Synthesis of sugar-derived alkyl sulfones using a versatile transsulfonylation process

Article abstract of DOI:10.1055/s-1998-2173

A range of sugar-derived alkyl sulfones were obtained from heteroaryl sulfones using an ipso-substitution/alkylation sequence.

Full text of DOI:10.1055/s-1998-2173

SYNTHESIS
Papers
1506
Synthesis of Sugar-Derived Alkyl Sulfones Using a Versatile Transsulfonylation
Process
C. Lorin, P. Rollin*
Institut de Chimie Organique et Analytique, associé au CNRS, Université d'Orléans, BP6759, F-45067 Orléans Cedex 2, France
E-mail: patrick.rollin@univ-orleans.fr
Received 19 January 1998; revised 16 March 1998
Abstract: A range of sugar-derived alkyl sulfones were obtained
from heteroaryl sulfones using an ipso-substitution/alkylation
sequence.
we needed a convenient odorless process to prepare mis-
cellaneous sugar-derived sulfones.
Heteroaryl sulfones of type 2 can be readily prepared by
oxidation with mCPBA or MMPP of the corresponding
aza-heterocycle/thiosugar hybrids 1, which were shown in
our laboratory to be accessible by direct Mitsunobu thio-
substitution of protected sugars.11
Key words: heteroaryl sulfones, sugars, ipso substitution, ben-
zothiazol-2-yl group, alkyl sulfones
In spite of the increasing attention given to sulfones in or-
ganic synthesis, in sugar chemistry the almost exclusive
use of phenyl sulfones, in particular anomeric ones, has
been reported emphasizing new methodologies to attain
glycals,1 C-glycosides2, 3 and C-disaccharides.4
Table 1. Introduced Substituent R through Transsulfonylation
In other respects, non-anomeric sugar sulfones have been
sparingly described although diverse analytical,5
synthetic6–8 or technical9 applications have been outlined
for such a family of compounds. Most of the sugar-de-
rived sulfones described so far are arylsulfonyl deriva-
tives, usually obtained either through oxidation of sulfide
precursors1, 10 or by arenesulfinate nucleophilic displace-
ment of a halogenated sugar.5, 6
Compound
R
Compound
R
4aa
4ab
4ac
4ad
4ae
4af
Me
Pr
4ai
4aj
4b
4c
4d
4e
(CH2)3CH2Br
(CH2)5CH2Br
(CH2)7Me
(CH2)15Me
allyl
farnesyl
CH2Ph
CH2CO2Me
Me
Me
Me
Me
Me
4ag
4ah
4f
In the course of an ongoing program centered on novel
synthetic pathways to chiral oxa- and aza-heterocycles,7, 8

SYNTHESIS
October 1998
1507
Several aza-heterocyclic moieties can allow the above se- As expected, an increase in length of the alkyl halide re-
quence and the corresponding heteroaryl sulfones 2 are sulted in lower transsulfonylation yields. Attempts to
generally prone to nucleophilic ipso-substitutions,12 as build up bridged structures featuring two sugar sulfone
previously exemplified for simple13 or more complex units linked by a spacer chain (entries 4ai and 4aj using
benzothiazol-2-yl (Btz) sulfones such as the D-galacto de- 1,4-dibromobutane and 1,6-dibromohexane, respectively)
rivative 2a.14 Other aza-heterocyclic ligands such as 2-py- failed and only the corresponding bromoalkyl sulfones
rimidyl and 1-phenyltetrazol-5-yl were also tested, the were obtained.
transsulfonylation process (R = Me) being successful al-
In order to extend the scope of this method, the same
beit with inferior yields15 as compared to the efficient
transsulfonylation process was applied to different pyra-
transformation of 2a into the methyl sulfone 4aa. There-
no- and furano-sugar templates 2b–2f (Tables 3 and 4) us-
fore only benzothiazol-2-yl sulfones were used through-
ing iodomethane as standard electrophilic reagent in the
out the entire study.
quenching step. The corresponding sugar methyl sulfones
Base-catalyzed reaction of methanol with protected het- 4b–4f were obtained in moderate to good yields (Table 2).
eroarylsulfonyl sugars 2a–f produced sugar sulfinates 3a–
Further investigations towards an extension of the syn-
f, which could be quenched with alkyl halides to yield
thetic potential of this transsulfonylation process to sec-
sugar alkyl sulfones of type 4a–f (Table 1).
ondary sites in sugars are in progress.
