Synthesis of new N-glycosides based on Valproic acid analogs tetrazole derivatives

Article abstract of DOI:10.1007/s13738-017-1055-7

New N-glycosides based on valproic acid analogs tetrazole derivatives were synthesized. The bis-tetrazole derived from 1,6-hexandiol was also connected to acetylated glucose and formed bis-N-glycoside. Structures characterizations have been performed using FT IR, ¹H and ¹³C NMR spectroscopy.

Full text of DOI:10.1007/s13738-017-1055-7

J IRAN CHEM SOC
DOI 10.1007/s13738-017-1055-7
ORIGINAL PAPER
Synthesis of new N‑glycosides based on Valproic acid analogs
tetrazole derivatives
Nader Noroozi Pesyan1 · Marziyeh Ebrahimi1
Received: 25 June 2016 / Accepted: 7 January 2017
© Iranian Chemical Society 2017
Abstract New N-glycosides based on valproic acid ana-
logs tetrazole derivatives were synthesized. The bis-tetra-
zole derived from 1,6-hexandiol was also connected to
acetylated glucose and formed bis-N-glycoside. Structures
characterizations have been performed using FT IR, 1H and
13C NMR spectroscopy.
in several psychiatric disorders, a bipolar disorder [3–6],
use in cancer, neuroprotection, and schizophrenia therapy
[7–11].
Tetrazoles are aromatic heterocyclic compounds that
have a 6π-electron system [12–15]. The free N–H bond
of 5-substituted tetrazoles as tetrazolic acids is seen in two
tautomeric forms [12–16], and also this group turns them
into an acidic molecule in which the pKα value is the same
as its corresponding carboxylic acid [12]. Because of this
extensive similarity, tetrazole ring is a suitable alterna-
tive for VPA in pharmaceutical compounds [17–20]. As in
conventional papers listed, some of tetrazoles derivatives’
applications are seen in the field of medicinal chemistry
[19, 21, 22], agricultural [23, 24] and explosive materials
[25].
Based on these concepts, we decided to synthesize the
VPA derivatives based on tetrazole and coupled them to
glucose for the synthesis of new N-glycosides. According
to our search in the literature, there is no report of N-glyco-
sides based on valproic acid analogs tetrazole derivatives.
Keywords Valproic acid · Antiepileptic · 5-(heptan-4-yl)-
1H-tetrazole · Ethyl cyanoacetate · Tetrazole · N-glycoside
Introduction
Valproic acid (VPA 6, in Fig. 1) has found clinical use as
an anticonvulsant and mood-stabilizing drug, bipolar dis-
order, primarily in the treatment of epilepsy and preven-
tion of migraine headaches. The acid, salt or mixture of the
two (valproate semi-sodium) are marketed under a number
of several trade names, including: Depakote, Convulex,
Valparin, Epilim, Valpro, Stavzor and Vilapro. VPA is a
branched side chain carboxylic acid, and it has eight car-
bon atoms. This compound is a slightly viscous, colorless
to pale yellow, with a boiling point of 219.5 °C and its pKa
is 4.6 [1]. VPA is also known as 2-propylpentanoic acid and
n-dipropylacetic acid. It is effective to treat antiepileptic,
and prophylaxis, neuropathic pain and migraine [2], use
Experimental
General
The drawing and nomination of compounds were done
by ChemDraw Ultra 8.0 version software. Melting points
were estimated with a digital melting point apparatus (elec-
trothermal) and were uncorrected. The IR spectra were
determined in the region 4000–400 cm−1 on a NEXUS
Electronic supplementary material The online version of this
article (doi:10.1007/s13738-017-1055-7) contains supplementary
material, which is available to authorized users.
1
670 FT IR spectrometer by KBr pellets. The H and 13C
* Nader Noroozi Pesyan
n.noroozi@urmia.ac.ir; nnp403@gmail.com
NMR spectra were registered on Bruker 300 FT-NMR at
300 and 75 MHz, respectively (Urmia University, Urmia,
1
Department of Organic Chemistry, Faculty of Chemistry,
1
Iran). The H and 13C NMR spectra were obtained on a
Urmia University, 57159 Urmia, Iran
1 3

J IRAN CHEM SOC
1
(C=N), 1462 (N=N); H NMR (300 MHz, CDCl3) δ (ppm)
0.83 (s, 6H, J = 6.9 Hz, 2CH3), 1.13–1.26 (m, 8H, 4CH2), 1.84–
1.88 (m, 4H, 2CH2), 3.29 (quin, 1H, CH); 13C NMR (75 MHz,
CDCl3) δ (ppm) 160.2, 36.3, 35.1, 34.0, 29.3, 22.4.
