Synthesis of imidazo[2,1-b]thiazoles linked to an unprotected carbohydrate moiety

Article abstract of DOI:10.1016/j.carres.2012.04.011

Two series of imidazo[2,1-b]thiazoles substituted on C-3 or C-5 with an unprotected carbohydrate moiety were synthesized. Different protective groups for position 3 of the carbohydrate moiety were tested (acetyl, tert-butyldimethylsilyl (TBDMS), and p-met

Full text of DOI:10.1016/j.carres.2012.04.011

Carbohydrate Research 355 (2012) 79–86
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Carbohydrate Research
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Note
Synthesis of imidazo[2,1-b]thiazoles linked to an unprotected
carbohydrate moiety
José Sebastián Barradas a, María Inés Errea b, Norma Beatriz D’Accorso a, ,
⇑
a CIHIDECAR-CONICET, Departamento de Química Orgánica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Pabellón 2, Ciudad Universitaria,
1428 Buenos Aires, Argentina
b Departamento de Ingeniería Química, Instituto Tecnológico de Buenos Aires, Av. Eduardo Madero 399, 1106 Buenos Aires, Argentina
a r t i c l e i n f o
a b s t r a c t
Article history:
Two series of imidazo[2,1-b]thiazoles substituted on C-3 or C-5 with an unprotected carbohydrate moiety
were synthesized. Different protective groups for position 3 of the carbohydrate moiety were tested
(acetyl, tert-butyldimethylsilyl (TBDMS), and p-methoxybenzyl (PMB)) and the latter turn out to be the
best strategy to obtain the desired products. Full deprotection of the carbohydrate was performed suc-
cessfully in only one step.
Received 25 February 2012
Received in revised form 10 April 2012
Accepted 12 April 2012
Available online 21 April 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Heterocycles
Carbohydrates
Protective groups
Imidazo[2,1-b]thiazoles
Recently much interest has been focused on the chemistry and
the biological activity of imidazo[2,1-b]thiazoles and their deriva-
tives. Compounds containing this heterocycle in their structure have
been reported as antihelmintic,1 antiviral,2 anti-hypertensives,3
antiinflammatories,4,5 fungicides,6 herbicides,7 antitumor,8–13 and
cardiotonic agents.14 The broad spectrum of biological activities of
imidazo[2,1-b]thiazoles, turn this heterocyclic nuclei in an interest-
ing synthetic target for biological studies.15
(2 and 3), had an inhibitory activity against JUNV one order higher
than ribavirin, the reference substance for this study. These results
encourage us to extend the study of imidazo[2,1-b]thiazoles. Tak-
ing into account that the highest antiviral activity was detected
when the phenyl group was p-substituted with either bromine or
chloride,17 the synthetic targets of the present work were their
unprotected sugar analogous, for further analysis of the impact of
this structural change in their antiviral activity.
Moreover, the attraction of including asymmetric centers in
compounds when their biological activity is a focus of interest is
also known. In that context, carbohydrates are especially attrac-
tive. They have many asymmetric carbons and depending on their
protective group the hydrophilicity or lipophilicity of the final
compounds can be easily controlled.
Taking into account the above discussion, in previous works we
reported the synthesis and antiviral evaluation against the etiolog-
ical agent of Argentine hemorrhagic fever (Junin virus (JUNV)), of
two series of imidazo[2,1-b]thiazoles,16,17 linked to a sugar residue.
Both series differed in the position of the heterocyclic ring sub-
stituent. Series 1 had the carbohydrate residue bonded to C-5 while
in the series 2 the sugar was bonded to C-3 of the heterocyclic moi-
ety (Fig. 1).
The main challenge of this work was to find a suitable protec-
tive group for position 3 of the carbohydrate. Therefore, different
protected groups were evaluated to achieve that goal.
Our selected approach to obtain the target compounds was
based on the synthesis of a suitable 6-bromo-6-deoxy-1,2-O-iso-
propylidene-3-O-protected-
as the precursor 1,2:5,6-di-O-isopropylidene-a-D
a
-
D
-xylo-hexofuranos-5-ulose using
-glucofuranose
(Scheme 1).19–25 After testing different protective groups, the acetyl,
the tert-butyldimethylsilyl (TBDMS), and the p-methoxybenzyl
(PMB) group were selected for further transformation. Derivates
20, 21, 23 and 24, are described here for the first time and were fully
characterized by physical and spectroscopic techniques. Besides,
since bibliographic data of the isopropylidene derivates 14 and 17
were incomplete, their spectroscopic characterization was also
included in this paper (see Section 1).
Argentine hemorrhagic fever is an important disease recognized
as a major public health problem in the richest agriculture zones of
our country.18 We found that two of the investigated compounds
Substituted imidazo[2,1-b]thiazoles were obtained by conver-
gent synthetic pathways (Schemes 2 and 3).26 Heterocycles 25–28
(series 1), were achieved by coupling one of the 6-bromo-6-deoxy-
1,2-O-isopropylidene-3-O-protected-a-D-xylo-hexofuranos-5-ulose
⇑
Corresponding author. Tel./fax: +54 11 45763346.
E-mail address: norma@qo.fcen.uba.ar (N.B. D’Accorso).
Research member of the National Research Council of Argentina (CONICET).
(22–24) with N0-(5-arylthiazol-2-yl)-N,N-dimethylimidoforma-
mide (Scheme 2).17,27 Reactions were not complete and starting
0008-6215/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.carres.2012.04.011

80
J. S. Barradas et al. / Carbohydrate Research 355 (2012) 79–86
Although the methodology to synthesize the thiazolylimidofor-
O
mamides 29–31 was previously reported,17 particularly these der-
ivates had not been published before and they were fully
characterized here (see Section 1).
S
N
N
O
N
S
OMe
OR1
Even the synthetic strategy employed in this work allow us to
obtain all the protected heterocyclic compounds belonging to ser-
ies 1, in the case of series 2, the 3-O-acetylated sugar derivates
could not be obtained (Scheme 3). During the coupling step of
the thiazolylimidoformamides 29 with the corresponding p-halo-
benzoyl group, an elimination reaction occurred and, instead of
the desired product, the dehydrated derivates 36 and 37 were ob-
tained (Scheme 4).
On the other hand, although the heterocycles belonging to both
series could be obtained from the TBDMS or PMB derivates, in the
case of TBDMS derivates, deprotection strategies failed, since many
secondary products were obtained becoming the purification of the
unprotected sugar derivate very difficult.
R2
N
O
O
O
O
O
O
O
O
Me Me
Me Me
Series 1
R
Series 2
1. R1= CH3; R2= H
2. R1= CH3; R2= Br
3. R1= CH3; R2= Cl
4. R1= CH3; R2= F
9. R= H
10. R= Br
11. R= Cl
12. R= F
5. R1= COCH3; R2= H
6. R1= COCH3; R2= Br
7. R1= COCH3; R2= Cl
8. R1= COCH3; R2= F
Deprotection of the PMB derivates was achieved by treatment
with trifluoracetic acid (TFA) in dichloromethane (CH2Cl2) over-
night (Scheme 5). In these conditions the isopropylidene group
was also removed28,29 affording compounds 38–41 as a mixture
Figure 1. Substituted imidazo[2,1-b]thiazoles.
a
and b anomers (50:50), as it was determined by 1H NMR
materials were detected in all of the cases. Higher yields of the PMB
with respect to the TBDMS derivates could be attributed to the
higher steric hindrance of the latter protective group.
Complete mechanism of the transformation was described by
Landreau et al.,27 but in our case the N-alkylation step was assisted
by microwave radiation.
Imidazo[2,1-b]thiazoles belonging to series 2 were synthesized
by coupling the thiazolylimidoformamides 29–31 with the
commercially available 2-bromo-1-(4-chlorophenyl)ethanone or
2-bromo-1-(4-bromophenyl)ethanone (Scheme 3).
of the
(see Section 1).
The one-pot deprotection reaction described here, allowed us to
obtain the final product with moderate yield.
The new compounds were completely characterized by physical
and spectroscopic methods as shown in Section 1.
In summary, in this work the synthesis and characterization
of 21 new compounds is reported and the goal of obtaining
imidazo[2,1-b]thiazoles linked to an unprotected carbohydrate
residue was achieved.
Me
Me
O
O
HO
HO
Br
HO
Br
O
OR1
OR1
OR1
OR1
O
O
O
c)
O
a)
b)
O
O
O
O
O
O
O
O
Me Me
Me Me
Me Me
Me Me
13 16
16 16
19.16 R1= Ac
22.16 R1= Ac
23. R1= TBDMS, 99.3%
24
.
R1= Ac
.
