Highly Discriminative and Chemoselective Deprotection/Transformations of Acetals with the Combination of Trialkylsilyl Triflate/2,4,6-Collidine

Article abstract of DOI:10.1021/acs.joc.8b00675

Acetals are the most useful protecting groups for carbonyl functional groups. In addition to the role of protection, they can also be used as synthons of carbonyl functions. Previously, we developed a chemoselective deprotection and nucleophilic substitution of acetals from aldehydes in the presence of ketals. This article describes the highly discriminative and chemoselective transformations of acetals bearing different substitution patterns, different types of acetals, as well as mixed acetals. These reactions can achieve the transformations that cannot be attained by conventional methods, and their results strongly suggest the combination of R₃SiOTf/2,4,6-collidine to promote such unprecedented phenomena.

Full text of DOI:10.1021/acs.joc.8b00675

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Article
Highly Discriminative and Chemoselective Deprotection/Transformations
of Acetals with the Combination of Trialkylsilyl Triflate/2,4,6-Collidine
Reiya Ohta, Nao Matsumoto, Yoshifumi Ueyama, Yuichi Kuboki, Hiroshi Aoyama,
Kenichi Murai, Mitsuhiro Arisawa, Tomohiro Maegawa, and Hiromichi Fujioka
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00675 • Publication Date (Web): 21 May 2018
Downloaded from http://pubs.acs.org on May 21, 2018
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Highly
Discriminative
and
Chemoselective
Deprotec-
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tion/Transformations of Acetals with the Combination of Trialkylsilyl
Triflate/2,4,6-Collidine
Reiya Ohta, Nao Matsumoto, Yoshifumi Ueyama, Yuichi Kuboki, Hiroshi Aoyama, Kenichi Murai, Mitsuhiro Arisawa,
Tomohiro Maegawa† and Hiromichi Fujioka*
Graduate School of Pharmaceutical Sciences, Osaka University, 1ꢀ6 Yamadaꢀoka, Suita, Osaka, 565ꢀ0871, Japan.
ABSTRACT: Acetals are the most useful protecting groups for carbonyl functional groups. In addition to the role of
protection, they can also be used as synthons of carbonyl functions. Previously, we have developed a chemoselective
deprotection and nucleophilic substitution of acetals from aldehydes in the presence of ketals. This article describes the
highly discriminative and chemoselective transformations of acetals bearing different substitution patterns, different
types of acetals, as well as mixed acetals. These reactions can achieve the transformations which can’t be attained by
conventional methods, and their results strongly suggest the combination of R3SiOTf/2,4,6ꢀcollidine to promote such
unprecedented phenomena.
INTRODUCTION
Acetals including ketals are the most useful protecting groups for carbonyl functions, and are widely used in synthetic
organic chemistry.1) Moreover, acetals are the synthetic equivalent of carbonyl functions. This then gave the impetus for
the development of several protection methods that are used nowadays. Generally, deprotection of acetals proceeds via
the formation of oxocarbenium ion A (Figure 1, eq. 1). Lewis acid treatment of an acetal then gives the same oxocarbeꢀ
nium ion , which spontaneously reacts with a nucleophile in the reaction mixture (Figure 1, eq. 2, Trimethylsilyl enol
A
ether is shown as a nucleophile.). The extent of deprotection depends on the rate of formation of the oxocarbenium ion
.
A
On the other hand, ketals are deprotected more readily than acetals because of the faster formation of the oxocarbenium
ion due to the additional electronꢀdonating alkyl groups.2) The same principle can also be applied to acetals containing
various functionalities.3) Since the rateꢀdetermining step of acetal deprotection is the formation step of the oxocarbenium
ions via the C–O cleavage of the acetal, factors affecting this step will influence the rate of deprotection. For example, it
has been reported that acetals containing electronꢀdonating alkyl group at the at the αꢀposition undergo faster deprotecꢀ
tion compared to unsubstituted ones.2) Moreover, when comparing different acetals bulkier alkoxy acetals are deproꢀ
tected more readily than smaller alkoxy ones or cyclic acetals3b, c, 4) (Figure 1, eq. 3). Since the previous notions have
been the standard beliefs in organic chemistry and a methodology with the inverse reactivity of acetal deprotection has
not been reported until now, development of such methodology is both conceptually new and synthetically useful.
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Previously, we reported a novel method of deprotection and nucleophilic substitution of acetals using the combination
of trialkylsilyl triflate (R3SiOTf) and pyridines (Figure 1, eq. 4 and 5).5) While it is interesting that the reaction proceeds
under weakly basic conditions, its usefulness has been validated by the recent wide applications of the method to total
synthesis of natural products or bioactive compounds.6) It is noteworthy that this method can be used to deprotect an
acetal in the presence of a ketal, as ketals had been known to be deprotected much faster than acetals until then.2) To the
best of our best knowledge, this is the only method that allows the deprotection of acetals in the presence of ketals. In
2006, we reported the detailed study of the above chemistry including mechanistic considerations via a pyridiniumꢀtype
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6
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salt intermediate which is an acidic species that reacts with many nucleophiles including H O.7)
B
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Figure 1. Reactivity of acetal via oxocarbenium ion and our reported work.
In this article, we developed highly discriminative and chemoselective transformations of acetals such as: 1) Reverse
reactivity of deprotection [(1ꢀ1) deprotection of acetals with different substitution patterns, and (1ꢀ2) deprotection of
different types of acetals (Figure 1, eq. 6)] and 2) Formation of single ether product from mixed acetal (Figure 1, eq. 7).
We believe that these unprecedented reactions will add value to the field of acetal chemistry.
RESULTS AND DISCUSSION
1. Reverse Reactivity of Deprotection
The nucleophilic substitution of a 1:1 mixture of dimethyl acetal
1-1. Acetals with Different Substitution Patterns.
1
and dimethyl acetals with methyl group(s) at the αꢀposition ( or ) with benzyl alcohol (BnOH) was selected as the
2a 2b
model reaction to confirm the reactivity of acetals with different substitution patterns. Initially, we examined dimethyl
acetal with αꢀmonomethylated dimethyl acetal . Treatment of the mixture with trimethylsilyl triflate (TMSOTf) and
2a
1
2,4,6ꢀcollidine followed by addition of BnOH produced mixed acetal in 49% yield and mixed acetal
in 24% yield
4a
3
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(Table 1, entry 1). The use of triethylsilyl triflate (TESOTf) and 2,4,6ꢀcollidine produced mixed acetal in 40% yield and
3
1
2
3
4
5
6
7
mixed acetal in a much lower 7% yield (entry 2). We then examined dimethyl acetal with αꢀdimethylated dimethyl
4a
1
acetal . The use of TMSOTf and 2,4,6ꢀcollidine selectively produced mixed acetal in 37% yield with no detection of
2b
3
mixed acetal
at all (entry 3). Finally, the use of TESOTf instead of TMSOTf resulted in the exclusive formation of
4b
mixed acetal in 99% yield from with no formation of
from
(entry 4). This highlights the importance of the
2b
3
1
4b
bulkiness of R group in the R3SiOTf/2,4,6ꢀcollidine complex for the discrimination of the steric environments in the
substrates.
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9
Table 1. Evaluation of the selective deprotection of acetals with different substitution patterns.a
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4
entry
R1
R2
R3SiOTf 3 (%)b,c
(%)b,d
24
1
2
3
4
Me
Me
H
H
TMSOTf
TESOTf
49
40
37
99
7
Me Me TMSOTf
N.D.e
Me Me TESOTf
N.D.e
aReaction conditions. R3SiOTf (1.5 equiv) and 2,4,6ꢀcollidine (2.25 equiv) in CH2Cl2 at 0 °C for 1 h then BnOH (2.0
b
c
d
equiv). Determined by 1H NMR analysis of unpurified reaction mixture. SM was also recovered. SM was also
1
2
recovered. eNot detected.
The superiority of the combination of TESOTf/2,4,6ꢀcollidine was confirmed by the selective deprotection of acetals
with different substitution patterns using as a model substrate, which contains both an αꢀunsubstituted dimethyl acetal
5a
unit and an αꢀdimethylated one (Table 2). The reactions were allowed to stand until the disappearance of . The use of
5a
in 44% yield, along with the other
TMSOTf/2,4,6ꢀcollidine in CH Cl afforded the desired deprotected product
6a
2
2
monoꢀdeprotected product and bisꢀdeprotected product (entry 1). Changing the solvent to THF, CH CN or toluene
did not improve the yield and selectivity for (entries 2–4). However, to our delight, the use of TESOTf/2,4,6ꢀcollidine
6a
7a 8a
3
in CH Cl greatly increased the selectivity for , forming low amounts of
and no
at all (entry 5). Also, lowering
6a
8a
7a
2
2
the reaction temperature to −30 °C further improved the yield of to 94% (entry 6). Lastly, the use of other conventional
methods that utilize a Lewis acid such as TMSCl or a Brønsted acid such as pꢀTsOH only gave negligible amounts of
with no selectivity. Thus, our methodology using TESOTf/2,4,6ꢀcollidine combination induces an effective chemoseꢀ
lective deprotection of αꢀunsubstituted acetals in the presence of αꢀdisubstituted acetals.
6a
6a
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Table 2. Study of reaction conditions.a
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9
entry
1
reagent
TMSOTf CH2Cl2
solvent temp. (oC) 6a : 7a : 8ab 6a (%)c
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0
0
0
0
49 : 2 : 49
48 : 0 : 52
38 : 0 : 62
39 : 12 : 49
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35
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2
3
4
TMSOTf
THF
TMSOTf CH3CN
TMSOTf toluene
5
6
7d
TESOTf CH2Cl2
TESOTf CH2Cl2
0
ꢀ30
0
93 : 0 : 7
95 : 0 : 5
0 : 14 : 86
87
94
0
TMSI
CH2Cl2
acetone
/H2O
8d
pꢀTsOH
r.t.
14 : 23 : 63
10
aReaction conditions. R3SiOTf (2.0 equiv) and 2,4,6ꢀcollidine (3.0 equiv) in solvent then H2O. The ratio was deterꢀ
b
mined by 1H NMR analysis of the unpurified reaction mixture. cIsolated yield. dWithout 2,4,6ꢀcollidine.
