Indium-Mediated Cleavage of the Trityl Group from Protected 1 H -Tetrazoles

Article abstract of DOI:10.1055/s-0034-1379933

On treatment with indium metal in MeOH-THF, trityl groups undergo reductive removal from 1H-protected tetrazoles (including aliphatic, aromatic, and heteroaromatic substituents), affording the corresponding free tetrazoles in excellent yields, without any decomposition of the tetrazole ring or reduction of any other group.

Full text of DOI:10.1055/s-0034-1379933

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Indium-Mediated Cleavage of the Trityl Group from Protected
1H-Tetrazoles
Cherif Behloul*a
Kenza Bouchelouchea
N
N
R
i. In, MeOH–THF, reflux
N
N
N
N
N
David Guijarrob
Francisco Foubelob
Carmen Nájerab
Miguel Yus*b
R
ii. 1 M HCl
N
Ph
Ph
H
Ph
R = alkyl, aryl, benzyl
a Laboratoire des Produits Naturels d’Origine Végétale et de Synthèse Organique, Université
de Constantine, Constantine 25000, Algérie
afiza72@gmail.com
b Departamento de Química Orgánica, Facultad de Ciencias, and Centro de Innovación en
Química Avanzada (ORFEO-CINQA), Universidad de Alicante, Apdo. 99, 03080 Alicante,
Spain
yus@ua.es
Dedicated to the memory of Prof. Manfred Schlosser
Received: 28.01.2015
Accepted after revision: 11.05.2015
Published online: 19.06.2015
indium(III) chloride was also reported,6 this methodology
being also applied to the chemoselective deprotection of
different functional groups in polyfunctionalized sub-
strates.
On the other hand, in the world drug, there are more
than six types of sartans, which display different biological
activities. Some of them, such as candesartan, irbesartan,
losartan, olmesartan, and valsartan, bear a tetrazol unit in
their structures and have a variety of therapeutic targets
like angiotensin II receptor blocker, lowering blood pres-
sure, and playing a significant role in the progression of tis-
sue damage in cardiovascular diseases.7
The protection and deprotection of the nitrogen atom of
the tetrazole ring is a crucial operation during the synthesis
of these sartans. One group that can be used to protect the
tetrazole nitrogen is the triphenylmethyl (trityl) group.8
Detritylation of tetrazole N-trityl-protected sartan deriva-
tives to produce the free N–H bonds was carried out under
different conditions: hydrogenolysis in the presence of Pt/C
(5%)9 or with aqueous NaOH in MeOH.8 Surprisingly, in the
last case, the removal took place without any side reaction
and in excellent yields.
DOI: 10.1055/s-0034-1379933; Art ID: st-2015-s0063-c
Abstract On treatment with indium metal in MeOH–THF, trityl groups
undergo reductive removal from 1H-protected tetrazoles (including ali-
phatic, aromatic, and heteroaromatic substituents), affording the cor-
responding free tetrazoles in excellent yields, without any decomposi-
tion of the tetrazole ring or reduction of any other group.
Key words tetrazole, indium, detritylation, cleavage
Indium metal is an excellent, useful reagent for a broad
range of organic reductions.1 Indium has a first electrode
potential of 5.8 eV, which is similar to that of the alkali met-
als, such as sodium (5.1 eV) and lithium (5.4 eV), and much
lower than that of zinc and magnesium.2 Due to that, indi-
um has demonstrated to be an excellent single-electron-
transfer reducing reagent, and has been used for the remov-
al of many protecting groups. For instance, Moody et al. re-
ported the general reductive removal of 4-nitrobenzyl oxy-
gen protecting group with this reagent. In this reaction, the
nitro group is reduced first to give the corresponding ani-
line, which activates the benzilic carbon–oxygen bond to-
wards the addition of an electron.3
In addition, reductive dehalogenations of α-halocarbon-
yl compounds with indium in the presence of a catalytic
amount of sodium dodecyl sulfate in water were performed
to afford the corresponding parent carbonyl compounds in
excellent yields,4 and 2,2,2-trichloroethyl carboxylates
smoothly underwent deprotection to carboxylic acids and
reductive monodechlorination to 2,2-dichloroethyl esters.5
Furthermore, the selective cleavage of tert-butyldimethyl-
silyl ethers to give the corresponding alcohols by means of
Our research group has already reported the removal of
the trityl protecting unit in different functional groups us-
ing an arene catalyzed lithiation. All these reactions were
performed at –78 °C in excellent yields.10
N
N
R
i. In, MeOH–THF, reflux
N
N
N
N
N
R
ii. 1 M HCl
N
Ph
Ph
H
Ph
R = alkyl, aryl, benzyl
1
2
Equation 1
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Table 1 (continued)
Entry Substrate
In the course of developing deprotection methods of
many protecting groups, we attempt to remove the trityl
unit using different electron-transfer sources, such as lithi-
um, sodium, samarium, and indium.10,11 The application of
indium metal reductive removal of the trityl group from the
nitrogen atom of several protected tetrazoles under mild
reaction conditions is discussed below (Equation 1).
