Indium-, Magnesium-, and Zinc-Mediated Debenzylation of Protected 1 H -Tetrazoles: A Comparative Study

Article abstract of DOI:10.1055/s-0037-1610170

5-Substituted 1-benzyltetrazoles are easily debenzylated to give the corresponding deprotected tetrazoles using dissolved metals under protic conditions: Mg/MeOH, In/MeOH, or Zn/MeCO ₂ H are the procedures of choice for this transformation.

Full text of DOI:10.1055/s-0037-1610170

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
©
Georg Thieme Verlag Stuttgart · New York
2018, 50, A–F
paper
A
en
Synthesis
C. Behloul et al.
Paper
Indium-, Magnesium-, and Zinc-Mediated Debenzylation of
Protected 1H-Tetrazoles: A Comparative Study
Cherif Behloul*a
Meriem Benlahrecha
Francisco Foubelo*b,c,d
Carmen Nájerab,d
Miguel Yusb,d
Metal
N
N
R
R
N
N
N
N
N N
Solvent-H
H
a
Laboratoire des Produits Naturels d'Origine Végétale et de
Synthèse Organique, Université Frères Mentouri Constantine1,
R = Ph, PhCH , 4-NO C H , Ph CH, 2-pyridyl,
In (MeOH-THF) (50–95%)
Mg (MeOH-THF) (56–93%)
Zn (AcOH-THF) (58–88%)
2
2
6
4
2
25000 Contantine, Algeria
(4-HOC6H4)CH=C(CN), PhCH=C(CN),
afiza72@gmail.com
b
(4-ClC6H4)CH=C(CN), (4-MeOC6H4)CH=C(CN)
Departamento de Química Orgánica, Facultad de Ciencias,
Universidad de Alicante, Apdo. 99, 03080 Alicante, Spain
foubelo@ua.es
Instituto de Síntesis Orgánica (ISO), Universidad de Alicante,
Apdo. 99, 03080 Alicante, Spain
(
3-MeO-4-HOC6H3)CH=C(CN)
c
d
Centro de Innovación en Química Avanzada (ORFEO-CINQA),
Universidad de Alicante, Apdo. 99, 03080 Alicante, Spain
Dedicated to Professor Vicente Gotor on the occasion of his retirement
Received: 31.03.2018
Accepted after revision: 30.04.2018
Published online: 25.06.2018
the corresponding nitrile with sodium azide under reflux in
toluene. For tetrazoles 2f–j the corresponding carbonyl
compound, malononitrile, and sodium azide were reacted
in water at 50 °C.15
The benzylation of tetrazoles 2 was performed by treat-
ment of 1H-tetrazoles with benzyl bromide in DMF and us-
ing potassium carbonate as base.16 Once compounds 1 were
prepared, the corresponding debenzylation was carried out
using indium, magnesium, or zinc as the metallic compo-
nent according to the general Scheme 1.
DOI: 10.1055/s-0037-1610170; Art ID: ss-2018-z0217-op
Abstract 5-Substituted 1-benzyltetrazoles are easily debenzylated to
give the corresponding deprotected tetrazoles using dissolved metals
under protic conditions: Mg/MeOH, In/MeOH, or Zn/MeCO H are the
procedures of choice for this transformation.
2
Key words debenzylation, magnesium, indium, zinc, tetrazoles
The benzyl moiety is commonly used in synthetic or-
ganic chemistry as protecting group for heteroatoms (O, S,
N), mainly due its easy introduction and inherent stability.1
Concerning the corresponding deprotection, the hydroge-
nolysis has been widely used in multistep organic synthe-
N
N
N
N
Met
N
N
N
HN
conditions
2
R
R
sis, particularly for the debenzylation of N-benzylamines,
[Met = In, Mg, Zn]
1
2
3
4
5
benzyl ethers, benzyl esters, and benzyl carbamates. This
methodology has also been used for the debenzylation of
Scheme 1 Debenzylation of compounds 1; for R groups, see Table 1
6
nitrogen-containing heterocycles. Among this group of
compounds are tetrazoles, which represent an important
structural motif as an aromatic carboxylic acid surrogate in
medicinal chemistry since many pharmaceuticals contain
this unit. On the other hand, in the last few years we have
been interested in developing new methodologies based on
dissolved metals (lithium, zinc, and indium). Thus, we have
Indium-Promoted Debenzylation of Tetrazoles
(Method A)
1
Synthetic methodologies based on indium metal have
7
17
shown to be very versatile and productive, especially con-
cerning electron transfer processes,8 which led us to apply
this metal to the debenzylation of compounds 1. When the
tetrazole 1a was treated with indium metal (1:0.5 molar ra-
tio) in a mixture of methanol and THF at 0 °C for 24 hours
no reaction was observed. However, total conversion oc-
curred when the same reaction mixture was refluxed for 20
hours (Table 1, entry 1). These conditions were applied to a
series of tetrazoles 1b–j, some of them bearing functional
groups such as nitro (1c; entry 3), pyridyl (1e; entry 5), a
d,f
8
9
10
reported detritilations, depivaloylations, deacylations,
11
desilylations,
deallyloxy- and debenzyloxycarbonyla-
12
13
tions, and the reductive removal of the Boc group. In this
article, we report the use of indium, magnesium, and zinc
metals for the debenzylation of protected tetrazoles under
protic conditions to the corresponding 5-substituted tetra-
zoles under mild reaction conditions.
