An easy approach for the acetylation of saccharidic alcohols. Applicability for regioselective protections

Article abstract of DOI:10.1016/S0040-4039(03)01072-4

Cheap 4 ? molecular sieves can promote acetylation of carbohydrate hydroxyl functions with Ac₂O in absence of any co-reagent. The procedure is compatible with the presence of a variety of acid labile protecting groups and can be exploited for regioselective protections.

Full text of DOI:10.1016/S0040-4039(03)01072-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 4661–4663
An easy approach for the acetylation of saccharidic alcohols.
Applicability for regioselective protections
Matteo Adinolfi, Gaspare Barone, Alfonso Iadonisi* and Marialuisa Schiattarella
Dipartimento di Chimica Organica e Biochimica, Universita` degli Studi di Napoli Federico II, Via Cynthia 4,
I-80126 Napoli, Italy
Received 21 March 2003; revised 23 April 2003; accepted 25 April 2003
,
Abstract—Cheap 4 A molecular sieves can promote acetylation of carbohydrate hydroxyl functions with Ac2O in absence of any
co-reagent. The procedure is compatible with the presence of a variety of acid labile protecting groups and can be exploited for
regioselective protections. © 2003 Elsevier Science Ltd. All rights reserved.
Acetylation represents a very common approach for the
protection of hydroxyl groups in carbohydrate chem-
istry and, more in general, in organic synthesis. Installa-
tion of acetyl groups is routinely carried out by reacting
the alcoholic functions with acetic anhydride or acetyl
chloride in the presence of a base such as pyridine or
triethylamine.1 DMAP was disclosed to increase sensi-
bly the rates of the reaction due to its ability to act as
a nucleophilic catalyst.2 In the last decade many other
procedures were developed for this reaction, some of
which make use of phosphor-based nucleophilic cata-
lysts (Bu3P3 and aminophosphane base4), while others
are based on the activation of the acylating agent with
a variety of Lewis acids such as CoCl2,5 Sc(OTf)3,6,7
Sc(NTf2)3,8 TiCl4/AgClO4,9 TiCl(OTf)3,10 Sn(OTf)2,11
Cu(OTf)2,12 In(OTf)3,13 NBS,14 TMSOTf,15 Bi(OTf)3,16
I2.17 In recent years there has been wide interest in the
development of easily removable acetylation promoters.
Some solid acids such as Montmorillonite K-10,18,19
Zeolite HSZ-360,20 silica gel supported NaHSO4,21 sil-
ride at low temperature,28 iminophosphorane bases and
vinylacetate,29 distannoxane and enolacetates,30 NaH
and 3-acetyl-thiazolidine-2-thiones,31 PPh3/CBr4 in
ethyl acetate at high temperatures.32 These procedures
can suffer from some drawbacks such as the employ-
ment of moisture sensitive reagents, the recourse to
strictly controlled experimental conditions, the prelimi-
nary preparation of commercially unavailable reagents,
and slow reaction rates.
In this paper we wish to report a very mild and
experimentally simple acetylation procedure which can
be advantageously applied to the regioselective protec-
tion of saccharidic alcohols.
Starting from the idea of exploiting the surface sites of
commercially available molecular sieves to promote
synthetically useful transformations in carbohydrate
chemistry,33 we firstly considered the acetylation reac-
tion. In order to reveal a possible catalytic ability of
molecular sieves in this reaction, model compound 1a
(Table 1) was treated with neat acetic anhydride in the
ica gel supported TaCl5,22 Nafion H,23 and WO3-ZrO2
24
turned out to be suitable for that purpose.
,
presence and in absence of 4 A molecular sieves. In the
Acetylation of primary alcohols in the presence of
secondary ones is often problematic, and typically it
implies specific procedures. Regioselective acetylations
can be promoted by alumina in refluxing ethyl ace-
tate,25,26 silica gel supported lanthanide chlorides and
methylorthoacetate,27 an hindered base and acetyl chlo-
former case (entry 1) the protection went to completion
(98% yield) within 4 h at room temperature, while in
the second case (entry 2) appreciably high yields (85%)
could be achieved but sensibly longer times were
required. A model secondary saccharidic alcohol (2a)
was acetylated more slowly with acetic anhydride and 4
,
A molecular sieves and the reaction took 24 h to
achieve a high yield (entry 3).
Keywords: carbohydrates; protecting groups; acetylation; regioselec-
tivity; molecular sieves.
* Corresponding author. Tel.: +39 081 674153; fax: +39 081 674393;
e-mail: iadonisi@unina.it
The application of this procedure was next examined
for the protection of several saccharidic polyols (3a–6a)
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01072-4

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M. Adinolfi et al. / Tetrahedron Letters 44 (2003) 4661–4663
,
Table 1. Acetylation of saccharidic compounds promoted by 4 A molecular sieves

