Synthesis of d-mannitol substituted ether-linked bis-1,2,3-triazoles as models of gemini surfactants

Article abstract of DOI:10.1016/j.tetlet.2012.07.014

Readily available and low cost D-mannitol was converted into 1,2,5,6-di-O-isopropylidene-D-mannitol (1) in the presence of acetone and zinc chloride. Williamson etherfication of 1 with propargyl bromide afforded the bisalkyne 2 in a very good yield. 1,3-Dipolar cycloaddition of 2 with four different alkyl azides using click conditions gave four novel bistriazoles 3a-d. Removal of the acetal groups of 3a-d afforded the deprotected bistriazoles 4a-d in excellent yields. Products 3 and 4 represent models of gemini surfactants.

Full text of DOI:10.1016/j.tetlet.2012.07.014

Tetrahedron Letters 53 (2012) 5081–5083
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of D-mannitol substituted ether-linked bis-1,2,3-triazoles as models
of gemini surfactants
⇑
Adnan Ibrahim Mohammed , Zaid Hassan Abboud, Atheer Hamed Odda Alghanimi
Department of Chemistry, College of Science, Kerbala University, Kerbala, Iraq
a r t i c l e i n f o
a b s t r a c t
Article history:
Readily available and low cost D-mannitol was converted into 1,2,5,6-di-O-isopropylidene-D-mannitol
(1) in the presence of acetone and zinc chloride. Williamson etherfication of 1 with propargyl bromide
afforded the bisalkyne 2 in a very good yield. 1,3-Dipolar cycloaddition of 2 with four different alkyl
azides using click conditions gave four novel bistriazoles 3a–d. Removal of the acetal groups of 3a–d
afforded the deprotected bistriazoles 4a–d in excellent yields. Products 3 and 4 represent models of gem-
ini surfactants.
Received 16 May 2012
Revised 20 June 2012
Accepted 4 July 2012
Available online 11 July 2012
Keywords:
D-Mannitol
Ó 2012 Elsevier Ltd. All rights reserved.
Dialkyne
Bistriazoles
Click chemistry
Gemini surfactants
1,2,3-Triazoles are an important class of organic compounds
due to their wide applications in the synthesis of pharmaceuticals,1
receptors,2 antibiotics,3 antitubercular agents,4 ligands,5,6 fluori-
nated hydrogels,7 surfactants,8 nucleosides,9 and their applications
in radiochemistry.10 They have been synthesized by Cu(I)-cata-
lyzed 1,3-dipolar cycloadditions according to the procedures of
Sharpless11 and Meldal.12 Also, they have been prepared using
microwave irradiation13,14 and ultrasound.15 Introducing a carbo-
hydrate moiety to the triazole plays a significant role in biological
studies16–19 due to the increase of its solubility in water and reduc-
tion in toxicity.20 Sugar based bis-1,2,3-triazoles have been pre-
pared as nonionic surfactants starting from D-glucose and D-
galactose.21 As D-mannitol is a readily available and cheap starting
material for the synthesis of surfactants we decided to utilize it for
the design and synthesis of a number of protected and deprotected
bistriazoles as models of gemini surfactants that have two hydro-
phobic arms and two hydrophilic heads (Fig. 1).
volved DMF as the solvent and NaOH as the base at ꢀ20 °C to rt
for 24 h (Scheme 1). The Cu(I)-catalyzed 1,3-dipolar cycloadditions
of 2 with n-heptyl, n-octyl, n-decyl, and n-dodecyl azides in DMSO
at 50 °C for 36 h gave the bistriazoles 3a–d in very good yields; the
longer the alkyl chain the lower was the yield (Table 1). The final
step in the synthesis was the removal of the acetal groups of bistri-
azoles 3a–d by treatment with Amberlite IR 120 H+ in EtOH at re-
flux for 30 h to afford the corresponding bistriazoles 4a–d in
excellent yields.
The structures of all the compounds synthesized were deduced
from IR, 1H NMR, 13C NMR, and HRMS spectra. The surface activity
of both protected and deprotected bistriazoles in different solvents
and at various temperatures will be measured in subsequent stud-
ies in addition to the biological activity.