We then explored the substrate scope for the chemoselective deprotection of αꢀunsubstituted acetals in the presence of
αꢀsubstituted or aromatic acetals (Table 3). In the cases of cyclic acetals such as 1,3ꢀdioxolaneꢀtype
and
5b
1,3ꢀdioxaneꢀtype , acetals with no substitution at the αꢀposition were selectively deprotected to afford products and
5c 6b
respectively in excellent yields under our reaction conditions (entries 1 and 2). When the αꢀposition was substituted
6c
with an isopropyl group instead, the deprotection proceeded similarly to selectively give product
in 87% yield (entry
6d
3). In all cases, monoꢀdeprotected products and bisꢀdeprotected products were not produced. Furthermore, our
7
8
method proved to be useful for the selective deprotection of an aliphatic acetal in the presence of an aromatic acetal,
affording a good yield of the deprotected aliphatic aldehyde
(entry 4). This pattern of selectivity is the complete opꢀ
6e
posite from that of the conventional method.3d)
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. Substrate scope for the chemoselective deprotection of αꢀunsubstituted acetals.a
Table 3
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entry
1c
substrate
resultb
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6b (92%)
5b
2d
5c
6c (90%)
6d (87%)
3
4
5d
5e
6e (68%)
aReaction conditions. TESOTf (2.0 equiv) and 2,4,6ꢀcollidine (3.0 equiv) in CH2Cl2 at −30 °C then H2O. bIsolated yield.
cTESOTf (4.0 equiv) and 2,4,6ꢀcollidine (6.0 equiv) were used at −30 °C to 0 °C. TMSOTf (4.0 equiv) and
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2,4,6ꢀcollidine (6.0 equiv) were used at 0 °C.
The remarkable reversal of the reactivity of deprotection of acetals by our method is
1-2. Different Types of Acetals.
made more concrete in the reaction of different types of acetals. First, we investigated the reactivity of different types of
acetals via nucleophilic substitution using a 1:1 mixture of dimethyl acetal and diethyl acetal or diisopropyl acetal
1
9a
followed by BnOH produced mixed
from diethyl acetal accompanied
9a
(Table 4).8) The use of TMSOTf and 2,4,6ꢀcollidine to a mixture of and
9b
1
9a
10a
acetal from dimethyl acetal in 82% yield along with 31% of mixed acetal
3
1
with the recovered (17%) and (63%) (entry 1). The use of TESOTf and 2,4,6ꢀcollidine gave similar results (entry 2),
9a
1
while the reaction of TMSOTf and 2,4,6ꢀcollidine with a mixture of and did not result in improved selectivity either
(entry 3). Pleasingly, it was found that the use of TESOTf instead of TMSOTf resulted in exclusive reactivity for dimeꢀ
1
9b
thyl acetal , producing mixed acetal in quantitative yield with no formation of mixed acetal
from diisopropyl
1
3
10b
acetal
(entry 4).
9b
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1
2
Evaluation of the selective deprotection of different types of acetals.a
Table 4.
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3
10
1
9
entry R3SiOTf
1
R
(%)b
(%)b
(%)b
(%)b
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TMSOTf Et
82
92
75
31
33
49
0
17
0
63
61
2
3
4
TESOTf
Et
TMSOTf iPr
13
31
TESOTf iPr quant.
0
quant.
aReaction conditions. R3SiOTf (1.5 equiv) and 2,4,6ꢀcollidine (2.25 equiv) in CH2Cl2 at 0 °C for 1 h then BnOH (2.0
equiv) for 2 h. bIsolated yield.
Next, we examined the deprotection of acetal containing both a dimethyl and diisopropyl acetal unit. The diisopropyl
11
acetal unit of acetal
is quite labile under acidic conditions. 9) In fact, purification of
by SiO flash column chroꢀ
11
2
11
matography sometimes gave αꢀalkanoyl dimethyl acetal and less amount of dialdehyde (see Table 5) as a result of
13 14
the slightly long stay of in the column.
11
Even though the diisopropyl acetal unit is unstable under acidic conditions, our method didn’t affect it and αꢀalkanoyl
diisopropyl acetal was obtained selectively. The results of our method as well as conventional ones are shown in Table
5. The use of TESOTf and 2,4,6ꢀcollidine affected the deprotection of the dimethyl acetal unit with complete selectivity
12
to give
in 77% yield, leaving the diisopropyl acetal unit intact (entry 1). In contrast, the use of conventional methods
12
using TMSI or pꢀTsOH did not result to the formation of
but instead resulted to small amounts of diisopropyl aceꢀ
12
(entries 2 and 3).
talꢀdeprotected product and high yields of
13
14
Table 5. Selective deprotection of different types of acetals in the same molecule.
entry
1c
reagents
12 : 13 : 14a
12 (%)b
TESOTf/
100 : 0 : 0
77
2,4,6ꢀcollidine
2d
3e
pꢀTsOH
0 : 15 : 85
0 : 5 : 95
0
0
TMSI
aDetermined by H NMR analysis of unpurified reaction mixtures. Isolated yield. TESOTf (2.0 equiv) and
2,4,6ꢀcollidine (3.0 equiv) in CH2Cl2 at −30 °C for 1 h then H2O at r.t. dpꢀTsOH (1.0 equiv) in acetone/H2O (1:1) at r.t. for
2 h. eTMSI (1.0 equiv) in CH2Cl2 at 0 °C for 10 min.
1
b
c
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The usefulness of our method was further exemplified in the deprotection of acetal
which contains both a cyclic
15
1
2
3
4
acetal unit and a diisopropyl acetal one (Scheme 1). Treatment of with TESOTf and 2,4,6ꢀcollidine showed complete
15
selectivity and gave a
in 76% yield, leaving the diisopropyl acetal unit intact. These results support that our methꢀ
12
odology provides excellent chemoselectivity for the deprotection of acetals, which complements the conventional
methods.
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Deprotection of acetal
.
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Scheme 1.
Finally, we applied our method for the transformation of
2. Formation of Single Ether Product from Mixed Acetal.
mixed acetals to ethers. Alkyl ether moieties are found in many pharmaceutical and bioactive compounds because they
are often chemically and metabolically stable.10) Several methods, including the representative Williamson ether synꢀ
thesis, are available for ether synthesis.11) However, many of these methods involve harsh conditions, limited substrate
scopes or complicated operation procedures. Most methods of ether synthesis from acetals that have been reported to date
only work on symmetrical acetals. In 2009 and 2011, Bode et al. reported the nucleophilic substitution of unsymmetrical
acetals, methoxymethyl (MOM) ethers and their derivatives.12) However, these nucleophiles are limited to spꢀ and
sp2ꢀcarbon nucleophiles and do not include sp3ꢀones such as alkyl groups. We have recently developed a mild and verꢀ
satile method for the synthesis of alkyl ethers from MOM ethers and mixed acetals.13) The reaction proceeds by nucleꢀ
ophilic substitution reaction of the collidinium salts, which are derived from acetals by treatment with R3SiOTf and
2,4,6ꢀcollidine, with Gillman reagent.
In this section, we present an alternative method, namely reductive alkyl ether synthesis from acetals. The conventional
method uses a combination of TMSOTf and Et3SiH to convert acetals into ethers and is particularly useful for symmetric
acetals.14) However, this methodology gives poor results in the reactions of mixed acetals. In fact, the mixed acetal
16a
afforded the mixture of two ether compounds
and
equally in 51% and 48% respectively (Scheme 2).
17a’
17a
Reduction of mixed acetal
with TMSOTfꢀEt SiH.
3
Scheme 2.
16a
We used NaBH4 as a hydride source due to its easy handling and examined the reductive alkyl ether synthesis using
mixed acetal
. When CH Cl was used as the reaction solvent, the NaBH ꢀreduction did not work even though the
16a
collidinium salt was formed by treatment of
2
2
4
with TESOTf and 2,4,6ꢀcollidine. However, when THF was used in
was obtained in 74% and wit no formation of
16a
place of CH Cl , the desired
(Scheme 3).
17a’
17a
2
2
Reductive alkyl ether synthesis form mixed acetal
.
16a
Scheme 3.
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(Table 6). Entry 1 shows the
We then reexamined the reactions of several silyl triflates and pyridines in THF using
16a
1
2
3
4
5
6
7
8
same results in Scheme 3. The use of TMSOTf in place of TESOTf slightly increased the yield of
tertꢀbutyldimethylsilyl trifluoromethanesulfonate (TBSOTf) was completely ineffective (entry 3). Next, we examined
pyridines, 2,6ꢀlutidine, 2ꢀmethoxypyridine, and 2,2’ꢀbipyridyl using TMSOTf (entries 4ꢀ6). Although they afforded the
(entry 2), whereas
17a
desired ether
in high to moderate yields, 2,4,6ꢀcollidine still gave the most promising result (entry 2). The reaction
17a
conditions in entry 2 was then further optimized by forming the collidinium salt at −30 °C (entry 7) to avoid any deꢀ
composition of the rather unstable collidinium salt intermediate that occurred gradually at 0 °C. In all cases, ether
17a
) was obtained as the exclusive product. This selectivity is likely due to the bulkiness around the silicon
(and not
17a’
atom. Finally, we chose TMSOTf and 2,4,6ꢀcollidine at −30 °C as the optimal conditions (entry 7) for further studies of
the reduction of mixed acetals.15)
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a
Optimization for the reductive alkyl ether synthesis from mixed acetal
.
16a
Table 6.
entry
1
R3SiOTf
TESOTf
pyridines
17a (%)b
2,4,6ꢀcollidine
74
2
3
TMSOTf
TBSOTf
TMSOTf
2,4,6ꢀcollidine
2,4,6ꢀcollidine
2,6ꢀlutidine
80
ꢀc
4
77
73
51
91
5
TMSOTf 2ꢀmethoxypyridine
6
TMSOTf
TMSOTf
2,2’ꢀbipyridyl
2,4,6ꢀcollidine
7d
aReaction conditions: R3SiOTf (2.0 equiv) and pyridines (3.0 equiv) in THF at 0 °C for 0.5 h then NaBH4 (3.0 equiv) at
0 °C for 1 h. bIsolated yield. cSalt intermediate was not formed. dReaction was performed at −30 °C to 0 °C.
Using the optimized conditions, we investigated the substrate scope of this selective reduction of mixed acetals using
(Table 7). As a result, good to excellent yields were obtained in the presence of many functional groups, such as
16b 16k
acetoxy (OAc), benzoyloxy (OBz), tertꢀbutyldimethylsilyloxy (OTBS), trityloxy (OTr), and halogens (entries 1–6).
–
Pleasingly, both base labile substrates
,
, and
(entries 1, 2, and 7), which are typically sensitive in convenꢀ
16b 16c
tional etherification, as well as acid labile substrates
16h
16d
and
(entries 3 and 4) were tolerated under this reaction
16e
conditions. Furthermore, this method could be applied to the sterically crowded substrates
–
, where
16i 16k
2ꢀmethoxypyridine was used in place of 2,4,6ꢀcollidine (entries 8–10). These results show that our method is useful for
accessing various types of alkyl ethers.
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1
2
Table 7. Substrate scope of the mixed acetal for the reductive alkyl ether synthesis.a
3
4
5
6
7
8
9
entry
1
16
17 (%)b
10
11
12
13
14
15
16
17
18
19
20
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22
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60
89
16b (R2 = OAc)
16c (R2 = OBz)
16d (R2 = OTBS)
16e (R2 = OTr)
16f (R2 = Cl)
83
86
92
73
61
2
3
4
5
6
16g (R2 = Br)
7
90
65
16h
16i
8c
9c
70
76
16j
10c
16k
aReaction conditions; procedure A: TMSOTf (4.0 equiv) and 2,4,6ꢀcollidine (6.0 equiv) (for entries 1ꢀ4) or procedure
B: TMSOTf (2.0 equiv) and 2,4,6ꢀcollidine (3.0 equiv) (for entries 5ꢀ10) in THF at ꢀ30 oC then NaBH4 (3.0 equiv) at ꢀ30
oC to 0 oC. bIsolated yield. c2ꢀMethoxypyridine was used instead of 2,4,6ꢀcollidine.