An initial series of reactions was performed using solely
the protected D-galactopyrano template 2a bearing a 6-
All common reagents and solvents were used as obtained from com-
mercial suppliers without further purification, except Et2O which was
distilled over Na/benzophenone and mCPBA was dried over P2O5;
petroleum ether = PE. Products were purified by flash chromatogra-
(benzothiazol-2-yl)sulfonyl moiety14 and varying the
electrophilic partner RX, either iodo reagents for 4aa–ad
or bromo reagents for 4ae–ah (Tables 2 and 3).
Table 2. 6-Alkylsulfonyl Derivatives 4a
Entry
Starting
Material
Product
Molecular
Formula
MS (70 eV)
(m/z)
Yield (%)
[α]D
mp (°C)
(Solvent)
(c, g/100 mL)b
1
2
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2c
2d
2e
2f
4aa
4ab
4ac
4ad
4ae
4af
4ag
4ah
4ai
4aj
4b
C13H22O7S
(322.37)
323
351
421
533
349
513
398
381
443
471
544
297
314
256
256
88
–53 (0.9)
–47 (0.7)
–48 (1.2)
–37 (1.0)
–40 (1.0)
–50 (1.0)
–76 (1.0)
–82 (0.9)
–48 (0.6)
–46 (0.8)
+47 (1.0)
+153 (1.0)
–15 (0.8)
–193 (1.0)
+67 (1.0)
140 (Et2O)
98 (Et2O)
88 (Et2O)
87 (PE/EtOAc)
88 (Et2O)
oil
C15H26O7S
(350.43)
80
3
C20H36O7S
(420.56)
72
4
C28H52O7S
(532.78)
37
5
C15H24O7S
(348.41)
81
6
C27H44O7S
(512.70)
27
7
C19H26O7S
(398.47)
73
111 (Et2O)
oil
8
C15H24O9S
(380.41)
67
9
C16H27BrO7S
(443.35)
49
155 (PE/EtOAc)
75 (Et2O)
83 (PE/EtOAc)
142 (Et2O)
oil
10
11
12
13
14
15
C18H31BrO7S
(471.40)
47
C29H34O7S
(526.65)
87
4c
C11H20O7S
(296.33)
67
4d
C11H20O7S
(296.33)
63
4e
C8H14O6S
(238.25)
77
88 (Et2O)
oil
4f
C8H14O6S
(238.25)
65 (2 steps)
a Satisfactory microanalyses obtained.
b Solvent CHCl3.

SYNTHESIS
Papers
Table 3. 1H NMR Data for Sulfides, Sulfones and Alkylsulfones (CDCl3/TMS), δ, J (Hz)
1508
H-1
H-2
H-3
H-4
H-5
H-6a
H-6b
Miscellaneous
4aa
4ab
4ac
4ad
4ae
4af
4ag
4ah
4ai
d, 5.50
5.2
dd, 4.34
2.5
dd, 4.65 dd, 4.18
8.0 1.9
bd, 4.42
9.2
dd, 3.39
15.0
bd, 3.02
CH3; 1.34 (2), 1.45 and 1.60, SO2CH3: s,
2.99
d, 5.48
4.9
dd, 4.33
2.6
dd, 4.65 dd, 4.17
7.8 1.2
bd, 4.40
9.4
dd, 3.38
15.5
bd, 2.97
bd, 2.96
bd, 2.97
CH3: 1.36 (2), 1.45 and 1.59, propyl: 1.07, t,
CH3, 1.87, 3.05, 3.14, m, CH2
d, 5.47
5.0
dd, 4.32
2.6