Time Product
(h)
Yield
(%)a
O
N
N
O
N
N
N
N
8
20
88
N
N
H
Tr
2h
1h
Table 1 Indium-Mediated Cleavage of the Trityl Group under Reflux
from Protected 1H-Tetrazoles
Entry Substrate
Time Product
(h)
Yield
(%)a
9
23
82
N
N
N
N
N
N
HN
N
N
N
N
N
Tr
2i
1i
N
NH
N
N
Tr
1
26
93
10
20
77
1a
2a
Tr
N
N
N
HN
N
N
N
N
Tr
2j
1j
H
N
N
a Yield of isolated product after purification by column chromatography
(basic aluminum oxide, hexane–EtOAc), based on the starting material.
N
N
N
N
N
N
2
21
96
With the aim of determining the best reaction condi-
tions for the removal of the trityl group bonded to the ni-
trogen in different tetrazoles, we took 5-phenyl-1-trityl-
1H-tetrazole (1a) as the model compound. Unfortunately,
no reaction occurred when tetrazole 1a was treated with
indium metal (1:1 molar ratio) in a mixture of MeOH and
THF (2:1 volume ratio) at 0 °C for 24 hours. However, full
conversion was observed when this reaction mixture was
heated at reflux temperature for 26 hours, 5-phenyl-1H-
tetrazole (2a) being isolated in 93% yield after purification
by column chromatography (Table 1, entry 1). In the ab-
sence of indium, the cleavage did not take place under the
same reaction conditions. On the other hand, indium was
partially consumed during the reaction, before the acidic
hydrolysis. In order to broaden the scope of this indium-
mediated detritylation, we applied the same reaction con-
ditions to different 5-substituted tetrazoles. Detritylation of
tetrazoles bearing aromatic (1b and 1j) and benzylic (1c
and 1i) substituents at the 5-position occurred also in high
yields (Table 1, entries 2, 3, 9, and 10). Actually, compound
2b is a direct precursor of the sartans.9 Similar results were
also obtained for aliphatic substituted tetrazoles. Thus, for
compound 1d with a sterically demanding tert-butyl group
at the 5-position, detritylation produced 5-tert-butyl-1H-
tetrazole in 92% yield (Table 1, entry 4). In the case of tetra-
zole 1e bearing a long linear aliphatic chain, the detritylated
tetrazole 2e was obtained in 81% yield (Table 1, entry 5).
