Chemoselective Nucleophilic Functionalizations of Aromatic Aldehydes and Acetals via Pyridinium Salt Intermediates

Article abstract of DOI:10.1021/acs.joc.8b02965

The development of a novel chemoselective functionalization can diversify the strategy for synthesizing the target molecules. The perfect chemoselectivity between aromatic and aliphatic aldehydes is difficult to achieve by the previous methods. The aromatic aldehyde-selective nucleophilic addition in the presence of aliphatic aldehydes was newly accomplished. Namely, the aromatic aldehyde-selective nucleophilic addition using arenes and allyl silanes proceeded in the presence of trialkylsilyl triflate and 2,2′-bipyridyl, while the aliphatic aldehydes completely remained unchanged. The reactive pyridinium-type salt intermediate derived from an aromatic aldehyde chemoselectively underwent the nucleophilic substitution. Moreover, the aromatic acetals as the protected aldehydes could be directly transformed into similar pyridinium salt intermediates, which reacted with various nucleophiles coexisting with the aliphatic aldehydes.

Full text of DOI:10.1021/acs.joc.8b02965

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Article
Chemoselective Nucleophilic Functionalizations of Aromatic
Aldehydes and Acetals via Pyridinium Salt Intermediates
Takahiro Kawajiri, Maho Kato, Hiroki Nakata, Ryota Goto, Shin-yo Aibara,
Reiya Ohta, Hiromichi Fujioka, Hironao Sajiki, and Yoshinari Sawama
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02965 • Publication Date (Web): 12 Feb 2019
Downloaded from http://pubs.acs.org on February 12, 2019
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Chemoselective Nucleophilic Functionalizations of
Aromatic Aldehydes and Acetals via Pyridinium Salt
Intermediates
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a
a
a
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a
b
Takahiro Kawajiri, Maho Kato, Hiroki Nakata, Ryota Goto, Shin-yo Aibara, Reiya Ohta, Hiromichi
b
a
a
Fujioka, Hironao Sajiki* and Yoshinari Sawama*
a
Laboratory of Organic Chemistry, Gifu Pharmaceutical University, 1-25-4, Daigaku-nishi, Gifu, 501-
1196, Japan
b
Graduate School of Pharmaceutical Sciences, Osaka University, 1-6, Yamada-oka, Suita, Osaka, 565-
0
871, Japan
Phone/Fax: (+81)-58-230-8109; email: sawama@gifu-pu.ac.jp, sajiki@gifu-pu.ac.jp
CORRESPONDING AUTHOR
Yoshinari Sawama and Hironao Sajiki
*E-mail: sawama@gifu-pu.ac.jp; sajiki@gifu-pu.ac.jp
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ABSTRACT
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The development of a novel chemoselective functionalization can diversify the strategy for synthesizing
the target molecules. The perfect chemoselectivity between aromatic and aliphatic aldehydes is difficult
to be achieved by the previous methods. The aromatic aldehyde-selective nucleophilic addition in the
presence of aliphatic aldehydes was newly accomplished. Namely, the aromatic aldehyde-selective
nucleophilic addition using arenes and allyl silanes proceeded in the presence of trialkylsilyl triflate and
2
,2’-bipyridyl, while the aliphatic aldehydes completely remained unchanged. The reactive pyridinium-
type salt intermediate derived from an aromatic aldehyde chemoselectively underwent the nucleophilic
substitution. Moreover, the aromatic acetals as the protected aldehydes could be directly transformed
into similar pyridinium salt intermediates, which reacted with various nucleophiles coexisting with the
aliphatic aldehydes.
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INTRODUCTION
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The chemoselective reaction is important to effectively construct target molecules.1,2 Aldehydes are
widely utilized as reactive electrophiles in organic synthesis. However, the development of a perfectly
chemoselective reaction distinguishing aromatic from aliphatic aldehydes is still difficult and
challenging. We recently reported the chemoselective Mukaiyama aldol reaction of aromatic aldehydes
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with a silyl enol ether derived from acetaldehyde in the presence of trialkylsilyl triflate (SiOTf) and
3
2
,2’-bipyridyl (Scheme 1, eqs. 1 and 2). Both aromatic and aliphatic aldehydes (1 and 3) are smoothly
transformed into the corresponding pyridinium salt intermediates (A and C) in the presence of SiOTf
and 2,2’-bipyridyl. The pyridinium salt intermediate (A) derived from 1 easily reacts with silyl enol
ethers due to the preferential elimination of the pyridinium moiety on the benzylic carbon and the steric
repulsion between the aromatic ring (Ar) and pyridine ring, while the non-benzylic pyridinium salt C
derived from 3 is inert under the started reaction conditions and 3 was quantitatively reproduced after an
aqueous work-up. Namely, the aliphatic aldehyde 3 is masked and protected from the nucleophilic
attack by the silyl enol ether as the pyridinium salt C. The reaction of A with a silyl enol ether derived
from acetaldehyde produces the aliphatic aldehyde (2)-derived pyridinium salt intermediate B, which is
inert towards the nucleophilic attack by the silyl enol ether and the β-siloxy aldehyde derivative (2) is
produced after the aqueous work-up. We newly demonstrate the chemoselective nucleophilic addition
using arene as a nucleophile via the corresponding pyridinium salt intermediate (A) (3; eq. 3).
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Scheme 1. Outline of the chemoselective nucleophilic functionalizations via
pyridinium-type salts.
The Lewis acid-catalyzed Friedel-Crafts reaction is valuable from the viewpoint of atom economy,
because arene nucleophiles can be directly utilized without any preliminary functionalization.4-6 The
benzhydrol derivatives (4’) can be constructed by the nucleophilic addition of an arene nucleophile
1
(
Ar -H) to an aromatic aldehyde (1). However, the selective synthesis of 4’ from 1 as a substrate under
Lewis acid-mediated Friedel-Crafts reaction conditions is still challenging (Scheme 2[a]), because the
hydroxyl group of 4’ is easily eliminated to form the benzylic cation species stabilized by both aromatic
1
1
rings (Ar and Ar ), and the over-substitution of 4’ by Ar -H smoothly proceeds to generate the
7
triarylmethane (4”). Although the addition of the catalytic amount of pyridine was reported to suppress
the over-substitution under AlBr
3
-mediated reaction conditions, the selectivity was still inadequate and
8
the yields of the desired 4’ were not very high. Our research hypothesis for the selective preparation of
the benzhydrol derivative (silylated benzhydrol; 4) from 1 is shown in Scheme 2[b]. If the pyridinium
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salt intermediate (like A in Scheme 1) also undergoes the nucleophilic substitution by arenes, the silyl-
protected benzhydrol (4) can be generated and the undesirable over-substitution is avoidable due to the
reduction of the leaving-group ability of the corresponding siloxy group.9
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Scheme 2. [a] Friedel-Crafts reaction between arenes and aromatic aldehydes.
[b] Our strategy for the synthesis of the benzhydrol derivatives.
We have additionally demonstrated the nucleophilic addition using allylsilane derivatives as
nucleophiles via the reactive salt A in the presence of 3 (Scheme 1. eq. 3). Moreover, the aromatic
acetals (6) as protected aromatic aldehydes could be selectively transformed to 7-9 via the
corresponding pyridinium salt intermediate (D) in the presence of 3 (Scheme 1. eq. 4).
RESULTS AND DISCUSSION
The reaction of the pyridinium salt (like A in Scheme 1) with an arene nucleophile was initially
investigated using various pyridine derivatives (3 equiv.) in the presence of benzaldehyde (1a), 1,3,5-
o
trimethoxybenzene (2 equiv.) and trimethylsilyl triflate (TMSOTf: 2 equiv.) in CH
2
Cl
2
at 0 C (Table 1).
The reaction without a pyridine derivative gave the undesired triarylmethane derivative (4”a) as the sole
product in 94% yield, and the desired benzyl silyl ether (4aa) was not detected (entry 1). On the other
hand, the desired reaction using 1,3,5-trimethoxybenzene never proceeded after the preliminary
treatment of 1a with pyridine, N,N-dimethyl-4-aminopyridine (DMAP) or 2-picoline in the presence of
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TMSOTf, and 1a was recovered after the aqueous work-up (entries 2-4). The 2,6-lutidine and 2,4,6-
collidine-derived salts could be transformed into the desired 4aa in moderate yields (46 and 34%,
respectively; entries 5 and 6). The use of 2-phenylpyridine caused the generation of the triarylmethane
derivative (4”a) as a by-product together with 4aa and the recovered 1a (entry 7). 2,2’-Bipyridyl was a
good additive to give 4aa in 78% yield (entry 8), while 2,4’-bipyridyl led to the complete recovery of 1a
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(
entry 9). The effect of 2,2’-bipylidyl was unclear.
