Pyridine-free and solvent-free acetylation of nucleosides promoted by molecular sieves

Article abstract of DOI:10.1055/s-2006-958430

A practical method for the acetylation of purine and pyrimidine nucleosides employing a combination of acetic anhydride and potassium-exchanged molecular sieves is described. Besides the high yields obtained for the acylated nucleosides, the procedure is simple, inexpensive and environmentally benign, avoiding the use of pyridine or co-solvents as additives. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-958430

3
474
LETTER
Pyridine-Free and Solvent-Free Acetylation of Nucleosides Promoted by
Molecular Sieves
P
M
yridine-Free and
S
olv
a
ent-Fre
e
A
r
c
etylatio
c
n
of
N
ucleo
u
sides s Mandolesi Sá,* Lidiane Meier
Departamento de Química, Universidade Federal de Santa Catarina, Florianópolis, SC 88040-900, Brazil
Fax +55(48)33316850; E-mail: msa@qmc.ufsc.br
Received 1 September 2006
potassium-exchanged MS as solid catalysts under sol-
vent-free conditions.
Abstract: A practical method for the acetylation of purine and
pyrimidine nucleosides employing a combination of acetic an-
hydride and potassium-exchanged molecular sieves is described. Inosine (R = H) and guanosine (R = NH ) were selected
2
Besides the high yields obtained for the acylated nucleosides, the
procedure is simple, inexpensive and environmentally benign,
avoiding the use of pyridine or co-solvents as additives.
as model substrates for reactions with Ac O in the pres-
ence of a variety of catalysts in order to achieve the high-
est conversions to acetylated derivatives 1 and 2,
respectively (Table 1). Reactions were accompanied by
2
Key words: green chemistry, acylation, heterogeneous catalysis,
molecular sieves, nucleosides
TLC (EtOAc–MeOH, 9:1) following the consumption of
the starting nucleoside. In spite of the low conversions ob-
Nucleosides have been shown to exhibit interesting che-1
Table 1 Catalyst Screening for Acetylation of Inosine and
Guanosine
motherapeutic, biochemical and biophysical properties.
Fully acylated nucleosides and carbohydrates are useful
building blocks for the synthesis of modified analogues
and oligonucleotides with pharmacological application as
N
O
N
O
O
N
NH
R
Ac2O
O
N
NH
R
2
HO
AcO
antiviral and antineoplastic agents. However, acetylation
N
N
catalyst
of nucleosides with acetic anhydride by conventional
HO
OH
AcO
OAc
R = H
3
methods employs a great quantity of pyridine which is
1
4
5
both toxic and unpleasant. The alternative use of catalyt-
ic DMAP in combination with triethylamine and acetoni-
trile gives fully acetylated nucleosides in good yields, but
the required excess of reagents and solvents creates fur-
ther environmental and economic concerns. Chemical
transformations avoiding harmful reagents, expensive
catalysts, complex purification techniques and toxic waste
represent a fundamental target of modern organic synthe-
2 R = NH2
Entry Catalysta
Yield of 1 (%) Yield of 2 (%)
b
b
1
2
None
40
42
<5
39
35
Amberlist-15
I2
3
6
4
NaHSO ·SiO
2
36
<5
<5
45
48
52
50
52
53
71
84
35
sis. Heterogeneous catalysis and solvent-free techniques
4
allow operationally simple reactions to be performed with
5
Montmorillonite K-10
Montmorillonite KSF
Zeolite Beta
Zeolite NaY
Zeolite ZSM5
Zeolite ZSM5-H
3A-MS
7
safe and inexpensive reagents. Recyclable catalysts are
of particular interest due to an increasing demand for
cleaner processes in the chemical industry. While the acy-
lation of simple alcohols and carbohydrate derivatives has
been successfully achieved with solid catalysts such as ze-
6
7
45
47
46
48
55
50
74
78
38
8
8
olites, KF·Al O and NaHSO ·SiO , the acetylation of
2
3
4
2
9
nucleosides by heterogeneous catalysis is entirely unex-
plored.