1b
2b
3
25.5
80
N
N
N
Tr
N
HN
N
N
N
1c
2c
N
N
N
N
N
N
4
5
6
22
21
23
92
81
86
N
N
H
Tr
2d
1d
1e
1f
N
N
N
N
N
10
10
N
N
N
H
Tr
2e
2f
N
N
N
N
N
N
N
N
N
HN
Tr
Tr
N
N
N
HN
N
N
H2N
7
4
93
N
N
HN
2g
Tr
1g
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These reaction conditions were also highly effective in
the detritylation of functionalized tetrazoles. For instance,
tritylated tetrazole with a heteroaromatic 2-pyridyl substit-
uent at the 5-position gave 5-(2-pyridyl)-1H-tetrazole (2f)
in 86% yield (Table 1, entry 6). Even more interestingly, a
double deprotection of ditritylated 5-amino-substituted
tetrazole 1g was observed, leading to 5-amino-1H-tetrazole
(2g) in 93% yield (Table 1, entry 7). Comparing with the lith-
ium arene catalyzed detritylation, this methodology seems
to be superior, because previous deprotonation with n-bu-
tyllithium of tetrazole 1g was not necessary. The starting
material 1g has an N–H bond which is acidic enough to de-
compose the naphthalene radical anion and dianion that
act as lithiation agents. This is the reason why it has to be
removed first, beforethe lithium–arene combination is used
in these reductive reactions. This methodology was also
compatible with the presence of carbonyl groups. Detrityla-
tion of 1h gave 1-(1H-tetrazol-5-yl)propan-2-one (2h) in
88% yield (Table 1, entry 8), the removal of the trityl unit
taking place without affecting the carbonyl group under
these reductive reaction conditions.
eración for a cooperation grant (AP/039112/11). We are also very
grateful to Dr. Rosa Ortiz for her valuable help.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1379933.
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References and Notes
(1) (a) Woo, H. G.; Choi, H. T. Indium Properties, Technological Appli-
cations and Health Issues; Nova Science Publishers: New York,
2013. (b) Perchyonok, V. T. Radical Reactions in Aqueous Media;
Royal Society of Chemistry: Cambridge, 2010.
(2) For reviews, see: (a) Podlech, J.; Maier, T. C. Synthesis 2003, 633.
(b) Yadav, J. S.; Antony, A.; George, J.; Subba, R. B. V. Eur. J. Org.
Chem. 2010, 591. (c) Shen, Z. L.; Wang, S. Y.; Chok, Y. K.; Xu, Y.
H.; Loh, T. P. Chem. Rev. 2013, 113, 271.
(3) Moody, C. J.; Pitts, M. R. Synlett 1999, 1575.
(4) Leeyoung, P.; Gyochang, K.; Soon, B. K.; Kwan, S. K.; Youseung, K.
J. Chem. Soc., Perkin Trans. 1 2000, 4462.
(5) Tomoko, M.; Hisao, K.; Takehisa, K. Tetrahedron Lett. 2007, 48,
5027.
The progress of the reactions was monitored in all cases
by thin-layer chromatography. Once the reaction went to
completion, final hydrolysis with 1 M HCl led to the corre-
sponding tetrazoles 2. After hydrolysis, the triphenylmeth-
ane and the tetrazole products were extracted with EtOAc
and then easily separated by column chromatography.
The starting Tr-tetrazoles 1 were prepared by reaction
of the corresponding tetrazole 2 with trityl chloride in the
presence of triethylamine and a catalytic amount of 4-(di-
methylamino)pyridine. Compounds 2a,g,i are commercially
available and 2b–f,h,j were prepared by us.12 All of these
compounds were characterized by comparison of their
physical and spectroscopic data with authentic samples.
In summary, in this paper we have presented a very effi-
cient method for the detritylation of protected tetrazoles
using indium as an electron source. The methodology has
proven to be useful for the removal of the trityl group from
Tr-tetrazoles substituted on the carbon atom of the ring by
aromatic, heteroaromatic, aliphatic, or benzylic carbon
chains, with, in some cases, sensitive functionalities like
carbonyl and amino groups. The double detritylation of a
Tr-tetrazole in the presence of a secondary Tr-amine was
also observed. This method represents a good alternative to
the commonly used detritylation procedures, which are
sensitive to air moisture and acidic conditions.13,14
(6) Yadav, J. S.; Subba, B. V.; Madan, C. New J. Chem. 2000, 24, 853.
(7) Daugherty, A.; Cassis, L. Trends Cardiovasc. Med. 2004, 14, 117.
(8) Srimurugan, S.; Suresh, P.; Babu, B.; Hiriyanna, S. G.; Pati, H. N.
Chem. Pharm. Bull. 2008, 56, 383.