R1= Ac
14
20
21
. R1= TBDMS, 91%
15. R1= PMB, 95%
17. R1= TBDMS, 21.2%
18. R1= PMB, 95%
. R1= TBDMS, 55.4%
. R1= PMB, 87.4%
. R1= PMB, 82.5%
Scheme 1. Reagents and conditions: (a) 14–17: FeCl3 supported on Silicagel/CHCl3 48 h, 15–18: H2SO4 (0.8%)/MeOH (1:1), 24 h; (b) (i) NBS, PPh3, DMF, 8 h, (ii) MeOH 14 h; (c)
IBX, CH3CN reflux.
O
S
N
O
S
N
N
Br
O
OR1
OR1
N
R2
O
N
O
O
R2
O
O
O
O
Me Me
Me Me
22
6 16
.
. R1= Ac
R1= Ac; R2= Cl
7.16 R1= Ac; R2= Br
23. R1= TBDMS
24. R1= PMB
25. R1= TBDMS; R2= Cl, 25.4%
26. R1= TBDMS; R2= Br, 16.4%
27
28
. R1= PMB; R2= Cl, 47.7%
. R1= PMB; R2= Br, 43.1%
Scheme 2. Reagents and conditions: (a) (i) THF (anhyd), MW (300 W, 105 °C, 150 min), (ii) Et3N, rt, 16 h.

J. S. Barradas et al. / Carbohydrate Research 355 (2012) 79–86
81
N
O
Br
O
S
S
OR1
OR1
N
O
a)
N
O
N
N
N
N
+
O
O
O
O
Me Me
Me Me
22
. R1= Ac
29. R1= Ac, 85.2%
23. R1= TBDMS
24. R1= PMB
30
. R1= TBDMS, 95.4%
31. R1= PMB, 87.2%
b)
O
Br
R2
O
N
S
OR1
N
O
O
O
O
Me Me
R2
32
. R1= TBDMS; R2= Cl, 54.2%
33. R1= TBDMS; R2= Br, 76.9%
34
. R1= PMB; R2= Cl, 84.1%
35. R1= PMB; R2= Br, 86.9%
Scheme 3. Reagents and conditions: (a) (i) CH2Cl2 reflux, 3 h; (ii) Et3N (1.5 equiv) rt, 12 h; (b) (i) THF (anhyd), MW (300 W, 100 °C, 90 min); (ii) Et3N (1.5 equiv) rt, 16 h.
O
N
S
O
H
N
S
O
Br
OAc
N
N
N
O
O
R
O
O
O
O
a)
O
Me Me
Me Me
R
36
. R= Cl, 23.4%
37. R= Br, 32.3%
Scheme 4. Reagents and conditions: (a) (i) THF (anhyd), MW (300 W, 100 °C, 90 min); (ii) Et3N (1.5 equiv) rt, 16 h.
Moreover, the deprotection of both a PMB and an isopropyli-
dene group belonging to a sugar residue in a one-pot reaction
was reported .
We are working now to extend the methodology described here
to the synthesis of pirrolo[2,1-b]thiazoles in order to evaluate the
impact of this change in the antiviral activity.
on a Perkin Elmer 343 polarimeter, and melting points were uncor-
rected. NMR spectra were recorded on either a Bruker AC-200 or a
Bruker AMX-500 spectrometer. Assignments of the 1H and 13C
NMR spectra were confirmed with the aid of two dimensional
techniques (COSY, HSQC-DEPT, HMBC). Chemical shifts (d) are re-
ported in parts per million downfield from tetramethyl silane or
solvent residual peak as internal standard. High-resolution mass
spectra (HRMS) were obtained on a Bruker micrOTOF-Q II spec-
trometer using Electrospray Ionization (ESI) and a Q-TOF analyzer.
Compounds 6, 7, 13, 16, 19, and 22 were synthesized as we previ-
ously described,16 meanwhile 15 and 18 were synthesized and
spectroscopical characterized (1H and 13C NMR spectra) as de-
scribed in literature.17
1. Experimental
1.1. General remarks
Syntheses were carried out using reagents as purchased, with-
out further purification. Solvents were reagent grade and, in most
cases, dried and distillated before use according to standard proce-
dures. Analytical TLC was conducted on Silica Gel 60G (Merck) on
precoated plates and visualization was made by UV light and eth-
anol/sulfuric acid (10:1) or cerium molybdate followed by heating.
Column-chromatographic separations were performed on Silica
Gel (240–400 mesh, Merck). Microwave reactions were carried
out using an Anton-Paar Monowave 300 microwave reactor.
Elemental analysis was performed on an Exeter Analytical CE-
440 elemental analyzer. Optical rotations were recorded at 20 °C
1.2. 3-O-(tert-Buthyldimethylsilyl)-1,2:5,6-di-O-isopropylidene-
a-D-glucofuranose (14)
1,2:5,6-Di-O-isopropylidene-
a-D-glucofuranose was obtained
as described by Schmidt and col.19 Silylation was carried out from
1,2:5,6-di-O-isopropylidene-a-D-glucofuranose (758 mg, 2.99 mmol)
using the procedure described by Corey and col.20 affording com-
pound 14 as colorless syrup (986 mg, 2.63 mmol, 91% yield). 1H
NMR (200 MHz, CDCl3) d: 5.87 (d, 1H, J1,2 3.6 Hz, H-1), 4.35 (br d,

82
J. S. Barradas et al. / Carbohydrate Research 355 (2012) 79–86
O
O
S
S
N
N
N
N
OPMB
O
OH
R
R
OH
O
O
a)
O
O
O
OH
Me Me
38. R= Cl, 28%
27. R= Cl
28. R= Br
39. R= Br, 35.2%
O
O
N
S
N
S
OPMB
OH
O
N
N
O
a)
OH
O
O
O
O
Me Me
OH
R
R
34. R= Cl
35. R= Br
40. R= Cl, 36.5%
41. R= Br, 44%
Scheme 5. Reagents and conditions: (a) TFA 60% in CH2Cl2 (anhyd) rt 24 h.
1H, J2,1 3.6 Hz, H-2), 4.24 (d, 1H, J3,4 2.8 Hz, H-3), 4.22 (dt, 1H, J5,4
7.9 Hz, J5,6a 5.9 Hz, J5,6b 5.6 Hz, H-5), 4.11 (dd, 1H, J6a,5 6.0 Hz,
J6a,6b 8.3 Hz, H-6a), 4.02 (dd, 1H, J4,3 2.7 Hz, J4,5 8.1 Hz, H-4), 3.95
(dd, 1H, J6b,5 5.9 Hz, J6b,6a 8.3 Hz, H-6b), 1.49 (s, 3H, CMe2), 1.40
(s, 3H, CMe2), 1.32 (s, 3H, CMe2), 1.31 (s, 3H, CMe2), 0.90 (s, 9H,
CMe3Si), 0.13 (s, 3H, MeSi), 0.12 (s, 3H, MeSi). 13C NMR (50 MHz,
CDCl3) d: 111.8 (C Me2), 108.9 (C Me2), 105.3 (C-1), 85.6 (C-2),
82.3 (C-4), 75.5 (C-3), 72.2 (C-5), 67.7 (C-6), 27.0 (CMe2), 26.8
(CMe2), 26.4 (CMe3Si), 25.7 (CMe2), 25.3 (CMe2), 18.1 (CMe3Si),
ꢀ5.0 (MeSi), ꢀ5.2 (MeSi).
CH2Cl2 and dried (Na2SO4). The crude product was purified by col-
umn chromatography on silica gel using mixtures of cyclohexane/
acetone (90:10–75:25) as eluents. The 6-bromo derivative (20) was
afforded as pallid yellow oil (124 mg, 0.312 mmol, 55.4% yield);
½
a 2D5
ꢁ
ꢀ19.5 (c 2.8, chloroform). 1H NMR (200 MHz, CDCl3) d: 5.87
(d, 1H, J1,2 3.5 Hz, H-1), 4.36 (dd, 1H, J2,1 3.5 Hz, J2,3 0.5 Hz, H-2),
4.33 (dd, 1H, J3,2 0.5 Hz, J3,4 2.5 Hz, H-3), 4.07 (dd, 1H, J4,3 2.5 Hz,
J4,5 8.4 Hz, H-4), 3.92–4.09 (ddd, 1H, J5,4 8.6 Hz, J5,6a 5.9 Hz; J5,6b
2.7 Hz, H-5), 3.78 (dd, 1H, J6a,5 2.7 Hz, J6a,6b 10.5 Hz, H-6a), 3.65
(dd, 1H, J6b,5 6.0 Hz, J6b,6a 10.5 Hz, H-6b), 2.20 (broad signal, HO),
1.49 (s, 3H, CMe2), 1.33 (s, 3H, CMe2), 0.91 (s, 9H, CMe3Si), 0.16
(s, 3H, MeSi); 0.14 (s, 3H, MeSi). 13C NMR (50 MHz, CDCl3) d:
112.1 (C Me2), 105.1 (C-1), 85.4 (C-2), 81.5 (C-4), 75.4 (C-3), 67.8
(C-5), 39.5 (C-6), 27.0 (CMe2), 26.5 (CMe2), 25.0 (CMe3Si), 18.1
(CMe3Si), ꢀ4.8 (MeSi), ꢀ5.1 (MeSi). Anal. Calcd for C15H29BrO5Si:
C, 45.34; H, 7.36. Found: C, 45.35; H, 7.75.