Table 1. Effect of pyridine derivatives.
yield [%]a
entry
pyridine derivative
1
a
4aa
0
4”a
94
0
1
2
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5
6
7
8
9
—
0
pyridine
77
85
84
47
51
58
17b
95
0
DMAP
0
0
2-picoline
2,6-lutidine
2,4,6-collidine
2-phenylpyridine
2,2’-bipyridyl
0
0
46
34
15
78b
0
0
0
15
0
2,4’-bipyridyl
0
a
1
The yield was determined by H NMR using 1,2-methylenedioxybenzene as the internal
b
standard. Isolated yield.
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The ratio and use of TMSOTf and 2,2’-bipyridyl strongly influenced the reaction efficiency (Table 2).
While the desired reaction could proceed in the presence of TMSOTf (2 equiv.) and 2,2’-bipyridyl (3
equiv.) (Table 1, entry 8: Table 2, entry 1), the reduced use of both reagents by half significantly
decreased the yield of 4aa (entry 2). The use of an equal or excess amount of TMSOTf vs. the use of
8
9
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,2’-bipyridyl caused the formation of the undesired 4”a (entries 3-5).
Table 2. Ratio effect of TMSOTf and 2,2’-bipyridyl.
yield [%]a
entry
X (equiv.)
Y (equiv.)
1a
17b
90
39
13
0
4aa
78b
10
0
4”a
0
1
2
3
4
2
3
1
1.5
—
2
0
0.2
2
50
67
35
0
5
3
2
59
a
1
The yield was determined by H NMR using 1,2-methylenedioxybenzene as the
b
internal standard. Isolated yield.
The effect of other Lewis acids was next examined (Table 3). The use of triethylsilyl triflate
(
TESOTf) or tert-buthyldimethylsilyl triflate (TBSOTf) instead of TMSOTf significantly improved the
reaction efficiencies to produce 4ab (Si = TES) or 4ac (Si = TBS) in 92% or 91% yield (entries 2 and 3).
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While the formation of the key pyridinium salt intermediates could be detected by the combined use of
SiOTf and the pyridine derivative (entries 1-3; the spectra were attached in Supporting Information), the
less Lewis acidic TMSCl and TMSBr were inactive as a catalyst to generate the pyridinium salt as well
as the arene adduct (entries 4 and 5). When stopping the reaction using TESTf or TBSOTf in 3 min., it
was obvious that the reaction using TBSOTf was faster than that using TESOTf (entries 6 vs. 7). The
present reaction could be accelerated by the steric repulsion between the silyl moiety and the 2,2’-
bipyridyl.
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Table 3. Effect of Lewis acid.
yield [%]a
entry
Lewis acid
time
1a
17
0
4a
4”a
0
1
2
3
4
5
6
7
TMSOTf
TESOTf
TBSOTf
TMSCl
1 h
4aa: 78
4ab: 92
4ac: 91
0
1 h
0
1 h
0
0
1 h
83b
0
TMSBr
1 h
85b
0
0
24b
4ab: 70b
TESOTf
TBSOTf
3 min
3 min
0
8b
4ac: 90b
0
a
b
1
Isolated yield. The yield was determined by H NMR using 1,2-methylenedioxybenzene as
the internal standard.
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The preliminary formation process of the pyridinium salt by the stepwise addition of 2,2’-
bipyridyl, TESOTf, prior to the addition of 1,3,5-trimethoxybenzene (Table 3, entry 2) is not required,
and the direct addition of TESOTf to the mixture of 1a, 2,2’-bipyridyl, 1,3,5-trimethoxybenzene, also
gave 4ab in excellent yield (eq. 5).
8
9
1
1
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Various aromatic aldehydes (1) and arene nuclephiles were applicable to the present reaction
(
Table 4). Benzaldehyde derivatives (1b-1i) bearing OMe, NO
2
, Cl, Br, Ph, CO t-Bu, OTBS or OAc at
2
the 4-position of the aromatic ring could react with 1,3,5-trimethoxybenzene under the optimal reaction
conditions shown by eq. 5 to afford the corresponding benzhydrol silyl ether derivatives (4b-4i) in good
to excellent yields (entries 1-8). Benzaldehydes (1j and 1k) bearing a methoxy group at the 3 and 2-
positions and 1-naphthaldehyde (1l) were effectively converted to the corresponding silyl ether products
(
4j-4l) in good yields (entries 9-11). 1,3-Dimethoxybenzene as a nucleophile could also be applied to
the reactions of 1a, 1b and 1d to give the silyl ethers (4m-4o) in moderate to good yields (entries 12-14).
The reaction using 1-methoxynaphthalene gave the corresponding 4p (entry 14). The reaction using
indole-3-carboxaldehyde, furfural or pyrrole-2-carbaldehyde as
a
substrate with 1,3,5-
trimethoxybenzene gave complex mixture. When using heteroarenes such as indole, N-methylindole,
furan and N-methylpyrrole as nucleophiles, the reactions of 1b gave complex mixtures.
Table 4. Scope of aromatic aldehydes and arene nucleophiles.
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entry
substrate
Ar -H
product
CHO
R
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1b, R = OMe
4b, 95% (30 min.)
4c, 71% (24 h)
4d, 84% (24 h)
4e, 93% (2 h)
4f, 90% (2 h)
1c, R = NO
1d, R = Cl
1e, R = Br
1f, R = Ph
1g, R = CO
2
2
t-Bu
4g, 68% (24 h)
4h, 65% (6 h)
4i, 90% (1 h)
1h, R = OTBS
1i, R = OAc
TESO
OMe
MeO
CHO
MeO
9
OMe
MeO
1j
4
j, 86% (24 h)
TESO
OMe
MeO
1
1
0
1
OMe
MeO
1
k
4
k, 87% (2 h)
CHO
CHO
1
l
4
l, 70% (2 h)
TESO
OMe
R
R
OMe
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1
2a
3a
4a
1a, R = H
4m, 81% (24 h)
4n, 45% (24 h)
4o, 45% (24 h)
1b, R = OMe
1d, R = Cl
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
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4
4
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4
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4
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5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
5
1b
4
p, 32% (24 h)
a
10 equiv. of arene were used.
The pyridinium salt intermediates derived from aromatic aldehydes could also react with
allylsilanes as nucleophiles (Table 5). Various aromatic aldehydes (1a-1f, 1h, 1i and 1m) bearing an
electron-donating or electron-withdrawing group at the 4-position of each aromatic ring could be used
to produce the corresponding homoallyl silyl ethers (5a-5f, 5h, 5i and 5m) in good to excellent yields
(
entries 1-9). Trimethyl(2-methylallyl)silane was also used to give the desired 5n (entry 10).
Furthermore, the reaction with 5-trimethylsilyl-1,3-cyclopentadiene and 1b smoothly proceeded to
produce 5o as a consequence of the olefin isomerization (entry 11). Allyltriethylsilane also effectively
reacted with the pyridinium salt intermediate to produce the desired silyl ether (5bb) in excellent yield
(entry 12). The heteroaromatic aldehyde such as indole-3-carboxaldehyde or furfural were not
applicable in the reaction with allyltrimethylsilane to give a complex mixture, respectively.
Table 5. Scope of aromatic aldehydes and allylsilanes.
entry
substrate
allylsilane
product
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1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
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3
4
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5
5
5
6
CHO
R
0
1
2
3
4
5
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7
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9
0
1
2
3
4
5
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9
0
1
2
3
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8
9
0
1
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9
1a, R = H
5a, 89% (24 h)
5ba, 82% (24 h)
5c, 78% (24 h)
5d, 98% (24 h)
5e, 65% (24 h)
5f, 63% (24 h)
5h, 72% (24 h)
5i, 53% (24 h)
5m, 89% (24 h)
TMSO
1b, R = OMe
1c, R = NO
1d, R = Cl
1e, R = Br
1f, R = Ph
2
1h, R = OTBS
1i, R = OAc
1m, R = CO Me
2
CHO
10
MeO
MeO
1
b
5
n, 99% (3 h)
TMSO
CHO
CHO
1
1
1
2
MeO
MeO
MeO
1b
5
o, 74% (3 h)
1
b
5bb, 98% (24 h)
It is noteworthy that aliphatic aldehydes (3a and 3b) and ketones (10a and 10b) were inert under the
present reaction conditions using arenes and allylsilanes as nucleophiles and the substrates were
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completely recovered (eq. 6). While aliphatic aldehydes (3a and 3b) were converted to the less reactive
pyridinium salt intermediates in the presence of SiOTf and 2,2’-bipyridyl, ketones (10a and 10b) could
not be transformed into any of the pyridinium salt intermediates. (When using arene nucleophile,
TESOTf was used as SiOTf. When using allylTMS, TMSOTf was used as SiOTf.) Therefore, the
aromatic aldehyde-selective nucleophilic additions of arenes and allylTMS derivatives were
accomplished in the presence of the aliphatic aldehyde or ketone. When using a 1:1 mixture of an
aromatic aldehyde (1b) and an aliphatic aldehyde (3a) as substrates, the nucleophilic attack of 1,3,5-
trimethoxybenzene chemoselectively occurred at 1b to give 4b in 95% yield and 84% of 3a was
recovered (eq. 7, top). The present chemoselectivity was similarly observed in the allylation with
trimethyl(2-methylallyl)silane as a nucleophile (eq. 7, bottom). Furthermore, the substrate (1q) bearing
aromatic and aliphatic aldehydes within the same molecule was efficiently transformed into the
corresponding silyl ether (4q) as a result of the chemoselective reaction at the aromatic aldehyde (eq. 8).
