Palladium on Carbon-Catalyzed Benzylic Methoxylation for Synthesis of Mixed Acetals and Orthoesters

Article abstract of DOI:10.1002/chem.201702278

The palladium on carbon (Pd/C)-catalyzed direct methoxylation of the benzylic positions of linear benzyl and cyclic ether substrates proceeded in the presence of i-Pr₂NEt under an oxygen atmosphere to give the corresponding mixed acetals. Cyclic acetal derivatives could also be converted into orthoesters. The present direct methoxylation via a carbon-hydrogen (C?H) functionalization can be accomplished using the easily-removed Pd/C and molecular oxygen as a green oxidant. The obtained mixed acetals were transformed into the corresponding ether products by chemoselective substitution of the methoxy group using a silyltriflate, 2,4,6-collidine, and a nucleophile. The orthoester derivative could also be transformed into the cyclic ketal under similar reaction conditions.

Full text of DOI:10.1002/chem.201702278

A Journal of
Accepted Article
Title: Palladium on Carbon-Catalyzed Benzylic Methoxylation for
Synthesis of Mixed Acetals and Orthoesters
Authors: Naoki Yasukawa, Takafumi Kanie, Marina Kuwata, Yasunari
Monguchi, Hironao Sajiki, and Yoshinari Sawama
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To be cited as: Chem. Eur. J. 10.1002/chem.201702278
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COMMUNICATION
Palladium on Carbon-Catalyzed Benzylic Methoxylation for
Synthesis of Mixed Acetals and Orthoesters
Naoki Yasukawa[a], Takafumi Kanie[a], Marina Kuwata[a], Yasunari Monguchi[a], Hironao Sajiki* [a] and
Yoshinari Sawama*[a]
Abstract: The palladium on carbon (Pd/C)-catalyzed direct
methoxylation of the benzylic positions of linear benzyl and cyclic
ether substrates proceeded in the presence of i-Pr2NEt under
oxygen atmosphere to give the corresponding mixed acetals. Cyclic
acetal derivatives could also be converted into orthoesters. The
functionalization of the benzylic position of benzyl ethers into
mixed acetals has never been developed. We now demonstrate
a
palladium on carbon (Pd/C)-catalyzed intermolecular
methoxylation of linear and cyclic benzyl ethers (1) using oxygen
as a green oxidant in the presence of i-Pr2NEt in MeOH
(Scheme 1). Additionally, the methoxylation of cyclic acetals (1’)
into orthoesters (2’) was also accomplished under the present
Pd/C-catalyzed reaction conditions. Orthoesters are widely used
as dehydrating agents and alcohol sources,12 and applied to the
selective functionalization of steroid derivatives.13 We have also
achieved versatile nucleophilic substitutions based on the
elimination of the methoxy group of the prepared 2 and 2’ to give
the corresponding ether (5) and ketal (5’) derivatives.
present direct methoxylation via
a
carbon-hydrogen (C-H)
functionalization can be accomplished using the easily-removed
Pd/C, and molecular oxygen as a green oxidant. The obtained mixed
acetals were transformed into the corresponding ether products via
the chemoselective substitution of the methoxy group using a
silyltriflate, 2,4,6-collidine, and
a nucleophile. The orthoester
derivative could also be transformed into the cyclic ketal under
similar reaction conditions.
key reaction
OMe
[Nu]
H
Introduction
O
R
O
O
R
TESOTf
2,4,6-collidine
CH2Cl2, 0 C
R
Pd/C, O2
i-Pr2NEt
Mixed acetals bearing two different alkoxy groups on one
carbon atom are widely utilized as synthetic precursors, and
numerous preparation methods have been developed.1-12
Although the acid-catalyzed transacetalization of a symmetrical
acetal [-CH(OR1)2] with an alcohol (R2OH) is generally adopted
to produce the corresponding mixed acetal [-CH(OR1)(OR2)] as
a simple preparation method, the avoidance of the overreaction
into another symmetrical acetal [-CH(OR2)2] is generally
difficult.1 A reliable preparation method of mixed acetals from
symmetrical acetals has been developed by the Fujioka and Kita
group via the intermediary pyridinium salts using stoichiometric
pyridine and silyltriflate derivatives and the subsequent addition
1
2
5
MeOH, 80 C
then [Nu], rt
RO
OR
H
RO
OR
OMe
RO
OR
[Nu] = Nuclephile
[Nu]
1'
2'
5'
Scheme 1. Pd/C-catalyzed benzylic methoxylation under oxygen atmosphere
and its application.