10
Our ongoing studies on synthetic transformations of nu-
cleosides and carbohydrates as inhibitors of trypanosomal
1
1
1
1
2
3
9
5A-MS
gGAPDH enzyme motivated the development of a sim-
ple protocol for the acetylation of purine and pyrimidine
nucleosides. This communication describes a general and
environmentally benign approach to the preparation of 14
acetylated nucleosides using molecular sieves (MS) and
4A-MS
13X-MS
1
5c
13X-MS
a
Conditions: nucleoside (1.0 mmol), catalyst (0.6–1.3 g) and Ac O
2
SYNLETT 2006, No. 20, pp 3474–3478
Advanced online publication: 08.12.2006
DOI: 10.1055/s-2006-958430; Art ID: S16406ST
1
8
.1
2
.2
0
0
6
(
10–15 mmol) stirred at 100 °C for 6 h.
Isolated yields.
b
c
CH Cl (2.5 mL) was added as a co-solvent.
2
2
©
Georg Thieme Verlag Stuttgart · New York

LETTER
Pyridine-Free and Solvent-Free Acetylation of Nucleosides
3475
tained with most of the catalysts tested, more promising of 13X/KCl is worth mentioning, although 4A/KCl or 5A/
results were achieved with 13X-MS and, to a lesser ex- KCl can also be used as alternative catalysts without sig-
tent, 4A-MS (Table 1, entries 13 and 14). High yields of nificant decrease in yield.
pure triacetylinosine (1) and triacetylguanosine (2) were
accomplished by filtering the catalyst off followed by a
simple aqueous work-up. On the other hand, the use of a
co-solvent in the reaction dramatically reduced its effi-
ciency (Table 1, entry 15).
It is also important to note that the presence of reactive
functional groups such as bromo (Table 2, entry 3), thiol
(
entry 5) and acetal (entries 8–10) are well tolerated.
However, distinct reactivity patterns were observed for
the exocyclic amino groups in cytidine and guanosine de-
The superior activity of 4A-MS and 13X-MS indicated rivatives. While the amino group in cytidine is readily
that catalysts with more pronounced basic character10 acetylated to give 4-N-2¢,3¢,5¢-O-tetraacetylcytidine (7) in
should be preferred to the more acidic ones. Since a com- high yield (entry 7), no adducts arising from N-acetylation
plete ion exchange with alkali metal ions neutralizes not of guanosine or bromoguanosine were ever detected. In-
only the Brønsted acid centres presented in commercially stead, the corresponding tri-O-acetylated nucleosides 2
available MS but also creates weakly basic spots, we pre- and 3 were isolated as the sole products in each transfor-
pared potassium-exchanged catalysts 13X/KCl, 4A/KCl mation (entries 2, 3). Remarkably, the N-acetylation of
and 5A/KCl by treating the corresponding 13X-MS, 4A- 2¢,3¢-O-isopropylideneguanosine (11) could be easily
1
1
MS, and 5A-MS with 1 M KCl.
controlled by simply adjusting the reaction parameters
Table 2, entry 9). Accordingly, the 13X/KCl-promoted
acetylation of 11 performed in 20 minutes selectively
gave 2¢,3¢-O-isopropylidene-5¢-O-acetylguanosine (9a),
while the reaction under 13X catalysis and more extended
(
Gratifyingly, representative purine and pyrimidine nucle-
osides were acetylated to the corresponding products 1–
0 in high yield when potassium-exchanged MS were em-
ployed as the catalyst (Table 2). The results clearly show
that potassium-exchanged MS are more active than the
corresponding commercial MS, producing acetylated nu-
cleosides in higher yields and shorter reaction time.
Among the activated catalysts, the excellent performance
4c
1
periods furnished crystalline 2¢,3¢-O-isopropylidene-2-N-
11
5
¢-O-diacetylguanosine (9b) exclusively (Scheme 1).
