An improved transient method for the synthesis of N-benzoylated nucleosides

Article abstract of DOI:10.1081/SCC-120017200

The Jones' transient method for the synthesis of N-benzoylated nucleosides is improved by reducing the amounts of chlorotrimethylsilane (TMSCl) and benzoyl chloride to nearly equivalent quantities. The easy work-up and high yields of products are the major advantages of this approach. Jones' method is further simplified by omitting the addition of ammonium hydroxide. The utility of this modification for the preparation of some useful protected nucleosides is also presented.

Full text of DOI:10.1081/SCC-120017200

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An Improved Transient Method for the Synthesis of N-
Benzoylated Nucleosides
Xue-Feng Zhu a , Howard J. Williams Jr. a & A. Ian Scott a
a Center for Biological NMR, Department of Chemistry, Texas A & M University, College
Station, Texas, USA
Version of record first published: 21 Aug 2006.
To cite this article: Xue-Feng Zhu, Howard J. Williams Jr. & A. Ian Scott (2003): An Improved Transient Method for the
Synthesis of N-Benzoylated Nucleosides, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 33:7, 1233-1243
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SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 7, pp. 1233–1243, 2003
An Improved Transient Method for
the Synthesis of N-Benzoylated Nucleosides
Xue-Feng Zhu,Howard J. Williams Jr.,and
*
A. Ian Scott
Center for Biological NMR, Department of Chemistry,
Texas A & M University, College Station,
Texas, USA
ABSTRACT
The Jones’ transient method for the synthesis of N-benzoylated
nucleosides is improved by reducing the amounts of chlorotrimethyl-
silane (TMSCl) and benzoyl chloride to nearly equivalent quantities.
The easy work-up and high yields of products are the major advan-
tages of this approach. Jones’ method is further simplified by omit-
ting the addition of ammonium hydroxide. The utility of this
modification for the preparation of some useful protected nucleo-
sides is also presented.
*Correspondence: A. Ian Scott, Center for Biological NMR, Department of
Chemistry, Texas A & M University, P.O. Box 30012, College Station,
TX 77842-3012, USA; E-mail: scott@mail.chem.tamu.edu.
1233
DOI: 10.1081/SCC-120017200
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com

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1234
Zhu,Williams,and Scott
Key Words: Transient method; N-benzoylation; Protection;
Nucleosides
Exocyclic amino protection of nucleobases is one of the most impor-
tant steps in nucleoside chemistry. After protection, the nucleoside can be
further transformed into derivatives of biological importance, such as
20,30-dideoxycytidine (ddC) and 20,30-dideoxyinosine (ddI), which have
been used to treat HIV infected patients; or it can be used for making
building blocks for oligonucleotide synthesis. Usually an acyl group is
introduced to protect the exocyclic amino function. Among numerous
acyl groups the benzoyl group is still the most common because of its
low price and easy introduction,[1] although a variety of more easily
removed protecting groups (phenoxyacetyl (PAC) for A and G, iso-
butyryl (i-Bu) for C and phthaloyl) have been suggested for oligonucleo-
tide synthesis.[2–4]
In the literature at least three methods are available for N-mono-
benzoylation. The first is the so-called direct selective benzoylation.[5] In
principle, this is an atom-economy efficient procedure; in reality, how-
ever, it has been successful only with cytosine nucleosides using different
benzoylating reagents, since with other nucleosides concomitant
O-benzoylation invariably accompanies N-benzoylation. The second is
the perbenzoylation/selective debenzoylation strategy, developed by
Khorana, where the nucleoside is first perbenzoylated and subsequently
O-debenzoylated selectively upon alkaline treatment, to give the desired
N-benzoylated nucleoside in moderate to good yield.[6] This reliable two-
step procedure enjoyed considerable success until 1982 when the third
method of transient protection was developed by Jones and co-workers
as well as by Sung and Narang.[7] This strategy, now known as the Jones
method, can be considered a modification of the Khorana method in
which all of the hydroxyl groups of the nucleoside are first protected
by trimethylsilyl (TMS) ether. After N-benzoylation, they can be cleaved
‘‘in situ’’ upon treatment with ammonium hydroxide. This one-flask pro-
cedure takes full advantage of the high lability of TMS ether and there-
fore avoids the isolation of peracylated intermediate, which is required in
the Khorana method. Presently, this is the most widely used method for
the protection of the exocyclic amine group of nucleosides.[8]
However, the main problem of the procedure is that a large excess of
TMSCl (ca. 2.5–4eq./OH group) and 3–6 fold excess of benzoyl chloride
are used in order to secure a good yield of N-benzoylated nucleoside.
As a result, the work-up is complicated and problematic, especially in
large scale synthesis, since removal of impurities such as benzoic acid is

