Hydrosilane-Promoted Facile Deprotection of tert-Butyl Groups in Esters, Ethers, Carbonates, and Carbamates

Article abstract of DOI:10.1002/adsc.201801279

Combination of PdCl₂ with 1,1,3,3-tetramethyldisiloxane in the presence of activated carbon was found to be an effective catalyst system for the cleavage reaction of C?O bond of O?t-Bu moieties. The present catalytic reaction offers a practical method for the deprotection of tert-butyl esters, tert-butyl ethers, O-Boc, and N-Boc derivatives under mild conditions. The addition of activated carbon in the reaction mixture was proved to be crucial for not only sustaining the catalytic activity but also trapping the palladium species after the reaction. (Figure presented.).

Full text of DOI:10.1002/adsc.201801279

Title: Hydrosilane-Promoted Facile Deprotection of tert-Butyl Groups in
Esters, Ethers, Carbonates, and Carbamates
Authors: Takuya Ikeda, Zhenzhong Zhang, and Yukihiro Motoyama
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201801279
Link to VoR: http://dx.doi.org/10.1002/adsc.201801279

10.1002/adsc.201801279
Advanced Synthesis & Catalysis
Very Important Publication
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Hydrosilane-Promoted Facile Deprotection of tert-Butyl Groups
in Esters, Ethers, Carbonates, and Carbamates
Takuya Ikedaa, Zhenzhong Zhang,a and Yukihiro Motoyamaa*
a
Department of Advanced Science and Technology, Toyota Technological Institute, Nagoya, Aichi 468-8511, Japan
Phone: (+81)-52-809-1807, Fax: (+81)-52-809-1721, e-mail: motoyama@toyota-ti.ac.jp
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
or ether oxygen atom followed by deprotonation of
tetramethyldisiloxane in the presence of activated carbon the t-Bu group by the [Ru3–H]– species resulting in
Abstract. Combination of PdCl2 with 1,1,3,3-
was found to be an effective catalyst system for the
cleavage reaction of C–O bond of O–t-Bu moieties. The
present catalytic reaction offers a practical method for the
deprotection of tert-butyl esters, tert-butyl ethers, O–Boc,
and N–Boc derivatives under mild conditions. The addition
of activated carbon in the reaction mixture was proved to
be crucial for not only sustaining the catalytic activity but
also trapping the palladium species after the reaction.
the formation of silyl ester, isobutene, and hydrogen
gas (Scheme 1).[7] This catalytic system is attractive
because the procedure is simple and reaction
proceeds under neutral conditions, but the preparation
of triruthenium cluster complex is unavoidable.[8] In
addition, this system is not compatible towards a
compound having other ester groups in a molecule
because they are reduced under reaction conditions to
afford the corresponding silyl ethers.
Keywords: activated carbon; deprotection; hydrosilane;
palladium; tert-butyl group
H
R
O
R
O
[H–Ru3]–
O
O
or
[Si]+
[Si]
+
+
or
H2
The development of novel transformation method of
organic molecules, especially by virtue of catalysis, is
one of the most challenging and formidable
endeavours in organic synthesis. In addition, facile
removal of the metallic species from the product is
quite important for the design of the metal-catalyzed
reaction systems.[1]
[Si]+
[Si]
H
O
O
R
R
Scheme 1. Reaction mechanisms for the silane-induced
deprotection of tert-butyl esters and ethers by using
triruthenium cluster as a catalyst.
