2-(Azidomethyl)benzoyl as a new protecting group in nucleosides

Article abstract of DOI:10.1016/S0040-4039(00)02183-3

A new protecting group, 2-(azidomethyl)benzoyl (AZMB), which can be easily removed by treatment with MePPh₂ in dioxane-H₂O or reduction with HCOONH₄-Pd/C in dioxane-MeOH, was developed for protection of the hydroxy and amino functions of deoxyribonucleosides.

Full text of DOI:10.1016/S0040-4039(00)02183-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 1069–1072
2-(Azidomethyl)benzoyl as a new protecting group in nucleosides†
Takeshi Wada,‡ Akihiro Ohkubo, Akira Mochizuki and Mitsuo Sekine*
Department of Life Science, Tokyo Institute of Technology, Nagatsuta, Midoriku, Yokohama 226-8501, Japan
Received 28 September 2000; revised 21 November 2000; accepted 24 November 2000
Abstract—A new protecting group, 2-(azidomethyl)benzoyl (AZMB), which can be easily removed by treatment with MePPh2 in
dioxane–H2O or reduction with HCOONH4–Pd/C in dioxane–MeOH, was developed for protection of the hydroxy and amino
functions of deoxyribonucleosides. © 2001 Elsevier Science Ltd. All rights reserved.
A wide variety of protecting groups, which can be
removed indirectly via ‘assisted cleavage mechanism’ by
conversion of a stable inside functional group into a
reactive nucleophile capable of intramolecular attack
on the neighboring genuine protected site, have been
developed.1 The deprotection of these protecting groups
depends essentially on the chemical property of the
masked auxiliary group. Among the protecting groups
of this type, Kusumoto and co-workers reported 4-azi-
dobutyryl as the hydroxy protecting group that can be
removed via reduction of the azido group with H2–Pd/
C, H2S or PPh3.2 Complete removal of this protecting
group required additional conditions of reflux in EtOH
for 1–2 h at the second stage for intramolecular cy-
clization. It was also expected that the neighboring
group participation of the once-generated amino func-
tion toward the nearest ester function would be more
effective in geometrically locked aromatic ring systems
than in conformationally flexible aliphatic systems, as
exemplified by 2-substituted benzoyl groups such as
2-(chloroacetoxymethyl)benzoyl,3 2-(benzoyloxymethyl)-
benzoyl,4 2-(acetoxymethyl)benzoyl,5,6 and 2-[(t-butyl-
diphenylsilyoxy)methyl]benzoyl.7,8 From these exam-
ples, it was expected that 2-azidomethylbenzoyl must
be an ideal structure as the protecting group since,
once the azido group is reduced to an amino group,
rapid ring closure readily occurs because of stronger
nucleophilicity of the amino group than that of the hy-
droxy group, as well as accessibility to a stable five-mem-
bered ring system. Actually, Osborn has reported 2-
(azidomethyl)-5-methylbenzoyl and related polymer-
supported linkers involving the 2-azidomethylbenzoyl
O
O
O
O
OR
OR
OCH3
O
N3
CH3
NH2
1
HOR
O
e
f
a
HOR
O
O
O
O
b
c
d
Cl
N3
OCH3
N3
OH
N3
OCH3
NH
CH2Br
5
3
2
4
Scheme 1. (a) NBS (1.1 equiv.), (BzO)2 (0.02 equiv.), CCl4, reflux, 1 h; (b) TMGN3 (1.5 equiv.), CCl4–MeOH (1:1, v/v), reflux,
1.5 h; (c) 2 M NaOH–MeOH (1:1, v/v), rt, 30 min; (d) SOCl2 (1.5 equiv.), reflux, 1 h (no solvent); (e) Et(iPr)2NHN3, (3 equiv.),
140°C, 4.5 h (no solvent); (f) see Table 2.
Keywords: protecting group; AZMB; nucleosides; HCOONH4–Pd/C.
* Corresponding author. Fax: +81-45-924-5772; e-mail: msekine@bio.titech.ac.jp
†
This paper is dedicated to Professor Jan Michalsky on the occasion of his 80th birthday.
Present address: Department of Integrated Biosciences, The University of Tokyo, Japan.
‡
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)02183-3