Based on the above experimental results, we proposed a possible reaction mechanism (Scheme 4;
is shown as an
16a
example of substrate). TMSOTf in the presence of 2,4,6ꢀcollidine in situ generates a Lewis acid/base complex.16, 17) This
complex recognizes the steric environment around the oxygen atoms and preferentially activates the smaller alkoxyl
group in the mixed acetal to avoid steric hindrance (path a in Scheme 4). Subsequent hydride reduction of the resultant
salt intermediate produces the corresponding alkyl ether
. In this reaction, the other ether product
was not obꢀ
17a’
17a
tained, suggesting that the larger alkoxyl group in the mixed acetal is not activated by the complex because of unfavorꢀ
able steric repulsion (path b). As a result, reduction of the mixed acetal proceeds with highly discriminative control and
chemoselectivity. However, the conventional use of TMSOTf gives no selectivity because both alkoxyl groups are acꢀ
tivated by TMSOTf (paths c and d).
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Proposed mechanism.
Scheme 4.
CONCLUSION
In this article, we developed highly discriminative and chemoselective transformations of acetals using the combination
of R3SiOTf/2,4,6ꢀcollidine. It is noteworthy that the deprotections illustrated here are the first examples of discriminative
and chemoselective deprotections between acetals (acetal vs. acetal), where such selectivity has been unprecedented with
conventional methods. Furthermore, formation of a single ether product from a mixed acetal is noteworthy because
conventional reaction conditions that use Et3SiHꢀTMSOTf produce two different ethers from a mixed acetal. We anticꢀ
ipate that the R3SiOTf/2,4,6ꢀcollidine complex recognizes the steric environments in the substrate to effect deprotection
or nucleophilic substitution quite selectively. We expect that these reactions will widen the scope of synthetic utility of
acetal functions.
EXPERIMENTAL SECTION
General. All reagents were purchased from commercial sources and used without further purification, unless otherwise
noted. Reactions were performed under a nitrogen atmosphere using purchased anhydrous solvent. All reactions were
monitored by thinꢀlayer chromatography using Merck SiO2 gel 60 F254. The products were purified by column chroꢀ
matography over SiO2 Kieselgel 60 (70ꢀ230 mesh ASTM) purchased from Merck or SiO2 60N (40ꢀ50 ꢁm, spherical
neutral) purchased from Kanto Chemical. 1H NMR and 13C NMR spectra were recorded at 25 oC on a JEOL JNMꢀAL300
(at 300 MHz and 75 MHz, respectively), a JEOL JNMꢀECS 400 (at 400 MHz and 100 MHz, respectively) or a JEOL
JNMꢀLA 500 (at 500 MHz and 125 MHz, respectively), and the chemical shifts are reported relative to internal TMS (1H,
δ = 0.00) and CDCl3 (13C, δ = 77.0). Data for 1H NMR spectra are reported as follows: chemical shift (δ ppm) (integraꢀ
tion, multiplicity, coupling constant (Hz)). Multiplicity and qualifier abbreviations are as follows: s = singlet, d = douꢀ
blet, t = triplet, q = quartet, m = multiplet, br = broad. Highꢀresolution mass spectra (MALDIꢀTOF) were performed by
the Elemental Analysis Section of Graduate School of Pharmaceutical Science in Osaka University.
The substrates 118), 319), 4a19), 4b19), 9a20), 9b20), 10a19), 10b19) and 17a’21) are known compounds.
Synthesis of Substrates and Experimental Details for Table 1, 2, 3, 5 and Scheme 1.
1,1ꢀDimethoxyꢀ2ꢀmethyldodecane (2a). To a solution of 2ꢀmethyldodecanal (1.21 g, 6.10 mmol) in MeOH (20
mL)/CH2Cl2 (20 mL) were added 10ꢀcamphorsulfonic acid (CSA) (141.7 mg, 0.610 mmol) and MS3A (0.50 g) at r.t.
After stirring for overnight, the reaction mixture was quenched with sat. NaHCO3 aq., and the mixture was extracted with
CH2Cl2. The extract was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified
by flash SiO2 column chromatography to afford 2a (1.36 g, 5.55 mmol, 91%). Colorless oil; 1H NMR (CDCl3, 500 MHz):
δ 4.02 (d, 1H, J = 6.9 Hz), 3.35 (s, 6H), 1.74ꢀ1.71 (m, 1H), 1.10ꢀ1.48 (m, 18H), 0.88 (m, 6H).; 13C NMR (CDCl3, 125
MHz): δ 109.0, 54.0, 53.9, 35.7, 31.9, 31.7, 29.9, 29.6, 29.3, 26.9, 22.7, 14.3, 14.1.; HRMS (MALDIꢀTOF) m/z: [M +
Na]+ calcd for C15H32O2Na 267.2295, found 267.2295.
1,1ꢀDimethoxyꢀ2,2ꢀdimethyldodecane (2b). (Step 1) To a solution of methyl 2,2ꢀdimethyldodecanoate (3.25 g, 13.4
mmol) in THF (134 mL) was added dropwise diisobutylaluminum hydride (DIBALꢀH) (1 M in THF, 40.2 mL, 40.2
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mmol) at ꢀ78 oC. After stirring for overnight at r.t., the reaction mixture was quenched with H2O at 0 oC, and the mixture
was extracted with EtOAc. The extract was dried over Na2SO4, filtered, and concentrated under reduced pressure. The
residue was purified by flash SiO2 column chromatography (nꢀhexane/EtOAc = 4/1) to afford the corresponding alcohol
(2.58 g, 12.1 mmol, 90%). (Step 2) Then, to a solution of the alcohol (0.50 g, 2.3 mmol) in DMSO (1.2 ml) was added
2ꢀiodoxybenzoic acid (IBX) (0.98 g, 3.5 mmol) at r.t. After stirring for 2 h, the reaction mixture was diluted with EtOAc,
filtered through Celite pad, and washed with H2O and brine. The extract was dried over Na2SO4, filtered, and concenꢀ
trated under reduced pressure. The residue was used in the next reaction without further purifications. (Step 3) To a
solution of the residue in MeOH (2.3 mL)/CH2Cl2 (2.3 mL) were added pꢀTsOH (43.8 mg, 0.23 mmol) and MS3A (0.23
g). After stirring for overnight, the reaction mixture was quenched with sat. NaHCO3 aq., and the mixture was extracted
with CH2Cl2. The extract was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure.
The residue was purified by flash SiO2 column chromatography to afford 2b (232.2 mg, 5.76 mmol, 43% in 2 steps).
Eluent: nꢀhexane/EtOAc = 30/1. Colorless oil; 1H NMR (CDCl3, 500 MHz): δ 3.83 (s, 1H), 3.50 (s, 6H), 1.26 (bs, 18H),
0.88 (s, 6H), 0.88 (t, 3H, J = 6.9 Hz).; 13C NMR (CDCl3, 125 MHz): δ 114.1, 58.5, 39.3, 37.8, 31.9, 30.7, 29.7, 29.6, 29.3,
23.6, 22.7, 21.9, 14.1.; HRMS (MALDIꢀTOF) m/z: [M + Na]+ calcd for C16H34O2Na 281.2451, found 281.2457.
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2,2ꢀDimethyldodecanedial
(8a).
(Step
1)
To
a
solution
of
methyl
12ꢀ((tertꢀbutyldimethylsilyl)oxy)ꢀ2,2ꢀdimethyldodecanoate (1.91 g, 5.13 mmol) in THF (14 mL) was added dropwise
DIBALꢀH (1 M in THF, 12.1 mL, 12.1 mmol) at ꢀ78 oC. After stirring for 1 h, the reaction mixture was quenched with
H2O at 0 oC, and the mixture was extracted with EtOAc. The extract was dried over Na2SO4, filtered, and concentrated
under reduced pressure. The residue was used in the next reaction without further purifications. (Step 2) To a solution of
the residue in THF (26 mL) was added tetraꢀnꢀbutylammonium fluoride (TBAF) (1 M in THF, 10.3 mL, 10.3 mmol) at
r.t. After stirring for overnight, the reaction mixture was concentrated under reduced pressure. The residue was purified
by flash SiO2 column chromatography (nꢀhexane/EtOAc = 1/1) to afford the corresponding alcohol (1.07 g, 4.62 mmol,
90% in 2 steps). (Step 3) To a solution of oxalyl chloride (7.1 ml, 83.9 mmol) in CH2Cl2 (30 mL) was added dropwise a
solution of DMSO (7.1 mL) in CH2Cl2 (33 mL) at ꢀ78 oC. After stirring for 15 min, a solution of the above alcohol (3.85
g, 16.7 mmol) in CH2Cl2 (21 mL) was added to the reaction mixture by cannula. After stirring for 15 min, Et3N (23.5 mL,
16.7 mmol) was added to the reaction mixture. After stirring for 10 min, the reaction mixture was warmed to r.t., then
quenched with H2O at 0 oC. The mixture was extracted with CH2Cl2. The extract was dried over Na2SO4, filtered, and
concentrated under reduced pressure. The residue was purified by flash SiO2 column chromatography to afford 8a (2.59
g, 11.4 mmol, 68%). Eluent: nꢀhexane/EtOAc = 15/1. Colorless oil; 1H NMR (CDCl3, 500 MHz): δ 9.77 (t, 1H, J = 1.8
Hz), 9.45 (s, 1H), 2.42 (td, 2H, J = 7.4, 1.8 Hz), 1.67ꢀ1.58 (m, 2H), 1.47ꢀ1.41 (m, 2H), 1.26 (bs, 12H), 1.04 (s, 6H).; 13C
NMR (CDCl3, 125 MHz): δ 206.6, 202.9, 45.8, 43.8, 37.3, 29.30, 29.25, 29.1, 24.2, 22.0, 21.2.; HRMS (MALDIꢀTOF)
m/z: [M + Na]+ calcd for C14H26O2Na 249.1825, found 249.1823.
2ꢀIsopropyldodecanedial (8d). To a solution of Celite (1.0 g) and pyridinium chlorochromate (PCC) (544.7 mg, 2.53
mmol) in CH2Cl2 was added a solution of 2ꢀisopropyldodecaneꢀ1,12ꢀdiol (154.4 mg, 0.631 mmol) in CH2Cl2 (6.3 mL).