The tert-butyl substituent (t-Bu), which possesses
prominent stability under a variety of reaction
conditions, is widely recognized as one of the most
powerful protecting groups for alcohols and
carboxylic acids.[2] However, the harsh conditions are
commonly required to cleave the C–O bond of tert-
butoxy moiety (deprotection) by using strong
Brønsted- or Lewis acids.[2,3] In the past decades,
Jaime-Figueroa et al. developed a new deprotection
method of tert-butyl esters and carbonates using
fluorinated alcohols as a solvent at 100 °C.[4] Bartoli
and Sambri also developed a simple procedure for the
deprotection of tert-butyl esters and ethers: the
reaction proceeded smoothly in CH3CN at 40–70 °C
by using stoichimetric amounts of CeCl3 and NaI.[5]
In 2010, Nagashima and co-workers firstly
reported a catalytic method for C–O bond cleavage of
tert-butoxy moiety (O–t-Bu) using (3,2,3,5-
acenaphthylene)Ru3(CO)7 complex and Me2PhSiH.[6]
In this reaction, heterolytic cleavage of the Si–H bond
of hydrosilane is induced by the triruthenium cluster
to form an ionic intermediates, [Si]+•••[Ru3–H]–, then
the Lewis acidic [Si]+ species interacts with carbonyl-
We have recently reported the catalytic silane-
reduction of carbonyl compounds using commercially
available palladium on carbon (Pd/C) as a catalyst.[9]
During the course of these studies, we became aware
of the gas evolution and formation of silyl esters and
isobutene as a by-product in the Pd-catalyzed reaction
of tert-butyl esters with hydrosilanes.[10] Similar to
the triruthenium cluster system, the present Pd-
hydrosilane system also initiates the ring-opening
oligomerization of THF[7] (details see, Supporting
Information). Our efforts to achieve the selective
conversion of tert-butyl esters to the corresponding
carboxylic acids resulting the discovery that the
combination
of
1,1,3,3-tetramethyldisiloxane
(TMDS)[11] and PdCl2 in the presence of activated
carbon provides an efficient deprotection process of
tert-butyl groups in not only esters but also ethers,
carbonates, and carbamates under mild conditions.
Table 1 summarizes the results when tert-butyl 3-
phenylpropionate (1a) was treated with several
1
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10.1002/adsc.201801279
Advanced Synthesis & Catalysis
palladium compounds[12] and hydrosilanes in
dimethoxyethane (DME) at 40 °C for 24 h followed
by workup with methanol. Although the chemical
yield of the reaction of 1a and Me2PhSiH using Pd/C
as a catalyst was quite low, the reaction with
palladium salts or complexes proceeded smoothly in
the presence of activated carbon (AC) to give 3-
phenylpropionic acid (5a) in good to high yields
(Entries 1 vs. 2–5). The presence of AC in the
reaction mixture was crucial for the present
deprotection: when the reaction was carried out
without addition of AC, only trace amount of 5a was
obtained along with the formation of palladium
residues as black precipitates (Entry 6). As shown in
Entries 7–10, TMDS and alkoxysilanes were also
effective for the present reaction; Me2PhSiH and
TMDS gave the best results among them by the
reaction using 1 mol% of PdCl2 in the presence of
AC (details, see Supporting Information). It is
noteworthy that the present reaction was highly
dependent on the solvent used: no reaction took place
in toluene and hexane, however, the C–O bond
cleavage reaction smoothly proceeded in DME and
dichloromethane (see, Supporting Information).
(Entries 6 and 7). Comparing with the tert-butyl
esters and O-Boc derivatives, the reaction of tert-
butyl ethers 2a and 2b required prolonged reaction
time (20–24 h) to afford the desired alcohols 6a and
6b in high yields (Entries 4 and 5). Although the
reactivity of the N-Boc derivatives 4a, 4c and 4d
were relatively lower than that of the others, using 2
mol% of PdCl2 led to satisfactory yields (Entries 8,
10, and 11). Finally, the present procedure is
adaptable to a gram-scale reaction. For example, the
reaction of 1.782 g (10 mmol) of 1c with TMDS (10
mmol) in the presence of PdCl2 (0.5 mol% to 1c) at
40 °C for 24 h afforded 1.118 g (92%) of 5c.
Table 2. Deprotection of tert-butyl esters, tert-butyl ethers,
O–Boc, and N–Boc derivatives.a)
Entry
Substrate
Time
[h]
4
Product
Yield
[%]b)
1
2
>99
(97)
5a
5b
6
>99
(95)
Table 1. Catalytic deprotection of t-Bu group in 1a.a)
3
4
5
6
24
20
>99
(97)
>99
(86)
>99
(98)
5c
6a
6b
6
7
6
6
>99
(84)
>99
(99)
6a
6b
Entry Catalyst
Si–H
Yield
[%]b)
1
Pd/C
Me2PhSiH
Me2PhSiH
Me2PhSiH
Me2PhSiH
Me2PhSiH
Me2PhSiH
Me2PhSiH
TMDS
10
82
>99
>99
>99
<1
>99
>99
65
2
3
4
5
Pd(OAc)2–AC
Pd(dba)2(H2O)–AC
Pd(acac)2–AC
PdCl2–AC
PdCl2
8c)
9
24
6
>99
7a
7b
(80)d)
>99
(90)
6
7c)
PdCl2–AC
8c,d) PdCl2–AC
10c)
11c)
a)
24
24
>99
7c
9c)
PdCl2–AC
PdCl2–AC
(EtO)Me2SiH
(EtO)2MeSiH
(72)d)
10c)
39
a)
All reactions were carried out by using 1a (0.5 mmol),
hydrosilane (2 mmol), catalyst (0.1 equivalent to 1a),
activated carbon (AC: 100 mg) in DME (0.5 mL) at 40 °C
>99
(92)
7d
b)
1
for 24 h. Determined by H NMR analysis of the crude
c)
material. 1a (1 mmol), PdCl2 (0.01 mmol), AC (50 mg),
All reactions were carried out by using substrate (1
mmol), TMDS (1 mmol), PdCl2 (0.01 mmol), AC (50 mg)
in DME (2 mL) at 40 °C followed by workup with
and DME (2 mL) was used. d) TMDS (1 mmol) was used.