dd, 4.64 dd, 4.17
7.7 1.9
dt, 4.39
9.4
dd, 3.37
15.5
CH3: 1.33 (2), 1.44 and 1.58, octyl: 0.87, t,
CH3, 1.27, 1.42, 1.81, 3.05, 3.14, m, CH2
d, 5.48
5.0
dd, 4.34
2.6
dd, 4.65 dd, 4.19
7.8 1.9
dt, 4.40
9.5
dd, 3.39
15.4
CH3: 1.35 (2), 1.45 and 1.60, hexadecyl: 0.89,
t, CH3, 1.26, 1.42, 1.83, 3.05, 3.16, m, CH2
d, 5.51
5.0
dd, 4.34
2.6
dd, 4.65 dd, 4.18
7.7 2.0
dt, 4.43
9.5
dd, 3.49
15.5
dt, 2.89
1.9
CH3: 1.34, 1.35, 1.44 and 1.61, allyl: 3.74,
bdd, J = 18.8, 3.98, dd, J = 8.3, 5.92, m
d, 5.60
4.9
dd, 4.38
2.7
dd, 4.67 dd, 4.17
7.7 1.8
m, 4.50
10.0
dd, 3.49
15.5
bd, 2.82
bd, 3.04
bd, 2.97
bd, 2.96
bd, 2.87
CH3: 1.32, 1.37, 1.44 and 1.66, benzyl: 4.29,
bd, 7.26, m, 7.46, m
d, 5.49
5.1
dd, 4.35
2.8
dd, 4.66 dd, 4.18
7.8 1.9
bd, 4.42
10.0
dd, 3.94
15.2
CH3: 1.34 (2), 1.46 and 1.59, CO2Me: 3.80,
s, 3.97, d, 4.39, d, J = 15.6
d, 5.48
5.0
dd, 4.33
2.6
dd, 4.64 dd, 4.17
7.8 1.7
bd, 4.39
9.7
dd, 3.40
15.6
CH3: 1.33 (2), 1.44 and 1.58, (CH2)3CH2Br:
2.01, 3.14, m, CH2
d, 5.47
4.8
dd, 4.32
2.6
dd, 4.63 dd, 4.17
7.8 1.9
bd, 4.39
9.5
dd, 3.42
15.5
CH3: 1.33 (2), 1.44 and 1.58, (CH2)3CH2Br:
1.48, 1.86, 3.10, m, CH2
4aj
d, 5.50
5.0
dd, 4.34
2.6
dd, 4.65 dd, 4.18
bd, 4.44
9.5
dd, 3.43
15.5
CH3: 1.34 (2), 1.44 and 1.61 farnesyl: 1.62, s,
Me(13) and (17E); 1.68, s, Me(17Z); 1.76, s,
9Me; 1.94–2.16, m, 4CH2; 3.77, bdd, J =
14.2; 3.92, dd, J = 8.5 and 7.3; 5.06–5.14, m,
H-12 and H-16; 5.32, bt
7.8
1.6
1b
1c
1d
1e
1f
d, 4.61
3.7
dd, 3.58
–
m, 4.05
9.5
dd, 3.46
–
m, 4.05
3.0
AB, 3.94
7.7
AB, 3.52
13.0
OCH3: s, 3.40, OBn: 3 dd, 4.68; 4.81; 4.98,
m, 7.23–7.48, Btz: H-4: d, 7.83, H-7: d, 7.75,
H-5 and H-6: m, 7.23–7.48
d, 4.79
4.1
m, 3.87
6.7
t, 4.29
6.2
m, 4.37
2.4
m, 4.37
5.5
AB, 3.74
6.8
AB, 3.62
13.9
CH3: 2s, 1.39 and 1.54, OH: d, 2.32, JOH =
6.2, OCH3: s, 3.48, Btz: H-4: d, 7.96, H-7: d,
7.86, H-5 and H-6: bt, 7.78
d, 5.95
3.7
d, 4.65
–
d, 4.23
3.1
dd, 4.75
6.3
7.7
AB, 3.77
and 3.59
13.4
CH3: 2s, 1.32 and 1.46, OMOM: s, 3.45, Btz:
H-4: d, 7.87, H-7: d, 7.76, H-5: t, 7.42, H-6:
t, 7.30
s 5.06
–
d, 4.61
6.0
d, 4.78
–
t, 4.60
7.9
7.9
AB, 3.64
and 3.56
14.0
2s, 4.96 and 4.99
2s, 3.71 and 3.69
OCH3: s, 3.43, Btz: H-4: d, 7.89, H-7: d,