(9) García, G.; Rodríguez-Puyol, M.; Alajarín, R.; Serrano, I.;
Sánchez-Alonso, P.; Griera, M.; Vaquero, J.; Rodríguez-Puyol, D.;
Álvarez-Builla, J.; Díez-Marqués, M. J. Med. Chem. 2009, 52,
7220.
(10) (a) Yus, M.; Behloul, C.; Guijarro, D. Synthesis 2003, 2179.
(b) Behloul, C.; Guijarro, D.; Yus, M. Synthesis 2004, 1274.
(c) Behloul, C.; Guijarro, D.; Yus, M. Tetrahedron 2005, 61, 6908.
(d) Behloul, C.; Guijarro, D.; Yus, M. Tetrahedron 2005, 61, 9319.
(e) Behloul, C.; Guijarro, D.; Yus, M. Synthesis 2006, 309.
(f) Behloul, C.; Guijarro, D.; Yus, M. ARKIVOC 2007, (vii), 41.
(g) Behloul, C.; Bouchelouche, K.; Guijarro, D.; Najera, C.; Yus, M.
Synthesis 2014, 2065. (h) Behloul, C.; Chouti, A.; Guijarro, D.;
Najera, C.; Yus, M. Synthesis 2015, 47, 507.
(11) For reviews, see: (a) Yus, M. Chem. Soc. Rev. 1996, 25, 155.
(b) Ramón, D. J.; Yus, M. Eur. J. Org. Chem. 2000, 225. (c) Yus, M.
Synlett 2001, 1197. (d) Yus, M.; Ramón, D. J. Latv. J. Chem. 2002,
79. (e) Ramón, D. J.; Yus, M. Rev. Cubana Quim. 2002, 14, 76.
(f) Yus, M. In The Chemistry of Organolithium Compounds;
Rappoport, Z.; Mareck, I., Eds.; J. Wiley and Sons: Chichester,
2004, Chap. 1. For a mechanistic study, see: (g) Yus, M.; Herrera,
R. P.; Guijarro, A. Tetrahedron Lett. 2001, 42, 3455. (h) Yus, M.;
Herrera, R. P.; Guijarro, A. Chem. Eur. J. 2002, 8, 2574. (i) Herrera,
R. P.; Guijarro, A.; Yus, M. Tetrahedron Lett. 2003, 44, 1309.
(12) With the aim of trying to broaden the substrate scope, we tried
to prepare some other tetrazoles functionalized with either
ester or amide groups but, unfortunately, all our attempts were
unsuccessful.
Acknowledgment
(13) Typical Procedure
In a typical procedure, a mixture of 5-phenyl-1-trityl-1H-tetra-
zole (1a, 0.230 g, 0.5 mmol) and indium powder (0.058 g, 0.5
mmol) in MeOH (6 mL) and THF (3 mL) was stirred at 78 °C for
26 h. Then the resulting mixture was cooled to r.t., hydrolyzed
with 1 M HCl (2 mL), extracted with EtOAc (3 × 10 mL), dried
over anhydrous MgSO4, and evaporated (20 mbar). The resulting
This work was financially supported by the A.N.D.R.S (Agence Natio-
nale pour le Développement de la Recherche en Santé) (Algérie), the
Ministerio de Ciencia e Innovación of Spain (CTQ2011-24165, Consol-
ider Ingenio 2010 CSD2007-00006), The Generalitat Valenciana (PRO-
METEO/2009/039, PROMETEOII/ 2014/017 and FEDER). We are very
grateful to the Spanish Ministerio de Asuntos Exteriores y de Coop-
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residue was purified by column chromatography (silica gel,
hexane–EtOAc) to yield 5-phenyl-1H-tetrazole (2a, 0,134 g,
93%) as a white solid, mp 215–216 °C. 1H NMR (300 MHz,
DMSO-d6): δ = 7. 55–7.62 (m, 3 H), 8.01–8.10 (m, 2 H). 13C NMR
(75 MHz, DMSO-d6): δ = 124.1 (2 × CH), 127.0 (C), 129.4 (CH),
131.3 (2 × CH), 155.3 (C).10h
(14) For all detailed procedures, see the attached Supporting Infor-
mation.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2399–2402