b)
1
methanol or n-Bu4NF. Determined by H NMR analysis
The combination of TMDS and a catalytic amount
of PdCl2 (1–2 mol%) in the presence of AC also
induced deprotection of other tert-butyl esters 1 as
well as tert-butyl ethers 2, O-Boc and N-Boc
derivatives 3 and 4 in DME at 40 °C (Table 2).
Conversion of both aliphatic and aromatic tert-butyl
esters 1 to the corresponding carboxylic acids 5 was
accomplished within 6 h (Entries 1–3). Similarly,
deprotection of O-Boc derivatives 3a and 3b
proceeded smoothly under the same conditions
of the crude material. The yield in parentheses was the
isolated yield. 0.5 mmol of substrate was used. The
product was isolated as the corresponding acetamide.
c)
d)
Hydrolysis of esters is generally performed by
treatment with strong bases, but tert-butyl esters are
not hydrolyzed under these conditions.[2] One aspect
of the present hydrosilane-promoted reaction system
is the preparation of half esters from mixed esters by
2
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10.1002/adsc.201801279
Advanced Synthesis & Catalysis
the selective deprotection of t-Bu group. For example, catalytic activity towards silane-induced deprotection
tert-butyl ethyl succinate (8) was selectively
converted to mono-tert-butyl succinate (10) in 81%
isolated yield by treatment with NaOH in methanol.
In sharp contrast, the reaction of 8 with TMDS (1
equiv. to 8) in the presence of PdCl2 (1 mol%) and
activated carbon in DME at 40 °C for 6 h afforded
monoethyl succinate (9) in 89% isolated yield as a
single product (Scheme 2).[13]
of tert-butyl groups. After the reaction of 1a as
described in Table 2, Entry 1 (at 40 °C for 4 h), the
carbon material was recovered by decantation and
subjected to another catalytic run (Table 3). Although
the catalytic activity of the recovered Pd/AC
gradually decreased, the catalyst recovery/reuse cycle
was successfully repeated three times in almost
quantitative yields by extension of the reaction time
to 24 h. We also checked the transmission electron
microscopy (TEM) images of the recovered Pd/AC
and found that there is only trace amount of Pd
nanoparticles observed after the reaction as shown in
Table 2, Entry 1 (Figure 1, left). In sharp contrast,
many nano-sized particles were existed on the AC
after four recycling experiment (Figure 1, right).
Table 3. Recycle experiments of recovered Pd/AC in the
reaction of 1a.a)
Scheme 2. Selective conversion of tert-butyl ethyl
succinate (8) to monoethyl succinate (9). Conditions: a)
PdCl2/TMDS/DME/40 °C; b) NaOH/MeOH/25 °C
Run
Yield [%]b)
10 h
4 h
24 h
Another interesting application of the present
system is the preparation of esters from t-butyl esters
or carboxylic acids (Scheme 3). The reaction of t-
butyl ester 1a with Me2PhSiH followed by the
addition of MeOH gave methyl ester 11a in
quantitative yield.[14] Similarly, dehydrogenative
silylation of carboxylic acid 5a with Me2PhSiH gave
the corresponding silyl ester, which then was treated
with alcohols to afford esters 11 in good yields. The
source of alkyl groups of 11 was determined as
alcohols by the formation of PhCH2CH2CO2CD3
from CD3OD (see, Supporting Information).