Tetrazoles 2a–e, precursors of the starting materials 1a–
14
e, were prepared by the standard procedure by reacting
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–F

B
Synthesis
C. Behloul et al.
Paper
Table 1 Debenzylation of Tetrazoles 1 with Indium, Magnesium, or Zinc
N
method A
In (0.5 equiv), MeOH–THF (3:2), reflux, 20 h
N
R
R
N
N
N
NBn
N NH
method B
method C
Mg (2.0 equiv), I2 (cat.), MeOH–THF (5:3), reflux, 17–22 h
Zn (2.0 equiv), AcOH–THF (1:1), r.t., 2–3 h
1
2
Starting material
R
Tetrazole product; method and yield (%)a
Structure
Entry
1
A (In)
95
B (Mg)
93
C (Zn)
88
1a
Ph
2a
N
N
N
NH
NH
2
3
4
1b
PhCH
2
2b
2c
2d
N
80
76
80
85
80
84
87
80
84
N
N
1c
2 6 4
4-O NC H
NO2
N
N
N
NH
NH
1d
2
Ph CH
N
N
N
5
6
7
8
9
1e
1f
2-pyridyl
2e
2f
88
50
60
51
55
90
56
69
58
60
88
60
64
68
58
N
N
N
N
N
N
N
N
NH
NH
NH
NH
NH
(E)-C(CN)=CH(4-HOC
6
H
4
)
CN
OH
N
N
1g
1h
1i
(E)-C(CN)=CHPh
2g
2h
2i
CN
CN
CN
N
N
6 4
(E)-C(CN)=CH(4-ClC H )
Cl
N
N
6 4
(E)-C(CN)=CH(4-MeOC H )
OMe
N
N
OH
10
1j
(E)-C(CN)=CH(3-MeO-4-HOC
6
H
3
)
2j
CN
53
59
61
OMe
N
N
N
NH
a
Isolated yield after recrystallization based on the starting material 1.
conjugate cyano group (2g–j; entries 7–10), chlorine (2h;
entry 8), or phenolic OH (2j; entry 10), thus indicating that
this methodology tolerates several functionalities.
Although the mixture of magnesium and methanol has
been used for the hydrogenation of double bonds,18 as far as
we know it has been reported to be useful only for the de-
benzylation of benzyl ethers.19 In Table 1, the results from
the deprotection of tetrazoles 1 with magnesium in metha-
nol are shown. Treatment of the starting material 1a with
Magnesium-Promoted Debenzylation of Tetrazoles 1
(Method B)
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–F

C
Synthesis
C. Behloul et al.
Paper
magnesium in methanol or in mixture of methanol and THF
at room temperature did not produce the expected deben-
zylated tetrazoles 2a after 24 hour. However, after refluxing
the former mixture (MeOH–THF 2:1) for 22 hours, a 40%
yield of 2a was obtained. An important increase in the yield
was obtained (93%) when a flake of iodine was added to the
reaction mixture (Table 1, entry 1). As it can be seen from
Table 1, this methodology is also compatible with the same
functionalities shown in Table 1.
that are not sensitive to acetic acid. For acid sensitive com-
pounds, probably magnesium would be the best metal to be
used in debenzylation of protected tetrazoles due to reac-
tion times, yields, and metal price.
From the results shown here, we can conclude that the
debenzylation of 1-benzyl 5-substituted tetrazoles 1 can be
performed with indium/methanol, magnesium/methanol,
and zinc/acetic acid, in general in good yields to the corre-
sponding tetrazoles 2. Comparing the three procedures, and
taking into account financial aspects, the use of zinc seems
to be the most effective for substrates non-sensitive to acid-
ic conditions. For substrates sensitive to acid, magnesium or
indium metal can be used, the first one being preferable
considering reaction conditions and metal prices.
Zinc-Promoted Debenzylation of Tetrazoles 1 (Meth-
od C)
Zinc metal in combination with a proton source can also
be useful as dissolving metal for electron transfer reac-
8e
tions. Thus, by treating protected tetrazoles 1 with zinc
metal and acetic acid in THF at room temperature, the cor-
responding debenzylated products 2 were isolated after 2–
General Information
3
hours. Also in this case several functionalities were com-
FTIR spectra were obtained with a Nicolet Impact 400D spectropho-
tometer using KBr pellets. NMR spectra were recorded with a Bruker
AV400 (400 MHz for 1H and 100 MHz for C), DMSO-d6 as solvent
patible with the reaction conditions used in the deprotec-
tion, as it can be seen in Table 1.
13
1
and TMS (δ = 0.00 ppm, 1H) and DMSO-d (δ = 2.50 ppm, H and δ =
3
(
(
6
Discussion
13
9.75 ppm, C) as internal standards; chemical shifts are given in δ
ppm) and coupling constants (J) in Hz. High-resolution mass spectra
HRMS) were carried out in a Agilent 7200, in the electrospray ioniza-
In general, debenzylation of substituted tetrazoles with
indium, magnesium, or zinc metals works properly, espe-
cially for non-functionalized compounds 1, giving the ex-
pected deprotected tetrazoles in isolated yields over 80%.