The chemoselective reaction of 1r, having aromatic aldehyde and aromatic ketone, with 1,3,5-
trimethoxybenzene was also successfully accomplished to produce 4r with the ketone moiety intact (eq.
9). The side products, such as the silyl enol ether derivative and adduct to the ketone, were not observed.
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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1
1
1
1
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1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
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3
3
3
3
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5
5
5
5
5
6
OMe
or
TMS
MeO
OMe
2 equiv.)
(
aliphatic aldehyde 2,2'-bipyridyl (3 equiv.)
no reaction
(eq. 6)
or
ketone
o
CH Cl , 0 C
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
2
(SM was recovered)
then SiOTf (2 equiv.)
aliphatic aldehyde or ketone
CHO
O
O
CHO
n-C H
9
19
Ph
Ph
Ph
10b
3a
3b
10a
Aromatic aldehyde-selective nucleophilic addition of arene and allylsilane
TESO
Ar = 1,3,5-(MeO) C H
3
6
2
Ar
CHO
MeO
Ar-H (2 equiv.)
4b, 95% (30 min.)
(recovered 3a: 84%)
MeO
SiOTf (4 equiv.)
,2'-bipyridyl (6 equiv.)
1
b
2
TMSO
+
(eq. 7)
o
CH Cl , 0 C, 30 min.
CHO
2
2
TMS
2 equiv.)
n-C H
9
19
(
MeO
3
a
5
n, 95% (3 h)
recovered 3a: 86%)
TESO
(
CHO
Ar-H (2 equiv.)
2,2'-bipyridyl (6 equiv.)
Ar
(eq. 8)
o
CH Cl , 0 C
2
2
CHO 1q
then TESOTf (4 equiv.)
CHO 4q, 86% (1 h)
TESO
CHO
Ar-H (2 equiv.)
,2'-bipyridyl (6 equiv.)
Ar
2
(eq. 9)
o
CH Cl , 0 C
2
2
1r
then TESOTf (4 equiv.)
4r, 76% (24 h)
O
O
The resulting secondary benzyl silyl ether functional groups in the products (4 and 5) were
chemoselectively transformed into the newly functionalized products (11) via the FeCl -catalyzed
3
nucleophilc substitution accompanied by the elimination of the siloxy group (Scheme 3).10 4-
Hydroxymethylbenzaldehyde 1s underwent the present nucleophilic addition of an arene to produce 4s
bearing both primary and secondary benzyl silyl ether moieties within the molecule on a gram scale.
The secondary siloxy group of 4s could be chemoselectively transformed into the indolyl group by the
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FeCl
3
-catalyzed nucleophilic substitution to give the corresponding triarylmethane products (11a)
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
possessing three different aromatic nuclei, which is a useful basic skeleton for pharmaceuticals and
1
1
functional materials. The FeCl
3
-catalyzed azidation of 4s by the use of TMSN also proceeded to give
3
the corresponding 11b in 86% yield. Furthermore, the chemoselective azidation of 5s, which was the
allylated product, could be successfully performed to produce 11c in 73% yield.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
NH
Ar = 1,3,5-(MeO) C H
6 2
indole (3 equiv.)
3
FeCl (9 mol %)
Ar
3
TESO
CH Cl , rt
Ar-H (2 equiv.)
,2'-bipyridyl (6 equiv.)
2
2
Ar
2
OTES
o
11a, 87% (2 h)
CH Cl , 0 C
2
2
OTES
then TESOTf (4 equiv.)
N3
TMSN (1.1 equiv.)
3
4s, 87% (2 h)
FeCl (5 mol %)
3
[gram scale]
Ar
CHO
CH Cl , rt
2
2
OTES
11b, 86% (1 h)
1s
OH
TMS
TMSO
N3
(
2 equiv.)
TMSN (1.1 equiv.)
allyl FeCl3 (5 mol %)
3
2
,2'-bipyridyl (6 equiv.)
allyl
o
CH Cl , 0 C
CH Cl , rt
2
2
2
2
then TMSOTf (4 equiv.)
OTMS
5s, 87% (24 h)
OTMS
1c, 73% (2 h)
1
Scheme 3. Further chemoselective functionalizations of the obtained benzyl
silyl ethers.
Acetals are generally and frequently utilized as protecting groups of aldehydes and the direct
functionalizations without the deprotection steps were sometimes powerful tools to effectively
synthesize the target molecules.12,13 Although the reactivities of the pyridinium salt intermediates
13
derived from acetals, SiOTf and adequate pyridine derivatives have already been reported, the reaction
with arenes, allylsilanes or silyl enol ethers derived from acetaldehyde as nucleophiles have never been
reported in the literature. The reaction with the pyridinium salt (D) derived from benzaldehyde ethylene
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1
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1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
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4
4
4
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4
5
5
5
5
5
5
5
5
5
5
6
glycol acetal derivatives (6a and 6b), TESOTf and 2,2’-bipyridyl could react with 1,3,5-
trimethoxybenzene to produce the desired ethylene glycol asymmetric ether products (7a and 7b) (Table
6
, entries 1 and 2). 2-(Thiophen-2-yl)-1,3-dioxolane (6c) was also converted into the corresponding silyl
ether (7c) in moderate yield (entry 3). Pyridinium salt (D) derived from 6a or 6d could react with
allylsilanes to produce the desired homoallylalchol derivatives (8a, 8b and 8c) in excellent yields
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
entries 4-6). Acetal 6e was effectively transformed into the β-alkoxy aldehyde (9e) via the Mukaiyama
aldol reaction using TES enol ether derived from acetaldehyde as a nucleophile after an aqueous work-
up (entry 7: see also eq. 1). Various aromatic aldehyde dimethyl acetals (6f-6n) possessing electron-
donating or electron–withdrawing groups on the aromatic ring were applicable for the Mukaiyama aldol
reaction using the TMS enol ether (entries 8-16). The cyclic mixed acetal (6o) resulting from
isochroman was smoothly converted to the corresponding product (9o) by the selective elimination of
the methoxy group (entry 17). Decanal dimethyl acetal (6p) as an aliphatic acetal was also transformed
into 9p in a moderate yield after 24 h (entry 18). On the other hand, 2-nonyl-1,3-dioxolane as an
aliphatic acetal did not react with 1,3,5-trimethoxybenzene or allyltrimethylsilane to give a mixture of
the unchanged aliphatic acetal and deprotected aldehyde (see Supporting Information).
Table 6. Nucleophilic functionalization of acetals.
entry
1
acetal
nucleophile
product
6a
7a, 90% (1 h)a
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O
O
2
3
MeO C
2
6
b
b, 43% (2 h)a
7
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
6c
7
c, 63% (2 h)a
TMSO
O
4
5
Ph
6
a
8
a, 83% (24 h)
8
b, 99% (3 h)
6
7
6
d
8
c, 96% (24 h)
TESO
O
CHO
MeO
6
e
e, 84% (24 h)a
9
OMe
OMe
R
8
9
1
6f, R = H
9f, 94% (2 h)b
9g, 71% (2 h)b, c
6g, R = OMe
6h, R = NO
0
2
9h, quant. (6 h)c
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
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5
5
5
5
5
5
5
5
5
6
1
1
1
1
1
2
3
4
6i, R = CO
6j, R = Cl
6k, R = Br
2
Me
9i, quant. (2 h)
9j, 90% (1 h)
9k, 88% (2 h)
9l, 84% (6 h)b
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
6l, R = OTBS
OMe
OMe
OMe
OMe
CHO
1
1
5
6
7
OMe
9m, quant. (2 h)b
6m
OMe
OMe
OMe
MeO
MeO
CHO
6n
9n, quant. (2 h)
O
O
CHO
OMe
1
1
6o
9o, 84% (24 h)
8
6
p
9p, 53% (24 h)
a
b
TESOTf was used instead of TMSOTf. 1 equiv. of TMSOTf and 1.5 equiv. of 2,2’-bipyridyl
c
were used. The product was contaminated by trace amounts of inseparable by-products
including 2,2’-bipyridyl and α,β-unsaturated aldehyde.
