One step selective 5′-O-allylation of thymidine using microwave or ultrasound activation

Article abstract of DOI:10.1016/j.carres.2004.04.008

An improved procedures for the synthesis of 5′-O-allylthymidine via one step selective allylation of thymidine using either ultrasound or microwave activation is described.

Full text of DOI:10.1016/j.carres.2004.04.008

Carbohydrate
RESEARCH
Carbohydrate Research 339 (2004) 1829–1831
Note
One step selective 50-O-allylation of thymidine using microwave or
ultrasound activation
Vincent Roy, Ludovic Colombeau, Rachida Zerrouki* and Pierre Krausz
Universitꢀe de Limoges, Laboratoire de Chimie des Substances Naturelles, Facultꢀe des Sciences et Techniques,
123 Avenue Albert Thomas, F-87060 Limoges, France
Received 24 January 2004; received in revised form 19 April 2004; accepted 21 April 2004
Available online 11 June 2004
Abstract—An improved procedures for the synthesis of 50-O-allylthymidine via one step selective allylation of thymidine using either
ultrasound or microwave activation is described.
ꢀ 2004 Elsevier Ltd. All rights reserved.
Keywords: Selective allylation; Thymidine; Nucleoside; Ultrasound; Microwave
We recently described the homodimerization of a 30-C-
allyl derivative of thymidine.1 As part of this pro-
gramme, we became interested in the preparation of
50-O-allylthymidine. According to classical methods, 50-O-
substituted deoxynucleosides are obtained in several
steps starting from the corresponding deoxynucleosides.2
The first step involves protection of the 50 primary
hydroxyl group using selective silylation (TBDMS or
TBDPS) or tritylation. In a second step, the 30-hydroxyl
group is protected and the 50 protecting group then
removed in order to introduce the desired modification.
In our hands, 50-O-allylthymidine was prepared as
follows (Scheme 1). Thymidine 1 and tert-butyldimeth-
ylsilyl chloride3 in dry pyridine were stirred overnight,
then benzoyl chloride and 4-dimethylaminopyridine
(DMAP) were added and the reaction mixture was
stirred for 28 h. The silylated group was then removed
by treatment with carbon tetrabromide4 in dry methanol
to afford 3, which was then converted into 4 by O-
allylation of the C-50 hydroxyl group with NaH and allyl
bromide in DMF. Deacylation of 4, carried out in
methanolic ammonia at room temperature, gave 5.
Thymidine was thus converted in four steps to 50-O-
allylthymidine in 42.4% overall yield.
To minimize the steps and maximize the overall effi-
ciency of our strategy, we decided to examine the direct
allylation of thymidine without prior protection
(Scheme 2).
O
O
O
O
N
O
NH
NBz
O
NBz
NBz
O
NH
O
HO
O
O
N
O
HO
TBDMSO
O
N
N
N
O
O
O
O
O
b
a
c
d
OH
1
OBz
4
OBz
2
OBz
3
OH
5
Scheme 1. Reagents and conditions: (a) (1) TBDMSCl (1.05 equiv), dry pyridine, overnight; (2) BzCl (6 equiv), DMAP (1.5 equiv), 28 h; (b) CBr4
(0.1 equiv), dry MeOH, reflux, 1.5 h; (c) (1) NaH (1.2 equiv), dry DMF, 30 min, (2) BrCH2CH@CH2 (2 equiv), 1 h; (d) NH3/MeOH (7 M), rt, 2 days.
* Corresponding author. Tel.: +33-5-55-45-72-24; fax: +33-5-55-45-72-02; e-mail: rachida.zerrouki@unilim.fr
0008-6215/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2004.04.008

1830
V. Roy et al. / Carbohydrate Research 339 (2004) 1829–1831
O
N
O
N
NH
O
NR'
O
HO
O
5
6
R = R' = H
R = CH2CH=CH2 , R' = H
O
O
a
7
8
R = H, R' = CH2CH=CH2
R = R' = CH2CH=CH2
OH
1
OR
Scheme 2. Reagents and conditions: (a) (1) NaH (1.15 equiv), dry DMF; ))) or MW (100 W); (2) BrCH2CH@CH2 (1.2 equiv), ))) or MW (100 W).