After stirring for 3.5 h, the reaction mixture was filtered through a Celite pad. The filtrate was then concentrated to afford
8d without further purification. Colorless oil;1H NMR (CDCl3, 500 MHz): δ 9.77 (t, 1H, J = 1.8 Hz), 9.60 (d, 1H, J = 3.4
Hz), 2.42 (td, 2H, J = 7.3, 1.8 Hz), 2.04ꢀ1.95 (m, 2H), 1.47ꢀ1.43 (m, 4H), 1.29ꢀ1.18 (m, 12H), 0.961 (d, 3H, J = 6.9 Hz),
0.957 (d, 3H, J = 6.9 Hz).; 13C NMR (CDCl3, 125 MHz): δ 206.1, 202.9, 58.7, 43.9, 29.7, 29.31, 29.27, 29.1, 28.3, 27.6,
26.1, 22.0, 20.3, 19.8.; HRMS (MALDIꢀTOF) m/z: [M + Na]+ calcd for C15H28O2Na 263.1982, found 263.1982.
1,1,12,12ꢀTetramethoxyꢀ2,2ꢀdimethyldodecane (5a). To a solution of 2,2ꢀdimethyldodecanedial (8a) (1.00 g, 4.40
mmol) in MeOH (8.8 mL) were added pꢀTsOH･H2O (836 mg, 4.40 mmol) and MS3A (0.88 g). After stirring for 8 h, the
reaction mixture was quenched with sat. NaHCO3 aq., and the mixture was extracted with CH2Cl2. The extract was
washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by
flash SiO2 column chromatography to afford 5a (504.3 mg, 1.54 mmol, 35%). Eluent: CH2Cl2/EtOAc = 40/1. Colorless
1
oil; H NMR (CDCl3, 300 MHz): δ 4.36 (t, 1H, J = 5.7 Hz), 3.82 (s, 1H), 3.50 (s, 6H), 3.31 (s, 6H), 1.59 (m, 2H),
1.28ꢀ1.24 (m, 16H), 0.86 (s, 6H).; 13C NMR (CDCl3, 125 MHz): δ 114.0, 104.5, 58.5, 52.6, 39.2, 37.8, 32.5, 30.6, 29.63,
29.55, 29.46, 24.6, 23.6, 21.9.; HRMS (MALDIꢀTOF) m/z: [M + Na]+ calcd for C18H38O4Na 341.2662, found 341.2667.
2,2'ꢀ(10ꢀMethylundecaneꢀ1,10ꢀdiyl)bis(1,3ꢀdioxolane) (5b). To a solution of 5a (197.3 mg, 0.619 mmol) in ethꢀ
yleneglycol (0.17 mL, 3.04 mmol) was added pꢀTsOH･H2O (10.7 mg, 0.06 mmol) at 50 oC. After the disappearance of
5a (monitored by TLC), the reaction mixture was quenched with sat. NaHCO3 aq., and the mixture was extracted with
CH2Cl2. The extract was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to
afford 5b (185.1 mg, 0.588 mmol, 95%). Colorless oil; 1H NMR (CDCl3, 500 MHz): δ 4.84 (t, 1H, J = 5.0 Hz), 4.54 (s,
1H), 4.00ꢀ3.82 (m, 8H), 1.69ꢀ1.62 (m, 2H), 1.43ꢀ1.36 (m, 16H), 0.88 (s, 6H).; 13C NMR (CDCl3, 125 MHz): δ 110.0,
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104.7, 65.2, 64.8, 37.7, 37.0, 33.9, 30.6, 29.6, 29.5, 24.1, 23.5, 21.3.; HRMS (MALDIꢀTOF) m/z: [M + Na]+ calcd for
C18H34O4Na: 337.2349, found 337.2351.
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2,2'ꢀ(10ꢀMethylundecaneꢀ1,10ꢀdiyl)bis(1,3ꢀdioxane) (5c). To a solution of 5a (175.6 mg, 0.55 mmol) in
1,3ꢀpropanediol (0.20 ml, 2.75 mmol) was added pꢀTsOH･H2O (10.7 mg, 0.06 mmol) at 50 oC. After the disappearance
of 5a (monitored by TLC), the reaction mixture was quenched with sat. NaHCO3 aq., and the mixture was extracted with
CH2Cl2. The extract was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to
afford 5c (171.0 mg, 0.500 mmol, 91%). Colorless oil; 1H NMR (CDCl3, 500 MHz): δ 4.51 (t, 1H, J = 5.0 Hz), 4.13 (s,
1H), 4.13ꢀ4.08 (m, 4H), 3.80ꢀ3.68 (m, 4H), 2.13ꢀ1.98 (m, 2H), 1.61ꢀ1.55 (m, 2H), 1.36ꢀ1.23 (m, 18H), 0.86 (s, 6H).; 13C
NMR (CDCl3, 125 MHz): δ 107.6, 102.5, 67.1, 66.9, 37.8, 37.4, 35.3, 30.6, 29.65, 29.55, 29.53, 29.49, 26.0, 25.9, 24.0,
23.5, 22.0.; HRMS (MALDIꢀTOF) m/z: [M + Na]+ calcd for C20H38O4Na 365.2662, found 365.2662.
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11ꢀ(Dimethoxymethyl)ꢀ1,1ꢀdimethoxyꢀ12ꢀmethyltridecane (5d). To a solution of 8d in MeOH (0.65 ml) and CH2Cl2
(0.65 ml) were added pꢀTsOH･H2O (120.2 mg, 0.63 mmol) and MS3A (0.3 g) at r.t. After stirring for 11 h, the reaction
mixture was quenched with K2CO3 and sat. NaHCO3 aq. and extracted with CH2Cl2. The extract was dried over Na2SO4,
filtered, and concentrated under reduced pressure. The residue was purified by flash SiO2 column chromatography to
afford 5d (84.3 mg, 0.253 mmol, 40% in 2 steps). Eluent: CH2Cl2/EtOAc = 40/1. Colorless oil; 1H NMR (CDCl3, 500
MHz): δ 4.36 (t, J = 6.0 Hz, 1H), 4.18 (d, J = 6.0 Hz, 1H), 3.35 (s, 3H), 3.33 (s, 3H), 3.31 (s, 6H), 1.90ꢀ1.86 (m, 1H),
1.60ꢀ1.56 (m, 2H), 1.46ꢀ1.43 (m, 1H), 1.30ꢀ1.21 (m, 16H), 0.90 (d, 3H, J = 7.1 Hz), 0.87 (d, 3H, J = 7.1 Hz).; 13C NMR
(CDCl3, 125 MHz): δ 107.8, 104.5, 54.4, 53.7, 52.5, 45.7, 32.5, 30.2, 29.55, 29.46, 29.3, 27.4, 26.0, 24.6, 20.5, 18.8.;
HRMS (MALDIꢀTOF) m/z: [M + Na]+ calcd for C19H40O4Na 355.2819, found 355.2819.
1ꢀ(10,10ꢀDimethoxydecyl)ꢀ4ꢀ(dimethoxymethyl)benzene (5e). To a solution of 4ꢀbromobenzaldehyde dimethylacetal
(295.3 mg, 1.28 mmol) in Et2O (1.5 mL) was added dropwise nꢀBuLi (1.2 mL, 1.92 mmol) at ꢀ78 oC. After stirring for 30
min, 10ꢀbromoꢀ1,1ꢀdimethoxydecane in Et2O (1.0 mL) was added. Then the reaction mixture was warmed to reflux.
After stirring for 12 h, the reaction mixture was cooled to r.t., then the mixture was quenched with sat. NaHCO3 aq., and
extracted with EtOAc. The extract was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue
was purified by flash SiO2 column chromatography to afford 5e (111.7 mg, 0.320 mmol, 25%). Eluent: nꢀhexane/EtOAc
= 40/1. Colorless oil; 1H NMR (CDCl3, 300 MHz): δ 7.34 (d, 2H, J = 8.1 Hz), 7.17 (d, 2H, J = 8.1 Hz), 5.36 (s, 1H), 4.36
(t, 1H, J = 5.7 Hz), 3.33 (s, 6H), 3.31 (s, 6H), 2.60 (t, 2H, J = 7.7 Hz), 1.58 (m, 2H), 1.28 (bs, 14H).; 13C NMR (CDCl3,
125 MHz): δ 143.2, 135.3, 128.2, 126.5, 104.5, 103.3, 52.7, 52.6, 35.7, 32.5, 31.4, 29.5, 29.4, 29.2, 24.6.; HRMS
(MALDIꢀTOF) m/z: [M + Na]+ calcd for C21H36O4Na 375.2506, found 375.2504.
1,1ꢀDiisopropoxyꢀ10,10ꢀdimethoxydecane (11). (Step 1) To a solution of 6,6ꢀdimethoxyhexꢀ1ꢀene (0.33 g, 2.31 mmol)
in isopropanol (0.9 ml, 11.5 mmol) was added pꢀTsOH (43.9 mg, 0.23 mmol) at 50 oC. After the disappearance of starting
material (monitored by TLC), the reaction mixture was quenched with sat. NaHCO3 aq., and the mixture was extracted
with CH2Cl2. The extract was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure.
The residue was used in the next step without further purification. (Step 2) To a solution of the residue and
6,6ꢀdimethoxyhexꢀ1ꢀene (1.00 g, 6.93 mmol) in CH2Cl2 (92 mL) was added Grubbs 2nd catalyst (392 mg, 0.462 mmol, 20
mol%) at reflux. After stirring for overnight, the reaction mixture was concentrated under reduced pressure. Then 10%
Pd/C (29.2 mg) was added to the residue in MeOH (3.0 mL), and air was replaced to H2 gas (balloon). After stirring for 3
h, the reaction mixture was filtrated with Celite pad, and concentrated under reduced pressure. The residue was purified
by flash SiO2 column chromatography to afford 11 (243 mg, 0.83 mmol, 36%). Eluent: nꢀhexane/EtOAc = 40/1. Colꢀ
orless oil; 1H NMR (CDCl3, 300 MHz): δ 4.36 (t, 1H, J = 5.9 Hz), 4.18 (t, 1H, J = 5.9 Hz ), 3.34 (heptet, 2H, J = 6.2 Hz),
3.31 (s, 6H), 1.62ꢀ1.55 (m, 4H), 1.28 (m, 12H), 1.19 (d, 6H, J = 6.0 Hz), 1.14 (d, 6H, J = 6.0 Hz).; 13C NMR (CDCl3, 125
MHz): δ 104.5, 100.3, 67.4, 52.5, 35.4, 32.4, 29.5, 29.43, 29.39, 29.36, 24.83, 24.81, 24.5, 23.4, 22.6.; HRMS
(MALDIꢀTOF) m/z: [M + Na]+ calcd for C19H40O4Na 355.2819, found 355.2819.