Table 2 Yields (%) for the Acetylation of Nucleosides Promoted by Molecular Sieves
Entry
14a,12
Nucleoside
Inosine
Producta
13X/KCl
Time (h)]
13X
4A/KCl
4A
5A/KCl
5A
[
[Time (h)] [Time (h)] [Time (h)] [Time (h)] [Time (h)]
N
O
91 [2]
84 [6]
78 [6]
82 [2]
71 [6]
83 [2]
53 [6]
O
O
N
NH
AcO
N
N
N
N
N
AcO
OAc
1
24a,5a
Guanosine
90 [3]
74 [6]
50 [6]
N
O
N
NH
NH2
AcO
AcO
OAc
2
313
Bromoguanosine
Xanthosine
80 [4]
71 [2.5]
76 [3]
Br
N
O
O
O
O
N
NH
NH2
AcO
AcO
OAc
3
411
89 [1.5]
81 [3.5]
46 [6]
N
O
N
NH
OH
AcO
AcO
OAc
4
514
Thioinosine
73 [3.5]
N
SH
N
N
AcO
AcO
OAc
5
Synlett 2006, No. 20, 3474–3478 © Thieme Stuttgart · New York

3
476
M. M. Sá, L. Meier
LETTER
Table 2 Yields (%) for the Acetylation of Nucleosides Promoted by Molecular Sieves (continued)
Entry
615
Nucleoside
Uridine
Producta
13X/KCl
Time (h)]
13X
4A/KCl
4A
5A/KCl
5A
[
[Time (h)] [Time (h)] [Time (h)] [Time (h)] [Time (h)]
O
93 [1.5]
72 [6]
68 [6]
54 [7]
89 [1.5]
69 [6]
65 [6]
55 [7]
92 [1.5]
b
9
2 [2]
c
NH
O
93 [2]
O
N
AcO
AcO
OAc
6
716
Cytidine
86 [3]
85 [2.5]
NHAc
N
O
O
N
AcO
O
AcO
OAc
7
817
Isopropylidene-
inosine
82 [3]
78 [2.5]
O
N
N
NH
AcO
N
O
O
8
94c,11
Isopropylidene-gua-
nosine
82 [0.3]d
(R = H)
81 [8]e
(R = Ac)
N
O
O
N
NH
NHR
AcO
N
O
O
9
1
02e
Isopropylidene-uri-
dine
O
96 [1.5]
91 [1.5]
75 [6]
NH
O
O
N
AcO
O
O
1
0
a
b
c
d
e
Isolated yields (all reactions were carried out at 100 °C).11
Recycled catalyst was used without any treatment.
Recycled catalyst was used after a potassium-exchanged treatment with KCl.
11
2
¢,3¢-O-Isopropylidene-5¢-O-acetylguanosine (9a) was obtained as the single product.
2
¢,3¢-O-Isopropylidene-2-N-5¢-O-diacetylguanosine (9b) was obtained as the single product.
Since catalyst reutilization is a highly desirable feature for reduced under microwave-assisted conditions, but a finer
industrial processes, we studied the possibility of reusing tuning of the reaction parameters must be performed in or-
the potassium-exchanged MS without any special treat- der to achieve yields as high as those obtained under con-
ment. Indeed, the catalytic activity of reused 13X/KCl ventional heating.
was completely maintained and the triacetylated uridine 6
In conclusion, a straightforward acetylation of nucleo-
was obtained in yields comparable with those in the first
sides based on heterogeneous catalysis performed by po-
run (Table 2, entry 6). Furthermore, a control reaction per-
tassium-exchanged molecular sieves has been developed.
formed in the absence of a catalyst led to the expected
This new method is operationally simple, involves cheap
product 6 in only 15% yield, thus providing evidence for
reagents, and produces acetylated nucleosides in high
yield and selectivity, avoiding the use of harmful chemi-
the importance of MS in this transformation.
In order to expand the synthetic possibilities with hetero- cals such as solvents or organic additives. As additional
geneous catalysis, the acetylation of nucleosides under features, the possibility of recycling the catalyst and
microwave irradiation was briefly investigated adapting the reaction to a microwave reactor makes this
1
1
(
Table 3). The preliminary results with 13X and 13X/ procedure an attractive alternative to the existing meth-
KCl demonstrated that reaction time can be dramatically ods.