Table 1. Selected results of direct 50-O-allylation of 1: influence of the activation method
Entry
Activationa
Reaction time
first step/second step
5b (%)
6b (%)
7b (%)
8b (%)
1
2
3
Classical stirring
Ultrasound
Microwave
30 min/4 h
30 min/4 h
2 min/2 min
75
93
97
10
––
––
5
5
––
––
––
––
aConditions: (1) first step: NaH (1.15 equiv), dry DMF, activation; (2) second step: BrCH2CH@CH2 (1.2 equiv), activation.
bYield after purification.
Selected results of direct 50-O-allylation of thymidine
are summarized in Table 1. Our initial studies, which
traditionally used NaH and allyl bromide in DMF at
room temperature, resulted in the formation of 5
together with 30,50-bis(allylated) thymidine 6, 3,50-
bis(allylated) thymidine 7 and 3,30,50-tris(allylated) thy-
midine 8 (Table 1, entry 1). The effect of various
activation modes was studied. Using ultrasonication,5
the reaction gave 50-O-allylthymidine (5) in 93% yield
without secondary product (Table 1, entry 2). The best
result was obtained with microwave activation (Table 1,
entry 3). The product was obtained in quantitative yield
with a dramatic decrease in reaction times (4 min). It
displayed physical characteristics strictly identical to
those of 5 obtained according to the classical method in
Scheme 1.
University Pierre et Marie Curie (Paris VI). Optical
rotation was measured with a Jasco (DIP-370) polari-
meter in a 1 dm quartz cell at 22 ꢁC.
1.2. Di-N-3,O-30-benzoyl-50-O-tert-butyldimethylsilyl-
thymidine (2)
To a soln of thymidine (1.5 g, 6.19 mmol) in dry
pyridine (25 mL) was added 1.05 equiv of TBDMSCl
(0.980 g, 6.50 mmol) and the reaction was stirred
at room temperature overnight. DMAP (1.13 g,
9.28 mmol) and benzoyl chloride (4.21 mL, 37.14 mmol)
were then added. After 28 h stirring at room tempera-
ture, the mixture was diluted with CHCl3, neutralized
with NaHCO3 and extracted with CHCl3 (3 · 20 mL).
The organic layer was dried (MgSO4), filtered and the
solvent removed. The residue was purified by chromato-
graphy over silica gel (toluene–EtOAc) to give 2 as a
1
foam (2.897 g, 83%); Rf 0.55 (4:1, toluene–EtOAc); H
1. Experimental
NMR (CDCl3): thymine 7.72 (q, 1-H, JH ;CH 1.0 Hz, H-
6
3
0
0
6), 1.98 (d, 3H, CH3); dRib: 6.49 (dd, 1-H, J1 ;2 a 5.2 Hz,
1.1. General methods and equipments
J1 ;2 b 9.3 Hz, H-10), 5.52 (m, 1-H, H-30), 4.28 (m, 1-H, H-
0
0
40), 4.04 (dd, 1-H, J5 a;5 b 11.4, J5 a;4 2.0 Hz, H-50a), 4.02
0
0
0
0
Microwave irradiation was performed in a monomode
reactor (MicroSYNTH from Milestone) with focused
waves (T ¼ 40 ꢁC, P ¼ 100 W). Sonication was per-
formed in a LEO-80 ultrasonic cleaner with a frequency
of 46 kHz and a power of 30 W. Analytical TLC was
performed on E. Merckaluminium precoated Silica Gel
60 F254 sheets, with detection by UV and also by
spraying with H2SO4 (6 N) and heating to 200 ꢁC. Silica
Gel (E. MerckKieselgel 60, 15–40 lm) was used for
(dd, 1-H, J5 b;5 a 11.4 Hz, J5 b;4 2.0 Hz, H-50b), 2.42 (ddd,
0
0
0
0
1-H, J2 a;3 3.6 Hz, J2 a;1 5.2 Hz, J2 b;2 a 13.8 Hz, H-20a),
0
0
0
0
0
0
2.09 (ddd, 1-H, J2 b;1 9.3 Hz, J2 b;3 6.1 Hz, H-20b); pro-
tecting groups: 0.20 (s, 6H, CH3-Si), 0.99 (s, 9H, CH3,
t-Bu), 7.17–8.02 (m, 10H, H-Ar).