However, for highly functionalized tetrazoles 1f–j contain-
ing a conjugate nitrile, isolated yields decrease to 50–70%
due to secondary reactions and/or partial decomposition of
the starting material/product under the assayed reaction
conditions. Concerning the reaction conditions, whereas Zn
works at room temperature, In and Mg need refluxing in
THF–MeOH for the reaction to proceed. The reaction times
for Zn reductions (2–3 h) were significantly shorter than
those for In and Mg deprotections (17–22 h).
tion mode (ESI) using a TOF analyzer. All reagents used for the syn-
thesis of tetrazoles 2 and N-benzyltetrazoles 1 were commercially
available and used without any further purification.
Tetrazoles 2a–e;14 General Procedure
A mixture of the corresponding nitrile (50 mmol), NaN3 (65 mmol)
and Et N·HCl (150 mmol) in toluene (100 mL) was stirred at 110 °C for
3
17–30 h (TLC monitoring). After cooling to r.t., the mixture was ex-
tracted with H O (100 mL) and the aqueous phase was acidified with
2
aq 36% HCl. The solid formed was filtered, washed with H O (3 × 10
2
mL), and dried under reduced pressure to give the corresponding
product 2a–e.
Concerning a possible reaction mechanism, we presume
that a single electron transfer (SET) takes place from the
metal to the starting tetrazole 1 cleaving the benzyl–nitro-
gen bond to give a benzyl radical I and the heterocyclic an-
ion II, both stabilized by delocalization (Figure 1). Benzyl
radical I decomposes by a hydrogen atom abstraction to
5-Phenyl-1H-tetrazole (2a)8c
White solid; yield: 3.0 g (41%); mp 215–216 °C.
IR (KBr): 3333, 2588, 2511, 1055, 925, 789, 643, 619 cm–1
.
1
H NMR (400 MHz, DMSO-d ): δ = 7.55–7.62 (m, 3 H), 8.01–8.10 (m, 2
6
H).
20
give toluene, meanwhile the hydrolysis of heterocyclic an-
ion II leads to the formation of deprotected tetrazole 2. A
similar mechanism could be also involved in the detrityla-
13
C NMR (101 MHz, DMSO-d ): δ = 124.1 (CH), 127.0 (C), 129.4, 131.3
6
(CH), 155.3 (C).
+
HRMS (ESI): m/z calcd for C H N (M ): 146.0592; found: 146.0598.
7
6
4
8
tion of protected tetrazoles.
5
-Benzyl-1H-tetrazole (2b)8c
–
N
N
White solid; yield: 2.0 g (25%); mp 123–124 °C.
IR (KBr): 2949, 2864, 2709, 1073, 961, 835, 694, 608 cm–1
N
N
.
R
1
H NMR (400 MHz, DMSO-d ): δ = 4.31 (s, 2 H), 7.25–7.37 (m, 5 H).
6
I
II
13
C NMR (101 MHz, DMSO-d ): δ = 29.0 (CH ), 127.1, 128.7, 128.8
6
2
Figure 1 Proposed radical intermediates in the metal debenzylation of
tetrazoles 1
(
CH), 136.0, 155.3 (C).
+
HRMS (ESI): m/z calcd for C H N (M ): 160.0749; found: 160.0748.
8
8
4
5
-(4-Nitrophenyl)-1H-tetrazole (2c)22
Considering the obtained results, and taking into ac-
count reaction conditions and the price of metals, we con-
sider that zinc would be the metal of choice for compounds
Green solid; yield: 2.9 g (32%); mp 146–147 °C.
IR (KBr): 3453, 2543, 1018, 988, 978, 851, 702, 634 cm–1
21
.
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–F

D
Synthesis
C. Behloul et al.
Paper
1
IR (KBr): 3158, 2359, 1585, 1497, 930, 810, 691, 623 cm–1
.
H NMR (400 MHz, DMSO-d ): δ = 8.29–8.33 (m, 2 H), 8.43–8.46 (m, 2
6
H).
1
H NMR (400 MHz, DMSO-d ): δ = 7.62–7.72 (m, 2 H), 8.05 (d, J = 8.6
6
13
C NMR (101 MHz, DMSO-d ): δ = 125.0, 128.6 (CH), 131.0, 149.1,
Hz, 2 H), 8.41 (s, 1 H).
6
1
55.8 (C).
13
C NMR (101 MHz, DMSO-d ): δ = 98.1 (CN), 115.8 (C), 129.15, 129.8
6
+
HRMS (ESI): m/z calcd for C H N O (M ): 191.0443; found: 191.0452.
(CH), 131.5 (C), 131.9 (CH), 137.3, 147.3 (C).
7
5
5
2
HRMS (ESI): m/z calcd for C10H ClN (M+ – HN ): 188.0141; found:
188.0140.
5
2
3
5
-Benzhydryl-1H-tetrazole (2d)8c
White solid; yield: 3.0 g (27%); mp 165–166 °C.
IR (KBr): 3360, 2680, 1082, 990, 845, 695, 617 cm–1
(E)-3-(4-Methoxyphenyl)-2-(1H-tetrazol-5-yl)acrylonitrile (2i)24
.
