A novel, efficient, and highly selective O-Bn bond cleavage reaction via a rare K-induced electron transfer process

Article abstract of DOI:10.1055/s-2002-33519

A new, efficient and highly selective deprotective method of both benzyl and benzylidene groups for protection of monohydroxyl and dihydroxyl, respectively, has been developed by using the system K-t-BuNH₂-t-BuOH-18-crown-6. This method is valu

Full text of DOI:10.1055/s-2002-33519

LETTER
1505
A Novel, Efficient, and Highly Selective O–Bn Bond Cleavage Reaction via a
Rare K-Induced Electron Transfer Process
H
e
e
O
BnBo
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ndCleavage
R
S
eaction hi, Wu Jiong Xia, Fu Min Zhang, Yong Qiang Tu*
Department of Chemistry & National Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, P. R. China
Fax +86(931)8912582; E-mail: tuyq@lzu.edu.cn
Received 4 June 2002
been widely used in organic synthesis. It is quite different
Abstract: A new, efficient and highly selective deprotective meth-
from catalyzed hydrogenolysis1, Birch-like reduction2 or
od of both benzyl and benzylidene groups for protection of mono-
hydroxyl and dihydroxyl, respectively, has been developed by using
the system K–t-BuNH2–t-BuOH–18-crown-6. This method is valu-
ozonization,3 it did not reduce either a separate or conju-
gated C=C bonds, active epoxy; and also the experimental
able since it can not only selectively protect the TBDMS and THP conditions are mild and the procedure is simple.7 Further
groups and the ethylene ketal from cleavage, but also keep the sep-
arate or conjugated C=C bonds from reduction. A possible electron
transfer reaction process was also suggested.
investigation showed that absent or less equivalents of t-
BuOH (0.5 equiv) and/or 18-crown-6 will delay the reac-
tion time (2–10 h) and sometimes gave lower yield of the
product. In addition, excess (10 equiv) of the potassium
Key words: selective, benzyl, benzylidene, potassium, electron
transfer
was essential and lower equivalents will slow the reaction.
Furthermore, the metals Li or Na proved to be effective to
this reaction, but the yields of the deprotection products
were lower in some cases. Herein, we present our experi-
ment results in detail.
In the course of design and practical performance of or-
ganic synthesis, protection of the active monohydroxyl
and 1,2-, 1,3- or 1,4-dihydroxyl with the benzyl and ben-
zylidene groups, respectively, are the widely used strate-
gies, because so many important organic compounds
contain these oxygenated functions. In particular, the ben-
zyl protective group exhibits more advantages. For exam-
ple, formed benzyl ethers are stable to basic and acidic
reaction conditions in most cases, and in some cases to the
reduction and oxidation. To our knowledge, the efficient
and general cleavage procedures for benzyl ethers are by
use of catalyzed hydrogenolysis,1 and in fewer cases the
complicated Birch-like reduction2 and two-stepped ozo-
nization.3 Some other procedures, such as those with
Lewis acids4 or through electrolysis,5 are limited individ-
ual molecular structures. However, the generally applica-
ble cleavage procedures listed above destroy the olefin,
arene and ketone or aldehyde carbonyl functions. Thus
these problems, to a large extent, limit the application of
benzyl protective groups.
In our recent synthetic studies of natural products,6 we
have found that the system K (10 equiv)–t-BuNH2 (2
equiv)–t-BuOH (2 equiv)–18-crown-6 (0.1 equiv) (or that
without t-BuOH/18-crown-6) in THF solvent could effec-
tively cleave benzyl ethers and benzylidene acetals within
1–6 hours in high yields (73–99%). This discovery en-
courages us to make a further extensive investigation and
develop a new cleavage method of benzyl ethers and the
benzylidene acetals. The advantages of this method over
the previous generally used procedures is that it is effec-
tive in basic medium and thus did not destroy TBDMS or
THP protective groups and ethylene ketal, which have
The benzyl ether substrates (entries 2–4 and 6) were pre-
pared by treatment of corresponding commercially avail-
able monoterpene alcohols with NaH–BnBr, and those
(entries 9 and 10) from the corresponding trans,trans-
spirodiol were prepared using the literature procedure.8
All structures of both the substrates and products were de-
termined using NMR (400 MHz) and mass spectroscopy.
The benzyl ether cleavage experimentals with K–t-
BuNH2–t-BuOH–18-crown-6 were conducted in a stan-
dard procedure (Scheme 1).7 And the results were listed in
Table 1. So it was notable that all the benzyl deprotection
reactions (entries 1–6, 9 and 10) completed well within 1–
3 h and gave the corresponding alcohol products in high
yields (92–99%). Particularly in entries 3–5, both isolated
and conjugated C=C bonds were not attacked. More im-
portantly in entry 6, the active epoxy still survived under
this reaction condition. In the comparative experiments,
the t-butyl-dimethyl-silyl ethers (entries 7–9) appeared in-
active. Similarly, no reaction with the tetrahydropyrane
ether (entry 10) was found.
Scheme 1
The benzylidene acetals we tested were prepared by treat-
ment of the corresponding diol substrates with
PhCH(OMe)2,9 among which the 1,3-diols (entries 2 and
3) were obtained in our reported procedure,8 and the 1,4-
diols (entries 4–6) obtained as the intermediates in the
course of our synthesis of dihydroagarofuran sesquiterpe-
noids.6 Therefore, the benzylidene acetal substrates were
Synlett 2002, No. 9, Print: 02 09 2002.
Art Id.1437-2096,E;2002,0,09,1505,1507,ftx,en;Y07102ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