7.76, H-5: t, 7.43, H-6: t, 7.31
s, 5.00
d, 4.52
5.1
dd, 4.72 m, 4.39
3.7
t, 4.07
dd, 4.23
11,1
OCH3: s, 3.34, Btz: H-4: d, 7.87, H-7: d,
7.75, H-5: t, 7.42, H-6: t, 7.30
–
2b
2c
2d
d, 4.45
3.7
dd, 3.46
–
ft, 4.02
9.5
ft, 3.28
ft, 4.35
dd, 3.82
dd, 3.54
OCH3: s, 3.52, OBn: 4.60, 4.77, and 4.95,
3dd, 6H, 7.20–7.37, m, 15H, Btz: H-4: d,
8.21, H-7: d, 8.01, H-5 and H-6: m, 7.63
J
5,6b = 10.4 14.8
d, 4.64
4.1
m, 3.79
6.6
t, 4.29
6.4
dd, 4.19
2.8
ddd, 4.76
dd, 403
15.2
dd, 3.84
–
OCH3: s, 3.49, OH: d, 2.40, J = 4.1, CH3: 2s,
6H, 1.30 and 1.46, Btz: H-4: d, 8.22, H-7: d,
8.02, H-5 and H-6: m, 7.64
J
J
5,6a = 9.1
5,6b = 3.3
d, 5.78
3.7
d, 4.62
–
d, 4.25
3.3
m, 4.83
dd, 3.96
–
CH3: 2s, 6H, 1.29 and 1.46, MOM: 3.41, s,
3H, CH3, 4.72, AB, 2H, CH2, JAB = 6.8, Btz:
H- 4: d, 8.22, H-7: d, 8.02, H-5 and H-6: m,
7.64
J
J
4,5a = 8.0 14.7
4,5b = 8.5 dd, 3.91

SYNTHESIS
October 1998
1509
Table 3. (continued)
H-1
H-2
H-3
H-4
H-5
H-6a
H-6b
Miscellaneous
2e
2f
s, 4.98
d, 4.55
5.7
d, 4.82
–
ft, 4.82
dd, 3.91
s, 4.97
s, 4.94
OCH3: s, 3.31, Btz: H-4: d, 8.23, H-7: d,
8.03, H-5 and H-6: m, 7.63
J
J
4,5a = 6.7 14.7
4,5b = 7.0 dd, 3.80
s, 4.95
–
d, 4.50
5.7
dd, 4.68 m, 4.61
3.7
dd, 3.98
s, 4.90
s, 4.83
OCH3: s, 3.25, Btz: H-4: d, 8.23, H-7: d,
8.02, H-5 and H-6: m, 7.62
J
4,5a = 9.1 15.2
dd, 3.96
4b
dd, 3.50
–
ft, 4.04
–
m, 3.25
–
ddd, 4.20
dd, 3.25
14.7
dd, 2.93
OCH3: s, 3.46, OBn: 4.62, 4.82 and 4.97,
3dd, 6H, 7.24–7.40, m, 15H, SO2CH3: s, 2.92
–
J
J
5,6a = 2.2
5,6b = 9.6
4c
d, 4.76
3.0
s, 3.82
–
ft, 4.28
6.2
dd, 4.14
2.3
ddd, 4.61
dd, 3.56
dd, 3.14
–
OCH3: s, 3.51, OH: s, 2.38, CH3: 2s, 6H, 1.35
and 1.51, SO2CH3: s, 3.05
J
5,6a = 10.2 15.2
4d
d, 5.92
3.7
d, 4.61
–
d, 4.15
3.3
m, 4.72
dd, 3.45
15.0
–
CH3: 2s, 6H, 1.33 and 1.51, MOM: 3.39, s,
3H, CH3, 4.65 and 4.74, AB, 2H, CH2, JAB =
J
4,5a 9.5
dd, 3.14
6.9, SO2CH3: s, 3.03
4e
4f
s, 5.05
–
d, 4.56
5.7
d, 4.76
–
ft, 4.74
dd, 3.44
s, 5.02
s, 4.99
s, 4.99
s, 4.92
OCH3: s, 3.42, SO2CH3: s, 3.02
OCH3: s, 3.35, SO2CH3: s, 3.04
J
J
4,5a = 8.5 14.5
4,5b = 5.0 dd, 3.21
s, 4.99
–
d, 4.55
5.7
dd, 4.66 m, 4.50
3.7 4,5a = 9.1 15.2
dd, 3.34
dd, 3.45
J