1.3. 3-O-(tert-Buthyldimethylsilyl)-1,2-O-isopropylidene-a-D-
glucofuranose (17)
Deprotection of 3-O-(tert-buthyldimethylsilyl)-1,2:5,6-di-O-
isopropylidene- -glucofuranose (850 mg, 2.27 mmol) was car-
a
-D
ried out following the procedure described by Kim and col.22 Com-
pound 17 was afforded as a white solid (313 mg, 0.93 mmol, after
two deprotection steps, 41.2% yield). 1H NMR (200 MHz, CDCl3) d:
5.89 (d, 1H, J1,2 3.7 Hz, H-1), 4.37 (d, 1H, J2,1 3.7 Hz, H-2), 4.32 (d,
1H, J3,4 2.6 Hz, H-3), 4.08 (dd, 1H, J4,3 2.7 Hz, J4,5 7.9 Hz, H-4),
3.93 (ddd, 1H, J5,4 8.1 Hz, J5,6a 5.1 Hz, J5,6b 3.3 Hz, H-5), 3.84 (dd,
1H, J6a,5 3.3 Hz, J6a,6b 11.4 Hz, H-6a), 3.76 (dd, 1H, J6b,5 5.1 Hz,
J6b,6a 11.4 Hz, H-6b), 1.49 (s, 3H, CMe2), 1.32 (s, 3H, CMe2), 0.91
(s, 9H, CMe3Si), 0.16 (s, 3H, MeSi); 0.14 (s, 3H, MeSi). 13C NMR
(50 MHz, CDCl3) d: 111.8 (C Me2), 105.0 (C-1), 85.3 (C-2), 80.9 (C-
4), 75.9 (C-3), 68.9 (C-5), 64.6 (C-6), 26.9 (CMe2), 26.3 (CMe2),
25.7 (CMe3Si), 18.0 (CMe3Si), ꢀ4.7 (CMeSi), ꢀ5.0 (CMeSi).
1.5. 6-Bromo-6-deoxy-1,2-O-isopropylidene-3-O-(p-
methoxybenzyl)-a-D-glucofuranose (21)
NBS (400.8 mg, 2.65 mmol) in DMF (5 mL) was added dropwise
to a stirred cooled (ice bath) solution of triphenylphosphine
(693.9 mg, 2.65 mmol) and compound 18 (455 mg, 1.32 mmol) in
dry DMF (15 mL) under argon atmosphere. Compound 21 was ob-
tained by the same procedure applied for compound 20, as color-
less oil (466.4 mg, 1.15 mmol, 87.4% yield); ½a D25
ꢀ39.6 (c 1.5,
ꢁ
chloroform). 1H NMR (200 MHz, CDCl3) d: 7.28 (d, 2H, J 8.8 Hz, aro-
matic protons), 6.90 (d, 2H, J 8.8 Hz, aromatic protons), 5.92 (d, 1H,
J1,2 3.7 Hz, H-1), 4.67 (d, 1H, J 14.4 Hz, methylene proton), 4.61 (d,
1H, J2,1 3.8 Hz, H-2), 4.49 (d, 1H, J 14.4 Hz, methylene proton),
4.04–4.17 (m, 3H, H-3, H-4, H-5), 3.81 (s, 3H, OMe), 3.71 (dd, 1H,
J6a,5 2.7 Hz, J6a,6b 10.7 Hz, H-6a), 3.57 (dd, 1H, J6b,5 5.4 Hz, J6b,6a
10.4 Hz, H-6b), 2.20 (broad signal, HO), 1.49 (s, 3H, CMe2), 1.32
(s, 3H, CMe2). 13C NMR (50 MHz, CDCl3) d: 159.6, 129.6, 129.1,
114.1 (aromatic carbons), 112.1 (C Me2), 105.2 (C-1), 82.3 (C-4),
81.0 (C-2), 80.7 (C-3), 72.0 (methylene carbon), 67.2 (C-5), 55.3
(CH3O), 38.0 (C-6), 26.9 (CMe2), 26.4 (CMe2). Anal. Calcd for
1.4. 6-Bromo-6-deoxy-1,2-O-isopropylidene-3-O-(tert-
buthyldimethylsilyl)-a-D-glucofuranose (20)
NBS (208 mg, 1.17 mmol) in dry DMF (5 mL) was added drop-
wise to a cooled (ice bath) solution of compound 17 (196 mg,
0.59 mmol) and triphenylphosphine (306 mg, 1.17 mmol) in dry
DMF (15 mL) under argon atmosphere.16,23 The mixture was stir-
red for 3.5 h at room temperature and quenched by addition of
MeOH. The solvent was evaporated and the residue extracted with
C17H23BrO6: C, 50.63; H, 5.75. Found: C, 50.55; H, 5.71.

J. S. Barradas et al. / Carbohydrate Research 355 (2012) 79–86
83
1.6. 6-Bromo-6-deoxy-1,2-O-isopropylidene-3-O-(tert-
buthyldimethylsilyl)- -xylo-hexofuranos-5-ulose (23)
H-3), 4.42 (d, 1H, J2,1 3.5 Hz, H-2), 1.53 (s, 3H, CMe2), 1.37 (s, 3H,
CMe2), 0.59 (s, 9H, CMe3Si), 0.04 (s, 3H, MeSi); ꢀ0.19 (s, 3H, MeSi).
13C NMR (50 MHz, CDCl3) d: 186.0 (C@O), 185.9 (C@O); 155.9,
147.1, 140.0, 127.8, 127.4 (imidazo[2,1-b]thiazole carbons), 140.0,
134.7, 130.3, 127.4 (aromatic carbons), 112.8 (CMe2), 106.0 (C-1),
86.3 (C-4), 84.6 (C-2), 78.1 (C-3), 26.9 (CMe2), 26.5 (CMe2), 25.2
(CMe3Si), 17.7 (CMe3Si), ꢀ4.8 (CMeSi), ꢀ5.5 (CMeSi). Anal. Calcd
for C26H31ClN2O6SSi: C, 55.45; H, 5.55; N, 4.97. Found: C, 55.72;
H, 5.29; N, 4.83.
a-D
1-Hydroxy-1,2-benziodoxol-3(1H)-one 1-oxide (IBX) (370,8
mg, 1.32 mmol) was added to a solution of 20 (105.2 mg, 0.26
mmol) in acetonitrile (15 mL) and the mixture was refluxed for
2.5 h. The reaction mixture was filtered to remove the excess of
IBX and the solution evaporated. The residue was purified by col-
umn chromatography on silica gel using mixtures of cyclohex-
ane/acetone (95:5–80:20) as eluents. Compound 23 was afforded
as a white solid (104 mg, 0.26 mmol, 99.3% yield): mp: 53–54 °C;
1.8.2. 3-(p-Bromobenzoyl)-5-(1,2-O-isopropylidene-3-O-tert-
buthyldimethylsilyl-a-D-xylofuranos-5-ulo-5-yl)imidazo[2,1-
b]thiazole (26)
½
a 2D5
ꢁ
ꢀ125.3 (c 1.1, chloroform). 1H NMR (200 MHz, CDCl3) d:
6.07 (d, 1H, J1,2 3.4 Hz, H-1), 4.76 (d, 1H, J2,1 3.2 Hz, H-2), 4.50 (d,
1H, J3,4 3.2 Hz, H-3), 4.44 (d, 1H, J6a,6b 16.4 Hz, H-6a), 4.38 (d, 1H,
J4,3 3.5 Hz, H-4), 4.26 (d, 1H, J6b,6a 16.4 Hz, H-6b), 1.47 (s, 3H,
CMe2), 1.33 (s, 3H, CMe2), 0.85 (s, 9H, CMe3Si), 0.10 (s, 3H, MeSi);
