-10), 157.8 (C@O), 168.5, 169.1, 169.4,
170.0 (4 · COCH3), 171.6 (C-3), 179.9 (C-5);
HRFABMS: (m/z): [M+H]+ calcd for C18H23N2O11S,
475.1023; found 475.1034. Anal. Calcd for C18H22-
N2O11S: C, 45.6; H, 4.6; N, 5.9; found: C, 45.3; H,
4.6; N, 5.7.
4.6. Generation and reactions of pyranosyl nitrile sulfides
4.6.1. Thermolyses of oxathiazolones 8 and 12. A solu-
tion of the oxathiazolone 8 (50 mg, 0.14 mmol) in dry
mesitylene (5 mL) was heated at reflux under nitrogen
for 12 h. The solvent was concentrated in vacuo and
the remaining solvent removed by azeptroping with tolu-
ene. The resulting white solid was identified as the glucu-
ronic acid nitrile 21 (40 mg, 97%) by comparison of its
spectroscopic properties with those of an authentic sam-
ple. Similarly, thermolysis of a solution of oxathiazolone
12 in xylene at reflux for 36 h afforded only the nitrile 10.
4.6.5. Microwave irradiation of oxathiazolone 8 with ethyl
cyanoformate (ECF). A solution of oxathiazolone 8
(100 mg, 0.238 mmol) and ECF (0.24 mL, 2.38 mmol)
in toluene (3 mL) was heated in the microwave at
200 ꢀC and with a 300 W power input for 55 min. After
cooling, the excess ECF and the solvent were removed
under reduced pressure. The resulting residue was puri-
fied by flash chromatography (silica; 0–40% ethyl ace-
4.6.2. Thermolysis of oxathiazolone 12 with ethyl cyano-
12
formate
(ECF). Xylopyranosyl-oxathiazolone
(100 mg, 0.28 mmol) and ECF (250 mg, 2.52 mmol)
were dissolved in m-xylene under nitrogen and the
solution heated at reflux for 72 h. The reaction mixture
was cooled, the solvent was removed in vacuo and the
resulting oil co-evaporated with toluene to remove the
tate/hexane) to yield
a white solid, which was
recrystallised from ethanol to afford the thiadiazole 22
as white crystals (71 mg, 63%). Similar experiments car-
ried out at 200 ꢀC for 10 min afforded a mixture of thi-
adiazole 22 and oxathiazolone 8. After 10 min at 160 ꢀC
only starting material was recovered.
1
residual ECF to give a white solid (38 mg). H NMR
and mass spectroscopy indicated that the product was
a 1:1 mixture of the starting material 12 and the nitrile
10.
4.7. Crystal structure of oxathiazolone 8
4.6.3. Thermolysis of oxathiazolone 12 with dimethyl
acetylenedicarboxylate (DMAD). A solution of xylo-
pyranosyl-oxathiazolone 12 (100 mg, 0.28 mmol) and
DMAD (358 mg, 2.52 mmol) in m-xylene under nitro-
gen was heated at reflux for 48 h. The reaction mixture
was cooled, the solvent was removed in vacuo and the
resulting oil was co-evaporated with toluene to remove
the residual DMAD. The only identifiable product was
the nitrile 10.