Results and Discussion
2
of an alcohol. Although direct alkoxylation reactions of the
We have recently accomplished the Pd/C-catalyzed oxygen
oxidation of aromatic cyclic acetals to benzoic acid hydroxyalkyl
ester derivatives via the direct C-H functionalization of the
benzylic positions.14 Benzyl n-butyl ether (1a) also underwent
the Pd/C-catalyzed oxidation in MeOH under an oxygen
benzylic positions of the benzyl ether derivatives using a
stoichiometric oxidant [e.g., tert-butyl peroxide (TBHP),3 2,3-
dichloro-5,6-dicyano-p-benzoquinone
(DDQ),4
oxide/N-
bis(trifluoroacetoxy)iodobenzene,5
or
nitric
hydroxyphthalimide (NHPI)6] could provide mixed acetals, the
applicable substrates were quite limited. On the other hand, the
intramolecular cyclization of ether substrates bearing a hydroxyl
group within the same molecule using DDQ7, an iodine oxidant8
or N-iodosuccinimide (NIS)9 has been accomplished to
synthesize the acetals. While the transition metal (Co10 or Ru11)-
catalyzed direct transformation methods into mixed acetals from
the corresponding allyl alcohols with an additional alcohol has
o
atmosphere at 80 C for 12 h to give the corresponding esters
(3a and 4a) in good total yields (73%, Table 1, entry 1). The
addition of inorganic bases, such as NaOH, NaHCO3, Na2CO3,
NaOtBu and KOtBu, allowed the formation of the mixed acetal
(2a) by the direct methoxylation of 1a in low to moderate yields
along with the generation of esters (3a and 4a) (entries 2-6). As
the result of the further screening using organic bases, such as
N-methyl
morpholine,
Et3N,
(DABCO)
i-Pr2NEt,
1,4-
1,8-
been reported,
a catalytic method based on the C-H
diazabicyclo[2.2.2]octane
and
diazabicyclo[5.4.0]undec-7-ene (DBU) (entries 7-12), i-Pr2NEt
was chosen as a relatively favorable base, although the starting
material (1a) was not completely consumed (entry 10). While
extension of the reaction time to 24 h was not effective (entry
13), the increased use of Pd/C (15 mol%) could improve the
reaction efficiency to give 2a in 84% (entry 14). Meanwhile,
[a]
Laboratory of Organic Chemistry, Gifu Pharmaceutical University,1-
25-4 Daigaku-nishi, Gifu 501-1196, Japan
E-mail: sajiki@gifu-pu.ac.jp
sawama@gifu-pu.ac.jp
Supporting information for this article is given via a link at the end of
the document.
o
heating at 60 C was not effective for the methoxylation (entry
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15), and the reaction hardly proceeded under argon (Ar) and
ambient air conditions (entries 16 and 17).
3
4
5
6
10% Ru/C
10% Rh/C
10% Ir/C
96
96
97
92
0
0
0
0
0
0
0
0
0
1
1
0
Table 1. Base efficiency in Pd/C-catalyzed methoxylation of benzyl butyl
ether (1a)
10% Au/C
10% Pd/C (5 mol%)
base (1 equiv)
OMe
O
O
O2
n-Bu
n-Bu
n-Bu
+
+
Ph
O
O
O
OMe
4a
Ph
Ph
Ph
The scope of the substrates was next investigated (Table 3).
MeOH (1 mL)
80 C, 12 h
1a (0.25 mmol)
2a
3a
Benzyl ethers (1a-1f) bearing kinds of various alkyl chains were
efficiently transformed into the corresponding mixed acetals (2a-
2f) (entries 1-6). Phthalane (1g) and isochroman (1h) as cyclic
entry
base
yield (%)
ethers
also
underwent
the
Pd/C-catalyzed
benzylic
SM (1a)
2a
0
3a
35
40
16
32
16
40
0
4a
methoxylation to be converted into the desired mixed acetals (2g
and 2h) in moderate yields along with the over-oxidized cyclic
esters (3g and 3h) (entries 7 and 8). 2-Phenyltetrahydrofuran
(1i) was also transformed into the corresponding mixed acetal
(2i) even in a moderate yield (entry 9). On the other hand,
aromatic 5-membered cyclic acetals (1’a and 1’b) efficiently
underwent the Pd/C-catalyzed methoxylation to give the
corresponding orthoesters (2’a and 2’b) (entries 10 and 11),
while the reaction of benzaldehyde dimethyl acetal (1’c) as an
acyclic substrate hardly proceeded (entry 12). The steric strain
of the benzylic position may be necessary to facilitate the
methoxylation of the 5-membered cyclic acetals (1’a and 1’b),
therefore, the over-reaction can be suppressed in the
methoxylation of the acyclic benzyl ethers (1a-1f) (entries 1-8).