Synlett 2006, No. 20, 3474–3478 © Thieme Stuttgart · New York

LETTER
Pyridine-Free and Solvent-Free Acetylation of Nucleosides
3477
Table 3 Microwave-Assisted Acetylation of Selected Nucleosides
Producta
Catalyst
Time (min)a
Max. potency (W) Max. temp (°C)c
b
Yield (%)d
Entry Nucleoside
1
2
3
Inosine
O
13X/KCl
11
13
50
50
120
120
79
43
N
1
3X
O
O
N
NH
AcO
N
N
AcO
OAc
1
Guanosine
Uridine
O
13X/KCl
3X
12
13
50
100
120
120
68
<5
N
1
N
NH
NH2
AcO
AcO
OAc
2
O
13X/KCl
3X
6
9
100
100
130
120
80
68
1
NH
O
O
N
AcO
AcO
OAc
6
a
b
c
d
Total reaction time after pulsed irradiations of 3–4 min (does not include the ramp period of 1 min).
Maximum potency (W) programmed in the microwave reactor.
Maximum temperature displayed on the microwave reactor.
11
Isolated yields.
(3) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis, 2nd ed.; John Wiley and Sons: New York, 1991.
(4) (a) Bredereck, H.; Martini, A. Chem. Ber. 1947, 80, 401.
N
O
N
O
O
N
NH
NH2
O
N
NH
NHR
HO
a or b
AcO
N
N
(
b) Ren, B.; Cai, L.; Zhang, L.-R.; Yang, Z.-J.; Zhang, L.-H.
Tetrahedron Lett. 2005, 46, 8083. (c) Nowak, I.; Robins, M.
J. Org. Lett. 2003, 5, 3345.
O
O
O
O
11
9a R = H
9b R = Ac
a: Ac2O, 13X/KCl, 100 °C, 20 min
b: Ac2O, 13X, 100 °C, 8 h
(
(
(
(
5) (a) Matsuda, A. Synthesis 1986, 385. (b) Gupta, M.; Nair,
V. Tetrahedron Lett. 2005, 46, 1165. (c) Jagtap, P. G.;
Chen, Z.; Szabó, C.; Klotz, K.-N. Bioorg. Med. Chem. Lett.
Scheme 1
2004, 14, 1495.
6) (a) Clark, J. H. Green Chem. 2006, 8, 17. (b) da Silva, F.
M.; de Lacerda, P. S. B.; Jones, J. Quim. Nova 2005, 28,
Acknowledgment
103. (c) Anastas, P. T.; Kirchhoff, M. M. Acc. Chem. Res.
The authors wish to thank Central de Análises (Departamento de
Química, UFSC) for spectroscopic analysis. L.M. is grateful to
CAPES (Brazil) for a fellowship. Financial support by CNPq (Bra-
zilian Research Council) and FAPESC (Santa Catarina State Rese-
arch Council, Brazil) is also gratefully acknowledged. We also
thank Prof. Sibele Pergher (URI), Prof. Heloise Pastore (UNI-
CAMP) and Prof. Dilson Cardoso (UFSCar) for their helpful sugge-
stions and for the generous gift of the zeolites.
2002, 35, 686.
7) (a) Sartori, G.; Ballini, R.; Bigi, F.; Bosica, G.; Maggi, R.;
Righi, P. Chem. Rev. 2004, 104, 199. (b) Corma, A.;
Garcia, H. Chem. Rev. 2003, 103, 4307. (c) Clark, J. H.;
Macquarrie, D. J. Org. Process Res. Dev. 1997, 1, 149.
8) (a) Bhaskar, P. M.; Loganathan, D. Synlett 1999, 129.
(
b) Adinolfi, M.; Barone, G.; Iadonisi, A.; Schiattarella, M.
Tetrahedron Lett. 2003, 44, 4661. (c) Yadav, V. K.; Babu,
K. G.; Mittal, M. Tetrahedron 2001, 57, 7047. (d) Yadav,
V. K.; Babu, K. G. J. Org. Chem. 2004, 69, 577. (e)Breton,
G. W. J. Org. Chem. 1997, 62, 8952. (f) Heravi, M. M.;
Behbahani, F. K.; Bamoharram, F. F. J. Mol. Catal. A:
Chem. 2006, 253, 16. (g) Kumareswaran, R.; Pachamuthu,
K.; Vankar, Y. D. Synlett 2000, 1652.
References and Notes
(
1) (a) Pathak, T. Chem. Rev. 2002, 102, 1623. (b) Gupte, A.;
Buolamwini, J. K. Bioorg. Med. Chem. Lett. 2004, 14, 2257.