1506
L. Shi et al.
LETTER
Table 1 The Cleavage of the Benzyl Ethera
Entry Substrates
Time Products
(h)
Isolated
yield
(%)
1
2
2
1
98
99
Scheme 2
To investigate the reaction mechanism, the benzyl ether in
Table 1, entry 6 was selected to repeat the cleavage exper-
imental on a larger scale. As a result, a combination prod-
uct, the 1,2-diphenylethane, of the benzyl was isolated in
5% yield. But we were not able to isolate the coupling
product of the monoterpene moiety, or the cross coupling
product of Bn with the monoterpene. On the basis of this
and above facts and, in consideration of the literature re-
sult,13 a possible reaction mechanism was deduced prima-
rily as shown in Scheme 3. Firstly, The reaction process
would involve the electron transfer from K to the ether,
which would be promoted by the linking of K+ with 18-
crown-6.14 This then activated the O-Bn bond and led it to
cleave to form the anions RO– (or Bn–) and free radicals
3
3
3
94
90
4
5
2
3
93
90
6
7
Table 2 The Cleavage of the Benzylidene Acetala
Entry Substrate
Time Product
(h)
Isolated
yield
(%)
10
b
b
–
1
2
2
2
87
94
8
9
10
1
–
96
92
3
4
1
6
96
73
10
1
a The results were obtained using the general procedure.7
b No reaction in 10 h.
subjected to a general cleavage with K–t-BuNH2–t-
BuOH–18-crown-6 system (Scheme 2),7 and the results
are listed in Table 2. All the benzylidene 1,2-dioxacetal
(entry 1), 1,3-dioxacetals (entries 2 and 3) and 1,4-dioxac-
etals (entries 4–6) were cleaved in yields of 73–96% with-
in 2–6 h. Importantly, both the methyl ethers (entry 5) and
the ethylene ketals (entries 5 and 6) were not destroyed in
this reaction process, and also, the C=C bond (entry 6) still
survived. In comparison with some established cleavage
methods, the Pd-C–hydrazine–MeOH10 or DIBAL-H11
systems could not cleave the benzylidene 1,4-dioxacetals
(entries 4–6), while I2–MeOH12 system gave the complex
products.
5
6
6
6
89
76
a The results were obtained using the general procedure.7
Synlett 2002, No. 9, 1505–1507 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Highly Selective O_Bn Bond Cleavage Reaction
1507
Bn•(or RO•). The following steps would be the proton
transfer from t-BuOH or t-BuNH2 to the anions RO– (or
Bn–), the coupling of the radical Bn•, or the electron trans-
fer from K to the radical RO• (or Bn•). This mechanism is
uncommon, since the only reported K-induced electron
transfer reaction involved two mixed bonds cleavages.13
In conclusion, we have successfully developed a new and
practical cleavage method of benzyl ether and benz-
ylidene acetal. Further investigation on its application and
a more detailed mechanism are still on going.
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(7) One equiv of substrate dissolved in dried THF was
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as the general procedure to afford the corresponding
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Scheme 3 The suggested mechanism of the O-Bn bond cleavage
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Acknowledgement
This work was supported by NSFC (No. 29972019, 29925205 and
QT program), FUKTME of China, the Young Teachers’ Fund of
Ministry of Education and the Fund of Ministry of Education (No.
99209). We thank Ms. Wang Kai Qiu and Mr. Qi Xiu Zhu for their
assistance in NMR and MS measurements.
(14) Organic Chemistry, 6th ed.; Solomons, T. W. G., Ed.; John
Wiley and Sons Inc.: New York, 1996, 460.
Synlett 2002, No. 9, 1505–1507 ISSN 0936-5214 © Thieme Stuttgart · New York