These reactions could be realized as the chemoselective transformation of acetals, which are
generally utilized as the protected form of aldehydes, in the presence of aliphatic aldehydes (Scheme 4).
For the 1 : 1 mixture of an aromatic acetal 6a and an aliphatic aldehyde 3a under SiOTf and 2,2’-
bipyridyl conditions, the nucleophilic attack of 1,3,5-trimethoxybenzene or trimethyl(2-
methylallyl)silane into the pyridinium salt intermediate derived from 6a gave the desired products 7a or
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b, respectively, while 3a was completely recovered. The chemoselective reaction between the TMS
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
vinyl ether and benzaldehyde dimethyl acetal (6f) coexisting with an aliphatic aldehyde (3a) could be
similarly accomplished to give the desired aldol adduct (9f).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 4. Chemoselective functionalization of aromatic acetal.
CONCLUSION
We have developed the aromatic aldehyde and acetal-selective nucleophilic functionalization
methods via the pyridinium salt intermediates mediated by a silyl triflate and 2,2’-bipyridyl in the
presence of the aliphatic aldehyde. Arenes, allylsilanes and silyl enol ethers derived from acetaldehyde
could be used as nucleophiles to give the corresponding benzyl silyl ether products. The present
chemoselective C-C bond formations are useful to formulate novel synthetic strategies of the target
molecules.
EXPERIMENTAL SECTION
1. General Information
All reactions were performed in an oven-dried glassware under argon. Unless otherwise noted, substrates and
anhydrous solvents were purchased from commercial sources and used without further purification. Flash column
1
13
1
chromatography was performed with Silica Gel 60 N (63–210 μm spherical, neutral). H and C { H} NMR spectra
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9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
as a solvent and internal standard ( H NMR: δ = 7.26; 13C
1
3 2 2
were recorded at room temperature in CDCl or CD Cl
{1H} NMR: δ = 77.0 for CDCl
; H NMR: δ = 5.32; 13C NMR: δ = 53.5 for CD
1
Cl ) with tetramethylsilane as an
3
2
2
additional internal standard. ESI high resolution mass spectra (HRMS) were measured IT-TOF mass spectrometer.
2. Procedures to prepare the substrates and their spectroscopic data.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2-1. Preparation of 4-(tert-butyldimethylsilyloxy)benzaldehyde (1h)14a
To a solution of 4-hydroxybenzaldehyde (2.40 g, 19.6 mmol) in anhydrous DMF (30 mL) were added
o
imidazole (2.0 g, 29.3 mmol) and TBSCl (4.5 g, 29.8 mmol) at 0 C under argon. After stirring for 22 h at room
temperature, the reaction mixture was quenched with sat. NaHCO
3
aq. (20 mL) and extracted with mixture of
SO and
hexane and AcOEt (Hex/EtOAc = 4/1, 20 mL × 3). The combined organic layers were dried over Na
2
4
concentrated in vacuo. The residue was purified by silica-gel column chromatography (Hex/EtOAc = 15/1) to
1
give 1h (3.99 g, 16.9 mmol, 86% yield). Colorless oil; H NMR (500 MHz, CDCl
3
): δ 9.89 (s, 1H), 7.79 (d, 2H, J
1
= 8.6 Hz), 6.94 (d, 2H, J = 8.6 Hz), 1.00 (s, 9H), 0.25 (s, 6H). Spectroscopic date of H NMR was identical to
that of reference 14a.
2
-2. Preparation of 4-formylphenyl acetate (1i)14b
To a solution of 4-hydroxybenzaldehyde (610.6 mg, 5 mmol) in pyridine (5 mL) were added Ac O (510.5 mg,
2
1
0 mmol) and DMAP (30.5 mg, 0.25 mmol) at room temperature under argon. After stirring for 20 h, the reaction
O (5 mL) and extracted with Et O (10 mL × 3). The combined organic layers were
aq. (40 mL), dried over Na SO and concentrated in vacuo. The residue was purified by
mixture was quenched with H
washed with sat. CuSO
2
2
4
2
4
silica-gel column chromatography (Hex/EtOAc = 3/1) to give 1i (450.2 mg, 2.49 mmol, 49% yield). Colorless
1
oil; H NMR (500 MHz, CDCl
3
): δ 9.99 (s, 1H), 7.92 (d, J = 8.0 Hz, 2H), 7.28 (d, 2H, J = 8.0 Hz), 2.34 (s, 3H).
1
Spectroscopic date of H NMR was identical to that of reference 14b.
2
-3. Preparation of tert-butyl-4-formylbenzoate (1g)14c
To a solution of 4-formylbenzoic acid (1.0 g, 6.7 mmol) in t-BuOH (20 mL) were added (Boc) O (1754.3 mg,
2
8
.0 mmol) and DMAP (491.1 mg, 4.0 mmol). After stirring for 24 h at room temperature, the reaction mixture
O (30 mL) and extracted with Et O (30 mL × 3). The combined organic layers were dried
was quenched with H
2
2
over Na
2
SO
4
and concentrated in vacuo. The residue was purified by silica-gel column chromatography
1
(
Hex/EtOAc = 5/1) to give 1g (1063.9 mg, 5.14 mmol, 77% yield). Colorless oil; H NMR (400 MHz, CDCl
3
): δ
1
1
0.10 (s, 1H), 8.13 (d, 2H, J = 7.6 Hz), 7.93 (d, 2H, J = 7.6 Hz), 1.62 (s, 9H). Spectroscopic date of H NMR
was identical to that of reference 14c.
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-4. Preparation of 4-(3-oxopropyl)benzaldehyde (1q)
The reaction scheme is depicted in the Supporting Information.
Step 1: To a solution of 4-bromobenzaldehyde (1e: 1.85 g, 10.0 mmol) in anhydrous DMF (50 mL) were added
acrylic aldehyde (0.8 mL, 12.0 mmol), tetrabutyl-anmonium chloride (5.6 mL, 20.6 mmol), NaHCO (1.26 g,
3
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o
1
5.0 mmol) and Pd(OAc)
2
(22.4 mg, 0.10 mmol) under argon. After stirring for 40 h at 80 C, the reaction
mixture was passed through a celite pad. The filtrate was extracted with AcOEt (30 mL ×3) and the combined
organic layers were dried over Na SO , and concentrated in vacuo. The residue was purified by silica-gel column
2
4
chromatography (Hex/EtOAc = 3/1) to give (E)-4-(3-oxoprop-1-en-1-yl)benzaldehyde (861 mg, 5.4 mmol, 54%
1
yield). Colorless solid; H NMR (500 MHz, CDCl
3
): δ 10.06 (s, 1H), 9.77 (d, 1H, J = 7.5 Hz), 7.95 (d, 2H, J =
8.3 Hz), 7.73 (d, 2H, J = 8.3 Hz), 7.53 (d, 1H, J = 16.0 Hz), 6.81 (dd, 1H, J = 16.0, 7.5 Hz). Spectroscopic date
1
of H NMR was identical to that of the reference 14d.
Step 2 was carried out according to reference 14e: To a solution of a (E)-4-(3-oxoprop-1-en-1-yl)benzaldehyde
o
(32.0 mg, 0.2 mmol) in methanol (1 mL) was added Pd/C(Ph
2
S) (2.1 mg, 0.002 mmol) at 0 C under H
2
. After
stirring for 3 h, the reaction mixture was passed through a membrane filter (Millipore, Millex-LH, 0.20 mm) to
remove Pd/C(Ph S). The filtrate was concentrated in vacuo. The residue was purified by silica-gel column
chromatography (Hex/EtOAc = 5/1) to give 4-(3,3-dimethoxypropyl)benzaldehyde (24.9 mg). Then, to this
compound in CH CN (0.5 mL) was added 1N HCl (1 mL) at room temperature. After stirring for 42 h, the
reaction mixture was extracted with CH Cl (10 mL × 2) and the combined organic layers were dried over
2
3
2
2
Na
2
SO , and concentrated to give 4-(3-oxopropyl)benzaldehyde (1q; 16.7 mg, 0.10 mmol, 49%). Colorless solid;
4
1H NMR (500 MHz, CDCl
); δ 9.98 (s, 1H), 9.84 (s, 1H), 7.82 (d, 2H, J = 8.0 Hz), 7.37 (d, 2H, J = 8.0 Hz), 3.04
3
(t, 2H, J = 7.5 Hz), 2.85 (t, 2H, J = 7.5 Hz). Spectroscopic date of 1H NMR was identical to that of the reference
14f.