(
c) Santaniello, E.; Ciuffreda, P.; Alessandrini, L. Synthesis
005, 509. (d) De Clercq, E.; Field, H. J. Brit. J. Pharmacol.
006, 147, 1.
2
2
(
9) (a) Sá, M. M.; Silveira, G. P.; Castilho, M. S.; Pavão, F.;
Oliva, G. ARKIVOC 2002, (viii), 112. (b) Leitão, A.;
Andricopulo, A. D.; Oliva, G.; Pupo, M. T.; de Marchi, A.
A.; Vieira, P. C.; Silva, M. F. G. F.; Ferreira, V. F.; Souza,
M. C. B. V.; Sá, M. M.; Morais, V. R. S.; Montanari, C. A.
Bioorg. Med. Chem. Lett. 2004, 14, 2199.
(
2) (a) Hocek, M.; Hol, A.; Votruba, I.; Dvoráková, H. J. Med.
Chem. 2000, 43, 1817. (b) Véliz, E. A.; Beal, P. A. J. Org.
Chem. 2001, 66, 8592. (c) Lin, X.; Robins, M. J. Org. Lett.
2
000, 2, 3497. (d) Prasad, A. S. B.; Stevenson, T. M.;
Citineni, J. R.; Nyzam, V.; Knochel, P. Tetrahedron 1997,
3, 7237. (e) Danishefsky, S. J.; DeNinno, S. L.; Chen, S.-
H.; Boisvert, L.; Barbachyn, M. J. Am. Chem. Soc. 1989,
11, 5810. (f) Vorbrüggen, H.; Krolikiewicz, K.; Bennua, B.
Chem. Ber. 1981, 114, 1234.
(
10) (a) Wallau, M.; Schuchardt, U. J. Braz. Chem. Soc. 1995, 6,
5
393. (b) Martins, L.; Cardoso, D. Quim. Nova 2006, 29,
358. (c) Kartha, K. P. R.; Mukhopadhyay, B.; Field, R. A.
1
Carbohydr. Res. 2004, 339, 729.
Synlett 2006, No. 20, 3474–3478 © Thieme Stuttgart · New York

3
478
M. M. Sá, L. Meier
LETTER
(
11) Preparation of Potassium-Exchanged Molecular Sieves.
A suspension of the appropriate molecular sieves (1.0 g) and
M KCl (10 mL) was stirred at r.t. for 15–18 h, followed by
H, H-4¢), 5.18 (dd, J = 3.5, 6.5 Hz, 1 H, H-3¢), 5.30 (dd,
J = 2.0, 6.5 Hz, 1 H, H-2¢), 6.11 (d, J = 2.0 Hz, 1 H, H-1¢),
1
8.16 (s, 1 H, H-8), 11.54 (s, 1 H, D O exchange), 12.07 (s, 1
2
1
3
vacuum filtration and air-drying, obtaining a clear
amorphous solid that can be stored for months without any
special precautions.
H, D O exchange). C NMR (100 MHz, DMSO-d ): d =
2
6
21.19 (CH ), 24.61 (CH ), 26.04 (CH ), 27.69 (CH ), 64.54
3
3
3
3
(CH ), 81.47 (CH), 84.29 (CH), 84.92 (CH), 89.24 (CH),
2
General Procedure for the Synthesis of Acetylated
Nucleosides 1–10.
114.15 (C), 121.33 (C), 139.19 (CH), 148.56 (C), 148.64
(C), 155.46 (C), 170.76 (C=O), 174.23 (C=O). Anal. Calcd
for C H N O ·H O (%): C, 48.00; H, 5.45; N, 16.46.
Nucleoside (1.0 mmol), catalyst (0.6 g) and Ac O (8–10
2
17 21
5
7
2
mmol) were stirred at 90–100 °C for the time indicated in
Table 2. The final mixture was cooled to r.t., filtered, the
catalyst was rinsed with CH Cl , and the filtrate was
Found: C, 47.92; H, 5.80; N, 16.41.
General Procedure for the Microwave-Assisted
Synthesis of Acetylated Nucleosides.