1
Green solid; yield: 0.20 g (88%); mp 76–78 °C.
IR (KBr): 3120, 2773, 1589, 1462, 954, 864, 651, 604 cm–1
H NMR (400 MHz, DMSO-d ): δ = 5.97 (s, 1 H), 7.11–7.48 (m, 10 H).
6
13
.
C NMR (101 MHz, DMSO-d ): δ = 46.2 (CH), 127.65, 128.9, 129.15
6
1
(CH), 140.5, 158.5 (C).
H NMR (400 MHz, DMSO-d ): δ = 3.85 (s, 3 H), 7.14 (d, J = 8.6 Hz, 2
6
HRMS (ESI): m/z calcd for C14H12N (M+ – N ): 194.0970; found:
H), 8.01 (d, J = 8.6 Hz, 2 H), 8.25 (s, 1 H).
3
13
194.0954.
C NMR (101 MHz, DMSO-d ): δ = 56.1 (CH ), 93.9 (CN), 115.35 (CH),
6 3
1
16.6 (C), 125.3, 132.6 (CH), 148.05, 155.9, 163.0 (C).
-(1H-Tetrazol-5-yl)pyridine (2e)22
+
2
HRMS (ESI): m/z calcd for C10H N O (M – CN ): 187.0746; found:
9
3
2
Brown solid; yield: 3.0 g (27%); mp 208–210 °C.
187.0733.
IR (KBr): 3091, 2650, 1539, 1114, 975, 899, 695, 615 cm–1
.
(
E)-3-(4-Hydroxy-3-methoxyphenyl)-2-(1H-tetrazol-5-yl)acryloni-
1
H NMR (400 MHz, DMSO-d ): δ = 7.54–7.75 (m, 1 H), 8.04–8.19 (m, 1
6
24
trile (2j)
H), 8.27 (dd, J = 7.4, 3.8 Hz, 1 H), 8.84 (t, J = 4.3 Hz, 1 H).
Green solid; yield: 0.16 g (75%); mp 88–89 °C.
IR (KBr): 3121, 2225, 1574, 1458, 998, 844, 644, 620 cm–1
1H NMR (400 MHz, DMSO-d
H), 7.53 (d, J = 8.4 Hz, 1 H), 7.75 (s, 1 H), 8.22 (s, 1 H).
13
C NMR (101 MHz, DMSO-d ): δ = 123.0, 126.5, 138.65 (CH), 144.1
6
.
(
C), 150.5 (CH), 155.3 (C).
HRMS (ESI): m/z calcd for C H N (M+ – N ): 119.0483; found:
6
): δ = 3.88 (s, 3 H), 7.00 (d, J = 8.3 Hz, 1
6
5
3
2
119.0491.
1
3
C NMR (101 MHz, DMSO-d ): δ = 56.0 (CH ), 91.9 (CN), 113.2, 116.4
6
3
Tetrazoles 2f–j;15 General Procedure
(CH), 116.8 (C), 124.0, 126.3, (CH), 148.2, 148.9, 151.9, 155.75 (C).
+
A mixture of the corresponding carbonyl compound (1 mmol), malo-
HRMS (ESI): m/z calcd for C10
H
6
N
3
O (M – N
2
CH
3
O): 184.0511; found:
nonitrile (1 mmol), and NaN3 (2 mmol) in H O (5 mL) was stirred at
184.0537.
2
5
0 °C until the starting materials were consumed (TLC monitoring).
Benzylation of Tetrazoles 2;16 General Procedure
The reaction mixture was filtered and to the filtrate was added aq 2 N
HCl (30 mL) until a precipitate was formed. The solid was filtered and
dried in a drying oven to furnish the expected tetrazoles 2f–j.
A mixture of the corresponding tetrazole 2 (1 mmol), benzyl bromide
(
1 mmol), and K CO (2 mmol) in DMF (5 mL) was stirred a 0 °C until
2 3
the conversion was complete (TLC monitoring). The reaction mixture
(
E)-3-(4-Hydroxyphenyl)-2-(1H-tetrazol-5-yl)acrylonitrile (2f)23
was filtered and to the filtrate was added H O (15 mL) and extracted
2
White solid; yield: 0.20 g (94%); mp 159–161 °C.
IR (KBr): 3330, 2642, 1509, 1411, 988, 821, 653, 604 cm–1
with EtOAc (3 × 10 mL). The combined organic layers were dried (Na
SO ), and after evaporation of the solvent (15 Torr) the resulting resi-
due was purified by recrystallization (EtOH) to yield tetrazoles 1.
2
-
4
.
1
H NMR (400 MHz, DMSO-d ): δ = 6.99 (d, J = 8.3 Hz, 2 H), 7.96 (d,
6
J = 8.3 Hz, 2 H), 8.23 (s, 1 H), 10.68 (br s, 1 H).
1
-Benzyl-5-phenyl-1H-tetrazole (1a)25
White solid; yield: 0.18 g (77%); mp 78–80 °C.
13
C NMR (101 MHz, DMSO-d ): δ = 91.9 (CN), 116.3 (C), 116.75 (CH),
6
123.7 (C), 133.1 (CH), 148.8, 155.6, 162.2 (C).
IR (KBr): 1651, 1274, 979, 854, 773, 615 cm–1
.
