An efficient and selective method for the preparation of triphenylmethyl ethers of alcohols and nucleosides

Article abstract of DOI:10.1139/V10-042

A very simple and efficient method is described for the protection of alcohols and nucleosides with benzyl monomethoxytrityl and benzyl dimethoxytrityl ethers in the presence of diethylazodicarboxylate and a catalytic amount of ceric triflate. High selectivity was observed for the tritylation of 5'-OH function of nucleosides.

Full text of DOI:10.1139/V10-042

563
An efficient and selective method for the
preparation of triphenylmethyl ethers of alcohols
and nucleosides
Negar Zekri and Reza Fareghi Alamdari
Abstract: A very simple and efficient method is described for the protection of alcohols and nucleosides with benzyl
monomethoxytrityl and benzyl dimethoxytrityl ethers in the presence of diethylazodicarboxylate and a catalytic amount of
ceric triflate. High selectivity was observed for the tritylation of 5’-OH function of nucleosides.
Key words: selective hydroxyl-group protection, benzyl dimethoxytrityl ether, ceric tiflate, nucleosides.
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Resume : On a developpe une methode tres simple et efficace de proteger des alcools et des nucleosides par formation
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d’ethers benzylmonomethoxytrityle et benzyldimethoxytrityle, en presence d’azodicarboxylate de diethyle et d’une quan-
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tite catalytique de triflate cerique. On a observe une grande selectivite lors de la tritylation de la fonction 5’-OH des
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nucleosides.
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Mots-cles : protection selective d’un groupe hydroxyle, ether benzyldimethoxytrityle, triflate cerique, nucleosides.
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[Traduit par la Redaction]
chromatography was very difficult. Hakimelahi et al. re-
ported a method for the tritylation of alcohols and nucleo-
sides by the use of silver ion as catalyst.8 The use of silver
ion for the tritylation of alcohols and nucleosides increased
the rate of tritylation, so the selectivity of the tritylation of
nucleosides decreased. Recent work has included variations
and improvements of the well-established tritylation proce-
dures and the discovery and application of entirely new
methods. The use of different reagents and media, such as
acid-washed molecular sieves for the tritylation of sacchari-
dic hydroxyls,9 tetrabutyl ammonium bromide medium for
the dimethoxy-tritylation of –OH function of nucleosides,10
and 1-butyl-3-methylimidazolium chloride for the tritylation
of cellulose,11 is reported. Several other reagents, such as
TrODT-TrTCl5,12 AgOTf-TrCl,13 prenyl trityl ether (PTE)-
DDQ,14 and B(C6F5)3,15 are also available. However, most
of these methods suffer from one or more disadvantages, in-
cluding long reaction times, vigorous reaction conditions,
and poor yields of the products in many cases. Oikawa et
al. reported benzyl trityl ether and DDQ as alternative trity-
lation reagents.16 However, the conditions of that reaction
have been found to have limited applicability, and it is used
only for the tritylation of alcohols and not for any nucleo-
sides.
Introduction
Hydroxyl-group protection is important in the synthesis of
some organic molecules. One way to protect hydroxyl
groups is to transform the molecules to their corresponding
trityl (Tr) ethers.1 Distinctive features of the trityl group are
the following: (i) owing to its bulkiness, selective protection
of polyols as monotritylated ethers is easily achieved, (ii) re-
moval (deprotection) of the trityl group is easily affected by
the action of mild acids such as formic acid2 or Amberlyst
resin.3 There are several methods for the preparation of trityl
ethers from the corresponding alcohols. Use of trityl chlor-
ides in the presence of pyridine as a base and a solvent
seems to be the most popular method for the preparation of
trityl ethers.4,5 This method requires the use of pyridine as a
solvent, which is a toxic compound with high boiling point,
and needs an aqueous work-up. In addition, this method suf-
fers from prolonged reaction time. Other reagents for the tri-
tylation of alcohols include a complex of trityl chloride and
4-dimethoxytrityl pyridine (DMAP) prepared beforehand.6
Selective protection of hydroxyl groups is an important
synthetic strategy for the preparation of nucleoside deriva-
tives. This work has been performed with varying degrees
of success. The general procedure used for the tritylation of
nucleosides is on the basis of that originally developed by
Khorona.7 Using Khorona’s procedure for the tritylation of
nucleosides, a mixture of monotritylated materials (i.e., 5’-
OTr, 2’-OTr, and 3’-OTr) and ditritylated materials (2’,5’-
OTr, 3’,5’-OTr, and 2’,3’-OTr) was obtained, and the separa-
tion of unreacted remaining starting materials with column
We have reported the deprotection of trityl ethers by the
use of a catalytic amount of ceric tiflate [Ce(OTf)4], and we
showed that the rate-determinating step of that reaction is
involved in the production of trityl cation step.17 So, we de-
cided to study the tritylation of alcohols and nucleosides by
Received 21 September 2009. Accepted 23 November 2009. Published on the NRC Research Press Web site at canjchem.nrc.ca on
17 May 2010.
N. Zekri and R.F. Alamdari.1 Department of Chemistry and Chemical Engeenering, Faculty of Material and Chemical Engineering,
Malek-Ashtar University of Technology (MUT), Lavizan, Tehran, P.O. Box 16765-3454, Iran.