CN4H
CO2H
5‑Butyl‑1H‑tetrazole (5d)
5-(Heptan-4-yl)-1H-tetrazole (5a)
Valproic acid (VPA, 6)
Yield: 0.35 g (57%); cream solid; M.p.: 60–61 °C. FT IR
(KBr, ν, cm−1) 2471–3420 (NH-tetrazole), 2963, 2939,
2875 (CH-aliph.);1H NMR (300 MHz, CDCl3) δ (ppm)
0.93 (t, 3H, J = 7.2 Hz, CH3–CH2–CH2–CH2–), 1.43 (sex-
tet, 2H, CH3–CH2–CH2–CH2–), 1.89 (quin, 2H, CH3–CH2–
CH2–CH2–), 3.16 (t, 2H, CH3–CH2–CH2–CH2–), 15.91
(bs, 1H, tetrazole-H); 13C NMR (75 MHz, CDCl3) δ (ppm)
157.0, 29.7, 23.1, 22.1, 13.5.
Fig. 1 Formula structures of valproic acid (VPA 6) and its tetrazole
analog (5a)
solution in DMSO-d6 and/or CDCl3 as solvent using TMS
as an internal standard. The data were reported as (s = sin-
glet, d = doublet, t = triplet, q = quartet, m = multiplet or
unresolved, bs = broad singlet, coupling constant(s) in Hz,
1
integration). The H and 13C NMR spectra were opened
and analyzed via MestReC software from original spectra
files. Alkyl halides, ethyl cyanoacetate, sodium azide and
used solvents purchased from Merck and Aldrich without
further purification.
(2R,3R,4S,5R,6R)‑2‑(Acetoxymethyl)‑
6‑(5‑butyl‑2H‑tetrazol‑2‑yl)
tetrahydro‑2H‑pyran‑3,4,5‑triyl triacetate (7d)
In a 25-mL round-bottomed flask equipped with a mag-
netically heater stirrer 5-n-butyl-1H-tetrazole 5d (0.06 g,
0.5 mmol) was dissolved in 3 mL acetonitrile and then
added K2CO3 (0.5 mmol) with 3 drops of DMF and stirring
it during 1 h at room temperature. Afterward, dissolved
(2R,3R,4S,5R,6S)-2-(acetoxymethyl)-6-bromotetrahydro-
2H-pyran-3,4,5-triyl triacetate 6 (0.24 g, 0.6 mmol) in
acetonitrile was added dropwise into the reaction mixture,
stirred for 16 h at room temperature, filtered off and evapo-
rated. The residue was dissolved in 3 mL ethyl acetate and
washed with distilled water (2 × 5 mL). The organic phase
was dried with sodium sulfate, filtered off, and lastly, evap-
orated. The residue was purified by silica gel-coated plate,
and the eluent solvent was the mixture of n-hexane: ethyl
acetate/1: 1/V: V, (0.10 g, yield 45%).
2‑Butyl‑2‑cyanohexanoic acid (3b)
Yield: 2.24 g (65%); brown viscous solid. FT IR (KBr, ν,
cm−1) 2400–3600 (OH), 2960, 2933, 2870 (CH-aliph.),
2253 (C≡N), 1728 (C=O), 1210 (C–O) cm−1; H NMR
1
(300 MHz, CDCl3) δ (ppm) 0.92 (t, 6H, J = 6.9 Hz, 2CH3),
1.26–1.37 (m, 4H), 1.59 (m, 4H), 1.79–2.00 (m, 4H), 8.95
(bs, 1H, OH); 13C NMR (75 MHz, CDCl3) δ (ppm) 174.6,
119.0, 50.4, 37.0, 27.5, 22.4, 13.7.