Table 4. Benzothiazol-2-yl Sulfides and Sulfonesa
Entry
Starting
Material
Product
Molecular
Formula
MS (70 eV)
(m/z)
Yield (%)
[α]D
mp (°C)
(Solvent)
(c, g/100 mL)b
1
2
3
4
5
6
7
8
9
10
1b
1c
1d
1e
1f
C35H35NO5S2
(613.78)
614
614
383
325
325
647
416
416
358
358
88
+ 8 (0.9)
±78 (1.2)
–58 (1.0)
+1 (1.0)
78 (PE/EtOAc)
C17H21NO5S2
(383.48)
65
oil
C17H21NO5S2
(383.48)
29 (2 steps)
oil
C14H15NO4S2
(325.39)
67
72
70
54
45
55
61
83 (Et2O)
oil
C14H15NO4S2
(325.39)
+31 (1.0)
+37 (1.0)
+54 (1.0)
–31 (1.0)
–21 (1.0)
+45 (1.0)
1b
1c
1d
1e
1f
2b
2c
2d
2e
2f
C35H35NO7S2
(645.78)
101 (Et2O)
120 (Et2O)
oil
C17H21NO7S2
(415.48)
C17H21NO7S2
(415.48)
C14H15NO6S2
(357.39)
110 (E/EtOAc)
oil
C14H15NO6S2
(357.39)
a Satisfactory microanalyses obtained.
b Solvent CHCl3.
phy on silica gel (36–63 mesh). Mps were measured with a Kofler hot analysis: Centre National de la Recherche Scientifique, Service Cen-
stage apparatus and are uncorrected. Specific optical rotations were tral d’Analyse, Vernaison, France.
measured with a Perkin–Elmer (model 41) polarimeter in CHCl3 us-
ing a 1.00 dm cell. 1H NMR spectra were recorded on a Bruker AM Benzothiazol-2-yl Sulfides 1; General Procedure:
300 spectrometer in CDCl3 using TMS as internal standard. MS were To a solution of the protected sugar (11 mg, 0.25 mmol) in anhyd
recorded on a VG Analytical 70-VS mass spectrometer. Elemental toluene (5 mL) were added, under argon, 2-mercaptobenzothiazole

SYNTHESIS
Papers
1510
(84 mg, 0.50 mmol), Ph3P (131 mg, 0.50 mmol) and diisopropyl
azodicarboxylate (DIAD) (0.1 mL, 0.50 mmol). The mixture was
stirred and heated at 80 ˚C for 8 h. After concentration under reduced
pressure, the sulfide was purified by flash chromatography (petro-
leum ether/EtOAc 8:2 for 1b, 1e, and 1f; petroleum ether/EtOAc 7:3
for 1c and 1d).
column, petroleum ether/EtOAc). Eluents used for chromatography:
4ab, 4ad, 4aj: petroleum ether/EtOAc 9:1 then 8:2; 4ac, 4ah, and 4ai:
petroleum ether/EtOAc 8:2; 4aa and 4b: petroleum ether/EtOAc 8:2
then 7:3; 4ae, 4af, and 4ag: petroleum ether/EtOAc 7:3; 4d, 4e, and
4f: petroleum ether/EtOAc 7:3 then 6:4; 4c: petroleum ether/EtOAc
3:7.