+
HRMS (ESI): m/z calcd for C10H NO (M – HN ): 156.0449; found:
6
4
1
H NMR (400 MHz, DMSO-d ): δ = 5.80 (s, 2 H), 7.32–7.50 (m, 8 H),
156.0452.
6
8.13 (dd, J = 7.5, 2.3 Hz, 2 H).
1
3
E)-3-Phenyl-2-(1H-tetrazol-5-yl)acrylonitrile (2g)23
C NMR (101 MHz, DMSO-d ): δ = 56.8 (CH ), 126.9, 128.4, 128.8,
(
6
2
1
28.9, 129.0, 130.3 (CH), 133.4, 162.7, 165.4 (C).
Pale yellow solid; yield: 0.10 g (51%); mp 168–170 °C.
IR (KBr): 3310, 2641, 1570, 1477, 982, 848, 669, 608 cm–1
+
HRMS (ESI): m/z calcd for C14
H
N
(M ): 236.1062; found: 236.1051.
12
4
.
1
H NMR (400 MHz, DMSO-d ): δ = 7.58–7.63 (m, 3 H), 8.00–8.15 (m, 2
6
,5-Dibenzyl-1H-tetrazole (1b)26
1
H), 8.42 (d, J = 3.6 Hz, 1 H).
White solid; yield: 0.2 g (80%); mp 140–142 °C.
IR (KBr): 1604, 1278, 976, 854, 693, 601 cm–1
1H NMR (400 MHz, DMSO-d
): δ = 4.21 (s, 2 H), 5.68 (s, 2 H), 7.18–
.37 (m, 10 H).
1
3
C NMR (101 MHz, DMSO-d ): δ = 97.4 (CN), 115.9 (C), 129.6, 130.0,
6
.
1
30.3, 132.6 (CH), 148.8, 155.9 (C).
HRMS (ESI): m/z calcd for C10H N (M+ – HN ): 168.0562; found:
1
6
6
3
2
7
68.0566.
13
C NMR (101 MHz, DMSO-d ): δ = 31.9, 56.6 (CH ), 126.9, 128.4,
6
2
E)-3-(4-Chlorophenyl)-2-(1H-tetrazol-5-yl)acrylonitrile (2h)24
128.6, 128.8, 128.9, 129.0 (CH), 133.35, 136.7, 165.9 (C).
(
White solid; yield: 0.16 g (75%); mp 158–160 °C.
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–F

E
Synthesis
C. Behloul et al.
Paper
HRMS (ESI): m/z calcd for C14H12N3 (M+ − CH N): 222.1031; found:
(E)-2-(1-Benzyl-1H-tetrazol-5-yl)-3-(4-chlorophenyl)acrylonitrile
2
222.1027.
(1h)
Green solid; yield: 0.14 g (45%); mp 170–172 °C.
IR (KBr): 2224, 1588, 1474, 1211, 962, 833, 687, 616 cm–1
1
-Benzyl-5-(4-nitrophenyl)-1H-tetrazole (1c)25
.
Green solid; yield: 0.18 g (66%); mp 76–78 °C.
1
H NMR (400 MHz, DMSO-d ): δ = 5.80 (s, 2 H), 7.32–7.53 (m, 7 H),
6
IR (KBr): 1604, 1282, 965, 852, 651, 601 cm–1
.
7.91 (d, J = 8.6 Hz, 2 H), 8.24 (s, 1 H).
1
13
H NMR (400 MHz, DMSO-d ): δ = 5.84 (s, 2 H), 7.33–7.52 (m, 5 H),
C NMR (101 MHz, DMSO-d ): δ = 57.3 (CH ), 99.1 (CN), 115.3 (C),
6
6
2
8
.30–8.33 (m, 4 H).
128.6, 129.1, 129.25, 129.5 (CH), 130.8 (C), 131.3 (CH), 132.7, 138.2
(C), 145.7 (CH), 161.6 (C).
13
C NMR (101 MHz, DMSO-d ): δ = 57.2 (CH ), 124.2, 127.7 128.5,
6
2
+
129.1, 129.2 (CH), 132.9, 133.2, 148.85, 163.6 (C).
HRMS (ESI): m/z calcd for C17H12ClN5 (M ): 321.0781; found:
+
321.0775.
HRMS (ESI): m/z calcd for C H N O (M ): 191.0443; found: 191.0452.
7
5
5
2
(
E)-2-(1-Benzyl-1H-tetrazol-5-yl)-3-(4-methoxyphenyl)acryloni-
5
-Benzhydryl-1-benzyl-1H-tetrazole (1d)
trile (1i)
White solid; yield: 0.27 g (84%); mp 133–135 °C.
IR (KBr): 1598, 1254, 953, 890, 688, 608 cm–1
Green solid; yield: 0.19 g (60%); mp 76–78 °C.
IR (KBr): 2221, 1594, 1497, 1217, 970, 825, 683, 613 cm–1
.
.
1
H NMR (400 MHz, DMSO-d ): δ = 5.35–5.37 (m, 3 H), 7.00–7.18 (m, 9
6
1
H NMR (400 MHz, DMSO-d ): δ = 3.87 (s, 3 H), 5.79 (s, 2 H), 6.98 (d,
H), 7.19–7.38 (m, 6 H).