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T. Wada et al. / Tetrahedron Letters 42 (2001) 1069–1072
Reaction of thymidine (10) with 1.5 equiv. of 4 in
pyridine in the presence of 1.5 equiv. Bop-Cl and 0.02
equiv. of 4-methoxypyridine N-oxide (NPO) at room
temperature for 14 h gave the 5%-O-acyalted product 11
(mp 150–152°C from MeOH) in 75% yield (Scheme 2).
skeleton, especially designed for the oligopeptide syn-
thesis.9 Nonetheless, the simplest mother structure of
2-(azidomethyl)benzoyl has not yet been reported to
date.
Here, we report 2-(azidomethyl)benzoyl (AZMB) as a
new protecting group of the hydroxy and amino func-
tions in deoxyribonucleosides. It was found that 2-(azi-
domethyl)benzoic acid (4)10 could be easily synthesized
by a three-step reaction from commercially available
methyl 2-methylbenzoate (1), as shown in Scheme 1.
The transformation of the bromomethyl group of 2 into
the azidomethyl group was achieved in situ by treat-
ment with tetramethylguanidinium azide (TMGN3) in
CCl4–MeOH (1:1, v/v). Heating of a mixture of benzo-
lactone and 3 equiv. of diisopropylethylammonium
azide at 140°C for 4.5 h gave 4 (mp 74°C) but in only
18% yield. In this reaction, the use of other ammonium
azide salts such as TMGN3, Bu4NN3, and DBUHN3
resulted in poorer yields of 4.
The exo-amino groups of deoxyribonucleosides 12a–c
could be monoacylated by the transient protection
method via trimethylsilylation.13 Thus, the N-AZMB-
deoxyribonucleosides 13a–c were obtained in good
overall yields, as summarized in Table 1. In these
reactions, 5 equiv. of 5 was required. Compounds 13a–c
were tritylated with 1.1 equiv. of DMTrCl in pyridine
at room temperature for 2.5 h in the usual manner to
give the 5%-O-protected products 14a–c in 80, 80, and
83% yields, respectively.
Detailed examination was made of the conditions pre-
scribed for removal of the AZMB group from 7. Three
kinds of phosphines, i.e. PBu3, PPh3, and MePPh2, were
tested. PBu3, which has been used for removal of the
2-(azidomethyl)-5-methylbenzoyl group,9 was less effec-
tive than the other two. PPh3 required 30 min for
complete reaction, while use of MePPh2 resulted in a
shorter time of 15 min with a t1/2 of 2 min. Thus,
compound 6 was obtained in 96% yield by treatment of
7 with 4 equiv. of MePPh2 in dioxane–water (9:1, v/v)
at room temperature (Method A) for 15 min. When
PPh3 was used as a reducing reagent, no intermediate
was observed on TLC. When PBu3 was used,
iminophosphorane intermediates were detected on TLC
but gradually converted to the deprotected products. In
the case of MePPh2, iminophosphorane intermediates
were also observed but more rapidly converted to the
products within 15 min. When PPh3 was employed in
anhydrous dioxane, the AZMB group could not be
removed.
For introduction of the AZMB group into the hydroxy
or amino functions of nucleosides, the acid chloride 5
was prepared quantitatively by reaction of 3 with thio-
nyl chloride in neat under reflux for 1.5 h, followed by
evaporation under reduced pressure. The acid chloride
5 was used in situ since all attempts to purify 5 by
distillation caused considerable decomposition. Reac-
tion of 5%-O-dimethoxytritylthymidine 6 with 5 in pyri-
dine at room temperature for
2
h
gave the
3%-O-acylated product 7 in 81% yield, as shown in
Table 1. Reaction of 3%-O-benzoylthymidine 8 with 5
gave the 5%-O-acylated product 9 in 98% yield. It was
observed that these O-acylations required more than
2.5 equiv. of the reagent for smooth reactions. It is
likely that the steric hindrance of the 2-azidomethyl
group influenced significantly the O-acylation. When
compound 4 was used in the presence of CIP11 or
Bop-Cl,12 the acylated products were obtained in some-
what lower yields, as shown in Table 1.
The AZMB group attached to the 5%-hydroxy group of
9 was more easily removed in 8 min under similar
Table 1. Introduction of the AZMB group into the hydroxy and amino functions of deoxyribonucleoside derivatives
Entry
Compd
Product
Conditionsa
Yield of product (%)
Reagent (equiv.)
Time
1
2
3
4
5
6
7
6
6
6
8
8
10
12a
7
7
7
9
9
11
13a
5 (2.5)
4 (2.0) CIP (2.5)
2 h
2 h
1 day
30 min
16 h
81
66
71
98
87
75
70
4 (1.5) BOP-Cl (2.0) NPO (cat.)
5 (2.5)
4 (1.5), BOP-Cl (2.0), NPO (cat.)
4 (1.5), BOP-Cl (1.5), NPO (cat.)
(1) Me3SiCl (5.0)
(2) 5 (5.0)
(1) Me3SiCl (5.0)
(2) 5 (5.0)
(1) Me3SiCl (5.0)
(2) 5 (5.0)
14 h
(1) 20 min
(2) 3 h
(1) 20 min
(2) 3 h
(1) 20 min
(2) 3 h
8
9
12b
12c
13b
13c
89
75
a All the reactions were carried out in pyridine at room temperature.