1Corresponding author (e-mail: reza_fareghi@yahoo.com).
Can. J. Chem. 88: 563–568 (2010)
doi:10.1139/V10-042
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Can. J. Chem. Vol. 88, 2010
Table 1. Investigation of the effect of various cerium anions and the presence of DEAD on the dimethoxytritylation of alco-
hols in acetonitrile at room temperature.
Molar Ratio
Entry
BDTE
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
DEAD
—
1.2
1.2
1.0
1.2
1.2
1.2
1.2
Ce(OTf)4
0.05
—
0.02
0.05
0.05
—
—
—
—
Ce(NO3)6(NH4)2
—
—
—
—
—
0.02
0.05
—
Ce(SO4)3(NH4)2
—
—
—
—
—
—
—
Time (min)
120
120
120
120
15
120
90
120
Yield (%)
1
2
3
4
5
6
7
8
9
—
—
42
73
95
15
85
27
93
0.02
0.05
1.2
1.2
—
50
the use of benzyl trityl ether (BTE) as well as benzyl mono-
methoxytrityl (BMTE) and benzyl dimethoxytrityl (BDTE)
ethers. In this work, we report a new, mild, and efficient
method for hydroxyl-group protection by the reaction of pri-
mary, secondary, and tertiary alcohols and nucleosides with
BMTE or BDTE ethers and ceric triflate in the presence of
diethylazodicarboxylate (DEAD). We found that Ce(OTf)4
catalyzes the efficient tritylation of alcohols and nucleosides
with BMTE and BDTE in the presence of DEAD.
and 2). The effect of different solvents on the yield of the
reaction is presented in Table 3.
A typical procedure for the preparation of
diphenylmethyl dimethoxytrityl ether with BDTE and
DEAD in the presence of Ce(OTf)4
A solution of benzhydrol (0.92 g, 5 mmol), DEAD
(1.05 g, 6 mmol), and BDTE (2.46 g, 6 mmol) in CH3CN
(50 mL) was prepared. Ce(OTf)4 (0.37 g, 0.5 mmol) and ac-
˚
tivated molecular sieves (4 A, 2 g) were added to this solu-
tion, and the mixture was stirred for a specified time (1.5 h)
at room temperature. When either the alcohol or BDTE was
completely consumed (TLC was used for monitoring), the
reaction was quenched by the addition of 50 mL of 5%
NaHCO3. The mixture was extracted with chloroform (3 Â
35 mL), and the combined extract was dried over Na2SO4.
After evaporation of the solvent, the resulting mixture was
introduced into a silica gel column eluted with CH2Cl2. The
pure diphenylmethyl dimethoxytrityl ether was obtained as a
pale yellow solid in 82% yield (Table 2); mp 62 8C. Rf
(EtOAc:n-hexane, 8:2): 0.3. 1H NMR (CDCl3, ppm) d:
7.49–6.91 (m, 23H, Ph–), 5.36 (s, 1H, CH–), 3.77 (s, 6H,
CH3–).
Experimental
The chemicals were either prepared in our laboratories or
purchased from Fluka or Merck Chemical Companies. All
yields refer to isolated products after column chromatogra-
phy. The products were characterized by their spectral data.
NMR spectra were recorded on a Bruker advanced DPX-
250 MHz, FTNMR spectrometer. Melting points were deter-
mined on a Buchi 510 in open capillary tubes circulating oil
melting point in open apparatus and are uncorrected. The
purity of the substance and the progress of the reactions
were monitored by TLC on silica gel polygram SILG/
UV254 plates. Column chromatography was carried out on
the medium column of silica gel 60 Merck (30–270 mesh)
in glass column (1 or 2 cm diameter) using 10–20 g of silica
gel per 1 g of mixture.