3,4-Bis-O-propargyl-1,2:5,6-di-O-isopropylidene-D-mannitol (2)
Gemini surfactants from alkyl glucosides have been synthesized
previously.22 This work commenced with the conversion of D-
mannitol into 1,2,5,6-di-O-isopropylidene-D-mannitol (1) using
the conditions of Schmid23 et al. Compound 1 was reacted with
propargyl bromide to give bisalkyne 2 as the platform for our work.
We studied the use of various basic reagents for this reaction: KOH,
NaH, and NaOH in solvents such as DMF, DMSO, and MeCN. We
found that the best conditions which gave a very good yield in-
1,2:5,6-Di-O-isopropylidene-D-mannitol (1) (0.787 g, 3 mmol)
was dissolved in DMF (30 mL) in a dry flask and treated with
crushed NaOH (0.48 g, 12 mmol). The flask was cooled in an ice-
salt bath at ꢀ20 °C and the contents stirred for 10 min before
propargyl bromide (0.76 mL, 8.54 mmol) was added dropwise.
The mixture was then allowed to stir for a further 24 h, while grad-
ually warming to rt. The mixture was quenched with H2O (30 mL)
and extracted with Et2O (3 ꢁ 30 mL). The combined organic layers
were washed with aqueous saturated NH4Cl (3 ꢁ 20 mL) and H2O
(30 mL), dried over Na2SO4 and filtered. The solvent was
evaporated under reduced pressure to yield a pale yellow oil. Flash
⇑
Corresponding author. Tel.: +964 7906 487332.
E-mail address: adnanimchem@yahoo.com (A.I. Mohammed).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.07.014

5082
A. I. Mohammed et al. / Tetrahedron Letters 53 (2012) 5081–5083
Junction spacer
N
HO
HO
O
N
O
N
N
N
Hydrophobic part
N
OH
OH
Hydrophilic part
Figure 1. Design of a surfactant derived from D-mannitol.
O
HO
HO
O
O
R
R
O
O
O
N
N
N
N
ii
i
iii
OH
O
O
O
N
N
N
HO
N
O
N
O
O
N
N
O
N
OH
O
O
R
R
O
1
OH
4a-d
O
2
O
3a-d
Scheme 1. Synthesis of
D
-mannitol bistriazoles. Reagents and conditions: (i) propargyl bromide, NaOH, DMF, ꢀ20 °C-rt, 24 h; (ii) R-N3, Na ascorbate, CuSO4ꢂ5H2O, DMSO,
50 °C, 36 h; (iii) Amberlite IR 120 H+, EtOH/reflux, 30 h R = C7H15, C8H17, C10H21, C12H25
.
Table 1
The physical properties of the synthesized compounds
Product
Physical state
Rf (eluent)
Mp (°C)
[
a
]D, (c 0.5/solvent)
Yield (%)
2
Prismatic crystals
White solid
White solid
White solid
White solid
White solid
White solid
White solid
White solid
0.72 (n-hexane/EtOAc, 3:1)
0.36 (n-hexane/EtOAc, 1:2)
0.36 (n-hexane/EtOAc, 1:2)
0.35 (n-hexane/EtOAc, 1:2)
0.34 (n-hexane/EtOAc, 1:2)
0.32 (CH2Cl2/MeOH, 15:1)
0.31 (CH2Cl2/MeOH, 15:1)
0.30 (CH2Cl2/MeOH, 15:1)
0.30 (CH2Cl2/MeOH, 15:1)
50–52
92–94
97–99
107–109
114–116
132–134
138–140
151–153
162–163
ꢀ92.7 (CH2Cl2)
+26.5 (CH2Cl2)
+33.2 (CH2Cl2)
+41.1 (CH2Cl2)
+13.2 (CH2Cl2)
ꢀ19.9 (MeOH)
ꢀ10.2 (MeOH)
ꢀ22.6 (MeOH)
+3.7 (MeOH)
81
89
86
84
80
99
98
99
99
3a
3b
3c
3d
4a
4b
4c
4d
chromatography (silica gel, 9:1–3:1, n-hexane:EtOAc) yielded
3,4-bis-O-propargyl-1,2:5,6-di-O-isopropylidene-D-mannitol (2)
as white prismatic crystals (0.82 g, 81%). IR (KBr) cmꢀ1: 3253,
2985, 2935, 2898, 2115, 1456, 1382, 1373, 1348, 1267, 1220,
1209, 1163, 1105, 1058, 1018, 964, 941, 916, 862, 821, 678, 513.
