Cleavage of the THP protecting group under Pd/C-catalyzed hydrogenation conditions

Article abstract of DOI:10.1016/S0040-4039(01)01630-6

Alcohol and phenol THP or ethoxyethyl ether protecting groups may be cleaved in high yield under Pd/C-catalyzed hydrogenation conditions in EtOH, owing to the inadvertent presence of small quantities of HCl in the reaction mixture. MOM ethers are not cleaved under these conditions.

Full text of DOI:10.1016/S0040-4039(01)01630-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 7699–7701
Cleavage of the THP protecting group under Pd/C-catalyzed
hydrogenation conditions
Leena H. Kaisalo* and Tapio A. Hase
Department of Chemistry, Laboratory of Organic Chemistry, University of Helsinki, PO Box 55, FIN-00014 Helsinki, Finland
Received 30 May 2001; revised 17 August 2001; accepted 30 August 2001
Abstract—Alcohol and phenol THP or ethoxyethyl ether protecting groups may be cleaved in high yield under Pd/C-catalyzed
hydrogenation conditions in EtOH, owing to the inadvertent presence of small quantities of HCl in the reaction mixture. MOM
ethers are not cleaved under these conditions. © 2001 Elsevier Science Ltd. All rights reserved.
1
Prompted by recent reports by Hattori and co-workers
of TBDMS ether cleavages under hydrogenolytic condi-
tions, we wish to report that analogous protecting
group cleavage occurs in THP and ethoxyethyl ethers.
In contrast to the Japanese workers, we do not visualise
any of these reactions as truly hydrogenolytic but
ascribe them to the presence of small quantities of HCl
It is obvious that a prime candidate responsible for
these unexpected acetal cleavages is an acidic impurity
in the reaction mixture, capable of catalysing a trans-
acetalization reaction between the THP ether and the
ethanol solvent. However, rinsing the catalyst with aq.
NaHCO before hydrogenation did not prevent depro-
3
tection of 4 (entry 6), while addition of a small amount
of pyridine to the reaction mixture (entry 7) did. No
in the reaction mixture, generated from residual PdCl2
in the commercial Pd/C catalyst. A hydroxylic solvent,
normally ethanol, appears to be essential in all these
cleavages.
reaction was detected in the absence of H (entry 4).
2
Interestingly, when 2-(dec-9-en-1-yloxy)tetrahydro-
pyran 4 was treated with Pd/C in the absence of H the
2
terminal double bond migrated to give a mixture of
decenol THP ether isomers (entry 8). As expected, the
Pd/C-catalyzed hydrogenation of the benzylic THP–
ether 6 gave the hydrogenolysis product p-cymene 6a
During recent studies concerning the synthesis and
reactions of certain macrolides, reduction of the THP-
2
protected macrolide 1 under standard conditions unex-
pectedly gave the g-hydroxylactone 1a as the sole
(
entry 10).
3
product instead of the THP ether of 1a (Scheme 1). In
4
the literature there are a few reports of complete or
In a comparison of various commercial Pd/C catalysts
Table 2), complete cleavage of the THP group took
5
partial deprotections of THP groups under hydrogena-
(
tion conditions but no comments were offered to
explain such phenomena. A study of a variety of alco-
hol or phenol THP ethers established that this is a
general deprotection method for THP ethers (Table 1).
7
place in 24 h only when Pd/C (Aldrich) was used in an
equal amount to the substrate (entry 3). Pd/C catalysts
from other suppliers (entries 4–6) were less effective in
promoting the THP cleavage. As expected, the THP
8
moiety ends up as EtOTHP, confirming an acid-cata-
lyzed acetal exchange with the solvent ethanol. In keep-
ing with this, the reaction fails completely in
cyclohexane solution (entry 7).
Pd/C
H2
O
O
O
O
EtOH
Pd/C catalysts are usually prepared by the reduction of
THPO
HO
9
PdCl in the presence of activated charcoal. If some
2
1
1a
residual PdCl remains in the catalyst it will liberate
2
HCl first during the hydrogenation (cf. Table 1, entries
Scheme 1.
10
6
and 8). Electron spectroscopic analysis ESCA of
Pd/C (10%, Fluka) showed that the palladium on the
surface layer of the catalyst was ca. 1:1 Pd(0):Pd(2 ) but
+
*
0
Corresponding author.
040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01630-6

