Unexpected reaction using methanol dried over molecular sieves

Article abstract of DOI:10.1081/SCC-120004262

The absolute methanol dried over 3A molecular sieves cleaves the O-acetyl group due to the existence of methoxy species generated by the 3A molecular sieves.

Full text of DOI:10.1081/SCC-120004262

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UNEXPECTED REACTION USING METHANOL DRIED OVER
MOLECULAR SIEVES
Mamoru Mizuno a , Katsuaki Kobayashi a , Hitoshi Nakajima a , Masahiko Koya a & Toshiyuki
Inazu b
a The Noguchi Institute, 1-8-1, Kaga, Itabashi-ku, Tokyo, 173-0003, Japan
b The Noguchi Institute, 1-8-1, Kaga, Itabashi-ku, Tokyo, 173-0003, Japan
Published online: 16 Aug 2006.
To cite this article: Mamoru Mizuno , Katsuaki Kobayashi , Hitoshi Nakajima , Masahiko Koya & Toshiyuki Inazu (2002)
UNEXPECTED REACTION USING METHANOL DRIED OVER MOLECULAR SIEVES, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 32:11, 1665-1670, DOI: 10.1081/SCC-120004262
To link to this article: http://dx.doi.org/10.1081/SCC-120004262
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SYNTHETIC COMMUNICATIONS, 32(11), 1665–1670 (2002)
UNEXPECTED REACTION
USING METHANOL DRIED OVER
MOLECULAR SIEVES
*
Mamoru Mizuno, Katsuaki Kobayashi,
Hitoshi Nakajima, Masahiko Koya, and
*
Toshiyuki Inazu
The Noguchi Institute, 1-8-1, Kaga,
Itabashi-ku, Tokyo 173-0003, Japan
ABSTRACT
The absolute methanol dried over 3A molecular sieves cleaves
the O-acetyl group due to the existence of methoxy species
generated by the 3A molecular sieves.
Molecular sieves are artificial zeolites consisting of the alkaline or
alkaline earth metal salt of aluminasilicate, and its pore size depends on the
metal ion. In organic synthesis, molecular sieves have been used as promot-
ers or catalysts. For instance, Y-type molecular sieves have dual functions as
Lewis acid and Lewis base, and the synthesis of benzyl decyl etherform
1-decanol and benzyl chloride using Kþ-exchanged Y-type molecularsieves
as a catalyst has been reported.[1]
Furthermore, molecular sieves are used as drying reagents for organic
solvents. Forexample, the sodium salt of the A-type molecularsieves is
called 4A and is used for dichloromethane and acetonitrile, DMF, etc.,
*Corresponding authors.
1665
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1666
MIZUNO ET AL.
the potassium salt is 3A and formethanol and ethanol, and the calcium salt
is 5A.
During the preparation of Fmoc-Asn(GlcNAc)-O0Bu as a building
block of N-glycopeptide,[2,3] we performed the deprotection of the
O-acetyl group of Fmoc-Asn(GlcNAc(OAc)3)-O0Bu (1) in ‘‘dry methanol’’
that was distilled by a conventional method and stored over 3A molecular
sieves. In this reaction, surprisingly, cleavage of the O-acetyl groups
occurred by only dissolving 1 in ‘‘dry methanol’’ without the addition of
a reagent[4] (e.g., sodium methoxide) (Scheme 1).
At first, we assumed that the glycosylasparagine derivative 1 was
the active species of the methoxy anion, so various O-acetyl protected
compounds were performed in ‘‘dry methanol’’, however, deacetylation
quantitatively proceeded in every case (Table 1).
Scheme 1.
Table 1. Deacetylation in Methanol Dried over 3A
MolecularSieves
Substrate
Condition
Sonication, r.t., 1 h
Sonication, r.t., 1 h
Reflux, 12 h

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METHANOL DRIED OVER MOLECULAR SIEVES
1667
Scheme 2.
From this result, we assumed that molecular sieves are the active species
of the methoxy anion in methanol. To prove our assumption, the O-acety-
lated compound 2 was dissolved in methanol that was not dried over the 3A
molecular sieves and stirred at room temperature with sonication or under
reflux conditions. In each case, cleavage of the O-acetyl group was not
observed at all. 3A molecular sieves were then added to these methanol solu-
tions, and deacetylation proceeded in both cases (Scheme 2). However, we
had a suspicion that only our3A molecularsieves were of low quality, so
various 3A molecular sieves from various manufacturers were checked. It was
found that all the 3A molecularsieves 3A caused cleavage of the O-acetyl
group.
From this result, it was clear that the 3A molecular sieves were the
active species of the methoxy anion in methanol.[5] Additionally, methanol
dried over 4A and 5A molecular sieves were checked for the same deacetyla-
tion, and it was found that the 4A molecularsieves were active species of the
methoxy anion and not the 5A. However, the 4A molecular sieves and 5A
are not used as a drying reagent for methanol due to their pore size, there-
fore, we focused on the 3A molecular sieves.
After concentration of the methanol dried over the 3A molecular
sieves, we found a slightly brown solid as a residue. This slightly brown
solid seemed to be insoluble small pieces of molecularsieves. In odrerto
remove this insoluble material, this dry methanol was filtered through a
membrane filter (ꢀ=0.45 mm), however, a slightly brown solid was
obtained again after concentration. From this result, we thought that
the obtained solid is not molecularsieves but the ture active species of
the methoxy anion. In fact, the methanol solution of the obtained residue
was able to cleave the O-acetyl groups.
The amount of soluble matterin the methanol form the 3A mole-
[6]
cularsieves is shown in Table 2.
On average, about 30 mg of the
residue was eluted from the pellet-shaped 3A molecular sieves into the
methanol.
The residue was analyzed by X-ray diffraction and electron micro-
probe analysis, and it was found that the residue did not have the crystal
structure of the zeolite any longer and its component was almost totally the