0.03 (s, 3H, MeSi). 13C NMR (50 MHz, CDCl3) d: 199.4 (C@O),
112.8 (CMe2), 106.1 (C-1), 86.0 (C-4), 84.7 (C-2), 78.0 (C-3), 36.9
(C-6), 27.1 (CMe2), 26.5 (CMe2), 25.6 (CMe3Si), 17.8 (CMe3Si), ꢀ5.1
(MeSi), ꢀ5.1 (MeSi). Anal. Calcd for C15H27BrO5Si: C, 45.57; H,
6.88. Found: C, 45.72; H, 6.99.
Compound 26 was obtained from 23 (215.3 mg, 0.54 mmol) and
p-bromobenzoyl-thiazolylimidoformamide (280.3 mg, 0.83 mmol)
as yellow amorphous solid (53.9 mg, 0.08 mmol, 16.4% yield): mp
72–75 °C; ½a 2D5
ꢁ
ꢀ119.0 (c 1.5, chloroform). 1H NMR (200 MHz,
CDCl3) d: 8.88 (s, 1H, imidazo[2,1-b]thiazole proton), 8.53 (s, 1H,
imidazo[2,1-b]thiazole proton), 7.71 (m, 4H, aromatic protons),
6.20 (d, 1H, J1,2 3.4 Hz, H-1), 5.01 (d, 1H, J4,3 3.1 Hz, H-4), 4.60 (d,
1H, J3,4 3.0 Hz, H-3), 4.42 (d, 1H, J2,1 3.3 Hz, H-2), 1.53 (s, 3H,
CMe2), 1.37 (s, 3H, CMe2), 0.59 (s, 9H, CMe3Si), 0.04 (s, 3H, MeSi);
ꢀ0.19 (s, 3H, MeSi). 13C NMR (50 MHz, CDCl3) d: 186.1 (C@O),
186.0 (C@O); 156.0, 147.1, 134.1, 128.7, 127.8 (imidazo[2,1-b]thia-
zole carbons), 135.1, 132.3, 130.4, 130.1 (aromatic carbons), 112.8
(CMe2), 106.0 (C-1), 86.3 (C-4), 84.6 (C-2), 78.1 (C-3), 27.1 (CMe2),
26.5 (CMe2), 25.2 (CMe3Si), 17.7 (CMe3Si), ꢀ4.8 (CMeSi), ꢀ5.5 (CMe-
Si). Anal. Calcd for C26H31BrN2O6SSi: C, 51.40; H, 5.14; N, 4.61.
Found: C, 51.72; H, 5.09; N, 4.49.
1.7. 6-Bromo-6-deoxy-1,2-O-isopropylidene-3-O-(p-
methoxybenzyl)-a-D-xylo-hexofuranos-5-ulose (24)
Compound 24 was obtained from compound 21 (445.3 mg,
1.10 mmol) by the same procedure applied for compound 23,
but, in this case, 4 h of reflux were needed to achieve the product
as white crystals (440.1 mg, 1.09 mmol, 82.5% yield): mp: 88–
89 °C; ½a 2D5
ꢁ
ꢀ95.9 (c 1.4, chloroform). 1H NMR (200 MHz, CDCl3)
d: 7.15 (d, 2H, J 8.8 Hz, aromatic protons), 6.87 (d, 2H, J 8.6 Hz, aro-
matic protons), 6.06 (d, 1H, J1,2 3.5 Hz, H-1), 4.82 (d, 1H, J2,1 3.7 Hz,
H-2), 4.59 (d, 1H, J 3.6 Hz, H-3), 4.51 (d, 1H, J 11.3 Hz, methylene
proton), 4.39 (d, 1H, J 11.3 Hz, methylene proton), 4.36 (d, 1H,
J6a,6b 15.9 Hz, H-6a), 4.29 (d, 1 H, J4,3 3.6 Hz, H-4), 4.25 (d, 1H,
J6b,6a 15.9 Hz, H-6b), 3.80 (s, 3H, OMe), 1.47 (s, 3H, CMe2), 1.33 (s,
3H, CMe2). 13C NMR (50 MHz, CDCl3) d: 199.0 (C@O), 159.6,
129.6, 128.5, 114.0 (aromatic carbons), 112.7 (CMe2), 106.2 (C-1),
84.9 (C-4), 83.3 (C-2), 81.8 (C-3), 72.5 (methylene carbon), 55.3
(CH3O), 35.9 (C-6), 27.0 (CMe2), 26.4 (CMe2). Anal. Calcd for
C17H21BrO6: C, 50.89; H, 5.28. Found: C, 50.72; H, 5.09.
1.8.3. 3-(p-Chlorobenzoyl)-5-(1,2-O-isopropylidene-3-O-p-
methoxybenzyl-a-D-xylofuranos-5-ulo-5-yl)imidazo[2,1-
b]thiazole (27)
Compound 27 was obtained from 24 (250 mg, 0.62 mmol) and
p-chlorobenzoyl-thiazolylimidoformamide (274.5 mg, 0.93 mmol)
as yellow amorphous solid (169.1 mg, 0.30 mmol, 47.7% yield):
mp 80–82 °C; ½a 2D5
ꢁ
ꢀ120.5 (c 1.3, chloroform). 1H NMR (200 MHz,
CDCl3) d: 8.82 (s, 1H, imidazo[2,1-b]thiazole proton), 8.40 (s, 1H,
imidazo[2,1-b]thiazole proton), 7.83 (d, 2H, J 8.6 Hz, aromatic pro-
tons), 7.55 (d, 2H, J 8.6 Hz, aromatic protons), 6.91 (d, 2H, J 8.6 Hz,
aromatic protons), 6.66 (d, 2H, J 8.6 Hz, aromatic protons), 6.19 (d,
1H, J1,2 3.6 Hz, H-1), 5.07 (d, 1H, J4,3 3.5 Hz, H-4), 4.61 (d, 1H, J2,1
3.6 Hz, H-2), 4.51 (d, 2H, J 11.8 Hz, methylene proton), 4.39 (d,
1H, J3,4 3.6 Hz, H-3), 4.32 (d, 2H, J 11.8 Hz, methylene proton),
3.72 (s, 3H, OMe), 1.52 (s, 3H, CMe2), 1.36 (s, 3H, CMe2). 13C NMR
(50 MHz, CDCl3) d: 185.9 (C@O), 185.0 (C@O); 156.1, 146.4,
134.2, 128.0 (imidazo[2,1-b]thiazole carbons), 140.0, 134.7, 130.3,
129.4, 128.8, 127.9, 113.6 (aromatic carbons), 112.7 (CMe2),
106.0 (C-1), 84.8 (C-4), 83.7 (C-2), 82.0 (C-3), 72.4 (methylene car-
bon), 55.2 (CH3O), 26.9 (CMe2), 26.3 (CMe2). Anal. Calcd for
1.8. General procedure to synthesize compounds 25–28
Compounds 25–28 were obtained by reaction of one of the 3-O-
protected sugar derivates 20 or 21 with the corresponding N0-[5-(4-
halobenzoyl)-1,3-thiazol-2-yl]-N,N-dimethylimidoformamide in a
molar relation of (1:1.5) in anhydrous THF (7 mL) under microwave
radiation (300 W, 105 °C, 150 min). A solution of triethylamine
(molar relation 1.5:1 amine/sugar) in 15 mL of anhydrous THF was
added and the mixture was stirred at room temperature over-
night.17 The crude products were purified by column chromato-
graphy on silica gel using mixtures of cyclohexane/acetone
(90:10–75:25) as eluents.
C28H25ClN2O7S: C, 59.10; H, 4.43; N, 4.92. Found: C, 58.97; H,
4.35; N, 4.77.