2‑Butylhexanenitrile (4b)
Yield: 1 g (45%); brown viscous solid. FT IR (KBr, ν,
cm−1) 2943, 2870 (CH-aliph.), 2233 (C≡N); 1H NMR
(300 MHz, CDCl3) δ (ppm) 0.91 (m, 6H), 1.27–2.10 (m,
12H); 13C NMR (75 MHz, CDCl3) δ (ppm) 119.8, 37.0,
29.7, 27.5, 22.4, 13.7.
Yellow solid, M.p.: 155–157 °C, FT IR (KBr, ν,
cm−1) 2956 (CH-aliph.), 1751 (C=O), 1437, 1376, 1229,
1
1046; H NMR (300 MHz, CDCl3) δ (ppm) 0.98 (t, 3H,
J = 6.9 Hz), 1.46 (sex, 2H, J = 7.5 Hz), 1.86 (s, 2H), 2.04,
2.08 (2 s, 12H), 2.96 (t, 3H, J = 7.5 Hz), 4.00–4.02 (m,
1H), 4.15–4.30 (m, 2H), 5.27 (t, 1H, J = 9.9 Hz), 5.43 (t,
1H, J = 9.3 Hz), 5.65 (t, 1H, J = 9.3 Hz), 5.82 (d, 1H,
J = 9.3 Hz); 13C NMR (75 MHz, CDCl3) δ (ppm) 170.37,
170.03, 169.27, 168.65, 156.11, 83.71, 72.55, 69.47, 69.46,
67.38, 61.38, 28.92, 23.44, 22.22, 20.68, 20.61, 20.53,
20.18, 20.11 (an equilibrium of β-anomer).
5‑(Heptan‑4‑yl)‑1H‑tetrazole (5a)
Yield: 0.25 g (34%); pale yellow solid; M.p.: 184–187 °C.
FT IR (KBr, ν, cm−1) 2400–3500 (NH-tetrazole), 2959,
1
2930, 2871 (CH-aliph.), 1661 (C=N), 1462 (N=N); H
NMR (300 MHz, CDCl3) δ (ppm) 0.92 (t, 6H, J = 6.9 Hz,
2CH3), 1.26–1.47 (m, 6H), 1.53–1.64 (m, 2H), 2.12 (m,
1H), 5.47 (bs, 1H), 5.67 (bs, 1H); 13C NMR (75 MHz,
CDCl3) δ (ppm) 178.7, 46.8, 20.7, 14.9, 13.3.
(2R,3R,4S,5R,6R)‑2‑(Acetoxymethyl)‑
6‑(5‑(nonan‑5‑yl)‑2H‑tetrazol‑2‑yl)
5‑(Nonan‑5‑yl)‑1H‑tetrazole (5b)
tetrahydro‑2H‑pyran‑3,4,5‑triyl triacetate (7b)
Yield: 0.33 g (38%); yellow viscous solid. FT IR (KBr, ν, cm−1)
2400–3500 (NH-tetrazole), 2939, 2869 (CH-aliph.), 1663
Yield: 0.09 g (35%); white solid; M.p.: 98–101 °C. FT IR
(KBr, ν, cm−1) 2944, 2872 (CH-aliph.), 1756 (C=O), 1446,
1 3

J IRAN CHEM SOC
1
1376, 1228, 1037; H NMR (300 MHz, CDCl3) δ (ppm)
0.82 (m, 2H), 1.22–1.39 (m, 2H), 1.77–1.81 (m, 2H), 1.99,
2.00, 2.06, 2.07 (4 s, 12H, 4CH3CO), 3.81–4.43 (m, 4H),
5.08–5.53 (m, 3H), 5.69 (d, 1H, J = 8.1 Hz), 6.30 (d, 1H,
J = 3.3 Hz), 6.61 (s, 1H); 13C NMR (75 MHz, CDCl3) δ
(ppm) 170.57, 170.11, 170.09, 169.38, 169.33, 168.92,
168.71 (C=O), 140.33, 138.12 (CN4), 93.01, 92.35, 91.03,
90.47, 89.64, 75.95, 73.70, 73.44, 72.11, 71.45, 71.06,
70.90, 69.39, 68.97, 68.68, 68.34, 67.07, 66.90, 63.29,
61.49, 61.26, 59.64, 59.40, 23.21, 22.49, 22.07, 21.76,
20.73, 20.67, 19.30, 19.00, 18.00 (an equilibrium mixture
of α and β-anomers).