Preparation of 5’-O-monomethoxytrityl thymidine with
BMTE and DEAD in the presence of Ce(OTf)4
A suspension of thymidine (0.48 g, 2 mmol), DEAD
(0.42 g, 2.4 mmol), and BMTE (0.9 g, 2.4 mmol) in
CH3CN (50 mL) was prepared. Ce(OTf)4 (147.2 mg,
General procedure for protection of alcohols and
nucleosides with BDTE or BMTE in the presence of
Ce(OTf)4 and DEAD
˚
0.2 mmol) and activated molecular sieves (4 A, 2 g) were
A solution of alcohol (5 mmol), DEAD (1.05 g, 6 mmol),
and BDTE (2.46 g, 6 mmol) or BMTE (2.25 g, 6 mmol) in
CH3CN (50 mL) was prepared. Ce(OTf)4 (0.37 g, 0.5 mmol)
added to this solution, and the mixture was stirred for the
specified time at room temperature. When either the alcohol
or BMTE was completely consumed (TLC was used for
monitoring), the reaction was quenched by the addition of
50 mL of 5% NaHCO3. The mixture was extracted with
chloroform (3 Â 35 mL), and the combined extract was
dried over Na2SO4. After evaporation of the solvent, the re-
sulting mixture was introduced into a silica gel column
eluted with EtOAc. The pure 5’-O-monomethoxytrityl thy-
midine was obtained as a white solid in 70% yield (Table 4);
˚
and activated molecular sieves (4 A, 2 g) were added to this
solution, and the mixture was stirred for a specified time at
room temperature. When either the alcohol or BDTE was com-
pletely consumed (TLC was used for monitoring), the reaction
was quenched by the addition of 50 mL of 5% NaHCO3.
The mixture was extracted with chloroform (3 Â 35 mL),
and the combined extract was dried over Na2SO4. After
evaporation of the solvent, the resulting mixture was intro-
duced into a silica gel column eluted with CH2Cl2. The
pure trityl ethers were obtained in 75%–95% yields (Tables 1
1
mp 103 8C (lit.18 mp 103–105 8C). H NMR (CDCl3, ppm)
d: 9.64 (s, 1H, NH), 7.64 (s, 1H, H-6), 7.45–7.26 (m, 14H,
Ph–), 6.88 (d, 2H, CH2-5’), 6.45 (t, 1H, H-1’), 4.61 (s, 1H,
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Zekri and Alamdari
565
Table 2. Dimethoxytritylation of alcohols by BDTE and DEAD in the presence of Ce(OTf)4
in acetonitrile at room temperature.
Table 3. The effect of different solvents on the protection of –OH
group of 3-phenyl propanol with benzyl dimethoxytrityl ether.
Fig. 1. The effect of different solvents used in the dimethoxytrity-
lation of 3-phenyl propanol in the presence of diethylazodicarboxy-
late and Ce(OTf)4 catalyst.
Entry
Solvent
CH2Cl2
THF
CH3NO2
CH3CN
Time
24 h
24 h
15 min
15 min
Yield (%)
1
2
3
4
40
85
90
95
Table 4. Selective protection of nucleosides with benzyl trityl
ethers (BTE, BDTE, and BMTE) in the presence of DEAD and
Ce(OTf)4 (0.1 equiv.).
Entry Substrate Reagent Product Time (h) Yielda (%)
1
2
3
4
5
6
7
1a
1b
1c
1d
1e
1f
BDTE
BDTE
BMTE
BMTE
BTE
2a
2b
2c
2d
2e
2f
2
3
7
7.5
12
10
10
87
90
75
70
45
57
18
Scheme 1. Tritylation of alcohols and nucleosides in the presence
of diethylazodicarboxylate and Ce(OTf)4 catalyst.
BTE
BTE
1g
2g
Note: The molar ratio of substrate/reagent/DEAD is 1:1.2:1.2.
aIsolated yield after column chromatography.
ature. The choice of solvent in the protection of –OH group
with Ce(OTf)4 is important, so the dimethoxytritylation of 3-
phenyl propanol in different solvents was investigated
(Fig. 1). On the basis of our results, which are shown in Ta-
ble 3, Ce(OTf)4 acts more efficiently in polar solvents, such
as CH3CN.
OH), 4.22–4.11 (m, 1H, H-3’), 3.82 (s, 3H, OCH3), 3.47–
3.36 (m, 3H, CH2-2’, H-4’), 2.38 (s, 3H, CH3–).
Results and discussion
Different alcohols and nucleosides were subjected to the
tritylation reaction in the presence of diethylazo-dicarboxy-
late and a catalytic amount of ceric tiflate at room temper-
The experiments were carried out in 1:1.2:1.2 molar ratio
of alcohol/DEAD/BMTE (or BDTE) (Scheme 1).
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566
Can. J. Chem. Vol. 88, 2010
Scheme 2. Plausible reaction mechanism of the tritylation reaction of this study.
