1978
K. Okano et al.
LETTER
loss of TBS and gave only a trace amount of the desired
product (entry 26).
Table 2 Optimization of the Reaction Conditions
OBn
OMe
OH
OH
BCl3
C6HMe5
Bn
In summary, we have established a mild and facile proce-
dure for debenzylation of aryl benzyl ethers by means of
a unique combination of BCl3 and non-Lewis-basic
C6HMe5 as a cation scavenger. The present procedure
proved to be particularly effective not only for substrates
having an electron-rich aromatic ring such as trialkoxy-
benzenes or indole derivatives, but also for those having
acid-labile functionalities such as Boc and TBS ether,
demonstrating our conditions’ superiority over the ones
using TFA and C6HMe5. In addition, the unreacted
C6HMe5 and benzylpentamethylbenzene can be easily re-
moved by column chromatography. The debenzylation
conditions we established should find a widespread use in
synthetic organic chemistry as a reliable alternative to the
conventional palladium-mediated hydrogenolysis.
+
CH2Cl2
–78 °C
20 min
MeO
MeO
MeO
OMe
OMe
3
4
5
Entry
BCl3 (equiv) C6HMe5 (equiv)
4 (%)a
85
5 (%)a
8
1
2
3
4
5
2
1
2
2
2
5
5
3
2
0
81
10
8
84
81
11
43
56
a Isolated yields.
Acknowledgment
we set two equivalents of BCl3 and three equivalents of
C6HMe5 as the standard conditions.
This work was supported by the Ministry of Education, Culture,
Sports, Science, and Technology, Japan, Tohoku University Global
COE program ‘International Center of Research and Education for
Molecular Complex Chemistry’, Kato Memorial Bioscience Foun-
dation, and Takeda Science Foundation. K.O. thanks the JSPS for a
predoctoral fellowship.
Next, we explored the scope and limitations of the deben-
zylation conditions using various aryl benzyl ethers8
(Table 3). Experiments on a series of resorcinol deriva-
tives revealed that methyl, isopropyl, and in particular
TBS ethers could tolerate the reaction conditions (entries
1–3). In the case of the substrate bearing the acid-labile si-
lyl ether, we found that the optimum conditions were to
use 1.1 equivalents of BCl3 followed by addition of a mix-
ture of THF and saturated aqueous NaHCO3 (entry 3).
References and Notes
(1) (a) Kocienski, P. J. Protecting Groups; Thieme: New York,
1994. (b) Wuts, P. G. M.; Greene, T. W. Protective Groups
in Organic Synthesis, 4th ed.; Wiley-Interscience: New
York, 2006.
A substantial desilylation took place when a combination
of TFA and C6HMe5 was used (entry 4).5a While acetate
did not survive the reaction conditions (entry 5), pivalate
and methanesulfonate remained intact during the reaction
(entries 6 and 7). The reaction conditions were also appli-
cable to substrates bearing carbonyl groups such as
formyl, methyl ketone, ester, and in particular thiol ester,
which does not survive hydrogenolysis (entries 8–11). Ni-
tro, iodo, and allyl group, which are reduced under reduc-
tive conditions, tolerated the reaction condition (entries
12–14). It should be noted that selective debenzylation of
a phenolic benzyl ether was possible in the presence of
alkyl benzyl ether and alkyl acetate (entries 15 and 16). As
to the compatibility with nitrogen protective groups, Boc,
Cbz, o-Ns, trifluoroacetyl, and Alloc groups were retained
in the debenzylated products (entries 17–22). In the case
of the acid-labile Boc-protected substrate, we used 1.1
equivalents of BCl3 and terminated the reaction with
THF-saturated aqueous NaHCO3 (entry 17). For an elec-
tron-rich indole derivative, a sizable effect of C6HMe5
was observed. Thus, the yield decreased from 93% to 78%
in the absence of C6HMe5 (entries 23 and 24). Finally,
usefulness of our debenzylation was clearly demonstrated
with the reaction of a multifunctional tetrahydroquinoline
derivative. Both acid-sensitive and reducible functional
groups were retained almost completely (entry 25). Reac-
tion with TFA–C6HMe5,5a on the other hand, resulted in
(2) (a) Okano, K.; Tokuyama, H.; Fukuyama, T. J. Am. Chem.
Soc. 2006, 128, 7136. (b) Okano, K.; Tokuyama, H.;
Fukuyama, T. Chem. Asian J. 2008, 3, 296.
(3) Chong, R.; Gray, R. W.; King, R. R.; Whalley, W. B.
J. Chem. Soc. D 1970, 101.
(4) (a) Kiso, Y.; Isawa, H.; Kitagawa, K.; Akita, T. Chem.
Pharm. Bull. 1978, 26, 2562; treatment of O-benzyltyrosine
with TFA yielded tyrosine and undesired 3-benzyltyrosine
in the ratio of 57:43. (b) Kiso, Y.; Ukawa, K.; Nakamura, S.;
Ito, K.; Akita, T. Chem. Pharm. Bull. 1980, 28, 673; a
combination of thioanisole with TFA was effective to
debenzylation of O-benzyltyrosine without formation of 3-
benzyltyrosine.
(5) (a) Various cation scavengers on debenzylation of O-
benzyltyrosine in TFA were investigated. It was reported
that pentamethylbenzene increased the rate of deprotection
most efficiently among other scavengers such as thioanisole,
anisole, 1,3-dimethoxybenzene, 1,2,3-dimethoxybenzene,
m-xylene, 1,2,3-trimethylbenzene, and 1,2,3,4-
tetramethylbenzene. Isolation and characterization of
benzylpentamethylbenzene generated by trapping of benzyl
cation were also reported. See: Yoshino, H.; Tsuchiya, Y.;
Saito, I.; Tsujii, M. Chem. Pharm. Bull. 1987, 35, 3438.
(b) Yoshino, H.; Tsujii, M.; Kodama, M.; Komeda, K.;
Niikawa, N.; Tanase, T.; Asakawa, N.; Nose, K.; Yamatsu,
K. Chem. Pharm. Bull. 1990, 38, 1735.
(6) Tummatorn, J.; Khorphueng, P.; Petsom, A.; Muangsin, N.;
Chaichit, N.; Roengsumran, S. Tetrahedron 2007, 63,
11878.
Synlett 2008, No. 13, 1977–1980 © Thieme Stuttgart · New York