T. Wada et al. / Tetrahedron Letters 42 (2001) 1069–1072
1071
O
O
N
O
O
N
NH
NH
NH
NH
N
O
O
N
O
O
HO
O
OBz
8
DMTrO
AMBO
DMTrO
O
O
OBz
9
O
OH
OAZMB
6
7
B
RO
O
O
O
OH
13a: R = H, B = 6-N-AZMB-adenin-9-yl
12b: R = H, B = cytosin-1-yl 13b: R = H, B = 4-N-AZMB-cytosin-1-yl
12c: R = H, B = guanin-9-yl
13c: R = H, B = 2-N-AZMB-guanin-9-yl
NH
NH
12a: R = H, B = adenin-9-yl
N
O
O
N
O
AZMBO
HO
O
OH
11
OH
14a: R = DMTr, B = 6-N-AZMB-adenin-9-yl
14b: R = DMTr, B = 4-N-AZMB-cytosin-1-yl
14c: R = DMTr, B = 2-N-AZMB-guanin-9-yl
15a: R = DMTr, B = adenin-9-yl
15b: R = DMTr, B = cytosin-1-yl
15c: R = DMTr, B = guanin-9-yl
10
Scheme 2.
conditions to give 8 in 98% yield. Similarly, it was also
found that the AZMB group could be uniformly
removed from 14a–c to the N-unprotected deoxynu-
cleoside derivatives 15a–c in 90, 94, and 91% yields,
respectively. Alternatively, 4 equiv. of ammonium for-
mate in MeOH–dioxane (3:1, v/v) in the presence of
Pd/C at room temperature (Method B) for 4 and 2 h
was also effective for removal of the AZMB group
from 7 and 9, respectively, as shown in Table 2.
CH2Cl2 at rt for 5 h. (4) DDQ (4 equiv.) in CH2Cl2–
H2O (1:1, v/v) at rt for 24 h.
As described above, the AZMB group could be intro-
duced into the primary and secondary hydroxy groups
as well as the exo-amino groups using the in situ
generated acid chloride 5 or the 1-Bop-Cl/NPO system.
The removal of the AZMB group could be easily
carried out by dimethyphenylphosphine or reduction
with ammonium formate on Pd/C. The AZMB group
could be a useful protecting group for hydroxy and
amino functions within the nucleic acid and other fields.
It should be noted that no intermediates formed by the
reduction of the AZMB group with ammonium for-
mate on Pd/C could be observed throughout this study.
This implies that, as expected, the second cyclization
occurred much faster than the reduction.
Acknowledgements
The AZMB group can be removed by treatment with
NaBH4 (Method C), as shown in Table 2. It also turned
out that the AZMB group was stable under the follow-
ing conditions: (1) Ce(NH4)2(NO2)6 (1 equiv.) in
CH3CN–H2O (9:1, v/v) at rt for 24 h. (2) Bu4NF (1
equiv.) in THF at rt for 24 h. (3) TMSOTf (1 equiv.) in
This work was supported by a Grant from ‘Research
for the Future’ Program of the Japan Society for the
Promotion of Science (JSPS-RFTF97I00301) and a
Grant-in-Aid for Scientific Research from the Ministry
of Education, Science, Sports and Culture, Japan.
Table 2. Conditions of removal of the AZMB group
Entry
Compd
Product
Conditionsa
Time
Yield of product (%)
Method
1
2
3
4
5
6
7
8
7
7
9
9
6
6
8
8
Method A
Method B
Method A
Method B
Method C
Method A
Method A
Method A
15 min
4 h
8 min
2 h
96
94
98
98
86
90
94
91
9
8
1 h
14a
14b
14c
15a
15b
15c
20 min
20 min
20 min
a Method A: MePPh2 (4 equiv.) in dioxane–H2O (9:1, v/v) at rt.
Method B: HCOONH4 (4 equiv.) on Pd/C in dioxane–MeOH (1:3, v/v) at rt.
Method C: NaBH4 (3 equiv.) in EtOH–THF (1:1, v/v) at rt.

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T. Wada et al. / Tetrahedron Letters 42 (2001) 1069–1072
for 1 h. A solution of 1.5 equiv. of TMGN3 in MeOH
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