However, the structurally distorted cyclic acetal products (2g and
2h) partially underwent the second methoxylation at the benzylic
positions into the comparatively unstable orthoesters bearing
two methoxy groups,15 which were converted to esters by partial
hydrolysis (3g and 3h). Meanwhile, the relatively flexible 6-
membered cyclic acetal (1’d) was less reactive. Consequently,
the desired orthoester (2’d) was obtained in a low yield, and
83% of the unchanged starting material (1’d) was recovered
(entry 13).
1
2
3
4
5
6
7
8
9
―
0
38
40
10
16
8
NaOH
0
5
NaHCO3
0
54
28
56
7
Na2CO3
0
NaOtBu
0
KOtBu
0
19
0
morpholine
N-methylmorpholine
Et3N
98
13
45
0
50
18
14
4
2
3
10
i-Pr2NEt
DABCO
DBU
37
0
44
65
0
7
3
2
0
5
4
5
0
0
11
13
0
12
100
34
1
13[a]
14[a,b]
15[a,c]
16[a,d]
17[a,e]
i-Pr2NEt
i-Pr2NEt
i-Pr2NEt
i-Pr2NEt
i-Pr2NEt
53
84
56
10
16
7
6
14
83
72
13
0
Table 3. Scope of substrates.
10% Pd/C (15 mol%)
i-Pr2NEt (1 equiv)
O2
1
[a] For 24 h. [b] 15 mol% of 10% Pd/C was used. [c] At 60 oC. [d] Under
Ar. [e] Under air.
substrate (1)
product (2)
MeOH (1 mL)
80 °C, 24 h
The present methoxylation of 1a could be smoothly catalyzed
by only Pd/C to give the desired mixed acetal (2a) (Table 2,
entry 1), while other platinum group metal on carbon (Pt/C, Ru/C,
Rh/C and Ir/C) and Au/C were all ineffective (entries 2-6).
entry
substrate
product
yield (%)
OMe
OR
Ph
Ph
OR
1
2
R = n-Bu (1a)
2a
2b
2c
2d
2e
2f
84
77
75
47
80
78
53
Table 2. Catalyst efficiency.
R = n-C12H25 (1b)
R = iso-Am (1c)
R = iso-Pr (1d)
R = c-Hex (1e)
R = tert-Bu (1f)
catalyst (15 mol%)
i-Pr2NEt (1 equiv)
3[a]
OMe
O
O
O2
n-Bu
n-Bu
n-Bu
4
+
+
Ph
O
O
O
OMe
4a
Ph
Ph
Ph
MeOH (1 mL)
80 C, 24 h
1a (0.25 mmol)
2a
3a
5
6[a]
7[a]
entry
catalyst
yield (%)
SM (1a)
1
2a
84
0
3a
6
4a
4
O
OMe
1
2
10% Pd/C
10% Pt/C
1g
O
54
0
0
2g
19
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10.1002/chem.201702278
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COMMUNICATION
O
hydroxyl radical to give the products (2) (route a). Alternatively,
A can be also reacted with a hydroxyl radical to be transformed
into the comparatively unstable hemiacetal intermediate (B)
(route b), which is converted to 2 via oxonium ion intermediate
(C).
O
3g
2h
OMe
O
8
O
Pd/C
54
17
MeOH
H
H
etc.
O
H2
MeOH
MeO
[route a]
[route b]
Pd/C
O2
O
O
1h
H2O
H
H2O2
OMe
H2O + HO
O
R
O
R
O
R
3h
2i
1
A
B
2
9
OMe
O
Ph
O
Ph
O
MeOH
45
88
OH
1i
O
R
O
R
10[b]
C
O
O
H
O
Ph
Ph
OMe
Scheme 2. Proposed reaction mechanism.