2-5. Preparation of 4’-acetyl-(1,1’-biphenyl)-4-carbaldehyde (1r)
This step was carried out according to reference 14g: To a solution of 4-bromobenzaldehyde (0.93 g, 5 mmol)
in H
(26.5 mg, 0.025 mmol, 0.5 mol%) and Na
room temperature for 30 h and then passed through a celite pat to remove the catalyst. The filtrate was extracted
with AcOEt (30 mL ×3) and the combined organic layers were dried over Na SO , and concentrated in vacuo.
2
O (10 mL) and i-PrOH (10 mL) was added 4-acetylphenylboronic acid (0.90 g, 5.5 mmol), 10% Pd/HP20
3
PO ･12H O (6.65 g, 17.5 mmol). The reaction mixture was stirred at
4
2
2
4
The residue was purified by silica gel column chromatography (Hex/EtOAc = 5/1) to give 4’-acetyl-(1,1’-
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biphenyl)-4-carbaldehyde (1r: 1.11 g, 4.95 mmol, 99%). Colorless solid; H NMR (400 MHz, CDCl
3
): δ 10.09 (s,
1
3
2
H), 8.08 (d, 2H, J = 8.4 Hz), 8.00 (d, 2H, J = 8.4 Hz), 7.80 (d, 2H, J = 8.4 Hz), 7.74 (d, 2H, J = 8.4 Hz), 2.66 (s,
1
H). Spectroscopic date of H NMR was identical to that of the reference 14h.
-6. Preparation of 4-(hydroxymethyl)benzaldehyde (1s)14i
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To a solution of terephthalaldehyde (1.28 g, 9.5 mmol) in THF (20 mL) and EtOH (15 mL) was added NaBH
4
o
(85 mg, 2.4 mmol) at 0 C. After stirring for 24 h at room temperature, the reaction mixture was concentrated in
vacuo. The residue was purified by silica-gel column chromatography (Hex/EtOAc = 1/1) to give 1s (873 mg, 6.4
1
mmol, 67% yield). H NMR (400 MHz, CDCl
3
): δ 10.09 (s, 1H), 7.88 (d, J = 8.4 Hz, 2H), 7.54 (d, J = 8.4 Hz,
1
2
H), 4.81 (d, 2H). Spectroscopic date of H NMR was identical to that of the reference 14i.
2-7. Preparation of benzaldehyde ethylene glycol acetal derivatives (6b-6e)
To a solution of benzaldehyde derivative (5 mmol) and triethyl orthoformate (0.9 mL, 5.5 mmol) in ethylene
glycol (1.1 mL, 20 mmol) was added tetrabutylammonium tribromide (24.1 mg, 0.05 mmol) at room temperature
under argon. The reaction mixture was stirred at room temperature and the progress of the reaction was monitored
by TLC. After adiquate time, the reaction mixture was quenched with sat. NaHCO
3
aq. (1 mL) and extracted with
Et O (10 mL × 2). The combined organic layers were dried over Na SO , and concentrated in vacuo. The residue
2
2
4
was purified by silica-gel column chromatography to give the corresponding acetal (6).
methyl 4-(1,3-dioxolan-2-yl)benzoate (6b)12b
When using methyl 4-formylbenzoate (1m; 985 mg, 6 mmol), methyl 4-(1,3-dioxolan-2-yl)benzoate (6b; 599
1
mg, 2.9 mmol) was obtained in 48% yield for 48 h. H NMR (400 MHz, CDCl
3
): δ 8.06 (d, 2H, J = 8.4 Hz), 7.56
1
(d, 2H, J = 8.4 Hz), 5.86 (s, 1H), 4.15―4.10 (m, 2H), 4.09–4.04 (m, 2H), 3.92 (s, 3H). Spectroscopic data of H
NMR was identical to that of the reference 12b.
2-(thiophen-2-yl)-1,3-dioxolane (6c)15a
When using thiophene-2-carbaldehyde (673 mg, 6 mmol), 2-(thiophen-2-yl)-1,3-dioxolane (6c; 337 mg, 2.2
1
mmol) was obtained in 36% yield for 24 h. H NMR (400 MHz, CDCl
3
): δ 7.36 (d, 1H, J = 5.0 Hz), 7.17 (d, 1H,
J = 3.7 Hz), 7.00 (dd, 1H, J = 5.0, 3.7 Hz), 6.13 (s, 1H), 4.18―4.10 (m, 2H), 4.07–3.99 (m, 2H). Spectroscopic
1
data of H NMR was identical to that of the reference 15a.
2-(4-chlorophenyl)-1,3-dioxolane (6d)12b
When using 4-chlorobenzaldehyde (1d; 422 mg, 3 mmol), 2-(4-chlorophenyl)-1,3-dioxolane (6d; 443 mg, 2.4
1
mmol) was obtained in 80% yield for 24 h. H NMR (400 MHz, CDCl
3
): δ 7.42 (d, 2H, J = 8.2 Hz), 7.35 (d, 2H,
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J = 8.2 Hz), 5.79 (s, 1H), 4.14―4.08 (m, 2H), 4.08–4.02 (m, 2H). Spectroscopic data of H NMR was identical to
that of the reference 12b.
2-(4-methoxyphenyl)-1,3-dioxolane (6e)15a
When using 4-methoxybenzaldehyde (1b; 0.6 mL, 5 mmol), 2-(4-methoxyphenyl)-1,3-dioxolane (6e; 829.9 mg,
0
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8
9
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2
3
4
5
6
7
8
9
0
1
4
2
.6 mmol) was obtained in 92% yield for 9 h. H NMR (400 MHz, CDCl
3
): δ 7.41 (d, 2H, J = 8.4 Hz), 6.91 (d,
1
H, J = 8.4 Hz), 5.76 (s, 1H), 4.15―4.12 (m, 2H), 4.04–4.00 (m, 2H), 3.81 (s, 3H). Spectroscopic data of H
NMR was identical to that of the reference 15a.
2-8. Preparation of dimethyl acetals (6g-n)15a
To a solution of aldehyde (5 mmol) in MeOH (5 mL) was added trimethyl orthoformate (5.5 mmol) at room
temperature under argon. After stirring for adequate time, the mixture was quenched by the addition of sat.
NaHCO
3
aq. (10 mL). The mixture was extracted with ethyl acetate (25 mL x 2). The combined organic layers
SO and concentrated in vacuo. The residue was purified by silica-gel column
were dried over Na
2
4
chromatography to give the corresponding dimethyl acetal.
1-(Dimethoxymethyl)-4-methoxybenzene (6g)15b
When using 4-methoxybenzaldehyde (1b; 0.6 mL, 5 mmol), 1-(dimethoxymethyl)-4-methoxybenzene (6g;
1
414.7 mg, 2.3 mmol) was obtained in 46% yield for 20 h. H NMR (500 MHz, CDCl
3
): δ 7.37―7.36 (m, 2H),
1
6.91―6.89 (m, 2H), 5.35 (s, 1H), 3.81 (s, 3H), 3.31 (s, 6H). Spectroscopic data of H NMR was identical to that
of the reference 15b.
1-(Dimethoxymethyl)-4-nitrobenzene (6h)15c
When using 4-nitrobenzaldehyde (1c; 755.6 mg, 5 mmol), 1-(dimethoxymethyl)-4-nitrobenzene (6h; 970.8 mg,
1
4.9 mmol) was obtained in 98% yield for 3 h. H NMR (500 MHz, CDCl
3
): δ 8.23 (d, J = 11.0 Hz, 2H), 7.64 (d,
1
2H, J = 11.0 Hz), 5.48 (s, 1H), 3.34 (s, 6H). Spectroscopic data of H NMR was identical to that of the reference
15c.
Methyl 4-(dimethoxymethyl)benzoate (6i)15a
When using 4-methoxycarbonylbenzaldehyde (820.8 mg, 5 mmol), methyl 4-(dimethoxymethyl)benzoate (6i;
1
817.7 mg, 3.9 mmol) was obtained in 78% yield for 1.5 h. H NMR (500 MHz, CDCl
3
): δ 8.04 (d, 2H, J = 8.5
1
Hz), 7.53 (d, 2H, J = 8.5 Hz), 5.44 (s, 1H), 3.92 (s, 3H), 3.33 (s, 6H). Spectroscopic data of H NMR was
identical to that of the reference 15a.