Benzothiazol-2-yl Sugar Sulfones 2; General Procedure:
Oxidation with mCPBA:
We thank Dr J. L. Gras (CNRS Marseille), Dr C. Marot (ICOA
Orléans) and V. Gardon (Albemarle PPC, Thann) for helpful discus-
sions.
Dried commercial mCPBA (70% estimated peracid content, 154 mg,
ca. 0.62 mmol) was added to the sulfide (0.26 mmol) in CH2Cl2
(5 mL). The mixture was stirred for 3 h at r.t. (monitored by TLC),
then extracted with aq NaHCO3 (3 × 5 mL); the organic layer was
dried (MgSO4) and evaporated under reduced pressure. The residue
was chromatographed (flash silica gel column, petroleum ether/
EtOAc).
(1) Fernandez-Mayoralas, A.; Marra, A.; Trumtel, M.; Veyrières,
A.; Sinaÿ, P. Carbohydr. Res. 1989, 188, 81.
(2) dePouilly, P.; Chénedé, A.; Mallet, J. M.; Sinaÿ, P. Bull. Soc.
Chim. Fr. 1993, 130, 256.
Oxidation with MMPP:
(3) Mazéas, D.; Skrydstrup, T.; Doumeix, O.; Beau, J. M. Angew.
Chem., Int. Ed. Engl. 1994, 33, 1383.
(4) Chénedé, A.; Perrin, E.; Rekaï, E. D.; Sinaÿ, P. Synlett 1994,
420.
(5) Aspinall, G. O. Pure Appl. Chem. 1977, 49, 1105.
(6) Pontén, F.; Magnusson, G. Acta Chem. Scand. 1994, 48, 566.
(7) Marot, C.; Rollin, P. Tetrahedron Lett. 1994, 35, 8377.
(8) Lorin, C. Ph. D. Thesis, Orléans, 1997.
(9) Léon-Ruaud, P.; Plusquellec, D. Tetrahedron 1991, 47, 5185.
(10) Beau, J. M.; Sinaÿ, P; Tetrahedron Lett. 1985, 26, 6185.
(11) Besson, T.; Al Neirabeyeh, M.; Viaud, M. C.; Rollin, P. Synth.
Commun. 1990, 20, 1631.
(12) Oae, S.; Furukawa, N. Adv. Heterocycl. Chem. 1990, 48, 1.
(13) Baudin, J. B.; Hareau, G.; Julia, S. A.; Ruel, O. Tetrahedron
Lett. 1991, 32, 1175.
(14) Lorin, C.; Marot, C.; Gardon, V.; Rollin, P. Tetrahedron Lett.
1995, 36, 4437.
Technical magnesium monoperoxyphtalate hexahydrate (80% perac-
id content, 180 mg, 0.29 mmol) was added to the sulfide (0.26 mmol)
in CH2Cl2/EtOH (9:1) (5 mL). The mixture was refluxed with stirring
for 2 h (monitored by TLC); after cooling, the mixture was treated in
the way described above. Eluents used for chromatography: 2a: pe-
troleum ether/EtOAc 8:2; 2b: petroleum ether/EtOAc 8:2 then 7:3;
2e: petroleum ether/EtOAc 7:3; 2c, 2d, and 2f: petroleum ether/
EtOAc 7:3 then 6:4.
Alkyl Sugar Sulfones 4; General Procedure:
The heteroaryl sulfone (0.24 mmol) was dissolved in anhyd MeOH
(5 mL), 1 M NaOMe (1 mL) was added until the pH value reached 8–
9. The mixture was stirred at r.t. for 45 min., TLC showed the com-
plete formation of the sulfinate and 2-methoxybenzothiazole. The sul-
finate was then quenched by MeI (2 mL, 2.4 mmol) or another alky-
lating reagent (1.2 mmol) at r.t. overnight. After neutralization with
acid resin (Dowex 50, 120 mg), the solvent was removed under re-
duced pressure. The residue was chromatographed (flash silica gel
(15) Transsulfonylation yields for 2-pyrimidyl and 1-phenyltetrazol-
5-yl D-galacto derivatives: 54% and 68%, respectively.