1.8.4. 3-(p-Bromobenzoyl)-5-(1,2-O-isopropylidene-3-O-p-
methoxybenzyl-a-D-xylofuranos-5-ulo-5-yl)imidazo[2,1-
1.8.1. 3-(p-Chlorobenzoyl)-5-(1,2-O-isopropylidene-3-O-tert-
b]thiazole (28)
buthyldimethylsilyl-
b]thiazole (25)
a
-
D
-xylofuranos-5-ulo-5-yl)imidazo[2,1-
Compound 28 was obtained from 24 (215.3 mg, 0.54 mmol) and
p-bromobenzoyl-thiazolylimidoformamide (280.3 mg, 0.83 mmol)
as yellow amorphous solid (141.8 mg, 0.23 mmol, 43.1% yield):
Compound 25 was obtained from 23 (260.4 mg, 0.66 mmol) and
p-chlorobenzoyl-thiazolylimidoformamide (293.2 mg, 0.99 mmol)
as yellow amorphous solid (141.5 mg, 0.25 mmol, 25.4% yield):
mp 87–90 °C; ½a 2D5
ꢁ
ꢀ113.0 (c 1.4, chloroform). 1H NMR (200 MHz,
CDCl3) d: 8.81 (s, 1H, imidazo[2,1-b]thiazole proton), 8.40 (s, 1H,
imidazo[2,1-b]thiazole proton), 7.73 (m, 4H, aromatic protons),
6.91 (d, 2H, J 8.6 Hz, aromatic protons), 6.65 (d, 2H, J 8.6 Hz, aro-
matic protons), 6.18 (d, 1H, J1,2 3.6 Hz, H-1), 5.06 (d, 1H, J4,3
3.5 Hz, H-4), 4.61 (d, 1H, J2,1 3.7 Hz, H-2), 4.50 (d, 2H, J 11.8 Hz,
methylene proton), 4.38 (d, 1H, J3,4 3.6 Hz, H-3), 4.31 (d, 2H, J
mp 77–78 °C; ½a 2D5
ꢁ
ꢀ154.6 (c 1.5, chloroform). 1H NMR (200 MHz,
CDCl3) d: 8.88 (s, 1H, imidazo[2,1-b]thiazole proton), 8.52 (s, 1H,
imidazo[2,1-b]thiazole proton), 7.81 (d, 2H, J 8.5 Hz, aromatic pro-
tons), 7.53 (d, 2H, J 8.5 Hz, aromatic protons), 6.20 (d, 1H, J1,2
3.4 Hz, H-1), 5.00 (d, 1H, J4,3 3.1 Hz, H-4), 4.60 (d, 1H, J3,4 3.1 Hz,

84
J. S. Barradas et al. / Carbohydrate Research 355 (2012) 79–86
11.8 Hz, methylene proton), 3.74 (s, 3H, OMe), 1.52 (s, 3H, CMe2),
1.35 (s, 3H, CMe2). 13C NMR (50 MHz, CDCl3) d: 186.1 (C@O),
185.0 (C@O); 156.1, 146.4, 134.1, 128.0 (imidazo[2,1-b]thiazole
carbons), 159.3, 135.1, 132.4, 130.2, 128.9, 113.6 (aromatic car-
bons), 112.7 (CMe2), 106.0 (C-1), 84.9 (C-4), 83.7 (C-2), 82.0 (C-
3), 72.4 (methylene carbon), 55.2 (CH3O), 27.0 (CMe2), 26.3
(CMe2). Anal. Calcd for C28H25BrN2O7S: C, 54.82; H, 4.11; N, 4.57.
Found: C, 54.87; H, 4.25; N, 4.77.
(50 MHz, CDCl3) d: 187.6 (C@O), 181.0, 148.8, 130.7 (thiazole car-
bons), 156.5 (–C@N), 159.3, 129.3, 129.0, 113.7 (aromatic carbons),
112.4 (CMe2), 105.8 (C-1), 85.0 (C-4), 83.3 (C-2), 82.2 (C-3), 72.2
(methylene carbon), 55.2 (CH3O), 41.1 (Me2N), 35.2 (Me2N), 27.0
(CMe2), 26.4 (CMe2). Anal. Calcd for C22H27N3O6S: C, 52.25; H,
5.90; N, 9.10. Found: C, 52.37; H, 5.95; N, 8.97.
1.10. General procedure to synthesize compounds 32–35
1.9. General procedure to synthesize compounds 29–31
Compounds 32–35 were obtained by reaction of 30 or 31 with
the corresponding 2-bromo-1-(4-chlorophenyl)ethanone or 2-bro-
mo-1-(4-bromophenyl)ethanone in anhydrous THF (7 mL) under
microwave radiation (300 W, 90 min, 100 °C). Then 15 mL of THF
and triethylamine (molar relation 1.5:1 amine/sugar) was added
and the mixture was kept stirring at room temperature overnight.
Solvent was evaporated and the crude products were purified by
column chromatography on silica gel using mixtures of cyclohex-
ane/acetone (90:10–75:25) as eluents.
6-Bromo-6-deoxy-1,2-O-isopropylidene-3-O-protected-a-D-xylo-
hexofuranos-5-ulose 22–24 was added to a solution of N,N0-
bis(dimethylaminomethylene)thiourea (1.2 equiv) in anhydrous
dicloromethane (25 mL), and refluxed for 3 h under argon atmo-
sphere. Et3N (1.5 equiv) was added and the mixture was stirred
for 12 h at room temperature. The crude product was purified by
flash column chromatography, using cyclohexane/acetone as
eluent.
1.10.1. 3-(1,2-O-Isopropylidene-3-O-tert-buthyldimethylsilyl-
-xylofuranos-5-ulo-5-yl)-5-(p-chlorobenzoyl)imidazo[2,1-
b]thiazole (32)
a-
1.9.1. N,N-Dimethylformamidyl-5-(1,2-O-isopropylidene-3-O-
acetyl-a-D-xylofuranos-5-ulo-5-yl)-1,3-thiazole (29)
D
Compound 29 was obtained from 22 (526.7 mg, 1.62 mmol) as a
Compound 32 was obtained from 30 (157.6 mg, 0.35 mmol) and
waxy yellow solid (532.5 mg, 1.38 mmol, 85.2% yield) using the
2-bromo-1-(4-chlorophenyl)ethanone (121.1 mg, 0.52 mmol) as a
procedure previously described:17
½
a 2D5
ꢁ
ꢀ80.5 (c 0.9, chloroform).
waxy yellow solid (105.6 mg, 0.19 mmol, 54.2% yield):
½ ꢁ
a 2D5
1H NMR (200 MHz, CDCl3) d: 8.36 (s, 1H, –HC@N), 8.31 (s, 1H, thi-
azole proton), 6.14 (d, 1H, J1,2 3.6 Hz, H-1), 5.57 (d, 1H, J3,4 3.4 Hz,
H-3), 5.16 (d, 1H, J3,4 3.4 Hz, H-4), 4.58 (d, 1H, J2,1 3.6 Hz, H-2), 3.16
(s, 3H, Me2N), 3.12 (s, 3H, Me2N), 1.89 (s, 3H, MeCO), 1.54 (s, 3H,
CMe2), 1.34 (s, 3H, CMe2). 13C NMR (50 MHz, CDCl3) d: 186.1
(C@O), 181.4, 149.2, 130.2 (thiazole carbons), 156.6 (–C@N),
169.3 (MeCO), 112.9 (CMe2), 105.4 (C-1), 83.2 (C-3), 82.6 (C-4),
77.7 (C-2), 41.2 (Me2N), 35.3 (Me2N), 26.9 (CMe2), 26.3 (CMe2),
20.6 (CH3CO). Anal. Calcd for C16H21N3O6S: C, 50.12; H, 5.52; N,
10.96. Found: C, 50.17; H, 5.52; N, 10.87.
ꢀ74.6 (c 2.1, chloroform). 1H NMR (200 MHz, CDCl3) d: 9.45 (s,
1H, imidazo[2,1-b]thiazole proton), 7.96 (s, 1H, imidazo[2,1-b] thi-
azole proton), 7.85 (d, 2H, J 8.4 Hz, aromatic protons), 7.51 (d, 2H, J
8.4 Hz, aromatic protons), 6.29 (d, 1H, J1,2 3.1 Hz, H-1), 5.05 (d, 1H,
J4,3 3.1 Hz, H-4), 4.64 (d, 1H, J3,4 3.4 Hz, H-3), 4.45 (d, 1H, J2,1 3.5 Hz,
H-2), 1.52 (s, 3H, CMe2), 1.37 (s, 3H, CMe2), 0.66 (s, 9H, CMe3Si),
0.07 (s, 3H, MeSi); ꢀ0.10 (s, 3H, MeSi). 13C NMR (50 MHz, CDCl3)
d: 190.4 (C@O), 181.5 (C@O); 156.9, 145.6, 133.4, 129.8, 129.1 (imi-
dazo[2,1-b]thiazole carbons), 139.1, 136.0, 130.0, 129.8 (aromatic
carbons), 112.9 (CMe2), 106.1 (C-1), 86.9 (C-4), 84.6 (C-2), 77.7
(C-3), 27.1 (CMe2), 26.5 (CMe2), 25.3 (CMe3Si), 17.8 (CMe3Si), ꢀ5.0
(CMeSi), ꢀ5.3 (CMeSi). Anal. Calcd for C26H31ClN2O6SSi: C, 55.45;
H, 5.55; N, 4.97. Found: C, 55.17; H, 5.25; N, 4.77.