M. Adinolfi et al. / Tetrahedron Letters 44 (2003) 4661–4663
4663
equipped with acid labile functionalities. In all cases
acetylations occurred in high yields at room tempera-
ture or at 60°C (entries 4–7). Interestingly, the results
listed on Table 1 show that the acetylation conditions
are compatible with the stability of several acid labile
groups such as primary acetonides, TBDMS ethers,
benzylidenes, enol ethers, trityl ethers. In contrast, in
some examples of the above cited acid Lewis promoted
acetylations the cleavage of acid labile acetal and silyl
ether functionalities has been reported.15,32
5. Iqbal, J.; Srivastava, R. R. J. Org. Chem. 1992, 57, 2001.
6. Ishihara, K.; Kubota, M.; Kurihara, H.; Yamamoto, H.
J. Org. Chem. 1996, 61, 4560.
7. Barrett, A. G. M.; Braddock, D. C. Chem. Commun. 1997,
351.
8. Ishihara, K.; Kubota, M.; Yamamoto, H. Synlett 1996, 265.
9. Miyashita, M.; Shiina, I.; Miyoshi, S.; Mukaiyama, T. Bull.
Chem. Soc. Jpn. 1993, 66, 1516.
10. Izumi, J.; Shiina, I.; Mukaiyama, T. Chem. Lett. 1995, 141.
11. Mukaiyama, T.; Shiina, I.; Miyashita, M. Chem. Lett. 1992,
625.
The different reactivity of primary and secondary
hydroxyl functions observed in these first experiments
suggested the potentiality of the protocol for regioselec-
tive protections of polyols. As shown in entries 9–12 of
Table 1, substrates 7a–10a could be acetylated at their
primary position in short reaction times and generally
in high yield. Representative experiments are consti-
tuted by entries 8 and 9, showing that compound 7a
can be alternatively converted into the mono acetylated
derivative 7c or the peracetylated derivative 7b by
simply changing the reaction temperature.
12. Saravanan, P.; Singh, V. K. Tetrahedron Lett. 1999, 40,
2611.
13. Chauhan, K. K.; Frost, C. G.; Love, I.; Waite, D. Synlett
1999, 1743.
14. Karimi, B.; Seradj, H. Synlett 2001, 519.
15. Procopiou, P. A.; Baugh, S. P. D.; Flack, S. S.; Inglis, G.
G. A. J. Org. Chem. 1998, 63, 2342.
16. Orita, A.; Tanahashi, C.; Kakuda, A.; Otera, J. Angew.
Chem., Int. Eng. Ed. 2000, 39, 2877.
17. Kharta, K. P. R.; Field, R. A. Tetrahedron 1997, 53, 11754.
18. Li, A.-X.;Li, T.-S.;Ding, T.-H. Chem. Commun. 1997, 1389.
19. Bhaskar, P. M.; Loganathan, D. Tetrahedron Lett. 1998,
39, 2215.
20. Ballini, R.; Bosica, G.; Carloni, S.; Ciaralli, L.; Maggi, R.;
Sartori, G. Tetrahedron Lett. 1998, 39, 6049.
21. Breton, G. W. J. Org. Chem. 1997, 62, 8952.
22. Chandrasekahar, R.; Ramachhander, T.; Takhi, M. Tetra-
hedron Lett. 1998, 39, 3263.
It should be outlined the simplicity of the proposed
procedure, cheap commercially available reagents being
used without resorting to particular experimental pre-
cautions. The molecular sieves can be used without any
preliminary activation and removed by simple filtration.
In many cases pure products were often obtained by a
simple dilution with dichloromethane and washings
with aqueous Na2CO3.
23. Kumareswaran, R.; Pachamutu, K.; Vankar, Y. D. Synlett
2000, 1652.
24. Reddy, B. M.; Sreekanth, P. M. Synth. Commun. 2002, 32,
2815.
25. Posner, G. H.; Oda, M. Tetrahedron Lett. 1981, 22, 5003.
26. Rana, S. S.; Barlow, J. J.; Matta, K. L. Tetrahedron Lett.
1981, 22, 5007.
27. Bianco, A.; Brufani, M.; Melchioni, C.; Romagnoli, P.
Tetrahedron Lett. 1997, 38, 651.
28. Ishihara, K.; Kurihara, H.; Yamamoto, H. J. Org. Chem.
1993, 58, 3791.
In conclusion we have shown that commercially avail-
able 4 A molecular sieves can promote the acetylation
,
of both primary and secondary alcoholic functionali-
ties. The proposed procedure is based on commercially
available and inexpensive reagents, and is experimen-
tally very simple.34 In addition, the procedure was
shown to be perfectly compatible with a variety of
functional and protecting groups adopted in carbohy-
drate chemistry and can even be usefully employed to
perform regioselective acetylations of saccharidic diols.
29. Ilankumaran, P.; Verkade, J. G. J. Org. Chem. 1999, 64,
9063.
30. Orita, A.; Mitsutome, A.; Otera, J. J. Org. Chem. 1998, 63,
2420.
31. Yamada, S. J. Org. Chem. 1992, 57, 1591.
32. Hagiwara, H.; Morohashi, K.; Sakai, H.; Suzuki, T.; Ando,
M. Tetrahedron 1998, 54, 5845.
33. Molecular sieves are routinely exploited as drying agents
in glycosidation reactions. Their involvement in the stereo-
controlled synthesis of a,a%-homodisaccharides has also
been reported: Posner, G. H.; Bull, D. S. Tetrahedron Lett.
1996, 37, 6279.
Acknowledgements
This work was supported by MIUR (Programmi di
Ricerca di Interesse Nazionale 2001 and 2002) and by a
grant (to M.S.) from Universita` Federico II di Napoli
(Progetto Giovani Ricercatori).
34. Typical procedure: compound 3a (724 mg) is suspended in
References
,
acetic anhydride (15 mL) and 4 A molecular sieves (1.5 g;
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The mixture is stirred at 60°C and after completion of the
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and the organic phase washed several times with a saturated
Na2CO3 aqueous solution. Combined aqueous phases are
extracted with dichloromethane, and the combined organic
phases are concentrated under vacuum and purified on a
short silica gel column to yield 3b (875 mg, 93%).
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