Diffraction data were collected with graphite-monochro-
mated Mo-Ka radiation (k = 0.71073 A) on a Bruker
˚
SMART Apex diffractometer equipped with an Oxford
Cryosystems low-temperature device operating at
150 K. The structure was solved by direct methods
(Shelxs) and refined by full-matrix least-squares against
F2 (Shelxl).24 All non-H atoms were refined with aniso-
tropic displacement parameters; H-atoms were placed
in idealised positions. Crystal data: C15H17N1O11S,
M = 419.36, orthorhombic, a = 8.8149(7), b = 12.787(1),
˚
4.6.4. Thermolysis of oxathiazolone 8 with ethyl cyano-
formate (ECF). A solution of oxathiazolone 8 (500 mg,
1.2 mmol) and ECF (2.0 mL, 20.2 mmol) in mesitylene
(30 mL) was heated at reflux in a nitrogen atmosphere
for 24 h. Having confirmed by TLC and MS analysis
that no starting material remained, the reaction mixture
was concentrated in vacuo and azeotroped with toluene
to give a solid. Chromatography (silica; cyclohexane/
EtOAc, gradient elution) to afford a mixed fraction
(212 mg) containing nitrile 21 (44%) and ethyl 3-
(1,2,3,4-tetra-O-acetyl-a-D-xylopyranos-5S-C-yl)-1,2,4-
thiadiazole 22 (5%). Traces of thiadiazole 22 were
isolated by preparative TLC as a white solid (6 mg,
c = 16.4247(13) A, a = 90ꢀ, b = 90ꢀ, c = 90ꢀ, V =
3
˚
1851.4(3) A , space group P212121 (the compound was
known to be chiral); T = 150 K, Z = 4, Dc =
1.504 Mg mꢀ3, colourless block, 0.14 · 0.23 · 0.24 mm3.
The final conventional R-factor (based on F and 4200
data with F > 4r(F) was 4.88%; wR2 (based on F2 and
all 4542 data used in refinement) was 10.88. The final dif-
ference map extremes were 0.42 and ꢀ0.28 e Aꢀ3. The
˚
Flack parameter25 was ꢀ0.08(9)); this is sufficient to con-
firm the hand of the molecule as predicted from the
synthesis.
Crystallographic data (excluding structure factors) for
the structure reported in this paper have been deposited
at the Cambridge Crystallographic Data Centre as
20
1%); mp 193–194 ꢀC; ½aꢂD +103 (c 1, CHCl3); 1H

48
K. G. McMillan et al. / Carbohydrate Research 341 (2006) 41–48
11. Bak, B.; Nielsen, O.; Svanholt, H.; Almenningen, A.;
Bastiansen, O.; Braathen, G.; Fernholt, L.; Gundersen,
G.; Nielsen, C. J.; Cyvin, B. N.; Cyvin, S. J. Acta Chem.
Scand. A 1982, 36, 283–295.
12. Bridson, J. N.; Copp, S. B.; Schriver, M. J.; Zhu, S.;
Zaworotko, M. J. Can. J. Chem. 1994, 72, 1143–1153.
13. Schriver, M. J.; Zaworotko, M. J. J. Chem. Crystallogr.
1995, 25, 25–28.
14. Damas, A.M. PhD thesis, University of Edinburgh, 1982.
15. March, J. A. Advanced Organic Chemistry, 4th ed.; Wiley
and Sons: New York, 1992; Chapter 1, pp 19–21, and
references cited therein.
16. Paton, R. M.; Stobie, I.; Mortier, R. M. Phosphorus Sulfur
1983, 15, 137–142.
supplementary publication number CCDC 287132. Cop-
ies can be obtained free of charge on application to
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (fax:
+44 1223 336 033 or email: deposit@ccdc.cam.ac.uk).
Acknowledgement
We are grateful to the EPSRC for research and mainte-
nance (K.G.Mc.M.) grants.
17. For recent reviews of microwave-assisted organic reac-
tions see: (a) Kappe, C. O. Angew. Chem., Int. Ed. 2004,
43, 6250–6284; (b) Hayes, B. L. Aldrichim. Acta 2004, 37,
66–76.
18. See for example: (a) Azizian, J.; Soozangarzadeh, S.;
Jadidi, K. Synth. Commun. 2001, 31, 1069–1073; (b) Xia,
M. J. Chem. Res. (S) 2003, 418–419; (c) Delgado, J. L.; de
la Cruz, P.; Lopez-Arza, V.; Langa, F.; Kimball, D. B.;
Haley, M. M.; Araki, Y.; Ito, O. J. Org. Chem. 2004, 69,
2661–2668.
19. See for example: (a) Lu, T.-J.; Tzeng, G.-M. J. Chin.
Chem. Soc. (Taipei) 2000, 47, 189–196; (b) Micuch, P.;
Fisera, L.; Cyranski, M. K.; Krygowski, T. M.; Krajcik, J.
Tetrahedron 2000, 56, 5465–5472; (c) Giacomelli, G.; De
Luca, L.; Porcheddu, A. Tetrahedron 2003, 59, 5437–5440.
20. Baker, K. W. J.; March, A. R.; Parsons, S.; Paton, R. M.;
Stewart, G. W. Tetrahedron 2002, 58, 8505–8513.
21. Barton, D. H. R.; Gero, S. D.; Quiclet-Sire, B.; Samadi,
M. Tetrahedron: Asymmetry 1994, 5, 2123–2126.
22. Baddeley, T. C.; Davidson, I. G.; Skakle, J. M. S.;
Wardell, J. L. Acta Crystallogr. Sect. E 2002, 58, o447–
o449.
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