(2S,3R,4R,5S,6S)‑2‑(Hydroxymethyl)‑6‑(5‑(6‑(2
‑((2R,3R,4S,5S,6R)‑3,4,5‑trihydroxy‑6‑(hydroxymethyl)
tetrahydro‑2H‑pyran‑2‑yl)‑2H‑tetrazol‑5‑yl)
hexyl)‑2H‑tetrazol‑2‑yl)tetrahydro‑2H‑pyran‑3,4,5‑triol
(14d)
Pale yellow solid; M.p.: 133–135 °C, FT IR (KBr, ν, cm−1
3424 (OH), 2923 (CH-aliph.), 1577, 1435, 1044; H NMR
)
1
(300 MHz, DMSO-d6) δ (ppm) 1.23 (m, 2H), 1.36 (q, 2H,
J = 6.9 Hz), 1.60–1.70 (m, 2H), 2.92 (t, 2H, J = 8.7 Hz),
3.20–3.50 (m, 3H), 3.66 (d, 1H, J = 11.1 Hz), 3.83 (t,
1H, J = 8.1 Hz), 5.53 (d, 1H, J = 9.3 Hz); 13C NMR
(75 MHz, DMSO-d6) δ (ppm) 156.64, 81.40, 81.02, 78.27,
75.00, 73.00, 71.00, 29.50, 22.00, 13.00 (an equilibrium of
α-anomer).
1,6‑Di(1H‑tetrazol‑5‑yl)hexane (12d)
In a 25-mL round-bottomed flask equipped with a mag-
netically heater stirrer was dissolved octanedinitrile 11d
(0.6 g, 3.3 mmol) in 15 mL DMF, then adding sodium
azide (0.43 g, 6.6 mmol) and ammonium chloride (0.35 g,
6.6 mmol) and refluxing at 120 °C for 6 days. The progres-
sion of the reaction was monitored by thin layer chroma-
tography (TLC) by the eluent solvents of EtOAc; n-hexane;
and EtOH (10: 3: 2, V: V: V). After the reaction completion,
acidified by concentrated hydrochloric acid (6 M) with stir-
ring, the tetrazole product precipitated, was washed by the
mixture of water and EtOH and then dried.
Results and discussion
This article describes the characterization and synthe-
sis of VPA tetrazole analog derivatives, 5a [26], with the
inspiration of VPA (6) as an antiepileptic drug and then
coupling them with pentaacetylated glucose for the syn-
thesis of new type N-glycosides based on tetrazole. First,
the twice alkylation of ethyl cyanoacetate (1) with the
Yield: 0.5 g (52%); pale yellow solid; M.p.: 164–168 °C.
FT IR (KBr, ν, cm−1) 2400–3127 (NH-tetrazole), 2864,
1
1730 (CH-aliph.), 1571, 1438, 1050; H NMR (300 MHz,
DMSO-d6) δ (ppm) 1.27 (m, 4H), 1.65 (m, 4H), 2.84
(m, 4H); 13C NMR (75 MHz, DMSO-d6) δ (ppm) 156.2
(CN4H), 28.2 (–CH2CH2CH2CN4H), 27.2 (–CH2CH-
2CH2CN4H), 23.0 (–CH2CH2CH2CN4H).
(2S,3S,4R,5S,6S)‑2‑(Acetoxymethyl)‑6‑(5‑(6‑(2
‑((2R,3R,4S,5R,6R)‑3,4,5‑triacetoxy‑6‑(acetoxymethyl)
tetrahydro‑2H‑pyran‑2‑yl)‑2H‑tetrazol‑5‑yl)
hexyl)‑2H‑tetrazol‑2‑yl)tetrahydro‑2H‑pyran‑3,4,5‑triyl
triacetate (13d)
Yield: 0.21 g (58%); Pale yellow solid; M.p.: 90–92 °C.