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N-Benzoylated Nucleosides
1235
necessary. Both silylation and benzoylation are very clean reactions, so
we decided to re-examine this useful N-benzoylation method by reducing
the amounts of TMSCl and benzoyl chloride (Sch. 1). The results are
shown in Table 1. For example, when 1.1 eq. of TMSCl is used for each
OH group together with 1.2 eq. of benzoyl chloride, adenosine (1a) can
be transformed into N6-benzoyladenosine (2a) in 96% yield, which is
superior to that reported in the literature,[7c] where large excess of
reagents are used. Another direct benefit of this modification is that the
work-up can be further simplified (see experimental). This improved
approach has proven to be general and highly efficient and can be used
to prepare mono-benzoylated ribonucleosides, ara-ribonucleosides and
20-deoxy ribonucleosides in high yield (Table 1).
Scheme 1.
Table 1. N-Benzoylation of ribo-, arabino-, 20-deoxy-ribo nucleosides.
TMSCI Silylation Benzoylation Yield
(%)
Entry
Substrate
adenosine
cytidine
(eq.)
time (h)
time (h)
1
2
3
4
5
6
3.3
3.6
3.6
3.6
3.6
3.6
0.5
0.5
0.5
1.0
1.0
1.0
2
4
2
2
4
4
96
95
99
95
98
93
guanosine
ara-adenosine
ara-cytidine
ara-cytidine
monohydrochloride
20-deoxycytidine
monohydrochloride
20-deoxycytidine
monohydrate
7
8
2.4
0.5
4
96
2.4
3.6
4.8
3.6
0.5
0.5
0.5
0.5
4
4
4
2
81
98
95
91
9
20-deoxyadenosine
monohydrate
20-deoxyguanosine
monohydrate
10
3.6
1.5
6
98

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1236
Zhu,Williams,and Scott
In the literature, all of the nucleoside substrates are pre-dried by
co-evaporation with dry pyridine at least twice. However, our study
reveals that this tedious step can be avoided. Thus using commercially
available nucleosides without purification we find that even nucleoside
monohydrates (Entries 8–10) can be used without any pre-treatment.
However, in the latter cases, one additional equivalent of TMSCl is
added to consume the water molecule associated with the nucleoside
substrate.
We also tried to isolate the fully TMS protected nucleoside in order
to prove the existence of this presumed intermediate and to study the
stability of its TMS groups under different conditions. After cytidine was
silylated and benzoylated, the reaction mixture was treated with
monobasic potassium phosphate, and the expected intermediate 3 was
isolated in high yield. In case of adenosine, more than one intermediate
was isolated even when the reaction mixture was treated with dibasic
potassium phosphate. Three of these isolated intermediates are shown
in Sch. 2.
It turns out that TMS protected cytidine is quite stable. For example,
under relatively neutral conditions (pyridine-H2O [4:1]), it requires about
two days to remove the TMS groups; while under basic condition (pyr-
idine-H2O-NH4OH (ca. 29%) (4:1:2)), it takes about 1 h to cleave them.
It is surprising that the TMS group is very unstable and easily cleaved
under mild acidic condition (THF-TFA-H2O (4:1:1)) in less than 1 min.
A similar result was obtained with the adenosine intermediate 4. Once
again this shows that the TMS groups of nucleoside 4 can be easily
removed under acidic conditions (Sch. 3).
During silylation and benzoylation, hydrogen chloride is formed and
captured by reaction solvent pyridine to form a salt. When water is added
Scheme 2.

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N-Benzoylated Nucleosides
1237
Scheme 3.
at the end of the reaction, this salt can be hydrolyzed to release species
8 that is believed to be acidic enough to cleave the nucleoside’s TMS
groups. Based on this analysis, our improved approach was further
simplified by adding only H2O and omitting the addition of ammonium
hydroxide during work-up. After stirring for 30 min, N-benzoylated
nucleosides are obtained in high yields (Sch. 4). In the case of adenosine,
N6, N6-dibenzoylated nucleoside 7 was isolated from the reaction mixture
when excess benzoyl chloride (2.4 eq.) is used. As expected, 7 can
be smoothly transformed into N-benzoyladenosine (2a) upon treatment
with aqueous ammonium hydroxide (Sch. 3).
The utility of this simplified procedure was further exemplified in the
synthesis of some other useful protected nucleosides. For example,
in nucleoside chemistry, not only do exocyclic amino groups need to be
protected, but in some cases, even the imide group of uridine and thymi-
dine have to be masked.[9] However, benzoylation of imides cannot
be achieved using the conventional Jones’ method, because the benzoyl
group of the imide is very unstable when treated with ammonium