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1668
MIZUNO ET AL.
Table 2. Residue Amount Released from the 3A Molecular
Sieves into the Methanol
MolecularSieve
(Shape)
Residue Amount
(mg)
Manufacture
Nacalai
3A 1/8 (pellet)
4A 1/16 (pellet)
3A (powder)
3A 1/8 (pellet)
3A 1/8 (pellet)
0.3 nm (beads)
3A 1/8 (pellet)
33
5
11
26
32
10
60
Wako
Junsei
Merck
Nishio
Figure 1. Titration of 0.1 M hydrochloric acid to the aqueous solution of the
residue eluted from the 3A molecular sieves.[7]
potassium salt. Furthermore, the neutralization titration curve was very
similarto the curve of K 2CO3 (Figure 1).
Two hypotheses that potassium salt was eluted were as follows: (1) It is
well known that zeolites have ion-exchange ability. We assumed that the
proton of MeOH was exchanged by Kþ of 3A molecularsieves, and K 2CO3
resulted from the combination of eluted Kþ and CO2 from the atmosphere
during the preparation of the residue. (2) In the preparation of 3A molecular

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METHANOL DRIED OVER MOLECULAR SIEVES
1669
sieves, Naþ of Na-type zeolite-A was exchanged to Kþ by KOH, and then
the resulting zeolite was washed and heated to dry. At this heating process,
KOH, which was not removed by the washing process, converted to K2O,
an absorbed CO2 in the atmosphere and changed to K2CO3. This K2CO3,
which is impurity in 3A molecular sieves, was eluted into methanol and
served as a methoxy species.
We checked acid-washed types of molecularsieves (AW-300)
[8]
and
found that no residue was obtained after concentration of the methanol
stored over these sieves. Furthermore the amount of residue eluted from
3A molecularsieves was depended on its manufacture orits shape (Table 2).
From these results, the later hypothesis was supported as the major origin of
methoxy species.
In conclusion, the 3A molecularsieves erlease methoxy species in
methanol and cleavage of the O-acetyl group was caused. If an acid catalyst
is used in methanol dried over the 3A molecular sieves, the reaction does not
proceed well.[9] To avoid this undesirable reaction, the use of ‘‘normal’’
molecularsieves formethanol is not ercommended while using acid-wash
type molecularsieves is recommended.
GENERAL PROCEDURE
O-acetylated compound (0.15 mmol) was dissolved in methanol
(10 ml) that was dried over 3A molecular sieves for over 24 h. The reaction
mixture was sonicated at room temperature, or refluxed until the starting
acetate was not observed on TLC. EtOAc was added to the mixture, and the
organic layer was washed with water and brine, and dried over Na2SO4.
After concentration of the organic layer, the crude product was purified
by preparative silica gel TLC to give the corresponding de-O-acetylated
compound.
REFERENCES
1. Izumi, Y.; Urabe, K.; Onaka, M. Zeolite, Clay, and Heteropoly Acid in
Organic Reactions; Kodansha Ltd.: Tokyo. 1992, pp. 2–21.
2. Inazu, T.; Kobayashi, K. Synlett 1993, 869.
3. Mizuno, M.; Muramoto, I.; Kobayashi, K.; Yaginuma, H.; Inazu, T.
Synthesis 1999, 162.
4. Greene, T.W.; Wuts, P.G.M. Protective Groups in Organic Synthesis,
3rd Ed.; Wiley: New York, 1999; pp. 150–157.

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1670
MIZUNO ET AL.
5. It was observed that ethanol dried over 3A molecular sieves also
cleaved the O-acetyl groups, however, the reaction was slower than
in methanol.
6. 3A molecularsieves (10 g) were added to methanol (100 ml) and left for
18 h at room temperature. After filtration on a membrane filter
(ꢀ ¼ 0.45 mm), the filtered methanol was concentrated to obtain the
resulting residue.
7. 200 g of 3A molecularsieves was dissolved in 30 ml of water.
8. The acid-washed type molecular sieve AW-300 was purchased from
Aldrich.
9. We observed that the methylesterification of N-acetylneuramic acid in
the methanol dried over 3A molecular sieves using an acid catalyst did
not proceed well.[10]
10. Kuhn, R.; Lutz, P.; MacDonald, D.L. Chem. Ber. 1966, 99, 611.
Received in Japan March 30, 2001