6
J = 8.9 Hz, 2 H), 7.36–7.47 (m, 5 H), 7.97 (d, J = 8.8 Hz, 2 H), 8.20 (s, 1
H).
13
C NMR (101 MHz, DMSO-d ): δ = 46.55 (CH), 51.1 (CH ), 127.5,
6
2
127.8, 128.6, 128.9, 129.2 (CH), 133.15, 138.1, 156.2 (C);
1
3
C NMR (101 MHz, DMSO-d ): δ = 55.6 (CH ), 57.4 (CH ), 95.2 (CN),
+
6
3
2
HRMS (ESI): m/z calcd for C21H18N (M ): 326.1531; found: 326.1522.
4
1
(
14.6, 116.2, 125.2 (C), 127.9, 128.5, 129.1, 129.2, 132.3 (CH), 132.9
C), 146.8 (CH), 162.25, 162.7 (C).
HRMS (ESI): m/z calcd for C18H15N O (M ): 317.1277; found:
2
-(1-Benzyl-1H-tetrazol-5-yl)pyridine (1e)27
Green solid; yield: 0.20 g (88%); mp 75–77 °C.
+
5
3
17.1268.
IR (KBr): 1589, 1263, 999, 876, 690, 601 cm–1
.
1
H NMR (400 MHz, DMSO-d ): δ = 6.25 (s, 2 H), 7.19–7.52 (m, 6 H),
(E)-2-(1-Benzyl-1H-tetrazol-5-yl)-3-(4-Hydroxy-3-methoxyphe-
6
7.82–7.92 (m, 1 H), 8.33 (d, J = 7.9 Hz, 1 H), 8.74 (s, 1 H).
nyl)acrylonitrile (1j)
13
C NMR (101 MHz, DMSO-d ): δ = 52.6 (CH ), 124.5, 125.5, 128.3,
Green solid; yield: 0.20 g (63%); mp 170–172 °C.
6
2
1
28.4, 128.7 (CH), 134.8 (C), 137.5 (CH), 144.7 (C), 149.3 (CH), 151.6
IR (KBr): 2225, 1512, 1426, 1253, 939, 801, 671, 603 cm–1
.
(C).
1
H NMR (400 MHz, DMSO-d ): δ = 3.96 (s, 3 H), 5.23 (s, 2 H), 5.78 (s, 1
6
HRMS (ESI): m/z calcd for C13H N (M+ – N H ): 207.0796; found:
9
3
2
2
H), 6.94 (d, J = 8.5 Hz, 1 H), 7.38–7.43 (m, 6 H), 7.79 (s, 1 H), 8.17 (s, 1
H).
207.0792.
13
C NMR (101 MHz, DMSO-d ): δ = 56.1 (CH ), 57.1 (CH ), 95.3 (CN),
6
3
2
(
E)-2-(1-Benzyl-1H-tetrazol-5-yl)-3-(4-hydroxyphenyl)acryloni-
1
1
13.0 (CH), 116.2 (C), 125.7, 127.2, 128.1, 128.5, 128.7 (CH), 132.8,
36.1 (C), 147.0 (CH), 149.6, 151.6, 162.1 (C).
28
trile (1f)
Orange solid; yield: 0.23 g (77%); mp 160–162 °C.
IR (KBr): 2360, 1511, 1439, 1261, 997, 895, 672, 614 cm–1
HRMS (ESI): m/z calcd for C18H15NO2 (M+ – N ) 277.1103; found:
277.1085.
4
.
1
H NMR (400 MHz, DMSO-d ): δ = 5.13 (s, 2 H), 5.78 (s, 1 H), 7.05 (d,
6
J = 8.9 Hz, 2 H), 7.33–7.46 (m, 5 H), 7.97 (d, J = 8.8 Hz, 2 H), 8.20 (s, 1
H).
Indium-Promoted Debenzylation of Tetrazoles 1; General Proce-
dure
1
3
C NMR (101 MHz, DMSO-d ): δ = 52.6 (CH ), 95.3 (CN), 115.5 (CH),
A mixture of the corresponding benzylated tetrazole 1 (0.1 mmol)
and In powder (58 mg, 0.5 mmol) in MeOH (6 mL) and THF (4 mL) was
refluxed until the starting material disappeared (20 h). After cooling
to r.t., aq 1 M HCl (0.5 mL) was added and the mixture was extracted
with EtOAc (3 × 15 mL). The combined organic layers were washed
with brine (5 mL), dried (Na SO ), and evaporated (15 Torr). The re-
6
2
1
1
16.2, 125.45 (C), 127.5, 128.5, 129.1, 132.4 (CH), 132.8, 136.0 (C),
46.7 (CH), 161.8 (C).
HRMS (ESI): m/z calcd for C17H11NO (M+ – N H ): 245.0841; found:
2
4
2
45.0829.
2
4
sulting residue was recrystallized to give the corresponding pure
product 2. All the products were fully characterized by comparison of
their physical and spectroscopic data with pure samples of 2 (Table
1).
(
E)-2-(1-Benzyl-1H-tetrazol-5-yl)-3-phenylacrylonitrile (1g)29
Green solid; yield: 0.19 g (67%); mp 190–192 °C.