7
700
L. H. Kaisalo, T. A. Hase / Tetrahedron Letters 42 (2001) 7699–7701
6
Table 1. Reactions of THP protected hydroxy compounds under Pd/C-catalyzed hydrogenation conditions
Table 2. Pd/C-catalyzed hydrogenation of ethyl 4-(2-tetrahydropyranyloxy)benzoate 2
OTHP
OH
Pd/C
H2
EtOH
COOEt
COOEt
2
2a
Pd/C catalysta
Amount of Pd/C (%)b
Solvent
Ratio OH:OTHP
c
Entry
1
2
3
4
5
6
7
8
A
A
A
J
F
D
25
50
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
Cyclohexane
EtOH
14:86
56:44
100:0
12:88
0:100
5:95
100
100
100
100
100
100
d
A
0:100
100:0
J+0.02 equiv. PdCl2
a
A=Aldrich, J=Johnson Matthey Chemicals Ltd, F=Fluka, D=Degussa.
Ratio Pd/C: 2 w/w%.
By GLC.
b
c
d
5
% Pd/C.
+
that Pd/C (10%, Aldrich) was nearly all Pd(2 ). Chlo-
rine values on the surface layers were 0.3 and 1.6 at%,
respectively. Total chlorine in bulk Pd/C (Aldrich) was
the presence of even major quantities of PdCl does not
2
appear to affect the reduction of double bonds (Table
+
1, entries 1, 5–7). Presumably all the Pd(2 ) is reduced
11
estimated as 0.65% (w/w, combustion analysis ) or
.4% (at%, X-ray). It is thus likely that there are
to Pd(0) during the course of the reaction.
0
significant quantities of PdCl2 particularly in the
Aldrich Pd/C material, and possibly of Pd/O also. In
O
O
OH
O
O
Pd/C
H2
Pd/C
H2
the event, the addition of 0.02 equiv. (w/w) of PdCl to
2
X
Johnson Matthey’s Pd/C, having a low THP-cleaving
tendency, resulted in a complete loss of the THP pro-
tecting group (Table 2, entries 4 and 8). The presence of
EtOH
EtOH
COOEt
COOEt
COOEt
7
8
PdCl in the catalyst also explains the isomerization of
2
1
2
the terminal double bond (Table 1, entry 8). However,
Scheme 2.

L. H. Kaisalo, T. A. Hase / Tetrahedron Letters 42 (2001) 7699–7701
7701
A complete deprotection also occurred during Pd/C-
catalyzed (Aldrich) hydrogenation of the EE protected
phenol 7 (Scheme 2). Interestingly, the corresponding
methoxymethyl (MOM) ether 8 tolerates the Pd/C–H2
conditions (Scheme 2), undoubtedly due to the less well
stabilized carbocation in the alcoholysis mechanism.
2. (a) Greene, T. W.; Wuts, P. G. M. Protective Groups in
Organic Synthesis, 2nd ed.; Wiley: New York, 1991; (b)
Paquette, L. A. Encyclopedia of Reagents for Organic
Synthesis; John Wiley & Sons: Chichester, 1995.
3. Kaisalo, L.; Hase, T. Synthesis 2001, 1619–1622.
4. Kitazime, T.; Asai, M.; Tsukamoto, T.; Yamazaki, T. J.
Fluorine Chem. 1992, 56, 271–284.
In conclusion, Pd/C catalysts may contain residual
5. (a) Mori, K.; Nomi, H.; Chuman, T.; Kohno, M.; Kato,
K.; Noguchi, M. Tetrahedron 1982, 38, 3705–3711; (b)
Terinek, M.; Kozmik, V.; Palecek, J. Collect. Czech.
Chem. Commun. 1997, 62, 1325–1341.
6. General procedure for hydrogenation: 10% Pd on activated
charcoal (in equal amount to the substrate) was added to
a THP protected starting material (0.15–0.3 mmol) in 10
mL of EtOH. After evaporation, the mixture was hydro-
amounts of PdCl , which during hydrogenation liberate
2
HCl and cause the cleavage of acid sensitive THP, EE
or silyl groups. If deprotection is not desired, MOM
ether protection should be used instead. The use of an
aprotic solvent or the addition of a small amount of
amine to the reaction mixture before hydrogenation
effectively prevents the deprotection of acid sensitive
protecting groups during Pd/C-catalyzed hydrogena-
tion.
genated under a H balloon at rt for 3 h (1) or overnight.
2
After filtration through a pad of Celite the filtrate was
8
evaporated to give the product.
7
. The deprotection reaction is slow. After 1 h only 12% of
product 2a was observed, and after 7 h there was still 6%
of the protected phenol left.
Acknowledgements
We thank Dr. Seppo Lindroos (University of Helsinki)
for the X-ray measurement.
8. Products were identified by GC and NMR comparison
with authentic material.
9
. Ref. 2b, Vol. 6, pp. 3872–3882; Augustine, R. L. In
Catalytic Hydrogenation; Marcel Dekker: New York,
1965; pp. 36–39 and 152.
References
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0. Chemical Analysis Center, Helsinki University of Tech-
1
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5