LiCl-mediated, easy, and low-cost removal of the trityl group from protected alcohols and diols: Dedicated to Professor Joaquín Plumet on occasion of his retirement

Article abstract of DOI:10.1016/j.tetlet.2016.06.110

The reaction of primary, secondary, phenyl, allyl, and benzyl trityl ethers with lithium chloride in methanol at reflux led to deprotection of the trityl group affording the corresponding alcohol in good to excellent yields under mild reaction conditions.

Full text of DOI:10.1016/j.tetlet.2016.06.110

Accepted Manuscript
LiCl-mediated, easy and low-cost removal of the trityl group from protected
alcohols and diols
Cherif Behloul, Aicha Chouti, Ihssen Chabour, Hind Bengliz Bey, David
Guijarro, Francisco Foubelo, Carmen Nájera, Miguel Yus
PII:
S0040-4039(16)30789-4
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.06.110
TETL 47837
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
12 May 2016
14 June 2016
23 June 2016
Please cite this article as: Behloul, C., Chouti, A., Chabour, I., Bey, H.B., Guijarro, D., Foubelo, F., Nájera, C., Yus,
M., LiCl-mediated, easy and low-cost removal of the trityl group from protected alcohols and diols, Tetrahedron
Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.2016.06.110
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LiCl-mediated, easy and low-cost removal of the trityl
group from protected alcohols and diols
Cherif Behloul,*a Aicha Chouti,a Ihssen Chabour,a Hind Bengliz Bey,a David Guijarro,b,c Francisco
Foubelo,b,c,d Carmen Nájera,b,d Miguel Yusb,d
a
Laboratoire des Produits Naturels d’origine Végétale et de Synthèse Organique, Université des Frères Mentouri-
Constantine 25000 (Algérie)
b
Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Alicante, Apdo. 99, 03080 Alicante
(Spain)
c Instituto de Síntesis Orgánica (ISO), Universidad de Alicante, Apdo. 99, 03080 Alicante (Spain)
d Centro de Innovación en Química Avanzada (ORFEO-CINQA), Universidad de Alicante, Apdo. 99, 03080 Alicante
(Spain)
Tel/Fax: 213 31 81 88 62
Email: afiza72@gmail.com
Received: The date will be inserted once the manuscript is accepted.
Dedicated to Professor Joaquín Plumet on occasion of his retirement
Keywords: lithium chloride, detritylation, trityl ethers, protected alcohols, protected diols
Abstract: The reaction of primary, secondary, phenyl, allyl and benzyl trityl ethers with lithium chloride in methanol at
reflux led to deprotection of the trityl group affording the corresponding alcohol in good to excellent yields under mild
reaction conditions.
The trityl (triphenylmethyl) group is often employed for the selective protection of primary
alcohols and amines in carbohydrate,1 peptide2 and nucleotide3 chemistry, due to its high steric
demand. On the other hand, the cleavage of trityl ethers is involved in the manufacture of a number
of pharmaceuticals, drugs and other fine chemicals.4
In the search for useful methods for the selective deprotection of trityl protected alcohols or
phenols,5 various conditions for reductive cleavage of the trityl-oxygen bond have been reported
including triethylsilane,6 or low-valent titanium reagents.7 Catalytic cerium(IV) ammonium nitrate
adsorbed onto silica gel can efficiently oxidatively cleave the trityl-oxygen bond in nucleosides and
nucleotides.8 This protecting group can be also easily removed using Brønsted9 and Lewis acids10 or
bases,11 electrolytically,12 and by catalytic hydrogenation13 or reduction with sodium in liquid
ammonia;14 however most of these procedures are incompatible with reducible functionalities,
including multiple bonds.
In the last few years, our group has been interested in the deprotection of several functional
groups using naphthalene-catalyzed lithiation,15 including trityl ethers,16 trityl amines,17 silylated
alcohols, amines and thiols,18 Alloc- or Cbz- or Boc-protected alcohols, amines or thiols,19 esters,
amides and thioesters,20 and N-pivaloyltetrazoles.15l Other metals, such as indium21 or zinc22 under
protic conditions (MeOH), have been used for the deprotection of N-tritylated tetrazoles.

In the present paper we describe the deprotection of trityl protected alcohols and diols with
lithium chloride. This methodology represents a milder procedure than those already described and
therefore may be more compatible with other functional groups present in a molecule.23
Treatment of several trityl ethers 1 with lithium chloride in methanol at reflux overnight gave,
after hydrolysis with water, the expected alcohols 2 (Scheme 1 and Table 1).
Scheme 1. Deprotection of trityl ethers 1 using LiCl.
Table 1. LiCl-mediated deprotection of trityl ethers 1 in MeOH at reflux
Entry
1
Substrate
t (h)
12
Product
Yield (%)a
88
2
3
12
25
72
71
4
5
12
12
71
60
6
7
8
12
12
12
93
84
63

9
12
12
87
80
10
a Isolated yield
The starting trityl ethers 1 were prepared from the corresponding commercially available
alcohols 2 by reaction with trityl chloride in the presence of triethylamine and catalytic 4-
dimethylaminopyridine. They were fully characterized by comparison of their spectroscopic data
with authentic samples.16 The reaction was first examined using trityl ether 1a with LiCl (1:1 molar
ratio) in DMSO at reflux for 24 h,24 however the reaction failed and the starting material was
recovered. However, the same reaction conducted in MeOH at reflux for 12 h afforded the expected
alcohol 2a in 88% yield (Table 1, Entry 1). Other protected primary or secondary alcohols, such as
1b, 1f and 1g gave the corresponding products 2b, 2f and 2g, respectively (Entries 2, 6, and 7).
Mono and diprotected primary and secondary diols 1c-e were fully deprotected under similar
reaction conditions, with the monotritylated diol 1c requiring a prolonged reaction time of 25 h
(Entries 2-4). The allyl (1h) and benzyl (1i) ethers were deprotected without producing any
deallylation or debenzylation products (Entries 8 and 9). Finally, aromatic trityl ether 1j was
deprotected liberating phenol (Entry 10).
Concerning a possible mechanism, we believe that a trityl cation is involved in the process and is
captured by chloride to give trityl chloride which was isolated during the deprotection of 1a in 65%
yield.
In conclusion, we report a simple, mild and inexpensive method for the deprotection of trityl
ethers derived from aliphatic primary and secondary alcohols, diols and phenol. This methodology
can advantageously compete with other reported procedures, which are not so tolerant of other
functional groups.25
Acknowledgements
This work was financially supported by the Agence National pour le Développement de la Research
en Santé (Algérie) and the Spanish Ministerio de Ciencia e Innovación (CTQ2011-24155,
CTQ2011-24165), the Ministerio de Economía y Competitividad (CTQ2013-43446-P, CTQ2014-
51912-REDC, CTQ2014-53695-P), FEDER, the Generalitat Valenciana (PROMETEO 2009/039,

PROMETEOII/2014/017), and the University of Alicante. We also thank the Spanish Ministerio de
Asuntos Exteriores y de Cooperación (AP/039112/11).
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combined organic phases washed with brine (2.5 mL) and dried over Na2SO4. After solvent
evaporation (15 Torr), the residue was purified by column chromatography.

Graphical Abstract

Highlights
Inexpensive deprotection of trityl ethers with LiCl was reported.
Mild reaction conditions included methanol at reflux.
Tritylated alcohols, diols and phenols were easily deprotected.