Tetrabutylammonium bromide: An efficient media for dimethoxytritylation of the 5'-hydroxyl function of nucleosides

Article abstract of DOI:10.1016/j.tetlet.2004.07.054

An efficient procedure for selective dimethoxytritylation of the 5'-hydroxyl function of nucleosides in the presence of DABCO in molten tetrabutylammonium bromide is described. The methodology is very practical, environmentally benign and produced the desired product in less than 5 min by grinding in a hot mortar. In addition, the effects of the room temperature ionic liquid (1-butyl-3-methylimidazolium chloride) and microwave irradiation on this system were also studied and the results showed that depurination of the nucleosides occurred under microwave irradiation.

Full text of DOI:10.1016/j.tetlet.2004.07.054

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 6737–6739
Tetrabutylammonium bromide: an efficient media for
dimethoxytritylation of the 50-hydroxyl function of nucleosides
Ali Khalafi-Nezhad* and Babak Mokhtari
Department of Chemistry, College of Science, Shiraz University, Shiraz 71454, Iran
Received 27 May 2004; revised 7 July 2004; accepted 13 July 2004
Available online 30 July 2004
Abstract—An efficient procedure for selective dimethoxytritylation of the 50-hydroxyl function of nucleosides in the presence of
DABCO in molten tetrabutylammonium bromide is described. The methodology is very practical, environmentally benign and pro-
duced the desired product in less than 5min by grinding in a hot mortar. In addition, the effects of the room temperature ionic liquid
(1-butyl-3-methylimidazolium chloride) and microwave irradiation on this system were also studied and the results showed that dep-
urination of the nucleosides occurred under microwave irradiation.
ꢀ 2004 Elsevier Ltd. All rights reserved.
Nucleoside derivatives are interesting classes of com-
pounds because they possess important biological activ-
ity and have found widespread application in anticancer
and antiviral drugs. These applications increase the
demand for synthetic oligonucleotides and stimulate
organic chemists to introduce efficient and practical
methods towards protected ribonucleosides.1
and triethylamine in N,N-dimethylformamide (DMF),6
and dimethoxytrityl or monomethoxytrityl tetrafluoro-
borate in nitromethane.7 Solid phase tritylation of nucleo-
sides and nucleotides has also been reported.8
The major challenging problem in protection and other
reactions of nucleosides is the insolubility of these com-
pounds in many organic solvents. Pyridine, DMF and
N-methylpyrrolidine (NMP) are usually used in nucleo-
side transformations, however, they are not environ-
mentally friendly solvents.
Among the various hydroxyl protecting groups, triphe-
nyl (Tr), monomethoxytriphenyl (MMTr) and dimeth-
oxytriphenyl (DMTr) methyl ethers have been widely
used for protection of hydroxyl moieties in saccharide
and nucleoside chemistry for about 50years. Their util-
ity is attributed to the high selectivity for protecting pri-
mary hydroxyl groups of polyols as well as the ease and
mildness in preparing and removing the trityl group.
Other less common derivatives of trityl have been used
for this purpose.2
The use of environmentally benign reaction media is
very important in view of todayÕs environmentally con-
scious attitude. In connection with this, molten salts9
and room temperature ionic liquids10 have received a
great deal of attention over the past decade as novel sol-
vent systems for organic transformations. More recently
the solubility of some deoxynucleosides and their acyl-
ation in various ionic liquids has been studied.11
The classical methods for introducing trityl and their
methoxy derivatives to the 50-hydroxyl function of nu-
cleosides include reaction of the appropriate chlorotri-
arylmethane with nucleosides in pyridine,2 which can be
speeded up by using a catalytic amount of silver nitrate.4
Other methods use N-tritylpyridinium tetrafluoroborate
in acetonitrile,5 or trityl chloride/dimethylaminopyridine
Herein, and as an extension of our previous studies on
the application of green chemistry principles in organic
synthesis,12 especially for the protection of nucleo-
sides,13 we wish to report a simple, remarkable fast
and selective procedure for dimethoxytritylation of the
50-hydroxyl function of various nucleosides in molten
tetrabutylammonium bromide as homogenizer in the
presence of an appropriate acid scavenger. The reaction
proceeded very quickly with high yields and gave the
desired dimethoxytrityl ethers at >140ꢁC in less than
Keywords: Protection; Nucleosides; Dimethoxytritylation; Ionic liq-
uids; Molten salts.
*
Corresponding author. Tel.: +98-711-2282380; fax: +98-711-
2280926; e-mail: khalafi@chem.susc.ac.ir
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.07.054