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1238
Zhu,Williams,and Scott
Scheme 4.
hydroxide. Fortunately, using our simplified procedure, benzoylated
thymidine (9a) and uridine (9b) are obtained in good yield. The same
approach has been used to prepare nucleoside 10, a key intermediate in
the synthesis of 20-O-methyl uridine, an important naturally occurring
nucleoside.[10] Using our simplified trasient method as a key step, nucleo-
side 10 is obtained in an efficient one-pot procedure. Starting from 10,
20-O-methyl uridine can easily be synthesized by literature procedures
(Sch. 5).[11]
EXPERIMENTAL
All reactions were performed using commercially available
nucleoside substrates, solvents and reagents without inert gas protection.
As new compounds, intermediates 3, 4, 5, 6 and nucleoside 7 were
characterized by high-resolution NMR spectroscopy and ESI Mass spec-
trometry. 1H (500 MHz) and 13C (125 MHz) NMR spectra were recorded
in CDCl3 on a Bruker ARX-500 spectrometer. ESI mass spectra were
obtained on a PE SCIEX API QSTAR PULSAR mass spectrometer.
Typical Procedure for N-benzoylation of nucleosides: Method 1 (Entry
5 of Table 1). To a mixture of cytosine-1-b-D-arabinofuranoside (99%)
1e (997 mg, 4.06 mmol) and pyridine (16 mL) was added TMSCl
(98%) (1.9 mL, 14.7 mmol) at r.t. After stirring for 1 h, the reaction

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N-Benzoylated Nucleosides
1239
Scheme 5.
mixture was cooled to 0ꢀC, and benzoyl chloride (99%) (0.58 mL,
4.95 mmol) was added dropwise by syringe. The ice-bath was then
removed and the reaction mixture stirred at r.t. for 4 h. The reaction
was quenched by the addition of water (4 mL); after stirring for 5 min
at r.t., concentrated aqueous ammonia (ca. 29%) (8 mL) was added and
the mixture was stirred at r.t. for 15 min. The resulting mixture was then
evaporated to dryness under reduced pressure. The dried residue was
stirred with cold water (20 mL) and filtered. After the solid product
was filter-washed with cold water (2 Â 5 mL) and ether (2 Â 5 mL) and
dried, the N-benzoylated nucleoside 2e was obtained (1.388 g, 98%) as a
white solid. Method 2: After silylation and benzoylation, the reaction was
stopped by the addition of water and stirred at r.t. Under these condi-
tions, hydrolysis of TMS groups is complete in 30 min. Following the
same work-up described in method 1, N-benzoylated nucleoside can be
obtained in high yield (Sch. 4).
0
0
0
O2 ,O3 ,O5 -tris-trimethylsilyl-N4-benzoylcytidine
(3).
Cytidine
(7.5 mmol, suspended in 30 mL of pyridine) was first silylated
and benzoylated (Sch. 2), and the reaction mixture cooled to 0ꢀC.
To this mixture was added KH2PO4 (10 g) and ice-water (48 g). After
the mixture was stirred for several minutes, a white precipitate appeared.