IR (KBr): 2332, 1596, 1443, 1211, 973, 856, 697, 605 cm–1
.
1
H NMR (400 MHz, DMSO-d ): δ = 5.80 (s, 2 H), 7.33–7.51 (m, 8 H),
6
Magnesium-Promoted Debenzylation of Tetrazoles 1; General Pro-
cedure
7
.91–8.02 (m, 2 H), 8.29 (s, 1 H).
13
C NMR (101 MHz, DMSO-d ): δ = 57.2 (CH ), 98.6 (CN), 115.6 (C),
6
2
To a solution of the corresponding benzylated tetrazole 1 (1 mmol) in
MeOH (5 mL) and THF (3 mL) was added freshly scratched Mg turn-
128.6, 129.1, 129.2, 129.3, 130.1, 132.1 (CH), 132.2 (C), 147.3 (CH),
161.8 (C).
ings (48 mg, 2 mmol) and a tiny crystal of I . The reaction mixture
2
+
HRMS (ESI): m/z calcd for C17H13N (M ): 287.1171; found: 287.1148.
5
was refluxed until the starting material was consumed (17–22 h) and
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–F

F
Synthesis
C. Behloul et al.
Paper
then cooled to 0 °C. The mixture was diluted with Et O (5 mL) and
(5) Papageorgiou, E. A.; Gaunt, M. J.; Yu, J.-q.; Spencer, J. B. Org. Lett.
2000, 2, 1049.
2
1
0% aq NH Cl was added. The mixture was stirred until it became
4
clear and then separated. The process was repeated once again and
the combined Et O extracts (2 × 5 mL) were dried (Na SO ) and evap-
(6) Tanielyan, S. K.; Alvez, G.; Marín, N.; Agustine, R. L. Top. Catal.
2014, 57, 1359.
2
2
4
orated (15 Torr) to give a residue that was purified by recrystalliza-
tion in EtOH, to afford the corresponding pure deprotected tetrazole
(7) Popova, E. A.; Protas, A. V.; Trifonov, R. E. Anticancer Agent Med.
Chem. 2017, 17, 1856.
2
. All the products were fully characterized by comparison of their
(8) (a) Yus, M.; Behloul, C.; Guijarro, D. Synthesis 2003, 2179.
(b) Behloul, C.; Guijarro, D.; Yus, M. Synthesis 2004, 1274.
physical and spectroscopic data with pure samples of 2 (Table 1).
(c) Behloul, C.; Bouchelouche, K.; Guijarro, D.; Nájera, C.; Yus, M.
Synthesis 2014, 46, 2065. (d) Behloul, C.; Bouchelouche, K.;
Guijarro, D.; Foubelo, F.; Nájera, C.; Yus, M. Synlett 2015, 26,
Zinc-Promoted Debenzylation of Tetrazoles 1; General Procedure
To a stirred solution of the corresponding benzylated tetrazole 1 (2.5
mmol) in THF (1.0 mL) at r.t. was added Zn dust (5 mmol) and stirring
was continued for an additional 30 min. The resulting suspension was
cooled with an ice-water bath and glacial AcOH (1.0 mL) was added
slowly. The cooling bath was removed and the final mixture was
stirred for further 1–3 h and then filtered. The collected solids were
washed with H O (3 × 10 mL) and CH Cl (3 × 15 mL). The organic
2
399. (e) Behloul, C.; Bouchelouche, K.; Hadji, Y.; Benseghir, S.;
Guijarro, D.; Nájera, C.; Yus, M. Synthesis 2016, 48, 2455.
f) Behloul, C.; Chouti, A.; Guijarro, D.; Foubelo, F.; Nájera, C.;
(
Yus, M. Tetrahedron 2016, 72, 7937. (g) Behloul, C.; Chouti, A.;
Chabour, I.; Bey, H. B.; Guijarro, D.; Foubelo, F.; Nájera, C.; Yus,
M. Tetrahedron Lett. 2016, 57, 3526.
2
2
2
(
9) Behloul, C.; Chouti, A.; Guijarro, D.; Nájera, C.; Yus, M. Synthesis
phases were separated, combined, and washed with H O (2 × 10 mL),
2
2015, 47, 507.
sat. aq NaHCO (3 × 10 mL), and brine (3 × 15 mL). After drying (Na -
3
2
(
(
(
(
10) Behloul, C.; Guijarro, D.; Yus, M. Synthesis 2006, 309.
SO ), and filtration, the solvent was evaporated under reduced pres-
4
11) Behloul, C.; Guijarro, D.; Yus, M. Tetrahedron 2005, 61, 6908.
12) Behloul, C.; Guijarro, D.; Yus, M. Tetrahedron 2005, 61, 9319.
13) Almansa, R.; Behloul, C.; Guijarro, D.; Yus, M. ARKIVOC 2007,
sure (15 Torr). The resulting residue was purified by recrystallization
to give the corresponding pure compound 2. All the products were
characterized by comparison of their physical and spectroscopic data
with pure samples of 2 (Table 1).
(vii), 41.
(
(
14) Koguro, K.; Oga, T.; Mitsui, S.; Orita, R. Synthesis 1998, 910.
15) Tisseh, Z. N.; Dabiri, M.; Nobahar, M.; Khavasi, H. R.; Bazgir, A.