1-Chloro-4-(dimethoxymethyl)benzene (6j)15b
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When using 4-chlorobenzaldehyde (1d; 421.7 mg, 3 mmol), 1-chloro-4-(dimethoxymethyl)benzene (6j; 515.7
1
mg, 2.8 mmol) was obtained in 92% yield for 24 h. H NMR (500 MHz, CDCl
3
): δ 7.39 (d, 2H, J = 8.5 Hz), 7.34
1
(
d, 2H, J = 8.5 Hz), 5.37 (s, 1H), 3.31 (s, 6H). Spectroscopic data of H NMR was identical to that of the
reference 15b.
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1-Bromo-4-(dimethoxymethyl)benzene (6k)15b
When using 4-bromobenzaldehyde (1e; 555.1 mg, 3 mmol), 1-bromo-4-(dimethoxymethyl)benzene (6k; 682.7
1
mg, 2.95 mmol) was obtained in 98% yield for 24 h. H NMR (500 MHz, CDCl3): δ 7.50 (d, 2H, J = 8.8 Hz),
1
7
.33 (d, 2H, J = 8.8 Hz), 5.36 (s, 1H), 3.31 (s, 6H). Spectroscopic data of H NMR was identical to that of the
reference 15b.
tert-Butyl(4-(dimethoxymethyl)phenoxy)dimethylsilane (6l)15d
When using 4-((tert-butyldimethylsilyl)oxy)benzaldehyde (1g; 0.4 mL, 2.5 mmol), tert-butyl(4-
1
(
dimethoxymethyl)phenoxy)dimethylsilane (6l; 80.5 mg, 0.3 mmol) was obtained in 11% yield for 16 h. H NMR
(
500 MHz, CDCl
3
): δ 7.30 (d, 2H, J = 8.5 Hz), 6.83 (d, 2H, J = 8.5 Hz), 5.33 (s, 1H), 3.31 (s, 6H), 0.98 (s, 9H),
1
0
.19 (s, 6H). Spectroscopic data of H NMR was identical to that of the reference 15d.
1-(Dimethoxymethyl)-2-methoxybenzene (6m)15e
When using 2-methoxybenzaldehyde (0.4 mL, 3 mmol), 1-(dimethoxymethyl)-2-methoxybenzene (6m; 687.4
1
mg, 3 mmol) was obtained in quantitative yield for 1 h. H NMR (500 MHz, CDCl
3
): δ 7.52 (dd, 1H, J = 7.5, 2.0
Hz), 7.32―7.29 (m, 1H), 6.97 (t, 1H, J = 7.5 Hz), 6.90 (d, 1H, J = 8.0 Hz), 5.68 (s, 1H), 3.85 (s, 3H), 3.36 (s,
1
6
H). Spectroscopic data of H NMR was identical to that of the reference 15e.
1-(Dimethoxymethyl)-3-methoxybenzene (6n)15f
When using 3-methoxybenzaldehyde (0.4 mL, 3 mmol), 1-(dimethoxymethyl)-3-methoxybenzene (6n; 668.1
1
mg, 3 mmol) was obtained in quantitative yield for 1 h. H NMR (500 MHz, CDCl
3
): δ 7.28 (t, 1H, J = 7.8 Hz),
7.04―7.01 (m, 2H), 6.87 (dd, 1H, J = 7.8, 2.3 Hz), 5.36 (s, 1H), 3.82 (s, 3H), 3.34 (s, 6H). Spectroscopic data of
1H NMR was identical to that of the reference 15f.
2-9. Preparation of 1-methoxyisochroman (6o)15g
To a solution of DDQ (1.34 g, 6.0 mmol) in CH
isochroman (650 µL, 5.0 mmol). The mixture was stirred at room temperature for 24 h, quenched with of sat.
NaHCO aq. (50 mL) and filtered through celite pad. The aqueous layer was extracted with CH Cl (60 mL x 2)
2
Cl
2
(50 mL) were added MeOH (280 µL, 6.0 mmol) and
3
2
2
and concentrated in vacuo. The crude mixture was purified by flash chromatography with silica-gel
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(
(
EtOAc/hexane 1/7, 3% Et N) to afford 1-methoxyisochroman (6o; 660 mg, 4.0 mmol, 80 % yield). H NMR
3
500 MHz, CDCl
3
): δ 7.25―7.23 (m, 3H), 7.16―7.12 (m, 1H), 5.46 (s, 1H), 4.13 (dt, 1H, J = 11.0, 3.5 Hz),
1
3
.93―3.89 (m, 1H), 3.55 (s, 3H), 3.08―2.97 (m, 1H), 2.63 (dd, 1H, J = 15.5, 1.8 Hz). Spectroscopic data of H
NMR was identical to that of the reference 15g.
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2-10. Preparation of 1,1-dimethoxydecane (6p)
To a solution of decanal (3a: 0.78 g, 5 mmol) in anhydrous methanol (0.8 mL, 20 mmol) was added palladium
acetate (112.3 mg, 0.5 mmol). After stirring for 48 h at room temperature, the reaction mixture was quenched
with sat. NaHCO
were dried over Na
chromatography (Hex/EtOAc = 10/1) to give 1,1-dimethoxy decane (6p; 0.83 g, 4.1 mmol, 82%). H NMR (500
3
aq. (1mL). The solution was extracted with Et
2
O (20 mL × 2), the combined organic layers
2
SO and concentrated in vacuo. The residue was purified by silica-gel column
4
1
MHz, CDCl
3
): δ 4.35 (t, 1H, J = 6.0 Hz), 3.31 (s, 6H), 1.60―1.55 (m, 2H), 1.30―1.27 (m, 14H), 0.88 (t, 3H, J =
1
6
.0 Hz). Spectroscopic data of H NMR was identical to that of the reference 13b.
2-11. Preparation of triethylsilyl vinyl ethers16a
o
2.6 M Hexane solution of n-butyllithium (15 mL, 39.0 mmol) was mixed with anhydrous THF (25 mL) at 0 C
under argon. After stirring for 5 h at room temperature, triethylsilyl chloride (30.0 mmol) was added to the
o
reaction mixture at 0 C, and reaction mixture was stirred for 24 h at room temperature under argon. The reaction
o
mixture was concentrated under reduced pressure. The residue was treated with water (30 mL) at 0 C, and the
aqueous layers were extracted with diethylether (20 mL × 3). The combined organic layers were washed with
brine and dried over Na
2
SO . The solvent was removed under reduced pressure and the residue was purified by
4
silica-gel column chromatography (Hex/Et N = 100/1) to give triethylsilyl vinyl ether (2.4 g, 15.3 mmol, 51%
3
1
yield). H NMR (500 MHz, CDCl
3
); δ 6.45 (dd, 1H, J = 13.1, 5.9 Hz), 4.44 (d, 1H, J = 13.1 Hz), 4.11 (d, 1H, J =
1
5.9 Hz), 0.98 (t, 9H, J = 8.0 Hz), 0.68 (q, 6H, J = 8.0 Hz). Spectroscopic date of H NMR was identical to that of
the reference 16b.
3. General procedures in key reactions.
Typical procedure A (Tables 1, 2 and 3)
To solution of benzaldehyde (1a: 0.15 mmol) in CH
2
Cl (0.75 mL) were added pyridine derivative (0.45 mmol)
2
o
and SiOTf (0.30 mmol) at 0 C and the reaction mixture was stirred for 30 min. Then 1,3,5-trimethoxybenzene
o
(
0.30 mmol) was added to the reaction mixture at 0 C. After stirring for 1 hour, the mixture was quenched with
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3
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2
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2
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2
SO ,
4
concentrated in vacuo and purified by silica-gel column chromatography to give the silylated benzhydrols 4.
Typical procedure B (Tables 4 and 5; eqs. 5, 8 and 9; Scheme 3, first step)
To the mixture of aromatic aldehyde (1: 0.15 mmol), 2,2’-bipyridyl (0.45 mmol) and arene or allylsilane (0.30
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5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
o
mmol) in CH
mixture was quenched with sat. NaHCO
were dried over Na SO , concentrated in vacuo and purified by silica-gel column chromatography to give the
silylated product 4 or 5.
2
Cl
2
(0.75 mL) was added SiOTf (0.30 mmol) at 0 C. After stirring for the adequate time, the
3
aq. and extracted with CH
2
Cl (5 mL x 2). The combined organic layers
2
2
4
Typical procedure C (Table 6)
To solution of acetal (6: 0.15 mmol) in CH
2
Cl (0.75 mL) were added 2,2’-bipyridyl (0.45 mmol) and SiOTf
2
o
(0.30 mmol) at 0 C and the reaction mixture was stirred for 30 min. Then nucleophile (1,3,5-trimethoxybenzene,
o
allylsilane or silyl enol ether; 0.30 mmol) was added to the reaction mixture at 0 C. After stirring for the
adequate time, the mixture was quenched with sat. NaHCO aq. and extracted with CH Cl (5 mL x 2). The
, concentrated in vacuo and purified by silica-gel column
3
2
2
combined organic layers were dried over Na
chromatography to give the product 7, 8 or 9.