1st
>99
99
49
–
–
89
–
–
–
>99
60
2nd
3rd
4th
20
a)
All reactions were carried out by using 1a (1 mmol),
TMDS (1 mmol), recovered Pd/AC in DME (2 mL) at
b)
40 °C followed by workup with methanol. Determined
by 1H NMR analysis of the crude material.
Figure 1. TEM images of the recovered Pd/AC: after the
reaction as shown in Table 1, Entry 1 (left), and after four
recycling experiment (right).
Scheme 3. Esterification or transesterification of 5a and 1a.
When developing a practical synthetic process
using metal catalyst, it is important for removal of
metal residues from the reactions, especially in
pharmaceutical synthesis.[15] Therefore, we checked
the amounts of residual palladium species in the
crude material obtained by the reaction of 1a as
described in Table 2, Entry 1 followed by workup
process. Microwave plasma-atomic emission
spectrometer (MP-AES) analysis revealed that only
0.121 g of Pd exists in the crude materials: this
corresponds to 0.01% of the Pd species used
(calculated amounts of charged Pd was 1.08 mg). The
remaining Pd species was trapped on the recovered
activated carbon (ca. 1 mg, 92% of the Pd species
used). It is noteworthy that the palladium on
activated carbon thus obtained (Pd/AC) showed
In the Pd/C-catalyzed Heck reaction, it is well
known that the soluble Pd species, which is generated
by the reaction of Pd/C with aryl halides, is the
catalytically active species.[16] Therefore, we next
examined the amounts of palladium species in the
solution obtained by the reaction of N-Boc compound
4a as shown in Table 2, Entry 8. After the reaction at
40 °C for 1 h, the solid AC was removed by filtration
with membrane filters (Durapore HV, 0.45 m) to
afford the brown solution, in which contained silane
residue, unreacted TMDS, 38% of the product, 62%
of 4a remained, and 41.9 g of Pd species (3.9% of
charged Pd). In addition, the filtrate thus obtained
was continuously stirred at 40 °C resulting in the
further formation of the product 7a: 47% for 4 h, and
3
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10.1002/adsc.201801279
Advanced Synthesis & Catalysis
56% for 24 h (Scheme 4). These results and the TEM
images suggested that the catalytically active species
of the present reaction is the small-sized, soluble Pd
clusters, which are initially formed by the reaction of
PdCl2 with TMDS. In the absence of carbon materials,
these Pd clusters are in contact with each other to
form black precipitates. While in the presence of
activated carbon, such palladium species is
immobilized on the AC and regenerates by the
reaction with TMDS.[17] During such reversible
immobilization-regeneration step, the Pd species on
the AC was gradually aggregated resulting in the
formation of large-size of palladium particles.
[1] a) C. E. Garrett, K. Prasad. Adv. Synth. Catal. 2004,
346, 889-900; b) C. J. Welch, J. Albaneze-Walker, W.
R. Leonard, M. Biba, J. DaSilva, D. Henderson, B.
Laing, D. J. Mathre, S. Spencer, X. Bu, T. Wang, Org.
Process Res. Dev. 2005, 9, 198-205; c) N. Galaffu, S. P.
Man, R. D. Wilkes, J. R. H. Wilson, Org. Process Res.
Dev. 2007, 11, 406-413.
[2] P. G. M. Wuts in Greene’s Protective Groups in
Organic Synthesis, 5th ed., John Wiley & Sons, New
Jersey, 2014, pp. 97-99, 750-758.
[3] L. Sambri, G. Bartoli, G. Bencivenni, R. Dalpozzo,
Curr. Org. Synth. 2012, 9, 137-148.
[4] a) J. Choy, S. Jaime-Figueroa, L. Jiang, P. Wagner,
Synth. Commun. 2008, 38, 3840-3853; b) J. Choy, S.
Jaime-Figueroa, T. Lara-Jaime, Tetrahedron Lett. 2010,
51, 2244-2246.
[5] a) E. Marcantoni, M. Massaccesi, E. Torregiani, G.
Bartoli, M. Bosco, L. Sambri, J. Org. Chem. 2001, 66,
4430-4432; b) G. Bartoli, M. Bosco, A. Carlone, M.
Locatelli, E. Marcantoni, P. Melchiorre, L. Sambri, Adv.
Synth. Catal. 2006, 348, 905-910.
Scheme 4. Deprotection of 4a after removal of the solid
carbon materials.