1.9.2. N,N-Dimethylformamidyl-5-(1,2-O-isopropylidene-3-O-
(tert-buthyldimethylsilyl)-a-D-xylofuranos-5-ulo-5-yl)-1,3-
thiazole (30)
Compound 30 was obtained from 23 (180.2 mg, 0.46 mmol) as
1.10.2. 3-(1,2-O-Isopropylidene-3-O-tert-buthyldimethylsilyl-
-xylofuranos-5-ulo-5-yl)-5-(p-bromobenzoyl)imidazo[2,1-
b]thiazole (33)
a-
it was previously described17,26 as
a
waxy yellow solid
ꢀ143.5 (c 0.7, chloro-
D
(198.4 mg, 0.44 mmol, 95.4%, yield): ½a D25
ꢁ
form). 1H NMR (200 MHz, CDCl3) d: 8.37 (s, 1H, –HC@N), 8.32 (s,
1H, thiazole proton), 6.14 (d, 1H, J1,2 3.4 Hz, H-1), 4.96 (d, 1H, J3,4
3.1 Hz, H-3), 4.57 (d, 1H, J3,4 3.1 Hz, H-4), 4.39 (d, 1H, J2,1 3.3 Hz
H-2), 3.14 (s, 3H, Me2N), 3.11 (s, 3H, Me2N), 1.49 (s, 3H, CMe2),
1.34 (s, 3H, CMe2), 0.70 (s, 9H, CMe3Si), 0.02 (s, 3H, MeSi); ꢀ0.14
(s, 3H, MeSi). 13C NMR (50 MHz, CDCl3) d: 188.5 (C@O), 180.9,
148.9, 131.0 (thiazole carbons), 156.5 (–C@N), 112.6 (CMe2),
105.8 (C-1), 86.5 (C-4), 84.8 (C-2), 78.1 (C-3), 41.2 (Me2N), 35.2
(Me2N), 27.1 (CMe2), 26.6 (CMe2), 25.4 (CMe3Si), 17.8 (CMe3Si),
ꢀ5.0 (MeSi), ꢀ5.4 (MeSi). Anal. Calcd for C20H33N3O5SSi: C, 52.72;
H, 7.30; N, 9.22. Found: C, 52.87; H, 7.25; N, 9.27.
Compound 33 was obtained from 30 (151.2 mg, 0.33 mmol) and
2-bromo-1-(4-bromophenyl)ethanone (113.7 mg, 0.49 mmol) as a
waxy yellow solid (155.4 mg, 0.26 mmol, 76.9% yield):
½ ꢁ
a 2D5
ꢀ67.5 (c 1.8, chloroform). 1H NMR (200 MHz, CDCl3) d: 9.43 (s,
1H, imidazo[2,1-b]thiazole proton), 7.94 (s, 1H, imidazo[2,1-b] thi-
azole proton), 7.76 (d, 2H, J 8.0 Hz, aromatic protons), 7.65 (d, 2H, J
8.0 Hz, aromatic protons), 6.27 (d, 1H, J1,2 3.3 Hz, H-1), 5.03 (d, 1H,
J4,3 3.1 Hz, H-4), 4.62 (d, 1H, J3,4 3.0 Hz, H-3), 4.44 (d, 1H, J2,1 3.4 Hz,
H-2), 1.52 (s, 3H, CMe2), 1.37 (s, 3H, CMe2), 0.65 (s, 9H, CMe3Si),
0.05 (s, 3H, MeSi); ꢀ0.11 (s, 3H, MeSi). 13C NMR (50 MHz, CDCl3)
d: 190.4 (C@O), 181.6 (C@O); 156.9, 145.6, 133.4, 129.5, 127.4 (imi-
dazo[2,1-b]thiazole carbons), 136.4, 132.1, 130.1, 127.6 (aromatic
carbons), 112.9 (CMe2), 106.1 (C-1), 86.9 (C-4), 84.6 (C-2), 78.4
(C-3), 27.1 (CMe2), 26.4 (CMe2), 25.3 (CMe3Si), 17.7 (CMe3Si), ꢀ5.0
(CMeSi), ꢀ5.3 (CMeSi). Anal. Calcd for C26H31BrN2O6SSi: C, 51.40;
H, 5.14; N, 4.61. Found: C, 51.47; H, 5.15; N, 4.57.
1.9.3. N,N-Dimethylformamidyl-5-(1,2-O-isopropylidene-3-O-
(p-methoxybenzyl)-a-D-xylofuranos-5-ulo-5-yl)-1,3-thiazole (31)
Compound 31 was obtained from 24 (443.7 mg, 1.11 mmol) as
it was previously reported in literature17 as a waxy yellow solid
(386.9 mg, 0.84 mmol, 87.2% yield): ½a D25
ꢀ25.9 (c 4.1, chloroform).
ꢁ
1H NMR (200 MHz, CDCl3) d: 8.30 (s, 1H, –HC@N), 8.24 (s, 1H, thi-
azole proton), 7.01 (d, 2H, J 8.6 Hz, aromatic protons), 6.73 (d, 2H, J
8.6 Hz, aromatic protons), 6.12 (d, 1H, J1,2 3.5 Hz, H-1), 5.04 (d, 1H,
J3,4 3.7 Hz, H-4), 4.57 (d, 1H, J2,1 3.7 Hz, H-2), 4.45 (d, 1H, J 11.5 Hz,
methylene proton), 4.34 (d, 1H, J 11.5 Hz, methylene proton), 4.33
(d, 1H, J3,4 3.7 Hz, H-3), 3.72 (s, 3H, OMe), 3.11 (s, 3H, Me2N), 3.08
(s, 3H, Me2N), 1.48 (s, 3H, CMe2), 1.31 (s, 3H, CMe2). 13C NMR
1.10.3. 3-(1,2-O-Isopropylidene-3-O-p-methoxybenzyl-a-D-
xylofuranos-5-ulo-5-yl)-5-(p-chlorobenzoyl)imidazo[2,1-
b]thiazole (34)
Compound 34 was obtained from 31 (406.5 mg, 0.88 mmol) and
2-bromo-1-(4-chlorophenyl)ethanone (312.5 mg, 1.32 mmol) as a
waxy yellow solid (422.1 mg, 0.74 mmol, 84.1% yield):
½ ꢁ
a 2D5
ꢀ64.8 (c 0.9, chloroform). 1H NMR (200 MHz, CDCl3) d: 9.52 (s,

J. S. Barradas et al. / Carbohydrate Research 355 (2012) 79–86
85
1H, imidazo[2,1-b]thiazole proton), 9.19 (s, 1H, imidazo[2,1-b]thi-
azole proton), 7.84 (d, 2H, J 8.8 Hz, aromatic protons), 7.52 (d, 2H, J
8.6 Hz, aromatic protons), 7.01 (d, 2H, J 8.6 Hz, aromatic protons),
6.65 (d, 2H, J 8.8 Hz, aromatic protons), 6.26 (d, 1H, J1,2 3.6 Hz, H-
1), 5.14 (d, 1H, J4,3 3.7 Hz, H-4), 4.66 (d, 1H, J2,1 3.7 Hz, H-2,), 4.53
(d, 2H, J 11.6 Hz, methylene proton), 4.42 (d, 1H, J3,4 3.7 Hz, H-3),
4.31 (d, 2H, J 11.7 Hz, methylene proton), 3.66 (s, 3H, OMe), 1.53
(s, 3H, CMe2), 1.37 (s, 3H, CMe2). 13C NMR (50 MHz, CDCl3) d:
190.6 (C@O), 180.1 (C@O); 156.7, 145.5, 133.1, 128.8 (imi-
dazo[2,1-b]thiazole carbons), 159.4, 139.1, 136.0, 130.1, 129.7,
129.1, 128.7, 128.3, 113.6 (aromatic carbons), 112.9 (CMe2),
106.1 (C-1), 85.3 (C-4), 83.1 (C-2), 81.9 (C-3), 72.2 (methylene car-
bon), 55.1 (OCH3), 27.0 (CMe2), 26.3 (CMe2). Anal. Calcd for
C28H25ClN2O7S: C, 59.10; H, 4.43; N, 4.92. Found: C, 59.17; H,
4.35; N, 4.77.
(CMe2). HR ESI MS found m/z [M+H]+ 431.0472, C20H16ClN2O5S+ re-
quires m/z 431.0468.
1.11.2. 3-(3-Deoxy-1,2-O-isopropylidene-a-D-glycero-pent-3-
enofuranosid-5-ulo-5-yl)-5-(p-bromobenzoyl)imidazo[2,1-
b]thiazole (37)
Compound 37 was obtained from 29 (92.1 mg, 0.24 mmol) and
2-bromo-1-(4-bromophenyl)ethanone (102.8 mg, 0.36 mmol) as a
waxy yellow solid (36.8 mg, 0.08 mmol, 32.3% yield): ½a D25
ꢀ23.9
ꢁ
(c 2.0, chloroform). 1H NMR (200 MHz, CDCl3) d: 9.56 (s, 1H, imi-
dazo[2,1-b] proton), 7.99 (s, 1H, imidazo[2,1-b] proton), 7.80 (d, J
8.8 Hz, aromatic proton), 7.70 (d, J 8.8 Hz, aromatic proton), 6.39
(d, 1H, J3,2 5.4 Hz, H-3), 6.33 (d, 1H, J1,2 2.7 Hz, H-1), 5.46 (dd, 1H,
J2,1 2.7 Hz, J2,3 5.4 Hz, H-2), 1.50 (s, 3H, CMe2), 1.49 (s, 3H, CMe2).