FT IR (KBr, ν, cm−1) 2953 (CH-aliph.), 1748 (C=O),
1378, 1237, 1038; 1H NMR (300 MHz, acetone-d6) δ
(ppm) 1.30 (m, 2H), 1.80–1.96 (m, 6H), 2.00–2.07 (4 s,
24H, 4CH3CO–), 2.78, 2.82 (2 s, 2H), 4.06–4.15 (m, 4H),
4.22–4.31 (m, 4H), 4.44–4.47 (m, 1H), 5.02–5.22 (m, 4H),
5.36–5.54 (m, 3H), 5.90 (d, 1H, J = 8.4 Hz), 6.28 (d, 1H,
J = 3.3 Hz); 13C NMR (75 MHz, acetone-d6) δ (ppm)
169.74, 169.41, 169.32, 168.47 (4CH3CO–), 150.00 (CN4),
91.45, 88.76, 71.66, 70.81, 69.53, 68.69, 67.59, 67.16,
65.86, 20.62, 19.67, 19.48, 19.20 (an equilibrium mixture
of α- and β-anomers).
Scheme 1 Synthesis of new tetrazole analogs (5)
1 3

J IRAN CHEM SOC
same or different alkyl halides afforded 2,2-dialkylated
ethyl cyanoacetates (2). The hydrolysis of 2 produced
2,2-dialkylated cyanoacetic acids (3) and following decar-
boxylation gave dialkylated acetonitriles (4). Finally, the
cycloaddition reaction of 4 with sodium azide in the pres-
ence of a catalytic amount of ammonium chloride gave tar-
get tetrazoles (5) in DMF under reflux (Scheme 1).
For a demonstration of the hydrolysis of 2, the IR spec-
tra of 3 obviously show the peak of the carboxylic acid
OH group at a frequency of 2400–3600 cm−1. The stretch-
ing frequency of the nitrile group remained at 2253 cm−1
and indicated that the CN group did not hydrolyze.
Decarboxylation of 3 to 4 was performed by the heating of
3 in toluene under reflux. The IR spectra of 4 show a peak
at 2233 cm−1 that indicates the nitrile group and followed
loss of carboxylic acid OH stretching frequency at 2400–
3600 cm−1. Representatively, for comparison, the IR spec-
tra of compounds 2b, 3b, 4b and 5b are shown in Fig. 2
(see also experimental and supplementary material).
1
The H NMR spectrum of 3b showed that a triplet
at δ 0.92 ppm corresponds to two equivalent methyl
groups (6H), and three multiplets at δ 1.37 (4H), 1.59
(4H) and 1.79–2.00 ppm (4H) correspond to methylene
groups, respectively. A broad peak at δ 8.95 ppm (1H)
Fig. 2 IR spectra of compounds 2b (c pink solid line), 3b (d red solid line), 4b (a blue solid line) and 5b (b violet solid line)
Scheme 2 Coupling reaction
R1
R2
OAc
of tetrazoles 5 with 6 for the
synthesis of 8
OAc
R1
N
K2CO3, DMF
CH3CN, r.t.
N
N
O
O
N
AcO
AcO
AcO
AcO
+
Br
N
N
R2
N
H
N
OAc
OAc
5
6
7
2 hrs
R1 = R2 = n-butyl (b)
R1 = H, R2 = n-propyl (d)
R1
R2
OH
O
HO
HO
N
N
N
OH
N
8
1 3

J IRAN CHEM SOC
corresponds to acidic proton. The 13C NMR spectrum
of this compound showed seven distinct peaks that con-
firmed the assigned structure (see experimental and sup-
plementary material).
For instance, the structure of 5b was characterized by
IR, 1H and 13C NMR spectroscopy. The 1H NMR spectrum
of 5b consists of a triplet at δ 0.83 ppm, two multiplets at δ
1.13–1.26 and at δ 1.84–1.88 ppm corresponding to methyl
and methylene groups and a quintet at δ 3.29 ppm for ter-
tiary methine proton, respectively. The 13C NMR spectrum
is in good agreement with the molecular structure and
shows six distinct peaks. Five peaks at δ 22.4, 29.3, 34.0,
35.1 and 36.3 ppm correspond to methyl, methylenes and
methine groups on the chain, respectively. The peak at δ
160.2 ppm corresponds to tetrazole carbon atom (Experi-
mental and supplementary material).