1H NMR (500 MHz, CDCl3) d ppm: 1.32, 1.39 (s, 12H, CH3 isopropyl-
idene), 2.45 (t, J 2.0 Hz, 2H, 2 ꢁ H30), 3.85 (d, J 4.4 Hz, 2H, 2 ꢁ H3),
4.04 (dd, J 8.3, 7.0 Hz, 2H, 2 ꢁ Ha1), 4.13 (dd, J 8.5, 6.4 Hz, 2H,
2 ꢁ Hb1), 4.21 (q, J 6.2 Hz, 2H, 2 ꢁ H, H2), 4.35 (dd, J 16.0, 2.3 Hz,
2H, 2 ꢁ Ha10), 4.39 (dd, J 15.9, 2.2 Hz, 2H, 2 ꢁ Hb10). 13C NMR
(125 MHz, CDCl3) d: 25.3, 26.6 [2 ꢁ –C(CH3)2], 59.7 (2 ꢁ C10), 66.2
(2 ꢁ C3), 74.9 (2 ꢁ C1), 76.5 (2 ꢁ C2), 78.6 (2 ꢁ C30), 79.9
(2 ꢁ C20), 108.5 [2 ꢁ –C(CH3)2]. HRMS-ESI [M+Na]+ calcd for
C18H26O6Na: 361.1621; found: 361.1622.
white solid (0.55 g, 89%). IR (KBr) cmꢀ1: 3128, 3076, 2985, 2929,
2858, 1550, 1460, 1375, 1332, 1263, 1213, 1166, 1112, 1050,
935, 871, 783. 1H NMR (500 MHz, CDCl3) d ppm: 0.87 (t, J 6.9 Hz,
6H, 2 ꢁ H70), 1.31 (m, 16H, 2 ꢁ H60–H30), 1.33, 1.41 (s, 12H,
4 ꢁ CH3 isopropylidene), 1.88 (quin, J 7.2 Hz, 4H, 2 ꢁ H20), 3.81
(d, J 5.7 Hz, 2H, 2 ꢁ H300), 3.93 (dd, J 8.4, 6.4 Hz, 2H, 2 ꢁ Ha100),
4.02 (dd, J 8.4, 6.4 Hz, 2H, 2 ꢁ Hb100), 4.23 (q, J 6.2 Hz, 2H,
2 ꢁ H200), 4.31 (t, J 7.3 Hz, 4H, 2 ꢁ H10), 4.83 (s, 4H, 2 ꢁ –CH2–),
13
7.53 (s, 2H, 2 ꢁ H5). C NMR (125 MHz, CDCl3) d: 14.1 (2 ꢁ C70),
22.7 (2 ꢁ C60), 25.3, 26.6 [2 ꢁ –C(CH3)2], 26.8, 28.8 [2 ꢁ (C30or C40
or C50)], 30.5 (2 ꢁ C20), 31.8 [2 ꢁ (C30or C40 or C50)], 50.5
(2 ꢁ C20), 66.3 (2 ꢁ –CH2–), 66.6 (2 ꢁ C100), 75.9 (2 ꢁ C10), 80.3 (2
ꢁ C300), 108.8 [2 ꢁ –C(CH3)2], 122.6 (2 ꢁ C5), 145.1 (2 ꢁ C4).
HRMS-ESI [M+Na]+ calcd for C32H56N6O6Na: 643.4153; found:
643.4155.