2ꢀ(9,9ꢀDiisopropoxynonyl)ꢀ1,3ꢀdioxolane (15). (Step 1) To a solution of 2ꢀ(pentꢀ4ꢀenꢀ1ꢀyl)ꢀ1,3ꢀdioxolane (0.33 g, 2.31
o
mmol) in isopropanol (0.9 ml, 11.5 mmol) was added pꢀTsOH･H2O (43.9 mg, 0.23 mmol) at 50 C. After the disapꢀ
pearance of starting material (monitored by TLC), the reaction mixture was quenched with sat. NaHCO3 aq., and the
mixture was extracted with CH2Cl2. The extract was washed with brine, dried over Na2SO4, filtered, and concentrated
under reduced pressure. The residue used the next step without further purification. (Step 1) To a solution of the above
residue and 2ꢀ(pentꢀ4ꢀenꢀ1ꢀyl)ꢀ1,3ꢀdioxolane (1.00 g, 6.93 mmol) in CH2Cl2 (92 mL) was added Grubbs 2nd catalyst (392
mg, 0.462 mmol, 20 mol%) at reflux. After stirring for overnight, the reaction mixture was concentrated under reduced
pressure. Then 10% Pd/C (29.2 mg) was added to the residue in MeOH (3.0 mL), replaced air to H2 gas (balloon). After
stirring for 3 h, the reaction mixture was filtrated with Celite pad, and concentrated under reduced pressure. The residue
was purified by flash SiO2 column chromatography to afford 15 (200 mg, 0.63 mmol, 27%). Eluent: nꢀhexane/EtOAc =
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40/1. Colorless oil; 1H NMR (300 MHz, CDCl3): δ 4.83 (t, 1H, J = 4.6 Hz), 4.52 (t, 1H, J = 5.5 Hz), 3.96 (q, 2H, J = 4.6
Hz), 3.97ꢀ3.70 (m, 6H), 1.66ꢀ1.51 (m, 4H), 1.39ꢀ1.21 (m, 12H), 1.17 (d, 3H, J = 6.0 Hz), 1.16 (d, 3H, J = 6.0 Hz), 1.12 (d,
3H, J = 6.0 Hz), 1.11 (d, 3H, J = 6.0 Hz).; 13C NMR (CDCl3, 76 MHz): δ 104.6, 100.3, 67.4, 64.8, 35.4, 33.9, 29.5, 29.5,
29.4, 24.8, 24.0, 23.4, 22.6.; HRMS (MALDIꢀTOF) m/z: [M + Na]+ calcd for C18H36O4Na 339.2505, found 339.2505.
1
2
3
4
5
6
7
8
Experimental Details of Table 1. To a solution of the 1 to 1 mixture of dimethyl acetal 1 (1.0 equiv) and 2 (1.0 equiv) in
CH2Cl2 were added dropwise 2,4,6ꢀcollidine (2.25 equiv) and TMSOTf (1.5 equiv) at 0 oC. After stirring for 1 h, BnOH
(2.0 equiv) was added to the reaction mixture at 0 oC. After disappearance of the polar component, the reaction mixture
was quenched with sat. NaHCO3 aq., and the mixture was extracted with CH2Cl2. The extract was dried over Na2SO4,
filtered, and concentrated under reduced pressure. The residue was purified by flash SiO2 column chromatography to
give the fractions which contain the mixed acetal 3 (with or without mixed acetal 4). The fraction was measured by 1H
NMR to determine the ratio of products.
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10
11
12
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15
16
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Experimental Details of Table 2. (entries 1ꢀ5) To a solution of 5a (1.0 equiv) in solvent were added 2,4,6ꢀcollidine (3.0
equiv) and R3SiOTf (TMSOTf or TESOTf) (2.0 equiv) at 0 oC. After checking the disappearance of 5a and the formation
of the polar compound on TLC, H2O was added to the reaction mixture, and the resulting mixture was allowed to warm to
r.t. After disappearance of the polar component, the reaction mixture was quenched with sat. NaHCO3 aq., and the
mixture was extracted with CH2Cl2. The extract was dried over Na2SO4, filtered, and concentrated under reduced
pressure. The residue was measured by 1H NMR to determine the ratio of products and purified by flash SiO2 column
chromatography to give 6a.
(entry 6) To a solution of 5a (75.7 mg, 0.238 mmol) in CH2Cl2 (2.4 mL) were added 2,4,6ꢀcollidine (94 ꢁL, 0.713 mmol)
and TESOTf (107 ꢁL, 0.475 mmol) at ꢀ30 oC. After checking the disappearance of starting material and the formation of
the polar compound on TLC, H2O (0.24 mL) was added to the reaction mixture at r.t. After disappearance of the polar
component, the reaction mixture was quenched with sat. NaHCO3 aq., and the mixture was extracted with CH2Cl2. The
extract was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was measured by 1H NMR
to determine the ratio of products and purified by flash SiO2 column chromatography to give 6a (60.9 mg, 0.223 mmol,
94%). Eluent: 1% Et3N in CH2Cl2.
(entry 7) To a solution of 5a (66.7 mg, 0.209 mmol) in CH2Cl2 (2.1 mL) was added TMSI (30 ꢁL) at 0 oC. After stirring
for 15 min, the reaction mixture was quenched with sat. NaHCO3 aq., and the mixture was extracted with CH2Cl2. The
extract was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was measured by 1H NMR
to determine the ratio of products and purified by flash SiO2 column chromatography to give 7a (8.0 mg, 0.029 mmol,
14%) and 8a (40.7 mg, 0.179 mmol, 86%). Eluent: 1% Et3N in CH2Cl2.
(entry 8) To a solution of 5a (102 mg, 0.319 mmol) in acetone (3.2 mL) and H2O (3.2 mL) was added pꢀTsOH･H2O (60.7
mg, 0.319 mmol) at r.t. After stirring for 1 h, the reaction mixture was added H2O, and the mixture was extracted with
CH2Cl2. The extract was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was measꢀ
ured by 1H NMR to determine the ratio of products and purified by flash SiO2 column chromatography to give 6a (8.7
mg, 0.032 mmol, 10%), 7a (14.8mg, 0.054 mmol, 17%) and 8a (33.2 mg, 0.147 mmol, 46%). Eluent: 1% Et3N in
CH2Cl2.
12,12ꢀDimethoxyꢀ11,11ꢀdimethyldodecanal (6a). Colorless oil; 1H NMR (CDCl3, 300 MHz): δ 9.77 (t, 1H, J = 1.9 Hz),
3.82 (s, 1H), 3.50 (s, 6H), 2.42 (td, 2H, J = 7.4, 1.9 Hz), 1.62ꢀ1.59 (m, 2H), 1.28ꢀ1.24 (m, 14H), 0.86 (s, 6H).; 13C NMR
(CDCl3, 100 MHz): δ 203.1, 114.0, 58.5, 43.9, 39.2, 37.7, 30.6, 29.6, 29.4, 29.3, 29.1, 23.5, 22.0, 21.9.; HRMS
(MALDIꢀTOF) m/z: [M + Na]+ calcd for C16H32O3Na 295.2244, found 295.2242.
12,12ꢀDimethoxyꢀ2,2ꢀdimethyldodecanal (7a). Colorless oil; 1H NMR (CDCl3, 500 MHz): δ 9.45 (s, 1H), 4.36 (t, 1H, J
= 5.8 Hz), 3.31 (s, 6H), 1.58 (m, 2H), 1.47ꢀ1.41 (m, 2H), 1.35ꢀ1.22 (m, 14H), 1.04 (s, 6H).; 13C NMR (CDCl3, 125 MHz):
δ 206.6, 104.5, 52.6, 45.8, 37.3, 32.4, 30.2, 29.5, 29.41, 29.39, 24.5, 24.2, 21.3.; HRMS (MALDIꢀTOF) m/z: [M + Na]+
calcd for C16H32O3Na 295.2244, found 295.2246.
Experimental Details of Table 3. To a solution of 5 (1.0 equiv) in CH2Cl2 were added 2,4,6ꢀcollidine (3.0 equiv) and
TESOTf (2.0 equiv) at −30 oC. After checking the disappearance of 5 and the formation of the polar compound on TLC,
H2O was added to the reaction mixture at r.t. After disappearance of the polar component, the reaction mixture was
quenched with sat. NaHCO3 aq., and the mixture was extracted with CH2Cl2. The extract was dried over Na2SO4, filtered,
and concentrated under reduced pressure. The residue was purified by flash SiO2 column chromatography to afford 6.
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11ꢀ(1,3ꢀDioxolanꢀ2ꢀyl)ꢀ11ꢀmethyldodecanal (6b). According to the general procedure, 5b (49.7 mg, 0.158 mmol),
2,4,6ꢀcollidine (126 ꢁL, 0.948 mmol), TESOTf (114 ꢁL, 0.632 mmol) and H2O (0.16 mL) gave 6b (39.4 mg, 0.146
mmol, 92%). Eluent: CH2Cl2/EtOAc = 40/1. Colorless oil; 1H NMR (CDCl3, 500 MHz): δ 9.77 (t, 1H, J = 1.9 Hz), 4.55
(s, 1H), 3.95ꢀ3.83 (m, 4H), 2.42 (td, 2H, J = 7.4, 1.9 Hz), 1.64ꢀ1.57 (m, 2H), 1.27 (m, 14H), 0.88 (s, 6H).; 13C NMR
(CDCl3, 125 MHz): δ 203.0, 110.0, 65.2, 43.9, 37.7, 37.0, 30.6, 29.5, 29.4, 29.3, 29.1, 23.5, 22.1, 21.3.; HRMS
(MALDIꢀTOF) m/z: [M + Na]+ calcd for C16H30O3Na 293.2087, found 293.2090.
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5
6
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8
9
11ꢀ(1,3ꢀDioxanꢀ2ꢀyl)ꢀ11ꢀmethyldodecanal (6c). According to the general procedure, 5c (47.8 mg, 0.140 mmol),
2,4,6ꢀcollidine (110 ꢁL, 0.840 mmol), TESOTf (101 ꢁL, 0.560 mmol) and H2O (0.14 mL) gave 6c (35.6 mg, 0.126
mmol, 90%). Eluent: CH2Cl2/EtOAc = 40/1. Colorless oil; 1H NMR (CDCl3, 500 MHz): δ 9.77 (t, 1H, J = 1.8 Hz), 4.13
(s, 1H), 4.13ꢀ4.09 (m, 2H), 3.75ꢀ3.69 (m, 2H), 2.42 (td, 2H, J = 7.3, 1.8 Hz), 2.08ꢀ1.99 (m, 1H), 1.64ꢀ1.58 (m, 1H),
1.32ꢀ1.23 (m, 16H), 0.86 (s, 6H).; 13C NMR (CDCl3, 125 MHz): δ 203.1, 107.6, 67.1, 43.9, 37.7, 37.4, 30.5, 29.6, 29.4,
29.3, 29.1, 26.0, 23.5, 22.1, 22.0.; HRMS (MALDIꢀTOF) m/z: [M + Na]+ calcd for C17H32O3Na 307.2244, found
307.2240.