0
0
0
0
1.3. Di-N-3,O-30-benzoylthymidine (3)
1
flash chromatography. H NMR spectra were recorded
To a soln of 2 (1.746 g, 3.096 mmol) in dry MeOH
(25 mL) was added CBr4 (0.105 g, 0.310 mmol).The
reaction mixture was heated at reflux for 1.5 h. The
solvent was then removed and the crude residue purified
on a silica gel column (CHCl3–EtOH) yielding 3 as a
foam (1.226 g, 88%); Rf 0.47 (95:5, CHCl3–EtOH);
using a Bruker DPX-400 spectrometer for solutions in
CDCl3 or CD3OD with tetramethylsilane as internal
standard. The chemical shifts are given in ppm and
coupling constants are in Hertz. Elemental analyses
were carried out by the Microanalytical Service of the

V. Roy et al. / Carbohydrate Research 339 (2004) 1829–1831
1831
1
1H NMR (CD3OD): thymine 8.09 (q, 1-H, JH ;CH 0.8 Hz,
CHCl3–EtOH); H NMR (CD3OD): thymine 7.85 (q,
1-H, JH ;CH 1.0 Hz, H-6), 1.91 (d, 3H, CH3); dRib: 6.30 (t,
6
3
0
0
H-6), 1.96 (d, 3H, CH3); dRib: 6.39 (dd, 1-H, J1 ;2 a
6
3
6.4 Hz, J1 ;2 b 7.9 Hz, H-10), 5.59 (dt, 1-H, J2 a;3 2.7 Hz,
1-H, J1 ;2 6.8 Hz, H-10), 4.39 (dt, 1-H, J3 ;4 3.5 Hz, J2 a;3
0
0
0
0
0
0
0
0
0
0
J2 b;3 5.4 Hz, J4 ;3 2.7 Hz, H-30), 4.26 (q, 1-H, J 2.7 Hz,
3.5 Hz,, J2 b;3 6.4 Hz, H-30), 3.91 (q, 1-H, J4 ;5 3.5 Hz, H-
0
0
0
0
0
0
0
0
H-40), 3.93 (dd, 1-H J5 b;5 a 12.1 Hz, J5 b;4 2.7 Hz, H-50b),
40), 3.80 (dd, 1-H J5 b;5 a 12.0 Hz, H-50b), 3.72 (dd, 1-H,
0
0
0
0
0
0
3.90 (dd, 1-H, J5 a;4 2.7 Hz, H-50a), 2.59 (ddd, 1-H, J2 a;2 b
H-50a), 2.27 (ddd, 1-H, J2 a;2 b 13.7 Hz, H-20b), 2.20 (ddd,
0
0
0
0
0
0
14.3 Hz, H-20a), 2.55 (ddd, 1-H, J2 b;3 5.4 Hz, H-20b).
Benzoyl groups: 7.48–8.04 (m, 10 H, H-Ar).
1-H, H-20a); allyl group: 5.86 (ddt, 1-H, Jb;c 10.4 Hz, Jb;c
0
0
0
17 Hz, Jb;a 5.6 Hz, H-b), 5.16 (dq, 1-H, H-c0), 5.12 (dq,
1-H, H-c), 4.51 (dt, 2H, Ja;b 5.6 Hz, Ja;c 1.4 Hz, H-a).
Anal. Calcd for C13H18O5N2: C, 55.31; H, 6.43; N, 9.92.
Found: C, 55.36; H, 6.39; N, 9.87.