3,4-Bis-O-[(1-heptyl-1H-1,2,3-triazol-4-yl)methyl]1,2:5,6-di-O-
isopropylidene-D-mannitol (3a)
3,4-Bis-O-[(1-heptyl-1H-1,2,3-triazol-4-yl)methyl]-D-mannitol
(4a)
A suspension of sodium ascorbate (0.0396 g, 0.2 mmol) and Cu-
SO4ꢂ5H2O (0.025 g, 0.01 mmol) in DMSO (2 mL) was added to a
solution of propargyl ether 2 (1.0 mmol, 0.34 g) in DMSO
(2 mL) and the mixture stirred for 10 min. Next, n-heptyl azide
(2.5 mmol, 0.35 g) was added and the mixture heated at 50 °C with
stirring for 36 h. The mixture was diluted with H2O (30 mL), ex-
tracted with EtOAc (3 ꢁ 30 mL), the combined organic layers
washed with satd NaCl (2 ꢁ 20 mL), dried over Na2SO4 and evapo-
rated under reduced pressure. The residue was flash chromato-
graphed (silica gel, 2:1 to 1:2, n-hexane:EtOAc) to yield 3a as a
3,4-Bis-O-[(1-heptyl-1H-1,2,3-triazol-4-yl)methyl]1,2:5,6-di-O-
isopropylidene-D-mannitol (3a) (0.29 mmol) was dissolved in
EtOH/H2O (1:1, 5 mL). To this solution was added Amberlite IR
120 H+ (290 mg, 1 g molꢀ1) and the mixture stirred at 60 °C for
30 h. The resin was filtered and washed with EtOH (3 ꢁ 5 mL).
The filtrate was evaporated to yield 4a as a white solid (0.15 g,
99%). IR (KBr) cmꢀ1: 3736, 3558, 3415, 2929, 2864, 1693, 1647,
1548, 1517, 1462, 1222, 1062, 675. 1H NMR (500 MHz, CDCl3) d
ppm: 0.89 (t, J 6.7 Hz, 6H, 2 ꢁ H70), 1.31 (m, 16H, 2 ꢁ H60-H30),

A. I. Mohammed et al. / Tetrahedron Letters 53 (2012) 5081–5083
5083
1.86 (quin, J 7.2 Hz, 4H, 2 ꢁ H20), 3.69 (dd, J 11.3, 5.0 Hz, 2H,
2 ꢁ Ha100) 3.81 and 3.83 [m, 4H, 2 ꢁ (Hb100 and H200)], 3.94 (d, J
8.3 Hz, 2H, 2 ꢁ H300), 4.36 (t, J 7.1 Hz, 4H, 2 ꢁ H10) 4.81 (dd, J 17.7,
11.7 Hz, 4H, 2 ꢁ –CH2–), 7.95 (s, 2H, 2 ꢁ H5). 13C NMR (125 MHz,
CDCl3) d: 14.4 (2 ꢁ C70), 23.6 (2 ꢁ C60), 27.4, 29.8 [2 ꢁ (C30or C40
or C50)], 31.3 (2 ꢁ C20), 32.8 [2 ꢁ (C30or C40 or C50)], 51.3
(2 ꢁ C10), 64.4 (2 ꢁ C100), 66.3 (2 ꢁ -CH2-), 72.1(2 ꢁ C200), 80.3
(2 ꢁ C300), 125.0 (2 ꢁ C5), 146.2 (2 ꢁ C4). HRMS-ESI [M+Na]+ calcd
for C26H48N6O6Na: 563.3527; found: 563.3526.
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We gratefully acknowledge Dr. Ahmed Al-Karawi, Al-Mustan-
siriyah University, Iraq and the Staff of Fakultät für Chemie,
Universität Bielefeld, Germany for their significant assistance in
NMR and HRMS measurements of the synthesized compounds.
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Supplementary data
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21. Mohammed, A. Proceedings of the International Conference on Global Trends
in Pure & Applied Chemical Sciences, Asian J. Chem., Udaipur, India, Poster
Presentation.
Supplementary data associated with this article can be found, in
the
online
version,
at
http://dx.doi.org/10.1016/j.tet-
let.2012.07.014. These data include MOL files and InChiKeys of
the most important compounds described in this article.
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