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11
12
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16
17
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11ꢀ(Dimethoxymethyl)ꢀ12ꢀmethyltridecanal (6d). According to the general procedure, 5d (41.8 mg, 0.126 mmol),
2,4,6ꢀcollidine (50 ꢁL, 0.251 mmol), TESOTf (57 ꢁL, 0.316 mmol), and H2O (0.13 mL) gave 6d (31.3 mg, 0.109 mmol,
87%). Eluent: CH2Cl2/EtOAc = 50/1. Colorless oil; 1H NMR (CDCl3, 500 MHz): δ 9.76 (t, 1H, J = 1.9 Hz), 4.18 (d, 1H,
J = 6.0 Hz), 4.18 (s, 1/2H), 3.35 (s, 3H), 3.33 (s, 3H), 2.42 (td, 2H, J = 7.4, 1.9 Hz), 1.90ꢀ1.87 (m, 1H), 1.64ꢀ1.60 (m, 2H),
1.46ꢀ1.44 (m, 1H), 1.37ꢀ1.21 (m, 14H), 0.90 (d, 3H, J = 7.0 Hz), 0.87 (d, 3H, J = 7.0 Hz).; 13C NMR (CDCl3, 125 MHz):
δ 203.0, 107.8, 54.4, 53.8, 45.7, 43.9, 30.2, 29.5, 29.4, 29.32, 29.26, 29.1, 27.4, 26.0, 22.1, 20.5, 18.8.; HRMS
(MALDIꢀTOF) m/z: [M + Na]+ calcd for C17H34O3Na 309.2400, found 309.2396.
10ꢀ(4ꢀ(Dimethoxymethyl)phenyl)decanal (6e). According to the general procedure, 5e (22.5 mg, 0.0638 mmol),
2,4,6ꢀcollidine (25 ꢁL, 0.191 mmol), TESOTf (29 ꢁL, 0.128 mmol), and H2O (65 ꢁL) gave 6c (13.3 mg, 0.0434 mmol,
68%). Eluent: CH2Cl2/EtOAc = 100/1. Colorless oil; 1H NMR (CDCl3, 300 MHz): δ 9.76 (t, 1H, J = 1.9 Hz), 7.35 (d, 2H,
J = 8.1 Hz), 7.18 (d, 2H, J = 8.1 Hz), 5.36 (s, 1H), 3.33 (s, 6H), 2.60 (t, 2H, J = 7.5 Hz), 2.42 (td, 2H, J = 7.5 Hz, 1.9 Hz),
1.64ꢀ1.57 (m, 2H), 1.28ꢀ1.25 (m, 12H).; 13C NMR (CDCl3, 125 MHz): δ 192.0, 150.5, 134.4, 129.9, 129.1, 104.5, 52.6,
36.2, 32.5, 31.0, 29.47, 29.44, 29.42, 29.38, 29.2, 24.5.; HRMS (MALDIꢀTOF) m/z: [M + Na]+ calcd for C19H30O3Na
329.2087, found 329.2088.
Experimental Details of Table 4. To a solution of the 1 to 1 mixture of dimethyl acetal 1 (1.0 equiv) and 9 (1.0 equiv) in
CH2Cl2 were added dropwise 2,4,6ꢀcollidine (2.25 equiv) and R3SiOTf (TMSOTf or TESOTf) (1.5 equiv) at 0 oC. After
stirring for 1 h, BnOH (2.0 equiv) was added to the reaction mixture at 0 oC. After disappearance of the polar component,
the reaction mixture was quenched with sat. NaHCO3 aq., and the mixture was extracted with CH2Cl2. The extract was
dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash SiO2 column
chromatography to give the fractions which contain the mixed acetal 3 (with or without mixed acetal 10). The fraction
was measured by 1H NMR to determine the ratio of products.
Experimental Details of Table 5. (entry 1) To a solution of 11 (30.2 mg, 0.09 mmol) in CH2Cl2 (0.9 mL) were added
2,4,6ꢀcollidine (37 ꢁL, 0.28 mmol) and TESOTf (43 ꢁL, 0.19 mmol) at ꢀ30 oC. After checking the disappearance of 11
and the formation of the polar compound on TLC, H2O was added to the reaction mixture and the resulting solution was
allowed to warm to r.t. After disappearance of the polar component, the reaction mixture was quenched with sat. Naꢀ
HCO3 aq., and the mixture was extracted with CH2Cl2. The extract was dried over Na2SO4, filtered, and concentrated
under reduced pressure. The residue was purified by flash SiO2 column chromatography to afford 12 (243 mg, 0.069
mmol, 77%). Eluent: CH2Cl2/EtOAc = 40/1.
(entry 2) To a solution of 11 (29.3 mg, 0.0920 mmol) in acetone (0.9 mL) and H2O (0.9 mL) was added pꢀTsOH (15.8
mg, 0.0920 mmol) at r.t. After stirring for 1 h, the reaction mixture was quenched with sat. NaHCO3 aq., and the mixture
was extracted with CH2Cl2. The extract was dried over Na2SO4, filtered, and concentrated under reduced pressure. The
residue was measured by 1H NMR to observe the component ratio, 12 (0%), 13 (15%) and 14 (86%).
(entry 3) To a solution of 11 (15.5 mg, 0.0487 mmol) in CH2Cl2 (0.5 mL) was added TMSI (7 ꢁL, 0.0493 mmol) at r.t.
After stirring for 15 min, the reaction mixture was quenched with sat. NaHCO3 aq., and the mixture was extracted with
CH2Cl2. The extract was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was measꢀ
ured by 1H NMR to observe the component ratio, 12 (0%), 13 (5%) and 14 (95%).
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10,10ꢀDiisopropoxydecanal (12). Colorless oil; 1H NMR (CDCl3, 300 MHz): δ 9.76 (t, 1H, J = 1.9 Hz), 4.53 (t, 3H),
3.90ꢀ3.82 (m, 2H), 2.42 (td, 2H, J = 7.4, 1.9 Hz), 1.65ꢀ1.53 (m, 4H), 1.29 (bs, 10H), 1.19 (d, 6H, J = 6.3 Hz), 1.14 (d, 6H,
J = 5.7 Hz).;13C NMR (CDCl3, 125 MHz): δ 203.0, 100.3, 67.5, 43.9, 35.4, 29.7, 29.44, 29.37, 29.3, 29.1, 24.8, 23.5,
22.6, 22.0.; HRMS (MALDIꢀTOF) m/z: [M + Na]+ calcd for C16H32O3Na 295.2244, found 295.2242.
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5
6
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8
Experimental Details of Scheme 1. To a solution of 15 (94.9 mg, 0.3 mmol) in CH2Cl2 (1.5 mL) were added
2,4,6ꢀcollidine (119 ꢁL, 0.9 mmol) and TESOTf (135 ꢁL, 0.6 mmol) at ꢀ30 oC. After checking the disappearance of 15
and the formation of the polar compound on TLC, H2O (0.3 mL) was added to the reaction mixture which was allowed to
warm to r.t. After disappearance of the polar component, the reaction mixture was quenched with sat. NaHCO3 aq., and
the mixture was extracted with CH2Cl2. The extract was dried over Na2SO4, filtered, and concentrated under reduced
pressure. The residue was measured by 1H NMR to observe the component ratio. The residue was purified by flash SiO2
column chromatography to afford 12 (49.0 mg, 0.23 mmol, 76%). Eluent: nꢀhexane/ EtOAc = 15/1.
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Synthesis of Substrates and Experimental Details for Scheme 2, 3, and Table 6, 7.
General Procedure for the Preparation of Mixed Acetals. To a solution of dimethyl acetal (1.0 equiv) in CH2Cl2 (0.1
M) were added dropwise 2,4,6ꢀcollidine (3.0 equiv) and TMSOTf (2.0 equiv) at 0 oC. After checking the disappearance
of starting material and the formation of the polar compound on TLC, alcohol (3.0 equiv) was added to the reaction
mixture at the same temperature. After disappearance of the polar component, the reaction mixture was quenched with
sat. NaHCO3 aq., and the mixture was extracted with CH2Cl2. The extract was dried over Na2SO4, filtered, and concenꢀ
trated under reduced pressure. The residue was purified by flash SiO2 column chromatography to afford the desired
mixed acetal.
3ꢀ((1ꢀMethoxydodecyl)oxy)propylbenzene (16a). According to the general procedure, 1,1ꢀdimethoxydodecane (2.0 g,
8.68 mmol), 2,4,6ꢀcollidine (3.4 mL, 26.0 mmol), TMSOTf (3.1 mL, 17.4 mmol), and 3ꢀphenylpropanꢀ1ꢀol (3.5 ml, 26.0
mmol) gave 16a (2.63 g, 7.90 mmol, 91%). Eluent: 1% Et3N in nꢀhexane/benzene = 3/2 to 2/3. Colorless oil; 1H NMR
(400 MHz, CDCl3): δ 7.30ꢀ7.17 (5H, m), 4.43 (1H, t, J = 5.8 Hz), 3.61 (1H, dt, J = 9.6, 6.4 Hz), 3.43 (1H, dt, J = 9.6, 6.4
Hz), 3.32 (3H, s), 2.71 (2H, t, J = 7.8 Hz), 1.94ꢀ1.87 (2H, m), 1.63ꢀ1.58 (2H, m), 1.37ꢀ1.24 (18H, m), 0.88 (3H, t, J = 6.9
MHz).; 13C NMR (100 MHz, CDCl3): δ 142.0, 128.4, 128.3, 125.8, 104.0, 64.9, 52.5, 33.0, 32.5, 31.9, 31.5, 29.7, 29.62,
29.57, 29.5, 29.3, 24.7, 22.7, 14.1.; HRMS (MALDIꢀTOF) m/z: [M + Na]+ calcd for C22H38O2Na 357.2770, found
357.2764.
12ꢀMethoxyꢀ12ꢀ(3ꢀphenylpropoxy)dodecyl acetate (16b). According to the general procedure, 12,12ꢀdimethoxydodecyl
acetate (310 mg, 1.07 mmol), 2,4,6ꢀcollidine (424 ꢁL, 3.22 mmol), TMSOTf (388 ꢁL, 2.15 mmol), and
3ꢀphenylpropanꢀ1ꢀol (438 ꢁL, 3.22 mmol) gave 16b (300 mg, 0.856 mmol, 80%). Eluent: nꢀhexane/benzene = 7/1.
Colorless oil; 1H NMR (400 MHz, CDCl3): δ 7.30ꢀ7.17 (5H, m), 4.41 (1H, t, J = 5.5 Hz), 4.05 (2H, t, J = 6.9 Hz), 3.61
(1H, dt, J = 9.4, 6.4 Hz), 3.43 (1H, dt, J = 9.4, 6.4 Hz), 3.32 (3H, s), 2.71 (2H, t, J = 7.8 Hz), 2.05 (3H, s), 1.95ꢀ1.90 (2H,
m), 1.64ꢀ1.58 (4H, m), 1.31ꢀ1.28 (16H, m).; 13C NMR (100 MHz, CDCl3): δ 171.3, 142.0, 128.4, 128.3, 125.8, 104.0,
65.0, 64.7, 52.6, 52.5, 33.0, 32.5, 31.5, 29.54, 29.52, 29.48, 29.45, 29.36, 29.25, 28.6, 25.9, 22.1, 21.0.; HRMS
(MALDIꢀTOF) m/z: [M + Na]+ calcd for C24H40O4Na 415.2824, found 415.2819.