Fig. 3 Representatively, the 1H (top) and 13C NMR spectra of 7d (bottom)
1 3

J IRAN CHEM SOC
O-acetylation of d-glucose followed by bromination
with HBr to obtain (2R,3R,4S,5R,6S)-2-(acetoxymethyl)-
6-bromotetrahydro-2H-pyran-3,4,5-triyl triacetate (6) has
been reported previously [27]. We performed the coupling
reaction of tetrazoles 5 with 6 for the synthesis of (7) as
new compounds and are shown in Scheme 2. Representa-
tively, the IR spectrum of 7d showed no tetrazole NH
confirmation of the nitrogen atoms of tetrazole in this
molecule) was performed by the Lassaigne’s test [28–30]
(appearance of Prussian blue color). Deprotection reac-
tion of 7d by sodium methoxide gave a good yield of 8d.
The 1H NMR spectrum of 8d showed the disappearance of
methyl protons on acetyl groups upon glucose ring moiety.
The 13C NMR spectrum of this compound also showed the
disappearance of carbonyl peaks at δ 170.37–168.65 ppm.
These observations demonstrated the formation of 8d. (see
experimental and supplementary material). The reaction
mechanism is according with Koenigs–Knorr [31] reaction
and is shown in Scheme 3. At first a lone pair of oxygen
atom A attacked to the C1 of α or β anomer, and removed
bromide ion out and then according by neighboring [32]
acteyl group of C2 in A was formed oxonium ion interme-
diate B by intramolecular reaction. The lone pair of nitro-
gen atom in tetrazole ring attacked to C1, and new C–N
bond was formed by nucleophilic substitution reaction.
We also examined and performed the conversion of
some diols (9) to bis-tetrazoles (12). Only the following
conversion of 1,6-hexanediol (9d) to 12d, 13d and 14d
was successful. No reason was offered for the unsuccess-
ful reactions of 9a–9c. Therefore, we chose 9d, and it
was converted to 1,6-dichlorohexane (10d) with excellent
yield in the reaction with phosphoryl chloride in acetoni-
trile. The cyanation of 10d yielded octanedinitrile (11d)
followed by a cycloaddition reaction with sodium azide
stretching frequencies at the range of 2471–3420 cm−1
.
Instead, the strong carbonyl stretching frequency at
1
1751 cm−1 appeared. The H NMR spectrum of this com-
pound showed a triplet at δ 0.98 ppm for the methyl group,
a sextet at δ 1.46, a multiplet at δ 1.86 and a triplet at δ
2.96 ppm for diastereotopic methylene protons in aliphatic
chain. Four methyl groups of acetoxy upon glucoside ring
moiety appeared at δ 2.04 and 2.08 ppm with the integra-
tion of twelve protons (three of these methyl singlets were
overlapped). A multiplet at δ 4.00–4.02 ppm corresponded
to diastereotopic methylene protons (Hf) and He, two tri-
plets at δ 5.43 and 5.65 ppm corresponded to Hb and Hd,
a triplet at δ 5.27 corresponded to Hc and finally a doublet
at δ 6.82 ppm corresponded to Ha (Fig. 3). In the 13C NMR
spectrum, the peaks at δ 170.37, 170.03, 169.27, 168.65
and 156.11 ppm corresponded to four carbonyl items and
one tetrazole carbon atom, respectively. The 13C NMR
spectrum of this compound showed twenty distinct peaks
that confirmed the assigned structure (Fig. 3). Other evi-
dence for the formation of 7d and 8d (the existence and
OAc
OAc
OAc
OAc
4
6
O
5
AcO
O
O
O
AcO
AcO
AcO
AcO
AcO
AcO
Br
AcO
2
1
3
O
OAc
O
R
O
O
6
O
Me
Me
O
Me
A
B
N
N
N
N
5
OAc
R
O
AcO
AcO
N
N
N
N
OAc
Scheme 3 Mechanism of glycosylation reaction of tetrazole 5
1 3

J IRAN CHEM SOC
Scheme 4 Conversion
of 1,6-hexanediol (9d) to
1,6-di(1H-tetrazol-5-yl)hexane
(12d), followed by the synthesis
of 13d and 14d
POCl3
HO
R
OH
Cl
R
Cl
CH3CN, r.t.