1'a
2'a
11[b]
O
O
H
O
O
After the formation of 2a in 84% for 24 h by the Pd/C-
catalyzed methoxylation of 1a (Table 1, entry 14), a very small
amount of Pd leaching [0.1% of Pd (1.7 ppm) based on the used
Pd amount on 10% Pd/C] was observed (See Supporting
Information). When the reaction was stopped in a short time (6
h), 45% of 2a, and 40% of the unreacted starting material (1a)
together with total 2% of ester products (3a and 4a) were
obtained (eq. 3, X = 0). After hot filtration19 of the reaction
mixture, the filtrate was heated again under oxygen atmosphere
for further 18 h to give 2a in 49%, the recovered 1a (29%) and
total 8% of ester products (3a and 4a) (eq. 3, X = 18). A small
amount of 1a was consumed and the yields of the oxidized
products (2a, 3a and 4a) slightly increased, but the reaction was
not completed. These results indicated that both leached Pd and
supported Pd species could additionally facilitate the oxidation of
1a. Because the property of Pd species activated on carbon may
be changed during the heating process, the yields of 2a
gradually decreased by the repeated use of recovered Pd/C (eq.
4.)
70
Ph
Ph
OMe
1'b
OMe
OMe
2'b
12[b]
OMe
OMe
OMe
trace (76%)[c]
17 (83%)[c]
Ph
Ph
1'c
2'c
13[b]
O
O
O
O
H
Ph
OMe
2'd
Ph
1'd
[a] 25 mol% of 10% Pd/C was used. [b] 5 mol% of 10% Pd/C was used.
[c] The recovered yield of the starting material.
Phenethyl n-butyl ether (1j) without the benzylic position
adjacent to the oxygen atom was inactive against the Pd/C-
catalyzed methoxylation and remained unchanged (eq. 1).
Furthermore, the methoxylation of 1a was completely inhibited
by the addition of 7,7,8,8-tetracyanoquinodimethane (TCNQ) or
tetracyanoethylene (TCNE) as a radical scavenger (eq. 2).
Based on these results, it is presumed that the present
methoxylation of benzyl ethers is initiated via the generation of a
benzylic radical intermediate,16 which is known to be
comparatively stable.
10% Pd/C (15 mol%)
i-Pr2NEt (1 equiv)
O2
O2
n-Bu
O
Ph
MeOH (1 mL)
80 C, 6 h
then hot filtration
1a (0.25 mmol)
80 C, x h
(eq. 3)
OMe
O
O
recovered
1a
n-Bu
n-Bu
+
+
+
O
O
OMe
Ph
Ph
Ph
2a
3a
10% Pd/C (15 mol%)
i-Pr2NEt (1 equiv)
x = 0
x = 18
40%
29%
45%
49%
1%
5%
1%
3%
O2
O
no reaction
(eq. 1)
n-Bu
Ph
MeOH (1 mL)
10% Pd/C (15 mol%)
i-Pr2NEt (1 equiv)
O2
1j
80 C, 24 h
OMe
n-Bu
n-Bu
10% Pd/C (15 mol%)
i-Pr2NEt (1 equiv)
TCNQ or TCNE (1 equiv)
O2
(eq. 4)
O
O
Ph
Ph
MeOH (1 mL)
80 C, 24 h
1a (0.25 mmol)
2a
1st
; 82% (recovered SM ; 3%)
nd ; 76% (recovered SM ; 7%)
; 38% (recovered SM ; 53%)
n-Bu
no reaction
(eq. 2)
2
O
Ph
MeOH (1 mL)
80 C, 24 h
3rd
1a
A presumable reaction mechanism is shown in Scheme 2.
Chemical modifications of the mixed acetals and orthoesters
were also investigated (Scheme 3). The methoxy group of 2e
and 2h could be chemoselectively activated using a combination
of triethylsilyl trifluoromethanesulfonate (TESOTf) and 2,4,6-
collidine,20 and the subsequent nucleophilic substitution using 1-
phenyl-1-trimethylsiloxyethylene gave 5e and 5h in good yields.