Typical procedure D (Scheme 3, second step)
2
SO
4
TMSN
derivative (4s or 5s: 0.15 mmol) in CH
the mixture was quenched with sat. NaHCO
3
(0.165 mmol) or indole (0.45 mmol) and FeCl
Cl (0.75 mL) at room temperature. After stirring for the adequate time,
aq. and the mixture was extracted with CH Cl (5 mL x 2). The
SO , concentrated in vacuo and purified by silica-gel column
3
(0.015 mmol) were added to a solution of the silyl ether
2
2
3
2
2
combined organic layers were dried over Na
2
4
chromatography to give the product 11.
4
. Spectroscopic data of the products.
Trimethyl(phenyl(2,4,6-trimethoxyphenyl)methoxy)silane (4aa) in Table 1, entry 8.
Benzaldehyde (1a: 15.7 mg, 0.15 mmol), 2,2’-bipyridyl (70.0 mg, 0.45 mmol), 1,3,5-trimethoxybenzene (50.0
mg, 0.30 mmol) and TMSOTf (55 µL, 0.30 mmol) were used according to the typical procedure A and
trimethyl(phenyl(2,4,6-trimethoxyphenyl)methoxy)silane (4aa: 43.2 mg, 0.12 mmol) was obtained in 78% yield
after 1 h stirring and purification by silica-gel column chromatography (Hex/EtOAc = 10/1). Colorless oil; IR
-1
1
(
ATR) cm : 2956, 2838, 1591, 1492, 1455, 1417, 1333, 1223, 1203, 1149, 1118, 1084, 1055; H NMR (500
MHz, CDCl
3
): δ 7.34 (d, 2H, J = 7.8 Hz), 7.23 (t, 2H, J = 7.8 Hz), 7.13 (t, 1H, J = 7.8 Hz), 6.42 (s, 1H), 6.11 (s,
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8
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1
1
1
1
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1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
2
H), 3.80 (s, 3H), 3.67 (s, 6H), 0.05 (s, 9H); C { H} NMR (125 MHz, CDCl
3
): δ 160.7, 159.4, 145.5, 127.3,
+
125.5, 125.4, 113.6, 91.3, 66.5, 55.8, 55.2, -0.0; HRMS (ESI-TOF) m/z: [M+Na] Calcd for C19
H
26
4
O SiNa
369.1493; Found 369.1506.
Triethyl(phenyl(2,4,6-trimethoxyphenyl)methoxy)silane (4ab) in Table 3, entry 2.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Benzaldehyde (1a: 16.6 mg, 0.17 mmol), 2,2’-bipyridyl (73.1 mg, 0.47 mmol), 1,3,5-trimethoxybenzene (52.5
mg, 0.31 mmol) and TESOTf (71 µL, 0.31 mmol) were used according to the typical procedure A and
triethyl(phenyl(2,4,6-trimethoxyphenyl)methoxy)silane (4ab: 56.6 mg, 0.14 mmol) was obtained in 92% yield
after 1 h stirring and purification by silica-gel column chromatography (Hex/EtOAc = 10/1). Colorless oil; IR
-1
1
(
ATR) cm : 2952, 2875, 2837, 1591, 1492, 1455, 1333, 1223, 1202, 1149, 1118, 1084; H NMR (400 MHz,
CDCl ): δ 7.36 (d, 2H, J = 7.4 Hz), 7.22 (t, 2H, J = 7.4 Hz), 7.11 (t, 1H, J = 7.4 Hz), 6.42 (s, 1H), 6.09 (s, 2H),
3
1
3
1
3
1
.79 (s, 3H), 3.67 (s, 6H), 0.87 (t, 9H, J = 8.0 Hz), 0.54 (q, 6H, J = 8.0 Hz); C { H} NMR (125 MHz, CDCl
3
): δ
60.6, 159.4, 146.0, 127.2, 125.4, 125.3, 114.4, 91.4, 66.4, 55.8, 55.2, 6.8, 4.7; HRMS (ESI-TOF) m/z: [M+Na]+
Calcd for C22
H
32
4
O SiNa 411.1962; Found 411.1982.
tert-Butyldimethyl(phenyl(2,4,6-trimethoxyphenyl)methoxy)silane (4ac) in Table 3, entry 3.
Benzaldehyde (1a: 15.7 mg, 0.15 mmol), 2,2’-bipyridyl (69.3 mg, 0.44 mmol), 1,3,5-trimethoxybenzene (49.8
mg, 0.30 mmol) and TBSOTf (68 µL, 0.30 mmol) were used according to the typical procedure A and tert-
butyldimethyl(phenyl(2,4,6-trimethoxyphenyl)methoxy)silane (4ac: 56.1 mg, 0.14 mmol) was obtained in 91%
yield after 1 h stirring and purification by silica-gel column chromatography (Hex/EtOAc = 10/1). Colorless
o
-1
solid; M. p. 63.1―64.7 C; IR (ATR) cm : 2954, 2929, 2854, 1590, 1492, 1457, 1334, 1223, 1202, 1184, 1150,
1
1118, 1085; H NMR (400 MHz, CDCl
3
): δ 7.37 (d, 2H, J = 7.4 Hz), 7.22 (t, 2H, J = 7.4 Hz), 7.11 (t, 1H, J = 7.4
1
3
1
Hz), 6.41 (s, 1H), 6.08 (s, 2H), 3.79 (s, 3H), 3.69 (s, 6H), 0.90 (s, 9H), 0.03 (s, 3H), -0.19 (s, 3H); C { H} NMR
(100 MHz, CDCl
3
): δ 160.6, 159.3, 146.0, 127.2, 125.4, 125.3, 114.4, 91.2, 66.6, 55.7, 55.2, 25.9, 18.3, -5.1, -
+
5.2; HRMS (ESI-TOF) m/z: [M+Na] Calcd for C22
H
32
O SiNa 411.1962; Found 411.1980.
4
Triethyl((4-methoxyphenyl)(2,4,6-trimethoxyphenyl)methoxy)silane (4b) in Table 4, entry 1.
4-Methoxybenzaldehyde (1b: 21.1 mg, 0.15 mmol), 2,2’-bipyridyl (72.6 mg, 0.45 mmol), 1,3,5-
trimethoxybenzene (52.1 mg, 0.31 mmol) and TESOTf (73 µL, 0.31 mmol) were used according to the typical
procedure B and triethyl((4-methoxyphenyl)(2,4,6-trimethoxyphenyl)methoxy)silane (4b: 59.6 mg, 0.14 mmol)
was obtained in 95% yield after 30 min stirring and purification by silica-gel column chromatography
-1
(Hex/EtOAc = 20/1). Colorless oil; IR (ATR) cm : 2951, 2874, 1589, 1508, 1457, 1415, 1298, 1223, 1203, 1149,
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9
1
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1
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1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
1
037; H NMR (400 MHz, CDCl
3
): δ 7.28 (d, 2H, J = 8.8 Hz), 6.77 (d, 2H, J = 8.8 Hz), 6.38 (s, 1H), 6.09 (s, 2H),
1
3
1
3.79 (s, 3H), 3.76 (s, 3H), 3.69 (s, 3H), 0.87 (t, 9H, J = 8.0 Hz), 0.53 (q, 6H, J = 8.0 Hz); C { H} NMR (100
MHz, CDCl
3
): δ 160.5, 159.3, 157.5, 138.1, 126.5, 114.5, 112.7, 91.4, 66.2, 55.8, 55.2, 6.8, 4.7; HRMS (ESI-
+
TOF) m/z: [M+Na] Calcd for C23
H
34
5
O SiNa 441.2068; Found 441.2061.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Triethyl((4-nitrophenyl)(2,4,6-trimethoxyphenyl)methoxy)silane (4c) in Table 4, entry 2.