13C NMR (50 MHz, CDCl3) d: 181.8 (C@O), 176.2 (C@O), 156.7,
145.7, 133.4, 129.7, 127.0 (imidazo[2,1-b] carbons), 154.8 (C-4),
136.3, 132.2, 130.1, 127.9 (aromatic carbons), 113.5 (CMe2),
111.4 (C-3), 107.6 (C-1), 82.1 (C-2), 28.0 (CMe2), 27.7 (CMe2). HR
ESI MS found m/z [M+H]+ 474.9967, C20H16BrN2O5S+ requires m/z
474.9963.
1.10.4. 3-(1,2-O-Isopropylidene-3-O-p-methoxybenzyl-a-D-
xylofuranos-5-ulo-5-yl)-5-(p-bromobenzoyl)imidazo[2,1-
b]thiazole (35)
Compound 35 was obtained from 31 (350.1 mg, 0.76 mmol) and
2-bromo-1-(4-bromophenyl)ethanone (321.5 mg, 1.14 mmol) as a
waxy yellow solid (404.5 mg, 0.66 mmol, 86.9% yield):
½
a 2D5
ꢁ
1.12. General procedure for carbohydrate deprotection
ꢀ50.1 (c 0.7, chloroform). 1H NMR (200 MHz, CDCl3) d: 9.52 (s,
1H, imidazo[2,1-b]thiazole proton), 9.19 (s, 1H, imidazo[2,1-b]thi-
azole proton), 7.85 (d, 2H, J 8.8 Hz, aromatic protons), 7.52 (d, 2H, J
8.6 Hz, aromatic protons), 7.01 (d, 2H, J 8.6 Hz, aromatic protons),
6.65 (d, 2H, J 8.8 Hz, aromatic protons), 6.26 (d, 1H, J1,2 3.6 Hz, H-
1), 5.14 (d, 1H, J4,3 3.7 Hz, H-4), 4.66 (d, 1H, J2,1 3.7 Hz, H-2), 4.53
(d, 2H, J 11.6 Hz, methylene proton), 4.42 (d, 1H, J3,4 3.7 Hz, H-3),
4.31 (d, 2H, J 11.8 Hz, methylene proton), 3.66 (s, 3H, OMe), 1.53
(s, 3H, CMe2), 1.37 (s, 3H, CMe2). 13C NMR (50 MHz, CDCl3) d:
189.1 (C@O), 181.6 (C@O); 156.7, 145.5, 133.1, 128.7, 126.8 (imi-
dazo[2,1-b]thiazole carbons), 159.4, 139.1, 136.0, 130.1, 129.8,
129.5, 128.7, 128.3, 113.6 (aromatic carbons), 112.9 (CMe2),
106.1 (C-1), 85.3 (C-4), 83.1 (C-2), 81.9 (C-3), 72.2 (methylene car-
bon), 55.1 (OCH3), 26.9 (CMe2), 25.8 (CMe2). Anal. Calcd for
Compounds 27, 28, 34, and 35 were dissolved in anhydrous
CH2Cl2 (5 mL) and the solutions were cooled to 0 °C in an ice bath
and then TFA (7 mL) was added stepwise up to 60% (v/v) final con-
centration. Reaction was kept stirring for 24 h at room temperature
and quenched by addition of water and NaHCO3 to pH 7. The solu-
tion was extracted with CH2Cl2/water and AcOEt/water, the com-
bined organic layers were dried (Na2SO4) and evaporated. The
crude product was purified by column chromatography on silica
gel using mixtures of toluene/ethanol (95:5–80:20) as eluents.
1.12.1. 3-(p-Chlorobenzoyl)-5-((a/b)-D-xylofuranos-5-ulo-5-
yl)imidazo[2,1-b]thiazole (38)
Deprotection of compound 27 (100 mg, 0.18 mmol) gave a
white solid product 38 which was characterized as a mixture of
C28H25BrN2O7S: C, 54.82; H, 4.11; N, 4.57. Found: C, 54.87; H,
4.25; N, 4.63.
a and b anomers (20.1 mg, 0.05 mmol, 28% yield, a/b = 52:48):
mp 118–120 °C (dec.);
½
a 2D5
ꢁ
ꢀ53.7 (c 0.4, DMSO). 1H NMR
1.11. General procedure to synthesize compounds 36–37
(500 MHz, DMSO-d6) d: 8.80 (s, 1H, imidazo[2,1-b]thiazole proton),
8.77 (s, 1H, imidazo[2,1-b]thiazole proton), 8.73 (s, 1H, imi-
dazo[2,1-b]thiazole proton), 8.46 (s, 1H, imidazo[2,1-b]thiazole
proton), 7.98–7.96 (m, 4H, aromatic protons), 7.75–7.74 (m, 4H,
aromatic protons), 6.48 (d, 1H, J 6.5 Hz, HOC-1 b-anomer), 6.35
A
mixture of N,N-dimethylformamidyl-5-(1,2-O-isopropyli-
dene-3-O-acetyl- -xylofuranos-5-ulo-5-yl)-1,3-thiazole and the
a
-D
corresponding 2-bromo-(4-halophenyl)etanone (1.2 equiv) in
anhydrous THF (6 mL) was heated under microwave irradiation
(300 W, 100 °C), for 90 min. The reaction mixture was diluted with
anhydrous THF (20 mL) and Et3N (1.5 equiv) was added under ar-
gon atmosphere and the mixture was stirred for 12 h at room tem-
perature. The crude product was purified by flash column
chromatography, using cyclohexane/acetone (90:10) as eluent.
(d, 1H, J 7.8 Hz, HOC-1
3.5 Hz, H-1 -anomer), 5.49 (d, 1H, J 3.7 Hz, HOC-2 b-anomer),
5.45 (d, 1H, J 4.8 Hz, HOC-3 -anomer), 5.21 (t, 3H, J 5.2 Hz, HOC-
-anomer, HOC-3 b-anomer, H-1 b-anomer), 5.08 (d, 1H, J4,3
5.2 Hz, H-4 -anomer), 4.93 (d, 1H, J4,3 4.8 Hz, H-4 b-anomer),
4.37 (dd, 1H, J3,HO 8.2 Hz, J3,4 4.9 Hz, H-3 -anomer), 4.25 (t, 1H, J
4.1 Hz, H-3 b-anomer), 3.90 (s, 1H, H-2 b-anomer), 3.84 (d, 1H,
J2,1 3.1 Hz, H-2
-anomer). 13C NMR (125 MHz, DMSO-d6) d:
a-anomer), 5.52 (dd, 1H, J1,HO 7.3 Hz, J1,2
a
a
2
a
a
a
1.11.1. 3-(3-Deoxy-1,2-O-isopropylidene-
enofuranosid-5-ulo-5-yl)-5-(p-chlorobenzoyl)imidazo[2,1-
b]thiazole (36)
aꢀD
-glycero-pent-3-
a
188.0 (C@O), 186.6 (C@O), 154.9, 146.7, 145.3, 133.5, 133.4,
129.3, 129.1, 127.7, 127.6 (imidazo[2,1-b]thiazole carbons),
138.8, 135.4, 131.2, 129.7 (aromatic carbons), 105.0 (C-1 b-ano-
Compounds 36 was obtained from 29 (130.3 mg, 0.34 mmol)
and 2-bromo-1-(4-chlorophenyl)ethanone (114.2 mg, 0.50 mmol)
mer), 98.4 (C-1
mer), 80.7 (C-2 b-anomer), 78.0 (C-3 b-anomer), 77.9 (C-3
-anomer), 76.1 (C-2
-anomer). HR ESI MS found m/z [M+H]+
409.0266, C17H14ClN2O6S+ requires m/z 409.0261.