9
10
NaCN,
DMF,
Reflux
1) NaN3,
H
N
H
NH4Cl, DMF,
N
R
Reflux
N
N
N
NC
R
CN
N
N
2) HCl (conc.)
N
12
6
11
CH3CN,
16 hrs., r.t.,
K2CO3
AcO
OAc
OAc
OAc
AcO
AcO
O
O
R
N
N
N
OAc
N
AcO
N
N
N
N
13
MeONa/MeOH
pH = 12
2 hrs
HO
OH
HO
HO
OH
OH
O
N
O
R
N
HO
OH
N
N
N
N
N
14
N
R = (CH2)2 (a), (CH2)4 (b), (CH2)2-O-(CH2)2 (c), (CH2)6 (d)
produced bis-tetrazole 12d (Scheme 4). The IR spectra of
compounds 9d–12d are merged and showed these conver-
sions successfully (Fig. 4). Obviously, in the conversion of
diol 9d to 10d, the OH frequency stretching at 3455 cm−1
has disappeared (spectrum b in Fig. 4). In the conversion
of 10d to octanedinitrile 11d, the CN frequency stretching
at 2246 cm−1 has appeared (spectrum c in Fig. 4). In the
cycloaddition reaction on nitrile groups in 11d by sodium
azide, the CN frequency stretching has disappeared;
instead, tetrazole 12d has formed and its tetrazole func-
tional peak at 2470–3127 cm−1 has appeared (spectrum d
in Fig. 4). These observations demonstrated the successful
conversion of 9d to 12d and then to 13d. The conversion
of 13d to 14d was carried out in the presence of sodium
methoxide at pH = 12 in 2 h (Scheme 4, see experimental).
The IR spectrum of 14d showed a sharp and broad absorp-
tion peak at 3424 cm−1 for hydroxyl groups, which indi-
cated the deprotection reaction of these groups. In the IR
spectrum of this compound, the loss of carbonyl frequency
stretching also supported release of the hydroxyl groups.
The 13C NMR spectrum of 14d also showed the loss of car-
bonyl peaks at δ 169.74, 169.41, 169.32 and 168.47 ppm;
instead, the distinct peak of the tetrazole carbon atom is
shown at 156.64 ppm (Fig. 5).
1 3

J IRAN CHEM SOC
a
b
c
d
Fig. 4 IR spectra of compounds 9d (a blue solid line), 10d (b green solid line), 11d (c pink solid line) and 12d (d red solid line)
Fig. 5 13C NMR spectrum of
compound 14d in DMSO-d6
coupled with 1-bromo glucose pentaacetate, and the cor-
responding structures were characterized. The mono- and
bis-tetrazoles, based on pentaacetylated glucose, were
deprotected under basic media and newly obtained N-gly-
cosides based on valproic acid analogs and other tetrazole
derivatives.
Conclusion
The valproic acid analogs based on tetrazole and other
5-alkyl tetrazoles were synthesized and characterized by
spectroscopic techniques. Bis-tetrazoles were also syn-
thesized in good yield. Mono- and bis-tetrazoles were
1 3

J IRAN CHEM SOC
Acknowledgements We thank the Urmia University Research Coun-
cil for supporting this work.
15. K. Jug, A.M. Köster, J. Am. Chem. Soc. 112, 6772–6777 (1990)
16. R.N. Butler, V.C. Garvin, J. Chem. Soc. Perkin Trans. 1 2, 390–
393 (1981)
17. T. Kimura, Y. Hamada, M. Stochaj, H. Ikari, A. Nagamine, H.
Abdel-Rahman, N. Igawa, K. Hidaka, J.T. Nguyen, K. Saito,
Y. Hayashi, Y. Kiso, Bioorg. Med. Chem. Lett. 16, 2380–2386
(2006)