To investigate the necessity of DEAD and the effect of
various cerium anion, several experiments were performed
and summarized in Table 1. As can be seen from Table 1,
the reactions did not proceed in the absence of either
DEAD or cerium complexes. On the other hand, among the
triflate, sulfate, and nitrate anions, the ceric triflate complex
showed the most catalytic effect while the ceric ammonium
nitrate did the least.
presence of DEAD with molar ratio 1:1.2:1.2 in the presence
of a catalytic amount of Ce(OTf)4 (0.1 equiv.) produced the
corresponding trityl nucleosides (2a–2f) in dry acetonitrile.
However, as can be seen in Table 2 (entry 7), the same re-
action did not proceed well for guanosine. The reactions are
outlined in Scheme 3.
Using our method, 5’-hydroxyl function of adenosine was
easily protected in 90% yield (Table 4, entry 2). The bis- and
tris-(tritylated) products were not produced at all in this case,
probably owing to the sever steric hindrance in the monotrity-
lated product. It is noteworthy that this monotrityl ether was
obtained in rather low yield (54%) under the conventional
conditions (1.2 equiv. of DMTCl, pyridine, 0 8C, and 48 h).4
Increasing the amount of BTE and DEAD to 1.5 equiv. to
improve the yield of the product, resulted in the production
of the undesired bis- and tris-(trityl) ethers (Fig. 2).
A plausible reaction mechanism of the present tritylation
reaction is illustrated in Scheme 2.
This observation is due to the strong electron withdrawal
nature of triflate anion which facilitates the exchange of
CeIV to CeIII besed on the proposed mechanism in Scheme 2.
˚
Molecular sieves (4 A) were also used to remove the
moisture from the reaction mixture. TLC monitoring indi-
cated that all of the alcohol was consumed, and no side
product was detected. Results of protection of several alco-
hols with BDTE are summarized in Table 2.
An interesting feature of the presented method is the con-
version of tertiary alcohols such as 1,1-diphenyl ethanol to
its corresponding dimethoxytrityl ether (75% yield at
120 min). As expected, protection of the more-hindered al-
cohols takes place in longer time and requires more amounts
of the reagents in comparison with the less-hindered ones
(Table 2, entries 6 and 7).
The use of DEAD for the tritylation reaction is essential
because a substantial amount of triphenyl methanol was ob-
tained as a byproduct in all the entries of Tables 2 and 4. To
prevent the reaction of benzyloxy anion with trityl cation,
DEAD was used as a proton acceptor.
To show more effectiveness of this method, selective di-
methoxytritylation of 1,2-propanediol was also investigated.
By using this method, 2-hydroxy-1-dimethoxytrityloxypro-
pane was obtained in 90% yield after 1 h (Table 2, entry 8).
Owing to the importance of selective protection of hy-
droxyl groups in ribonucleosides, we further applied this
procedure to the tritylation of ribonucleosides. Reaction of
nucleosides (1a–1f) with BDTE, BMTE, and BTE in the
It is also obvious that hydrolysis of the Tr cation is a seri-
ous side reaction. The use of molecular sieves was important
to suppress this side reaction. But in the case of nucleosides
as substrates whose hydroxyl groups are not reactive
enough, addition of molecular sieves was less effective. The
trace amount of water whose complete removal with the
molecular sieves was impossible may seriously compete
with the substrates.
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Zekri and Alamdari
567
Scheme 3. Tritylation of nucleosides in the presence of diethylazodicarboxylate and Ce(OTf)4 catalyst.
Fig. 2. Tritylation of adenosine in the presence of diethylazodicarboxylate and Ce(OTf)4 catalyst.
Fig. 3. Tritylation of 3-phenyl propanol in the presence of diethyla-
zodicarboxylate and Ce(OTf)4 catalyst.
In conclusion, a very simple and efficient method for the
protection of alcohols and nucleosides is described. It should
be mentioned that high rate of the reaction, high yields of
the products, accompanied with high selectivity, easy work-
up, and the use of a catalytic amount of Ce(OTf)4 are advan-
tages of the presented method. The Khorona’s method for
the tritylation of nucleosides suffers from prolonged reaction
times and time-consuming work-up due to the presence of
pyridine, which must be removed by repeated extraction of
the reaction mixture with water. Elimination of pyridine,
which is a toxic solvent, accompanied with an easy work-
up, are worthy of mention as additional advantages for this
method in the laboratory.
Acknowledgment
To verify the proposed mechanism, tritylation of 3-phenyl
propanol with BTE was carried out. Using 1.5 equiv. of
BTE and 1.5 equiv. of DEAD in the presence of 0.1 equiv.
of Ce(OTf)4 at room temperature, this reaction proceeded at
a slower rate than those with BDTE (Fig. 3). After 5 h, the
product was obtained in only 50% yield. This shows that the
rate of these reactions is dependent on the stability of the
trityl cations.
Financial support for this work by the Research Council
of Malek-Ashtar University of Technology, Tehran, Iran, is
gratefully acknowledged.
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