a-anomer), 86.4 (C-4 b-anomer), 82.6 (C-4 a-ano-
as a waxy yellow solid (34.2 mg, 0.08 mmol, 23.4% yield): ½a D25
ꢁ
ꢀ96.9 (c 1.8, chloroform). 1H NMR (200 MHz, CDCl3) d: 8.81 (s,
1H, imidazo[2,1-b] proton), 8.48 (s, 1H, imidazo[2,1-b] proton),
7.87 (d, J 8.5 Hz, aromatic proton), 7.53 (d, J 8.5 Hz, aromatic pro-
ton), 6.39 (d, 1H, J1,2 5.4 Hz, H-3), 6.32 (d, 1H, J3,2 2.6 Hz, H-1),
5.46 (dd, 1H, J2,1 2.6 Hz, J2,3 5.3 Hz, H-2), 1.50 (s, 3H, CMe2), 1.49
(s, 3H, CMe2). 13C NMR (50 MHz, CDCl3) d: 181.7 (C@O), 176.2
(C@O), 156.7, 145.6, 133.4, 129.7, 129.1 (imidazo[2,1-b] carbons),
154.7 (C-4), 139.3, 135.8, 130.0, 129.2 (aromatic carbons), 113.5
(CMe2), 111.4 (C-3), 107.6 (C-1), 82.1 (C-2), 28.1 (CMe2), 27.7
a
a
1.12.2. 3-(p-Bromo)-5-((a/b)-D-xylofuranos-5-ulo-5-
yl)imidazo[2,1-b]thiazole (39)
Deprotection of compound 28 (151.5 mg, 0.25 mmol) gave a
white solid product 39 which was characterized as a mixture of
a
and b anomers (39.4 mg, 0.09 mmol, 35.2% yield, a/b = 47:53):
mp 127–130 °C (dec.);
½
a 2D5
ꢁ
ꢀ34.5 (c 0.8, DMSO). 1H NMR

86
J. S. Barradas et al. / Carbohydrate Research 355 (2012) 79–86
(500 MHz, DMSO-d6) d: 8.80 (s, 1H, imidazo[2,1-b]thiazole proton),
8.77 (s, 1H, imidazo[2,1-b]thiazole proton), 8.73 (s, 1H, imi-
dazo[2,1-b]thiazole proton), 8.46 (s, 1H, imidazo[2,1-b]thiazole
proton), 7.89, 7.88 (s, 8H, aromatic protons), 6.47 (br s, 1H, HOC-
181.6 (C@O), 181.5 (C@O), 156.0, 155.8, 146.3, 133.7, 133.2,
129.9, 128.3, 127.1, 127.0 (imidazo[2,1-b]thiazole carbons),
136.6, 136.5, 132.4, 131.2, 131.1, 127.2, 127.1 (aromatic carbons),
105.5 (C-1 b-anomer), 99.2 (C-1
a
-anomer), 87.0 (C-4 b-anomer),
-anomer
1b-anomer), 6.35 (br s, 1H, HOC-1
a-anomer), 5.52 (br s, 1H, H-1
83.9 (C-4 -anomer), 80.9 (C-2 b-anomer), 78.4 (C-3 a
a
a
-anomer), 5.49 (br s, 1H, HOC-2 b-anomer), 5.45 (d, 1H, J 4.3 Hz,
and b-anomer), 76.0 (C-2 a-anomer). HR ESI MS found m/z
HOC-3
a
-anomer), 5.22 (s, 3H, HOC-2
a
-anomer, HOC-3 b-anomer,
-anomer), 4.93 (d, 1H,
J4,3 4.8 Hz, H-4 b-anomer), 4.38 (d, 1H, J3,4 3.2 Hz, H-3 -anomer),
4.25 (s, 1H, H-3 b-anomer), 3.90 (s, 1H, H-2 b-anomer), 3.84 (t,
1H, J 3.3 Hz, H-2
-anomer). 13C NMR (125 MHz, DMSO-d6) d:
[M+H]+ 454.9751, C17H14BrN2O6S+ requires m/z 454.9756.
H-1 b-anomer), 5.08 (d, 1H, J4,3 5.2 Hz, H-4
a
a
Acknowledgments
a
The authors acknowledge Agencia Nacional de Promoción
Científica y Tecnológica, Consejo Nacional de Investigaciones
Científicas y Técnicas (CONICET) and Universidad de Buenos Aires
(UBA) from Argentina for financial support. N.B.D. is member of Re-
search Career from CONICET and J.S.B. has a fellowship from
CONICET.
188.0 (C@O), 186.7 (C@O), 154.8, 146.7, 145.3, 134.4, 133.3,
129.3, 129.1, 127.7, 127.6 (imidazo[2,1-b]thiazole carbons),
135.7, 132.6, 131.2, 127.9 (aromatic carbons), 105.0 (C-1 b-ano-
mer), 98.4 (C-1
mer), 80.7 (C-2 b-anomer), 78.0 (C-3 b-anomer), 77.9 (C-3
-anomer), 76.1 (C-2
-anomer). HR ESI MS found m/z [M+H]+
454.9759, C17H14BrN2O6S+ requires m/z 454.9756.
a-anomer), 86.4 (C-4 b-anomer), 82.6 (C-4 a-ano-
a
a
Supplementary data
1.12.3. 5-(p-Chlorobenzoyl)-3-((
yl)imidazo[2,1-b]thiazole (40)
Deprotection of compound 34 (104.6 mg, 0.18 mmol) gave a
white solid product 40 which was characterized as a mixture of
a/b)-D-xylofuranos-5-ulo-5-
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.carres.2012.04.011.
a
References
and b anomers (27.4 mg, 0.07 mmol, 36.5% yield, a/b = 48:52): mp
97 °C (dec.); ½a 2D5
ꢁ
ꢀ31.4 (c 0.5, DMSO). 1H NMR (500 MHz, DMSO-
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d6) d: 9.77 (s, 1H, imidazo[2,1-b]thiazole proton), 9.32 (s, 1H, imi-
dazo[2,1-b]thiazole proton), 8.23 (s, 1H, imidazo[2,1-b]thiazole
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a-
a
a
J 3.8 Hz, HOC-3 b-anomer), 5.39 (s, 1H, HOC-2
(s, 1H, H-1 b-anomer), 5.21 (d, 1H, J 4.8 Hz, H-4
(d, 1H, J 4.7 Hz, H-4 b-anomer), 4.41 (s, 1H, H-3
a-anomer), 5.28
a-anomer), 5.08
a-anomer), 4.30
(s, 1H, H-3 b-anomer), 3.92 (s, 1H, H-2 b-anomer), 3.86 (d, 1H, J
2.8 Hz, H-2
a
-anomer). 13C NMR (125 MHz, DMSO-d6) d: 192.7
(C@O), 181.5 (C@O), 181.3 (C@O), 156.0, 155.8, 146.3, 133.7,
133.2, 130.0, 128.3, 127.1, 127.0 (imidazo[2,1-b]thiazole carbons),
138.1, 138.0, 136.3, 136.2, 131.1, 131.0, 129.5 (aromatic
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(C-4 b-anomer), 83.9 (C-4 -anomer), 80.9 (C-2 b-anomer), 78.4
(C-3 -anomer and b-anomer), 76.0 (C-2 -anomer). HR ESI MS
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a-anomer), 87.0
a
a
a
1.12.4. 5-(p-Bromobenzoyl)-3-((a/b)-D-xylofuranos-5-ulo-5-
yl)imidazo[2,1-b]thiazole (41)
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a
and b anomers (36.5 mg, 0.08 mmol, 44% yield, a/b = 52:48):
mp 103 °C (dec.); ½a D25
ꢁ
ꢀ31.6 (c 0.7, DMSO). 1H NMR (500 MHz,
DMSO-d6) d: 9.71 (s, 1H, imidazo[2,1-b]thiazole proton), 9.31 (s,
1H, imidazo[2,1-b]thiazole proton), 8.21 (s, 1H, imidazo[2,1-b]
thiazole proton), 8.20 (s, 1H, imidazo[2,1-b]thiazole proton),
7.87–7.79 (m, 8H, aromatic protons), 6.68 (d, 1H, J 6.4 Hz, HOC-1
b-anomer), 6.49 (d, 1H, J 7.5 Hz, HOC-1
3.8 Hz HOC-3 -anomer), 5.60 (s, 1H, H-1
HOC-2 b-anomer), 5.52 (d, 1H, J 3.8 Hz, HOC-3 b-anomer), 5.39
(br s, 1H, HOC-2 -anomer), 5.29 (d, 1H, J 5.2 Hz, H-1 b-anomer),
a
-anomer), 5.71 (d, 1H, J
a
a-anomer), 5.56 (s, 1H,
a
5.21 (d, 1H, J 4.8 Hz, H-4
anomer), 4.42 (m, 1H, H-3
3.93 (s, 1H, H-2 b-anomer), 3.86 (d, 1H, J 2.8 Hz, H-2
a
a
-anomer), 5.09 (d, 1H, J 4.7 Hz, H-4 b-
-anomer), 4.31 (m, 1H, H-3 b-anomer),
-anomer).
13C NMR (125 MHz, DMSO-d6) d: 192.7 (C@O), 192.7 (C@O),
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