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1240
Zhu,Williams,and Scott
The solid was collected by filtration, washed with cooled water
(8 Â 25 mL), and dried under reduced pressure overnight. 3 was obtained
1
as a white solid (4.16 g, 98%). H NMR (500 MHz, CDCl3) ꢀ8.68 (d,
J ¼ 6.96 Hz, 1H, 6-H), 8.62 (s, br, 1H, NH), 7.87 (d, J ¼ 6.70 Hz, 2H,
arom. H), 7.59 (t, J ¼ 7.40 Hz, 1H, arom. H), 7.51–7.45 (m, 3H, 2
arom. HþH-5), 5.79 (s, 1H, 10-H), 4.15 (ddd, J ¼ 8.32, 1.96, 1.32 Hz,
1H, 40-H), 4.11 (d, J ¼ 4.04 Hz, 1H, 20-H), 4.06 (dd, J ¼ 8.32, 4.04 Hz,
1H, 30-H), 4.03 (dd, J ¼ 11.75, 1.92 Hz, 1H, 50-H), 3.71 (dd, J ¼ 11.75,
1.36 Hz, 1H, 50-H), 0.20 (s, 9H), 0.19 (s, 9H), 0.10 (s, 9H); 13C NMR
(125 MHz, CDCl3) ꢀ166.8 (1C), 162.1 (1C), 154.7 (1C), 145.1 (1C),
133.2 (1C), 133.0 (1C), 128.9 (2C), 127.5 (2C), 95.6 (1C), 91.6 (1C),
82.6 (1C), 76.5 (1C), 68.1 (1C), 59.3 (1C), 0.27 (3C), 0.008 (3C), ꢁ0.73
(3C); HRMS [MþH]þ, Found: 564.2373, C25H42O6N3Si3 requires m/z
564.2381.
TMS protected adenosine intermediates. Adenosine (7.5 mmol,
suspended in 30 mL of pyridine) was first silylated and benzoylated
(Sch. 2), the reaction was then cooled to 0ꢀC. To this mixture was
added K2HPO4 (12 g) and ice-water (60 g). The mixture was then diluted
with 200 mL CH2Cl2 and washed with brine (40 mL). The organic phase
was dried over Na2SO4 and evaporated at reduced pressure. The residue
was subjected to flash chromatography on silica gel (Eluent:
EtOAc/Hexane ¼ 1:8 to 1:2) to provide three TMS protected intermedi-
0
0
0
ates 4, 5 and 6 as white solids. O2 ,O3 ,O5 -tris-trimethylsilyl-N6,N6-diben-
1
zoyladenosine (4) (0.99 g, 19%). H NMR (500 MHz, CDCl3) ꢀ 8.63 (s,
1H), 8.41 (s, 1H), 7.83 (d, J ¼ 7.37 Hz, 4H, arom. H), 7.45 (t, J ¼ 7.43 Hz,
2H, arom. H), 7.31 (dd, J ¼ 7.43, 7.37 Hz, 4H, arom. H), 6.09 (d,
J ¼ 4.80 Hz, 1H, 10-H), 4.63 (t, J ¼ 4.58 Hz, 1H, 20-H), 4.26 (t,
J ¼ 4.20 Hz, 1H, 30-H), 4.12 (m, 1H, 40-H), 3.90 (dd, J ¼ 11.46, 3.50 Hz,
1H, 50-H), 3.72 (dd, J ¼ 11.46, 2.72 Hz, 1H, 50-H), 0.14 (s, 18H), ꢁ0.054
(s, 9H); 13C NMR (125 MHz, CDCl3) ꢀ 172.2 (2C), 152.9 (1C), 152.1
(1C), 151.7 (1C), 143.8 (1C), 134.2 (2C), 132.8 (2C), 129.4 (4C), 128.6
(4C), 128.1 (1C), 88.6 (1C), 85.3 (1C), 75.8 (1C), 71.6 (1C), 61.4 (1C),
0.235 (3C), ꢁ0.092 (3C), ꢁ0.653 (3C); HRMS [MþH]þ, Found: 692.2742,
0
0
0
C33H46O6N5Si3 requires m/z 692.2756. O2 ,O3 ,O5 -tris-trimethylsilyl-N6-
1
benzoyladenosine (5) (1.32 g, 30%). H NMR (500 MHz, CDCl3) ꢀ 9.02
(s, 1H, NH), 8.79 (s, 1H), 8.43 (s, 1H), 8.00 (dd, J ¼ 7.19, 1.34 Hz, 2H,
arom. H), 7.58 (td, J ¼ 7.39, 1.34 Hz, 1H, arom. H), 7.49 (dd, J ¼ 7.39,
7.19 Hz, 2H, arom. H), 6.10 (d, J ¼ 4.31 Hz, 1H, 10-H), 4.62 (t,
J ¼ 4.35 Hz, 1H, 20-H), 4.28 (t, J ¼ 4.48 Hz, 1H, 30-H), 4.16–4.13 (m,
1H, 40-H), 3.94 (dd, J ¼ 11.44, 3.31 Hz, 1H, 50-H), 3.73 (dd, J ¼ 11.44,
2.56 Hz, 1H, 50-H), 0.17 (s, 9H), 0.14 (s, 9H), ꢁ0.0012 (s, 9H); 13C NMR
(125 MHz, CDCl3) ꢀ 164.5 (1C), 152.7 (1C), 151.6 (1C), 149.3 (1C),