[6] S. Hanada, A. Yuasa, H. Kuroiwa, Y. Motoyama, H.
Nagashima, Eur. J. Org. Chem. 2010, 1021-1025.
In conclusion, we have developed a simple process
for the Pd-catalyzed cleavage reaction of C–O bond
of O–t-Bu groups leading to the facile deprotection of
tert-butyl esters, tert-butyl ethers, O-Boc, and N-Boc
derivatives under mild conditions. The addition of
activated carbon was found to be crucial for the
present silane-induced deprotection. It is of practical
importance that inexpensive PdCl2 and 1,1,3,3-
tetramethyldisiloxane (TMDS) can be used, and the
present procedure can be scaled up to a gram-quantity
reaction. Further mechanistic studies on the
catalytically active species and detailed reaction
pathway are now under investigation.
[7] Nagashima et al. reported that the formed ionic
intermediates, [Si]+•••[Ru3–H]–, initiates cationic ring-
opening polymerization of cyclic ethers and addition
polymerization of vinyl ethers, see a) H. Nagashima, A.
Suzuki, T. Iura, K. Ryu, K. Matsubara,
Organometallics, 2000, 19, 3579-3590; b) H.
Nagashima, C. Itonaga, J. Yasuhara, Y. Motoyama, K.
Matsubara, Organometallics, 2004, 23, 5779-5786.
[8] Y. Motoyama, C. Itonaga, T. Ishida, M. Takasaki, H.
Nagashima, Org. Synth. 2005, 82, 188-195.
[9] a) S. Hosokawa, K. Teramoto, Y. Motoyama,
ChemistrySelect 2016, 1, 2594-2602; b) S. Hosokawa,
M. Toya, A. Noda, M. Morita, T. Ogawa, Y.
Motoyama, ChemistrySelect 2018, 3, 2958-2961.
Experimental Section
1
[10] H NMR (CDCl3) of isobutene in the reaction
Deprotection of 1c (10 mmol Scale). To a suspension of
AC (250 mg), 1c (1.782 g, 10 mmol), and PdCl2 (8.9 mg,
0.5 mol%) in DME (0.5 mL) was added a 0.83 mol•L-1
solution of TMDS in DME (12 mL, 10 mmol) at 25 °C.
After it was stirred at 40 ºC for 24 h, the reaction was
quenched by the addition of MeOH (3 mL). Following
stirring at 25 °C for 30 min, the reaction mixture was
filtered and the filtrate was concentrated. Purification by
silica gel chromatography gave 5c in 92% yield (1.118 g).
mixture:  = 1.72 (bs, 6H, CH3) and 4.65 (bs, 2H,
vinylic proton).
[11] Review: J. Pesti, G. L. Larson, Org. Process Res. Dev.
2016, 20, 1164-1181.
[12] For preliminary screening, we found some Ru, Rh, Ir,
and Pt compounds show catalytic activity towards the
deprotection reaction of 1a, see Supporting Information.
Acknowledgements
[13] We also examined the reactions of some compounds
having other functional groups and found that reduction
of formyl-, keto-, amido-, imino-, and nitro groups
proceeded smoothly, but methyl ether and nitrile
groups were tolerant under the present conditions.
Details see Supporting Information.
The authors are grateful to Prof. S.-H. Yoon and Dr. J. Miyawaki
(Kyushu University) for their help in the TEM analysis. Part of
this work was supported by JSPS through a Grants-in-Aid for
Scientific Research (C) (26390031) and MEXT through the
Strategic Research Foundation at Private Universities
(S1511022).
[14] Interestingly, the present Pd-catalyzed esterification
and transesterification did not proceed with TMDS.
References
[15] a) Guideline
for Elemental Impurities:
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Pr
4
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10.1002/adsc.201801279
Advanced Synthesis & Catalysis
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[17] We previously reported that the catalytically active
species in the Pd/C-catalyzed silane-reduction of
carboxamides is the soluble palladium species leached
out from the carbon support, see: ref. 9a.
5
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Advanced Synthesis & Catalysis
COMMUNICATION
Hydrosilane-Promoted Facile Deprotection of tert-
Butyl Groups in Esters, Ethers, Carbonates, and
Carbamates
Adv. Synth. Catal. Year, Volume, Page – Page
Takuya Ikeda, Zhenzhong Zhang, and Yukihiro
Motoyama*
6
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