References
1. S. Budavari (ed.), The Merck Index, 12th edn. (Merck and Co,
NJ, 1996), p. 1961
18. T. Pinter, S. Jana, R.J.M. Courtemanche, F. Hof, J. Org. Chem.
76, 3733–3741 (2011)
2. B.F.D. Bourgeois, Valproic acid—clinical efficacy and use in
epilepsy, in Antiepileptic Drugs, ed. by R.H. Levy, R.H. Matt-
son, B.S. Meldrum, E. Perucca (Lippincot, Williams & Wilkins,
Philadelphia, 2002), pp. 808–817
19. R.J. Herr, Bioorg. Med. Chem. 10, 3379–3393 (2002)
20. D. Moderhack, J. Prakt. Chem. 340, 687–709 (1988)
21. H. Singh, A.S. Chawla, V.K. Kapoor, D. Paul, R.K. Malhotra,
Prog. Med. Chem. 17, 151–183 (1980)
3. M.A. Rogawski, W. Loscher, Nat. Med. 10, 685–692 (2004)
4. E. Spina, G. Perugi, Epileptic Disord. 6, 57–75 (2004)
5. C.J. Landmark, Med. Sci. Mon. 13(1), 1–7 (2007)
6. B. Anmann, H. Grünze, E. Vieta, M. Trimble, Clin. EEG Neuro-
sci. 38, 116–123 (2007)
7. H. Dou, K. Birusing, J. Faraei, S. Gorantla, L.Y. Poluektova,
S.B. Maggirwar, S. Dewhurst, H.A. Gelbard, H.E. Gendelman, J.
Neurosci. 23, 9162–9170 (2003)
22. V.A. Ostaraovskii, G.I. Koldoboskii, Chem. Hetrocycl. Comp.
28, 626–631 (1992)
23. S.P. Cass, D. Borello-France, J.M. Furman, Am. J. Otol. 17,
581–594 (1996)
24. I.C. Richards, P.S. Thomas, Pestic. Sci. 30, 275–284 (1990)
25. M. Hiskey, D.E. Chavez, D.L. Naud, S.F. Son, H.L. Berghout,
C.A. Bome, Proc. Int. Pyrotech. Semin. 27, 3–14 (2000)
26. http://www.molbase.com/en/cas-85508-57-2.html Accessed:
4
8. S. Eyal, B. Yagen, J. Shimshoni, M. Bialer, Biochem. Pharmacol.
Feb 2016
69, 1501–1508 (2005)
9. J. Ichikawa, Y.C. Chung, J. Dai, Y.H. Meltzer, Brain Res. 1052,
56–62 (2005)
27. S.L. Warriner (ed.) Science of Synthesis: Houben-Weyl Methods
of Molecular Transformations Vol, 29, George Thieme Verlag
KG, Stuttgart, Germany, 2007, and refs. therein
10. W.S. Yeow, M.F. Ziauddin, J.B. Maxhimer, S. Shamimi-Noori,
A. Baras, A. Chua, D.S. Schrump, D.M. Nguyen, Br. J. Cancer
22, 1436–1445 (2006)
28. R.L. Schriner, R.C. Fusan, D.Y. Curtin, T.C. Morrill, The Sys-
tematic Identification of Organic Compounds, 6th edn. (Wiley,
New York, 1980), p. 78
11. I.A. Alsarra, M. Al-Omar, F. Belal, Profiles Drug Subst. Excip.
29. A.G. Sharpe, The Chemistry of Cyano Complexes of the Transi-
tion Metals (Academic Press, London, 1976)
Relat. Methodol. 32, 209–240 (2005)
12. R.N. Butler, in Comprehensive Heterocyclic Chemistry II, ed.
by A.R. Katritzky, C.W. Rees, E.F.V. Scriven (Pergamon Press,
Oxford, 4, 1996) pp. 621–678, 905–1006
30. R.P. Gower, I.P. Rhodes, J. Chem. Ed. 46(9), 606–607 (1969)
31. Z. Wimmer, L. Pechova, D. Saman, Molecules 9, 902–912
(2004)
13. R.E. Trifonov, V.A. Ostrovskii, Russ. J. Org. Chem. 42, 1585–
1605 (2006)
32. T. Nukada, A. Berces, M.Z. Zgierski, D.M. Whitfield, J. Am.
Chem. Soc. 120, 13291–13295 (1998)
14. N. Sadlej-Sosnowska, J. Org. Chem. 66, 8737–8743 (2001)
1 3