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N-Benzoylated Nucleosides
1241
141.9 (1C), 133.7 (1C), 132.7 (1C), 128.8 (2C), 127.8 (2C), 123.3 (1C), 88.7
(1C), 84.9 (1C), 75.9 (1C), 71.2 (1C), 61.1 (1C), 0.19 (3C), ꢁ0.04 (3C),
ꢁ0.66 (3C); HRMS [MþH]þ, Found: 588.2588, C26H42O5N5Si3 requires
0
0
m/z 588.2493. O2 ,O3 -di-trimethylsilyl-N6,N6-dibenzoyladenosine (6)
1
(0.37 g, 8%). H NMR (500 MHz, CDCl3) ꢀ 8.63 (s, 1H), 8.11 (s, 1H),
7.83 (d, J ¼ 7.64 Hz, 4H, arom. H), 7.47 (t, J ¼ 7.39 Hz, 2H, arom. H),
7.33 (dd, J ¼ 7.64, 7.39 Hz, 4H, arom. H), 5.86 (d, J ¼ 7.86 Hz, 1H, 10-H),
5.70 (dd, J ¼ 12.01, 1.76 Hz, 1H, 40-H), 4.95 (dd, J ¼ 7.86, 4.64 Hz, 1H, 20-
H), 4.29 (d, J ¼ 4.64 Hz, 1H, 30-H), 4.18 (s, 1H, OH), 3.93 (dd, J ¼ 13.07,
1.76 Hz, 1H, 50-H), 3.70 (dd, J ¼ 13.07, 12.01 Hz, 1H, 50-H), 0.16 (s, 9H),
ꢁ0.25 (s, 9H); 13C NMR (125 MHz, CDCl3) ꢀ 171.9 (2C), 152.9 (1C),
151.7 (1C), 151.5 (1C), 145.1 (1C), 133.7 (2C), 133.1 (2C), 129.4 (4C),
129.2 (1C), 128.8 (4C), 90.7 (1C), 89.5 (1C), 73.6 (1C), 73.5 (1C), 62.9
(1C), 0.29 (3C), ꢁ0.61 (3C); HRMS [MþH]þ, Found: 620.2446,
C30H38O6N5Si2 requires m/z 620.2360.
N6,N6-dibenzoyladenosine (7). After adenosine (7.5 mmol) was
silylated and benzoylated (Sch. 4), water (8 mL) was added to cleave
the TMS groups. The resulting mixture was stirred at r.t. for 30 min
and subsequently diluted with 100 mL CH2Cl2 and washed with brine
(40 mL). After separation, the aqueous layer was further extracted with
CH2Cl2 (3 Â 50 mL). The combined extracts were dried over Na2SO4 and
evaporated at reduced pressure. Purification by flash column chroma-
tography (silica gel, CH2Cl2/MeOH ¼ 100:1 to 100:4) yielded 7 as a
1
white solid (3.53 g, 99%). H NMR (500 MHz, CDCl3) ꢀ 8.55 (s, 1H),
8.14 (s, 1H), 7.79 (dd, J ¼ 7.26, 1.11 Hz, 4H, arom. H), 7.47 (td,
J ¼ 7.42, 1.11 Hz, 2H, arom. H), 7.33 (dd, J ¼ 7.42, 7.26 Hz, 4H, arom.
H), 5.80 (d, J ¼ 6.88 Hz, 1H, 10-H), 5.45 (d, J ¼ 9.59, 1H, 40-H), 4.68 (dd,
J ¼ 6.88, 5.86 Hz, 1H, 20-H), 4.43 (d, J ¼ 5.86 Hz, 1H, 30-H), 4.14 (s, br,
2H, 2 Â OH), 3.79 (d, J ¼ 12.54 Hz, 1H, 50-H), 3.70 (s, br, 1H, OH),
3.56 (dd, J ¼ 12.54, 9.59 Hz, 1H, 50-H); 13C NMR (125 MHz, CDCl3)
ꢀ 172.4 (2C), 152.1 (1C), 151.8 (1C), 151.6 (1C), 145.1 (1C), 133.5 (2C),
133.4 (2C), 129.5 (4C), 128.9 (4C), 128.4 (1C), 91.0 (1C), 87.3 (1C), 73.9
(1C), 71.8 (1C), 62.7 (1C); HRMS [MþH]þ, Found: 476.1603,
C24H22O6N5 requires m/z 476.1570.
ACKNOWLEDGMENTS
This work was supported by grants from the Texas Advanced
Technology Research Program and the Robert A. Welch Foundation.
We thank Dr. Clotilde Pichon-Santander for helpful discussion.

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Zhu,Williams,and Scott
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Received in the USA May 15, 2002

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