4-Nitrobenzaldehyde (1c: 22.4 mg, 0.15 mmol), 2,2’-bipyridyl (69.3 mg, 0.44 mmol), 1,3,5-trimethoxybenzene
(49.8 mg, 0.30 mmol) and TESOTf (67 µL, 0.30 mmol) were used according to the typical procedure B and
triethyl((4-nitrophenyl)(2,4,6-trimethoxyphenyl)methoxy)silane (4c: 46.1 mg, 0.11 mmol) was obtained in 71%
yield after 24 h stirring and purification by silica-gel column chromatography (Hex/EtOAc = 20/1). Colorless oil;
-
1
1
IR (ATR) cm : 2953, 2875, 2839, 1593, 1517, 1458, 1416, 1343, 1224, 1204, 1151, 1121, 1056; H NMR (400
MHz, CDCl ): δ 8.09 (d, 2H, J = 8.2 Hz), 7.52 (d, 2H, J = 8.2 Hz), 6.44 (s, 1H), 6.08 (s, 2H), 3.80 (s, 3H), 3.68 (s,
6H), 0.87 (t, 9H, J = 8.0 Hz), 0.54 (q, 6H, J = 8.0 Hz); C { H} NMR (100 MHz, CDCl
3
1
3
1
3
): δ 161.3, 159.2, 154.4,
+
146.0, 126.2, 122.6, 112.9, 91.1, 66.1, 55.6, 55.3, 6.7, 4.7; HRMS (ESI-TOF) m/z: [M+Na] Calcd for
C
22
H
31NO SiNa 456.1813; Found 456.1813.
6
((4-Chlorophenyl)(2,4,6-trimethoxyphenyl)methoxy)triethylsilane (4d) in Table 4, entry 3.
4-Chlorobenzaldehyde (1d: 22.3 mg, 0.16 mmol), 2,2’-bipyridyl (74.5 mg, 0.48 mmol), 1,3,5-trimethoxybenzene
(53.5 mg, 0.32 mmol) and TESOTf (72 µL, 0.32 mmol) were used according to the typical procedure B and ((4-
chlorophenyl)(2,4,6-trimethoxyphenyl)methoxy)triethylsilane (4d: 56.6 mg, 0.13 mmol) was obtained in 84%
yield after 24 h stirring and purification by silica-gel column chromatography (Hex/CH
2
Cl
2
= 1/1). Colorless oil;
-
1
1
IR (ATR) cm : 2952, 2874, 2837, 1591, 1488, 1457, 1415, 1335, 1223, 1150, 1116, 1055; H NMR (500 MHz,
CDCl
3
): δ 7.30 (d, 2H, J = 8.0 Hz), 7.18 (d, 2H, J = 8.0 Hz), 6.36 (s, 1H), 6.08 (s, 2H), 3.79 (s, 3H), 3.68 (s, 6H),
1
3
1
0.86 (t, 9H, J = 7.5 Hz), 0.57―0.48 (m, 6H); C { H} NMR (125 MHz, CDCl
3
): δ 160.8, 159.2, 144.6, 130.8,
+
127.2, 126.9, 113.7, 91.1, 65.9, 55.7, 55.2, 6.8, 4.6; HRMS (ESI-TOF) m/z: [M+Na] Calcd for C22
H
31
4
O SiClNa
445.1572; Found 445.1577.
((4-Bromophenyl)(2,4,6-trimethoxyphenyl)methoxy)triethylsilane (4e) in Table 4, entry 4.
4-Bromobenzaldehyde (1e: 27.8 mg, 0.15 mmol), 2,2’-bipyridyl (71.8 mg, 0.45 mmol), 1,3,5-trimethoxybenzene
(52.2 mg, 0.30 mmol) and TESOTf (68 µL, 0.30 mmol) were used according to the typical procedure B and ((4-
bromophenyl)(2,4,6-trimethoxyphenyl)methoxy)triethylsilane (4e: 56.1 mg, 0.14 mmol) was obtained in 93%
yield after 2 h stirring and purification by silica-gel column chromatography (Hex/EtOAc = 8/1). Colorless oil; IR
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1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
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3
3
3
3
3
3
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4
4
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4
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4
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5
5
5
5
5
5
6
(
ATR) cm : 2952, 2874, 1590, 1483, 1455, 1416, 1223, 1203, 1150, 1119, 1055, 1007; H NMR (500 MHz,
CDCl ): δ 7.34 (d, 2H, J = 8.6 Hz), 7.25 (d, 2H, J = 8.6 Hz), 6.35 (s, 1H), 6.08 (s, 2H), 3.79 (s, 3H), 3.68 (s, 6H),
0.87 (t, 9H, J = 8.0 Hz), 0.57―0.49 (m, 6H); C { H} NMR (125 MHz, CDCl
3
1
3
1
3
): δ 160.8, 159.2, 145.2, 130.1,
+
127.3, 119.0, 113.6, 91.1, 65.9, 55.7, 55.2, 6.7, 4.6; HRMS (ESI-TOF) m/z: [M+Na] Calcd for C22
H
31
4
O SiBrNa
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
489.1067; Found 489.1060.
([1,1'-Biphenyl]-4-yl(2,4,6-trimethoxyphenyl)methoxy)triethylsilane (4f) in Table 4, entry 5.
4-Phenylbenzaldehyde (1f: 36.6 mg, 0.20 mmol), 2,2’-bipyridyl (94.0 mg, 0.60 mmol), 1,3,5-trimethoxybenzene
(67.8 mg, 0.40 mmol) and TESOTf (90 µL, 0.40 mmol) were used according to the typical procedure B and
([1,1'-biphenyl]-4-yl(2,4,6-trimethoxyphenyl)methoxy)triethylsilane (4f: 83.5 mg, 0.18 mmol) was obtained in
90% yield after 2 h stirring and purification by silica-gel column chromatography (Hex/EtOAc = 10/1). Colorless
-
1
1
oil; IR (ATR) cm : 2953, 2874, 1591, 1487, 1456, 1224, 1204, 1151, 1120, 1056, 1006; H NMR (500 MHz,
CDCl
3
): δ 7.59―7.57 (m, 2H), 7.48―7.39 (m, 6H), 7.29 (t, 1H, J = 7.5 Hz), 6.47 (s, 1H), 6.11 (s, 2H), 3.81 (s,
3H), 3.70 (s, 6H), 0.89 (t, 9H, J = 7.5 Hz), 0.60―0.52 (m, 6H); 13C { H} NMR (125 MHz, CDCl
1
): δ 160.7,
3
159.4, 145.1, 141.5, 138.2, 128.6, 127.0, 126.7, 126.0, 125.9, 114.1, 91.3, 66.3, 55.8, 55.2, 6.8, 4.7; HRMS (ESI-
+
TOF) m/z: [M+Na] Calcd for C28
H
36
4
O SiNa 487.2275; Found 487.2302.
tert-butyl 4-(((triethylsilyl)oxy)(2,4,6-trimethoxyphenyl)methyl)benzoate (4g) in Table 4, entry 6.
tert-Butyl 4-formylbenzoate (1g: 30.8 mg, 0.15 mmol), 2,2’-bipyridyl (69.8 mg, 0.45 mmol), 1,3,5-
trimethoxybenzene (50.1 mg, 0.30 mmol) and TESOTf (67 µL, 0.30 mmol) were used according to the typical
procedure B and tert-butyl 4-(((triethylsilyl)oxy)(2,4,6-trimethoxyphenyl)methyl)benzoate (4g: 49.8 mg, 0.10
mmol) was obtained in 68% yield after 24 h stirring and purification by silica-gel column chromatography
-
1
(Hex/EtOAc = 5/1). Colorless oil; IR (ATR) cm : 2954, 2875, 1708, 1592, 1456, 1414, 1366, 1287, 1224, 1203,
1
1151, 1056; H NMR (400 MHz, CDCl
3
): δ 7.86 (d, 2H, J = 8.4 Hz), 7.41 (d, 2H, J = 8.4 Hz), 6.72 (s, 1H), 6.07
1
3
1
(s, 2H), 3.79 (s, 3H), 3.67 (s, 6H), 1.57 (s, 9H), 0.87 (t, 9H, J = 8.0 Hz), 0.54 (q, J = 8.0 Hz, 6H); C { H} NMR
(100 MHz, CDCl
3
): δ 166.2, 160.9, 159.3, 151.3, 129.2, 128.4, 125.2, 113.9, 91.3, 80.3, 66.3, 55.7, 55.2, 28.2,
+
6.7, 4.7; HRMS (ESI-TOF) m/z: [M+Na] Calcd for C27
H
40
O SiNa 511.2486; Found 511.2468.
6
tert-butyldimethyl(4-(((triethylsilyl)oxy)(2,4,6-trimethoxyphenyl)methyl)phenoxy)silane (4h) in Table 4,
entry 7.
4-((tert-Butyldimethylsilyl)oxy)benzaldehyde (1h: 36.6 mg, 0.15 mmol), 2,2’-bipyridyl (72.6 mg, 0.47 mmol),
1,3,5-trimethoxybenzene (52.1 mg, 0.31 mmol) and TESOTf (70 µL, 0.31 mmol) were used according to the
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