Hydrogen
(H2)
generated
by
the
Pd/C-catalyzed
dehydrogenation17 of MeOH is reacted with oxygen (O2) to
produce hydrogen peroxide (H2O2)18, which can be transformed
to a hydroxyl radical. The benzyl radical intermediate (A)
produced by the substrate (1) and hydroxyl radical is smoothly
trapped by a methoxy radical generated from MeOH and a
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10.1002/chem.201702278
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COMMUNICATION
It is noteworthy that the orthoester (2’a) was also transformed
into the corresponding ketal (5’a) in 69% yield under similar
conditions.
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O
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OMe
O
Ph
OMe
Ph
O
TESOTf (2 equiv)
2,4,6-collidine (3 equiv)
CH2Cl2 (1 mL)
c-Hex
c-Hex
Ph
O
2e
Ph
O
2h
5e : 71%
5h : 66%
0 C, 30 min
or
or
then
OTMS
[3]
[4]
[5]
O
(5 equiv)
O
O
O
O
Ph
Ph
OMe
Ph
Ph
rt, 3 h
2'a
5'a : 69%
R. Sakamoto, T. Inada, S. Selvakumar, S. A. Moteki, K. Maruoka,
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Scheme 3. Chemical modification of mixed acetals and orthoester.
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We have developed an efficient synthetic method of mixed
acetals starting from benzyl ethers by the Pd/C-catalyzed
oxidative benzylic methoxylation in the presence of i-Pr2NEt in
MeOH under atmospheric oxygen. Furthermore, the present
methoxylation method can also be applied to the orthoester
synthesis using aromatic cyclic acetals as substrates. The
present first catalytic method combined with molecular oxygen
as a clean oxidant is valuable from the viewpoint of green
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General Procedure for the Conversion of Benzyl Ester 1a to
Mixed Acetal 2a
To a test tube were added benzyl ester (1a; 41.1 mg, 0.25 mmol), 10%
Pd/C (39.9 mg 0.0125 mmol), i-Pr2NEt (44.5 µL, 0.25 mmol) and MeOH
(1 mL), then the test tube was sealed with a septum. The inside air was
replaced with O2 (ballon). The reaction mixture was stirred with a Chemi
Station (EYELA, Tokyo Rikakikai Co., Ltd., Tokyo, Japan) and refluxed
[80 oC outer aluminum heating block temperature]. After 24 h, the
reaction mixture was cooled to room temperature and passed through a
membrane filter (Millipore, Millex-LH, 0.20 mm) to remove Pd/C. The
filtrate was extracted with Et2O (10 mL × 2) and the combined organic
layers were dried over MgSO4 and concentrated in vacuo. The residue
was purified by silica-gel column chromatography using a mixed eluent
(hexane/AcOEt = 20/1) to give the corresponding mixed acetal (2a; 40.7
mg, 84 %). See the Supporting ionformation for characterization details.
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We thank the N. E. Chemcat Corporation for the kind gift of the
various metal on carbon catalysts.
Keywords: Green chemistry • Heterogeneous catalysis •
Oxygen • Palladium
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10.1002/chem.201702278
Chemistry - A European Journal
COMMUNICATION
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COMMUNICATION
Text for Table of Contents
Key Topic*
Author(s), Corresponding Author(s)*
Page No. – Page No.
Title
((Insert TOC Graphic here: max.
width: 5.5 cm; max. height: 5.0 cm;
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not be less than 2 mm.))
*one or two words that highlight the emphasis of the paper or the field of the study
Layout 2:
COMMUNICATION
C-H Methoxylation
Pd/C
O2
i-Pr2NEt
Naoki Yasukawa, Takafumi Kanie,
Marina Kuwata, Yasunari Monguchi,
Hironao Sajiki* and Yoshinari Sawama*
OMe
H
O
Ph
O
H
O
O
OMe
or
or
Ph
OR Ph
Ph
OR
MeOH
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Palladium on Carbon-Catalyzed
Benzylic Methoxylation for Synthesis
of Mixed Acetals and Orthoesters
The direct synthesis of mixed acetals and orthoesters from the corresponding
benzylic ethers has been accomplished using palladium on carbon catalyst in
MeOH under oxygen atmosphere in the presence of i-Pr2NEt. The present catalytic
method using molecular oxygen as a clean oxidant and easily-recovered Pd/C is
valuable from the viewpoint of green sustainable chemistry.
*one or two words that highlight the emphasis of the paper or the field of the study
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