1.4. Di-N-3,O-30-benzoyl-50-O-allylthymidine (4)
To a soln of 3 (1.267 g, 2.81 mmol) in dry DMF, was
added NaH (60%, 135 mg, 3.378 mmol) and the mixture
was stirred for 30 min under Ar. Allyl bromide (487 lL,
5.62 mmol) was then added to the mixture and stirring
was continued for 1 h. The reaction mixture was evapo-
rated and after usual workup, the residue was purified
on a silica gel column to give 4 as a viscous oil (0.963 g,
1.6. 50-O-Allylthymidine (5) via direct allylation
To a soln of thymidine (300 mg, 1.24 mmol) in dry
DMF (10 mL) was added NaH (60%, 57 mg,
1.425 mmol) and the mixture was stirred and irradiated
(first step, see Table 1) under argon. Allyl bromide
(0.129 mL, 1.49 mmol) was then added and the reaction
mixture was stirred and irradiated (second step, see
Table 1). After removal of the solvent, the syrup was
purified on a silica gel column yielding 5 as a white solid
(yields in Table 1). This product displayed physical
characteristics strictly identical to those of 5 obtained
according to the four steps sequence in Scheme 1.
1
70%); Rf 0.50 (95:5, CHCl3–EtOH); H NMR (CDCl3,
d): thymine 7.85 (q, 1-H, JH ;CH 1.0 Hz, H-6), 1.66 (d,
6
3
0
0
0
0
3H, CH3); dRib: 6.51 (dd, 1-H, J1 ;2 a 5.4 Hz, J1 ;2 b 8.7 Hz,
H-10), 5.65 (dt, 1-H, J2 a;3 1.6Hz, J2 b;3 6.6 Hz, J4 ;3
0
0
0
0
0
0
1.6 Hz, H-30), 4.80 (dd, 1-H J5 b;5 a 12.2 Hz, J5 b;4 3.0 Hz,
0
0
0
0
H-50b), 4.68 (dd, 1-H, J5 a;4 3.5 Hz, H-50a), 4.54 (m, 1-H,
0
0
H-40), 2.72 (ddd, 1-H, J2 a;2 b 14.0 Hz, H-20a), 2.20 (ddd,
0
0
1-H, H-20b); allyl group: 5.86 (ddt, 1-H, Jb;c 10.3 Hz, Jb;c
0
0
17.2 Hz, Jb;a 5.9 Hz, H-b), 5.25 (dd, 1-H, Jc;c 1.3 Hz, H-
c0), 5.13 (dd, 1-H, H-c), 4.54 (m, 2H, H-a). Benzoyl
groups: 7.48–8.05 (m, 10 H, H-Ar).
References
1. Batoux, N.; Benhaddou-Zerrouki, R.; Bressolier, P.; Gra-
net, R.; Laumont, G.; Aubertin, A. M.; Krausz, P.
Tetrahedron Lett. 2001, 42, 1491–1493.
1.5. 50-O-Allylthymidine (5)
ꢁ
2. Magdalena, J.; Fernandez, S.; Ferrero, M.; Gotor, V.
Compound 4 (0.705 g, 1.438 mmol) was dissolved in
MeOH (10 mL) and a soln of ammonia in MeOH
(7 M, 20 mL) was added. After 2 days at room temper-
ature, the soln was evaporated and the crude product
was purified using preparative TLC (9:1, CH2Cl2–
Tetrahedron Lett. 1999, 40, 1787–1790.
3. Corey, E. J.; Venkateswarlu, A. J. Am. Chem. Soc. 1972,
94, 6190–6191; Hanessian, S.; Lavallee, P. Can. J. Chem.
1975, 53, 2975–2977.
4. Lee, A. S.-Y.; Yeh, H. C.; Shie, J.-J. Tetrahedron Lett. 1998,
39, 5249–5252.
EtOH) yielding 5 as a white solid (0.336 mg, 83%);
5. Wu, J. C.; Xi, Z.; Gioeli, C. J.; Chattopadhyaya Tetrahe-
dron 1991, 47, 2237–2254.
25
D
½aꢀ +27.96 (c 0.8, EtOH); mp 97 ꢁC; Rf 0.45 (9:1,