6738
A. Khalafi-Nezhad, B. Mokhtari / Tetrahedron Letters 45 (2004) 6737–6739
Table 1. The results for dimethoxytritylation of uridine in the presence
of different solid bases at 140ꢁC
oxytrityl ether was formed after 3min at 900W (micro-
wave power) in moderately low yield. Efforts to obtain a
higher yield by increasing the irradiation time failed
resulting in depurination. To the best of our knowledge,
there is no previous report of the depurination of nucleo-
sides under microwave irradiation.
Base
Yield (%)
DABCO
DMAPa
84
72
15
20
27
Basic alumina
K2CO3
Cs2CO3
Because of the high relative solubility of the nucleosides
in 1-butyl-3-methyl imidazolium chloride (bmimCl),11
this ionic solvent was applied for the dimethoxytrityl-
ation of uridine. On this occasion the reaction took a long
time and did not give complete conversion of uridine to
50-dimethoxytrityluridine even after 6h at 120ꢁC. The
isolated yield of 50-dimethoxytrityluridine in this case
was less than 35%.
5min by grinding in a hot mortar. The results are sum-
marized in Table 2.
In order to choose the appropriate base, the reaction of
uridine with dimethoxytrityl chloride was carried out in
the presence of several solid bases. As shown in Table 1,
1,4-diazabicyclo[2,2,2]octane (DABCO) gave the highest
yield and was therefore selected as the base for subse-
quent reactions. Liquid bases cannot be used, because
of evaporation at the high temperature employed.
In conclusion, the use of this environmentally friendly
reaction system was found to be a very suitable proce-
dure for the preparation of some protected nucleosides.
Moreover, this methodology offers significant improve-
ments with regard to yield of the products and simplicity
of operation especially purification. We believe that this
procedure could be applied as a practical alternative to
previously reported methods.
The effect of temperature in the range of 100–150ꢁC was
investigated. The results showed that a temperature
range between 140 and 150ꢁC gave the best yields. Sub-
sequent studies showed that the presence of tetrabutyl-
ammonium bromide was essential for achieving an
efficient and fast reaction.
General procedure: Protection of the nucleoside was car-
ried out by grinding the mixture of nucleoside
(1.1mmol), dimethoxytrityl chloride (1mmol), DABCO
(1.3mmol) and tetrabutylammonium bromide (0.5g) in
a hot mortar for 5min (the mortar was placed in an oven
for 2h at 140ꢁC). The reaction mixture was then allowed
to cool, dissolved in EtOAc (50mL) and extracted with
5% NaHCO3. The organic layer was separated and
washed with water (2 · 30mL), dried over anhydrous
Na2SO4 and after evaporation of the solvent the product
was further purified by column chromatography using
ethyl acetate/n-hexane (9/1) as the eluent.
As shown in Table 2, uridine, thymidine and adenosine
(entries 1, 4 and 5, respectively), were easily protected
using dimethoxytrityl chloride (DMTrCl) in high yields.
Trityl chloride (TrCl) and monomethoxytrityl chloride
(MMTrCl) have also been used as protecting groups in
this reaction (entries 2 and 3, respectively). We found
that there were no significant differences on the rate
and yields of reaction between these protective groups
and dimethoxytrityl chloride. We also tried to protect
the 50-hydroxyl function of guanosine and cytidine using
this method but all efforts failed and a mixture of several
unidentified products was obtained.
Acknowledgements
To gain a comparison between the effect of conventional
heating and microwave irradiation on this reaction, di-
methoxytritylation of uridine in the presence of DABCO
and tetrabutylammonium bromide under microwave
irradiation was carried out. The corresponding dimeth-
We thank Shiraz University research council for finan-
cial support of this work. We are grateful to Dr. G. Abs-
alan for helpful discussions. We also thank Mr. Sajedian
Fard for running the NMR spectra.
References and notes
Table 2. Selective tritylation of the 50-hydroxyl group of nucleosides in
the presence of DABCO and tetrabutylammonium bromide
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O
B
R2O
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R2Cl, DABCO, n-Bu4NBr
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°
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Entry
B
R1
R2
DMTr 84
Tr 82
Yielda (%) Mp (ꢁC)
1
2
3
4
5
Uracil
Uracil
OH
OH
H
111–1124
105–10714
102–1043
121–1233
142–1444
Thymine
Thymine
Adenine OH
MMTr 85
DMTr 86
DMTr 79
H
a Isolated pure product.

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