12ꢀMethoxyꢀ12ꢀ(3ꢀphenylpropoxy)dodecyl
benzoate
(16c).
According
to
the
general
procedure,
12,12ꢀdimethoxydodecyl benzoate (60.1 mg, 0.171 mmol), 2,4,6ꢀcollidine (135 ꢁl, 0.514 mmol), TMSOTf (124 ꢁL,
0.342 mmol), and 3ꢀphenylpropanꢀ1ꢀol (70 ꢁL, 0.514 mmol) gave 16c (64.3 mg, 0.142 mmol, 83%). Eluent: 1% Et3N in
1
nꢀhexane/EtOAc = 10/1 to 8/1. Colorless oil; H NMR (400 MHz, CDCl3): δ 8.06ꢀ8.04 (2H, m), 7.58ꢀ7.54 (1H, m),
7.47ꢀ7.43 (2H, m), 7.31ꢀ7.20 (5H, m), 4.42 (1H, t, J = 5.5 Hz), 4.32 (2H, t, J = 6.9 Hz), 3.61 (1H, dt, J = 9.6, 6.0 Hz), 3.45
(1H, dt, J = 9.6, 6.4 Hz), 3.32 (3H, s), 2.72 (2H, t, J = 7.8 Hz), 1.93ꢀ1.90 (2H, m), 1.79ꢀ1.75 (2H, m), 1.60ꢀ1.57 (2H, m),
1.44ꢀ1.29 (16H, m).; 13C NMR (100 MHz, CDCl3): δ 166.7, 142.0, 132.8, 130.5, 129.5, 128.4, 128.3, 125.8, 104.0, 65.1,
64.9, 52.6, 33.0, 32.5, 31.5, 29.6, 29.3, 28.7, 26.0, 24.7.; HRMS (MALDIꢀTOF) m/z: [M + Na]+ calcd for C29H42O4Na
477.2981, found 477.2975.
tertꢀButyl((12ꢀmethoxyꢀ12ꢀ(3ꢀphenylpropoxy)dodecyl)oxy)dimethylsilane (16d). According to the general procedure,
tertꢀbutyl((12,12ꢀdimethoxydodecyl)oxy)dimethylsilane (100 mg, 0.277 mmol), 2,4,6ꢀcollidine (110 ꢁL, 0.831 mmol),
TMSOTf (100 ꢁL, 0.555 mmol), and 3ꢀphenylpropanꢀ1ꢀol (113 ꢁl, 0.831 mmol) gave 16d (132 mg, 0.277 mmol, quant.).
Eluent: 1% Et3N in nꢀhexane/benzene = 1/1. Colorless oil; 1H NMR (400 MHz, CDCl3): δ 7.31ꢀ7.20 (5H, m), 4.42 (1H,
t, J = 5.5 Hz), 3.63ꢀ3.58 (3H, m), 3.44 (1H, dt, J = 9.6, 6.4 Hz), 3.32 (3H, s), 2.72 (2H, t, J = 7.8 Hz), 1.95ꢀ1.90 (2H, m),
1.64ꢀ1.50 (4H, m)., 1.37ꢀ1.25 (16H, m), 0.90 (9H, s), 0.04 (6H, s).; 13C NMR (100 MHz, CDCl3): δ 142.0, 128.4, 128.3,
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125.8, 64.9, 63.3, 52.5, 33.0, 32.9, 32.5, 31.5, 29.62, 29.58, 29.56, 29.5, 29.4, 26.0, 25.8, 24.7, 18.4.; HRMS
(MALDIꢀTOF) m/z: [M + Na]+ calcd for C28H52O3NaSi 487.3583, found 487.3578.
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((12ꢀMethoxyꢀ12ꢀ(3ꢀphenylpropoxy)dodecyl)oxy)methanetriyltribenzene (16e). According to the general procedure,
(((12,12ꢀdimethoxydodecyl)oxy)methanetriyl)tribenzene (400 mg, 0.819 mmol), 2,4,6ꢀcollidine (324 ꢁL, 2.48 mmol),
TMSOTf (296 ꢁL, 1.64 mmol), and 3ꢀphenylpropanꢀ1ꢀol (338 ꢁL, 2.48 mmol) gave 16e (454 mg, 0.762 mmol, 93%).
Eluent: 1% Et3N in nꢀhexane/benzene = 1/2. Colorless oil; 1H NMR (300 MHz, CDCl3): δ 7.46ꢀ7.16 (20H, m), 4.42 (1H,
t, J = 5.8 Hz), 3.62ꢀ3.57 (1H, m), 3.47ꢀ3.39 (1H, m), 3.32 (3H, s), 3.02 (2H, t, J = 6.8 Hz), 2.71 (2H, t, J = 7.9 Hz),
1.95ꢀ1.88 (2H, m), 1.64ꢀ1.58 (4H, m), 1.33ꢀ1.24 (16H, m).; 13C NMR (100 MHz, CDCl3): δ 144.5, 142.0, 128.7, 128.4,
128.3, 127.7, 126.8, 125.8, 104.0, 86.2, 64.9, 63.7, 52.5, 33.0, 32.5, 31.5, 30.1, 29.58, 29.53, 29.51, 26.3, 24.7.; HRMS
(MALDIꢀTOF) m/z: [M + Na]+ calcd for C41H52O3Na 615.3814, found 615.3809.
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3ꢀ((12ꢀChloroꢀ1ꢀmethoxydodecyl)oxy)propylbenzene
(16f).
According
to
the
general
procedure,
12ꢀchloroꢀ1,1ꢀdimethoxydodecane (122 mg, 0.461 mmol), 2,4,6ꢀcollidine (182 ꢁL, 1.38 mmol), TMSOTf (166 ꢁL, 0.92
mmol), and 3ꢀphenylpropanꢀ1ꢀol (188 ꢁL, 1.38 mmol) gave 16f (74.2 mg, 0.203 mmol, 44%). Eluent: 1% Et3N in
nꢀhexane/benzene = 3/2. Colorless oil; 1H NMR (300 MHz, CDCl3): δ 7.31ꢀ7.19 (5H, m), 4.43 (1H, t, J = 5.8 Hz), 3.62
(1H, dt, J = 9.3, 6.5 Hz), 3.52 (2H, t, J = 6.9 Hz), 3.44 (1H, dt, J = 9.3, 6.5 Hz), 3.32 (3H, s), 2.72 (2H, t, J = 7.9 Hz),
1.95ꢀ1.86 (2H, m), 1.77 (2H, quin, J = 6.9 Hz), 1.62ꢀ1.55 (2H, m), 1.45ꢀ1.27 (16H, m).; 13C NMR (100 MHz, CDCl3): δ
128.42, 128.39, 128.3, 125.8, 104.0, 64.9, 52.5, 45.2, 33.0, 32.6, 32.5, 31.5, 29.52, 29.50, 29.47, 29.43, 28.9, 26.9, 24.7.;
HRMS (MALDIꢀTOF) m/z: [M + Na]+ calcd for C22H37ClO2Na 391.2380, found 391.2374.
3ꢀ((12ꢀBromoꢀ1ꢀmethoxydodecyl)oxy)propylbenzene
(16g).
According
to
the
general
procedure,
12ꢀbromoꢀ1,1ꢀdimethoxydodecane (353 mg, 1.14 mmol), 2,4,6ꢀcollidine (451 ꢁL, 3.42 mmol), TMSOTf (412 ꢁL, 2.28
mmol), and 3ꢀphenylpropanꢀ1ꢀol (465 ꢁL, 3.42 mmol) gave 16g (470 mg, 1.14 mmol, quant.). Eluent: 1% Et3N in
nꢀhexane/EtOAc = 15/1. Colorless oil; 1H NMR (500 MHz, CDCl3): δ 7.31ꢀ7.18 (5H, m), 4.43 (1H, t, J = 5.8 Hz), 3.62
(1H, dt, J = 9.8, 6.3 Hz), 3.47ꢀ3.40 (3H, m), 3.32 (3H, s), 2.59 (2H, t, J = 7.5 Hz), 1.82ꢀ1.70 (4H, m), 1.51ꢀ1.45 (2H, m),
1.31ꢀ1.16 (16H, m).; 13C NMR (125 MHz, CDCl3): δ 142.0, 128.4, 128.3, 125.8, 104.0, 64.9, 52.5, 34.1, 33.0, 32.8. 32.5,
31.5, 29.51, 29.49, 29.47, 29.41, 28.8, 28.2, 24.7.; HRMS (MALDIꢀTOF) m/z: [M + Na]+ calcd for C22H37O2NaBr
435.1875, found 435.1869.
Methyl 12ꢀmethoxyꢀ12ꢀ(3ꢀphenylpropoxy)dodecanoate (16h). According to the general procedure, methyl
12,12ꢀdimethoxydodecanoate (310 mg, 1.13 mmol), 2,4,6ꢀcollidine (446 ꢁL, 3.39 mmol), TMSOTf (408 ꢁL, 2.26
mmol), and 3ꢀphenylpropanꢀ1ꢀol (461 ꢁL, 3.39 mmol) gave 16h (290 mg, 0.768 mmol, 68%). Eluent: 1% Et3N in
nꢀhexane/EtOAc = 10/1 to 2/1. Colorless oil; 1H NMR (500 MHz, CDCl3): δ 7.31ꢀ7.08 (5H, m), 4.29 (1H, t, J = 5.8 Hz),
3.67 (3H, s), 3.61 (1H, dt, J = 9.5, 6.3 Hz), 3.44 (1H, dt, J = 9.5, 6.3 Hz), 3.32 (3H, s), 2.72 (2H, t, J = 7.7 Hz), 2.31 (2H,
d, J = 7.4 Hz), 1.94ꢀ1.89 (2H, m), 1.63ꢀ1.60 (4H, m), 1.37ꢀ1.28 (14H, m).; 13C NMR (125 MHz, CDCl3): δ 174.4, 142.0,
128.4, 128.3, 128.27, 125.8, 104.0, 64.9, 52.5, 51.4, 34.1, 33.0, 32.5, 32.46, 31.5, 29.5, 29.4, 29.2, 29.1, 24.9, 24.7.;
HRMS (MALDIꢀTOF) m/z: [M + Na]+ calcd for C23H38O4Na 401.2668, found 401.2662.