Tetrahedron 2012, 68, 1769.
Funding Information
(
(
(
(
16) Wuts, P. G. M.; Greene, T. W. Greene’s Protective Organic Synthe-
sis; Wiley-Interscience: Hoboken, 2007, 4th ed. 814.
17) See, for instance: (a) Cintas, P. Synlett 1995, 1087. (b) Auge, J.;
Lubin-Germain, N.; Uziel, J. Synthesis 2007, 1739.
18) Hutchins, R. O. In Encyclopedia of Reagents for Organic Synthesis;
Paquette, L. A., Ed.; Wiley: Chichester, 1995, 3202–3204.
19) Huang, W.; Zhang, X.; Liu, H.; Shen, J.; Jiang, H. Tetrahedron Lett.
This work was financially supported by the Agence National pour le
Développement de la Reserch en Santé (Algérie) and the Spanish Min-
isterio de Ciencia e Innovación (CTQ2011-24155, CTQ2011-24165),
the Ministerio de Economía y Competitividad (CTQ2013-43446-P,
CTQ2014-51912-REDC, CTQ2014-53695-P, CTQ2017-85093-P), FED-
ER, the Generalitat Valenciana (PROMETEO 2009/039, PROMETEOII
2005, 46, 5965.
2014/017), and the University of Alicante. We also thank the Spanish
(
(
20) Boyle, W. J.; Bunnett, J. F. J. Am. Chem. Soc. 1974, 96, 1418.
21) Prices for powdered metals from the Aldrich catalogue: In
Ministerio de Asuntos Exteriores y de Cooperación (AP/039112/11).
S
p
a
nshiMneist
r
idCeineac
I
in
o
v
a
ócinC(
T
Q
2
0
1
1-2
4
1
5
5
S)
p
a
nshiMneist
r
idCeinIeacni
o
v
a
ócinC(
T
Q
2
0
1
1-
2
4
1
6
5
M) neistri
o
de
E
co
n
o
ma
í
y
C
o
m
pvdteiat
d
C(
T
Q
2
0
1
3-4
3
4
4
6-PM) neist
r
i
de
E
co
n
o
ma
í
y
C
o
m
pvdteiat
d
C(
T
Q
2
0
1
4-5
1
9
1
2-R
E
D
C
M) neistri
o
de
E
co
n
o
ma
í
y
C
o
m
pvdteiat
d
C(
T
Q
2
0
1
4-5
3
6
9
5-PM) neist
r
i
de
E
co
n
o
ma
í
y
C
o
m
pvdteiat
d
C(
T
Q
2
0
1
7-8
5
0
9
3-PG)
e
n
eaarilt
Vaelnacni a
P(
R
O
M
E
T
E
O
2
0
0
9
0/
3
9
G)
e
n
earailt
Vaelnacni a
P(
R
O
M
E
T
E
O
I
2
0
1
4
0/
1
7
S)
p
a
nshi
M
neist
r
i
de
Asu
n
ot
s
E
x
etoires
y
de
C
o
o
p
e
arócin
A(
P
0/
3
9
1
1
2
1/1)
(
99.99%), 10 g/115.50 €; Mg (≥99%), 100 g/24.40 €; Zn (≥99%),
00 g/55.80 €.
22) Rama, V.; Kanagaraj, K.; Pitchumani, K. J. Org. Chem. 2011, 76,
090.
5
(
(
Supporting Information
9
23) Tisseh, Z. N.; Dabiri, M.; Nobahar, M.; Khavasi, H. R.; Bazgir, A.
Tetrahedron 2012, 68, 1769.
24) Ahmed, N.; Siddiqui, Z. N. RSC Adv. 2015, 5, 16707.
25) Katritzky, A. R.; Cai, C.; Meher, N. K. Synthesis 2007, 1204.
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1610170.
S
u
p
p
ortioIgnfrm oaitn
S
u
p
p
ortioIgnfrm oaitn
(
(
References
(26) Suzuki, H.; Hwang, Y. S.; Nakaya, C.; Matano, Y. Synthesis 1993,
218.
1
(
1) See, for instance: Wuts, P. G. M.; Greene, T. W. Greene’s Protec-
tive Groups in Organic Synthesis; Wiley-Interscience: Hoboken,
007, 4th ed..
(27) Kiselyov, A. S. Tetrahedron Lett. 2005, 46, 4851.
(28) Safaei-Ghomi, J.; Paymard-Samani, S.; Zahedi, S.; Shahbazi-
Alavi, H. Z. Naturforsch. B 2015, 70, 819.
2
(
2) Babu, S. N. N.; Srinivasa, G. R.; Santhosh, D. C.; Gowda, D. C. J.
Chem. Res. 2004, 66.
(29) Maddila, S.; Naicker, K.; Momin, M. I. K.; Rana, S.; Gorle, S.;
Maddila, S.; Yalagala, K.; Singh, M.; Koorbanally, N. A.;
Jonnalagadda, S. B. Med. Chem. Res. 2016, 25, 283.
(3) Felpin, F.-X.; Fouquet, E. Chem. Eur. J. 2010, 16, 12440.
4) Sultane, P. R.; Mete, T. B.; Bhat, R. G. Tetrahedron Lett. 2015, 56,
(
2067.
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–F