2
2
concentrated under reduced pressure. The resulting residue
Microwave reactions were performed in 10 mL sealed tubes
in a commercially available monomode reactor (CEM
Discover) with IR temperature monitoring and non-invasive
pressure transducer. In a typical procedure, nucleoside (1.0
was diluted in EtOAc and washed with sat. NaHCO and
3
H O. Then the aqueous phases were back-extracted with
2
CH Cl and the combined organic extracts were dried over
2
2
Na SO , filtered and concentrated to give a solid residue that
mmol), Ac O (8–10 mmol) and the catalyst (0.6 g) were
2
4
2
was purified by recrystallization with CH Cl .
Selected Data.
placed in a 10 mL glass tube. The vessel was then sealed
with a septum, placed into the microwave cavity and
irradiated with stirring under the conditions presented in
Table 3. After allowing the mixture to cool to r.t., the
reaction vessel was opened and the contents were treated as
above to give pure acetylated products after
recrystallization.
2
2
2
1
¢,3¢,5¢-O-Triacetylxanthosine (4): white solid; mp 135–
37 °C. IR (KBr): n = 3475, 3193, 1749, 1700, 1232
max
–
1 1
cm . H NMR (400 MHz, DMSO-d ): d = 2.04 (s, 3 H,
CH ), 2.10 (s, 6 H, CH ), 4.22–4.38 (m, 3 H, H-4¢ and H-5¢),
6
3
3
5
.39 (m, 1 H, H-3¢), 5.66 (t, J = 5.5 Hz, 1 H, H-2¢), 6.04 (d,
J = 5.5 Hz, 1 H, H-1¢), 7.86 (s, 1 H, H-8), 10.33 (s, 1 H, D O
(12) Ikehara, M. Chem. Pharm. Bull. 1960, 8, 367.
(13) Holmes, R. E.; Robins, R. K. J. Am. Chem. Soc. 1964, 86,
1242.
2
1
3
exchange). C NMR (100 MHz, DMSO-d ): d = 25.64
6
(CH ), 25.78 (CH ), 25.96 (CH ), 68.40 (CH ), 75.16 (CH),
3 3 3 2
7
7.69 (CH), 84.80 (CH), 89.98 (CH), 120.72 (C), 139.40
(14) (a) Lewis, L. R.; Robins, R. K.; Cheng, C. C. J. Med. Chem.
1964, 7, 200. (b) Ikehara, M.; Uno, H.; Ishikawa, F. Chem.
Pharm. Bull. 1964, 12, 267.
(15) Saladino, R.; Crestini, C.; Occhionero, F.; Nicoletti, R.
Tetrahedron 1995, 51, 3607.
(16) Kuboki, A.; Ishihara, T.; Kobayashi, E.; Ohta, H.; Ishii, T.;
Inoue, A.; Mitsuda, S.; Miyazaki, T.; Kajihara, Y.; Sugai, T.
Biosci., Biotechnol., Biochem. 2000, 64, 363.
(17) Ciuffreda, P.; Loseto, A.; Santaniello, E. Tetrahedron 2002,
58, 5767.
(
1
CH), 150.20 (C), 158.83 (C), 163.88 (C), 174.74 (C=O),
74.89 (C=O), 175.54 (C=O). Anal. Calcd for
C H N O ·2H O (%): C, 43.05; H, 4.97; N, 12.55. Found:
1
6
18
4
9
2
C, 43.28; H, 4.57; N, 12.74.
¢,3¢-O-Isopropylidene-2-N-5¢-O-diacetylguanosine (9b):
white solid; mp 124–125 °C. IR (KBr): n = 3454, 3202,
2
max
–1 1
3178, 1738, 1708, 1683, 1250 cm . H NMR (400 MHz,
DMSO-d ): d = 1.32 (s, 3 H, CH ), 1.52 (s, 3 H, CH ), 1.97
6
3
3
(s, 3 H, CH ), 2.20 (s, 3 H, CH ), 4.08 (dd, J = 7.0, 12.0 Hz,
3
3
1
H, H-5¢), 4.19 (dd, J = 4.5, 12.0 Hz, 1 H, H-5¢), 4.30 (m, 1
Synlett 2006, No. 20, 3474–3478 © Thieme Stuttgart · New York