3ꢀ((1ꢀMethoxydodecyl)oxy)butylbenzene (16i). According to the general procedure, 1,1ꢀdimethoxydodecane (1.04 g,
4.34 mmol), 2,4,6ꢀcollidine (1.72 mL, 13.1 mmol), TMSOTf (3.1 mL, 8.63 mmol), and 4ꢀphenylbutanꢀ2ꢀol (2.02 mL,
13.1 mmol) gave 16i (320 mg, 0.91 mmol, 21%). Eluent: 1% Et3N in nꢀhexane/EtOAc = 5/4 to 1/1. Colorless oil; H
NMR (400 MHz, CDCl3): δ 7.16ꢀ7.02 (5H, m), 4.39 (1H, t, J = 5.5 Hz) , 3.63 (1H, qt, J = 6.6, 6.0 Hz), 3.17 (3H, s),
2.67ꢀ2.61 (1H, m), 2.58ꢀ2.50 (1H, m), 2.28 (2/2H, t, J = 7.3 Hz), 2.279 (2/2H, t, J = 7.3 Hz), 1.82ꢀ1.73 (1H, m), 1.67ꢀ1.59
(1H, m), 1.53ꢀ1.40 (2H, m), 1.14 (18H, m), 1.03 (3H, d, J = 6.0 Hz), 0.76 (3 H, t, J = 6.9 Hz).; 13C NMR (100 MHz,
CDCl3): δ 142.2, 128.3, 128.3, 125.7, 104.5, 103.2, 72.9, 52.5, 51.2, 38.6, 33.6, 32.4, 31.9, 31.7, 29.6, 29.59, 29.55,
29.52, 29.49, 29.45, 29.3, 24.8, 24.6, 22.7, 21.1, 14.1.; HRMS (MALDIꢀTOF) m/z: [M + Na]+ calcd for C23H40O2Na
371.2926, found 371.2921.
1
3ꢀ((1ꢀMethoxydodecyl)oxy)ꢀ3ꢀmethylbutylbenzene (16j). According to the general procedure, 1,1ꢀdimethoxydodecane
(502 mg, 2.18 mmol), 2,4,6ꢀcollidine (0.86 mL, 6.54 mmol), TMSOTf (0.79 mL, 4.35 mmol), and
2ꢀmethylꢀ4ꢀphenylbutanꢀ2ꢀol (1.12 mL, 6.54 mmol) gave 16j (640 mg, 1.85 mmol, 85%). Eluent: 1% Et3N in
nꢀhexane/EtOAc = 1/1. Colorless oil; 1H NMR (300 MHz, CDCl3): δ 7.31ꢀ7.17 (5H, m), 4.73 (1H, t, J = 5.8 Hz), 3.26
(3H, s), 2.74ꢀ2.66 (2H, m), 1.84ꢀ1.78 (2H, m), 1.64ꢀ1.56 (2H, m), 1.31ꢀ1.25 (24H, m), 0.89 (3H, t, J = 6.8 Hz); 13C NMR
(100 MHz, CDCl3): δ 142.9, 128.3, 125.6, 97.3, 75.4, 49.5, 44.4, 34.0, 31.9, 30.5, 29.7, 29.66, 29.62, 29.56, 29.3, 26.7,
26.1, 24.9, 14.1.; HRMS (MALDIꢀTOF) m/z: [M + Na]+ calcd for C24H42O2Na 385.3080, found 385.3077.
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The Journal of Organic Chemistry
1ꢀ((1ꢀMethoxydodecyl)oxy)adamantine (16k). According to the general procedure, 1,1ꢀdimethoxydodecane (690 mg,
2.99 mmol), 2,4,6ꢀcollidine (1.08 mL, 8.98 mmol), TMSOTf (1.18 mL, 5.99 mmol), and adamantanꢀ1ꢀol (1.36 g, 8.98
mmol) gave 16k (856 mg, 2.41 mmol, 81%). Eluent: 1% Et3N in nꢀhexane/EtOAc = 1/4. Colorless oil; 1H NMR (300
MHz, CDCl3): δ 4.80 (1H, t, J = 5.5 Hz), 3.24 (3H, s), 2.15 (2H, brs), 1.81ꢀ1.80 (6H, m), 1.73ꢀ1.53 (12H, m), 1.27 (15H,
m), 0.88 (3H, t, J = 6.8 Hz).; 13C NMR (100 MHz, CDCl3): δ 95.9, 72.9, 49.9, 45.3, 42.7, 36.3, 36.0, 34.4, 31.9, 30.7,
30.6, 29.65, 29.62, 29.58, 29.53, 29.4, 29.3, 24.9, 22.7, 14.1.; HRMS (MALDIꢀTOF) m/z: [M + Na]+ calcd for
C23H42O2Na 373.3083, found 373.3077.
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Experimental Details of Scheme 2. To a solution of mixed acetal 16a (40.8 mg, 0.122 mmol) in CH2Cl2 (1.2 mL) were
added dropwise TMSOTf (3 ꢁL, 0.012 mmol) and Et3SiH (30 ꢁL, 0.183 mmol) at 0 oC. After stirring for 2 h, checking
the disappearance of 16a on TLC, the reaction mixture was quenched with sat. NaHCO3 aq., and the mixture was exꢀ
tracted with CH2Cl2. The extract was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue
was purified by flash SiO2 column chromatography to afford 17a (19.1 mg, 0.0622 mmol, 51%) and 17a’ (11.3 mg,
0.0586 mmol, 48%). Eluent: nꢀhexane/benzene = 5/2.
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3ꢀ(Dodecyloxy)propylbenzene (17a). Colorless oil; 1H NMR (400 MHz, CDCl3): δ 7.30ꢀ7.16 (5H, m), 3.41 (2H, t, J =
6.4 Hz), 3.40 (2H, t, J = 6.9 Hz), 2.70 (2H, t, J = 7.8 Hz), 1.91ꢀ1.87 (2H, m), 1.62ꢀ1.56 (2H, m), 1.40ꢀ1.26 (18H, m), 0.88
(3H, t, J = 6.4 Hz).; 13C NMR (100 MHz, CDCl3): δ 142.1, 128.5, 128.3, 125.7, 71.0, 69.9, 32.4, 31.9, 31.3, 29.8, 29.6,
29.7, 29.5, 29.3, 26.2, 22.7, 14.1.; HRMS (MALDIꢀTOF) m/z: [M + Na]+ calcd for C21H36ONa 327.2664, found
327.2658.
Experimental Details of Scheme 3. To a solution of mixed acetal 16a (50.0 mg, 0.149 mmol) in solvent (0.75 mL)
were added dropwise 2,4,6ꢀcollidine (59 ꢁL, 0.448 mmol) and TESOTf (63 ꢁL, 0.299 mmol) at 0 oC. After checking the
disappearance of 16a and the formation of the polar compound on TLC, NaBH4 (17 mg, 0.448 mmol) was added to the
reaction mixture at the same temperature and the mixture was allowed to warm to 0 oC. After disappearance of the polar
component, the reaction mixture was quenched with sat. NaHCO3 aq., and the mixture was extracted with CH2Cl2. The
extract was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash SiO2
column chromatography to afford 17a (solvent = CH2Cl2: 0%; solvent = THF: 33.5 mg, 0.110 mmol, 74%). Eluent:
nꢀhexane/benzene = 5/2.
Experimental Details of Table 7. To a solution of mixed acetal 16 (1.0 equiv) in CH2Cl2 were added dropwise pyridines
o
and TMSOTf at ꢀ30 C. After checking the disappearance of 16 and the formation of the polar compound on TLC,
NaBH4 (3.0 equiv) was added to the reaction mixture at the same temperature and the resulting mixture was allowed to
warm to 0 oC. After disappearance of the polar component, the reaction mixture was quenched with sat. NaHCO3 aq., and
the mixture was extracted with CH2Cl2. The extract was dried over Na2SO4, filtered, and concentrated under reduced
pressure. The residue was purified by flash SiO2 column chromatography to afford the corresponding ether 17. (Proꢀ
cedure A: pyridines (6.0 equiv), TMSOTf (4.0 equiv); Procedure B: pyridines (3.0 equiv), TMSOTf (2.0 equiv))
12ꢀ(3ꢀPhenylpropoxy)dodecyl acetate (17b). According to the general procedure A, 16b (58.0 mg, 0.140 mmol),
2,4,6ꢀcollidine (118 ꢁL, 0.838 mmol), TMSOTf (108 ꢁL, 0.558 mmol), and NaBH4 (15.9 mg, 0.420 mmol) gave 17b
1
(47.9 mg, 0.125 mmol, 89%). Eluent: nꢀhexane/EtOAc = 8/1. Colorless oil; H NMR (400 MHz, CDCl3): δ 7.23ꢀ7.09
(5H, m), 3.98 (2H, t, J = 6.9 Hz), 3.35 (2H, t, J = 6.4 Hz), 3.32 (2H, t, J = 6.9 Hz), 2.62 (2H, t, J = 7.8 Hz), 1.97 (3H, s),
1.85ꢀ1.79 (2H, m), 1.58ꢀ1.47 (4H, m), 1.29ꢀ1.20 (16H, m).; 13C NMR (100 MHz, CDCl3): δ 170.2, 142.1, 128.5, 128.3,
125.7, 71.0, 70.0, 64.7, 32.3, 31.3, 29.8, 29.5, 29.5, 29.2, 28.6, 26.2, 25.9, 21.0.; HRMS (MALDIꢀTOF) m/z: [M + Na]+
calcd for C23H38O3Na 385.2719, found 385.2713.
12ꢀ(3ꢀPhenylpropoxy)dodecyl benzoate (17c). According to the general procedure A, 16c (34.6 mg, 0.0761 mmol),
2,4,6ꢀcollidine (60 ꢁL, 0.457 mmol), TMSOTf (55 ꢁL, 0.304 mmol), and NaBH4 (8.6 mg, 0.1522 mmol) gave 17c (26.1
mg, 0.0632 mmol, 83%). Eluent: nꢀhexane/EtOAc = 15/1. Colorless oil; 1H NMR (400MHz, CDCl3): δ 8.06 (2H, d, J =
7.3 Hz), 7.56 (1H, t, J = 7.3 Hz), 7.45 (2H, t, J = 7.3 Hz), 7.31ꢀ7.17 (5H, m), 4.32 (2H, t, J = 6.9 Hz), 3.42 (2H, t, J = 6.4
Hz), 3.41 (2H, t, J = 6.4 Hz), 2.70 (2H, t, J = 7.6 Hz), 1.90 (2H, m), 1.77 (2H, m), 1.60ꢀ1.55 (2H, m), 1.47ꢀ1.41 (2H, m),
1.29 (14H, m). 13C NMR (125 MHz, CDCl3): δ 166.69, 142.05, 132.7, 130.5, 129.5, 128.50, 128.45, 128.3, 125.7,71.0,
69.9, 65.1, 32.3, 31.3, 29.8, 29.58, 29.56, 29.50, 29.49, 29.3, 28.7, 26.2, 26.0.; HRMS (MALDIꢀTOF) m/z: [M + Na]+
calcd for C28H40O3Na 447.2875, found 447.28701.
tertꢀButyldimethyl((12ꢀ(3ꢀphenylpropoxy)dodecyl)oxy)silane (17d). According to the general procedure A, 16d (56.7
mg, 0.122 mmol), 2,4,6ꢀcollidine (96 ꢁL, 0.732 mmol), TMSOTf (88 ꢁL, 0.488 mmol), and NaBH4 (13.8 mg, 0.366
1
mmol) gave 17d (45.7 mg, 0.105 mmol, 86%). Eluent: nꢀhexane/EtOAc = 30/1. Colorless oil; H NMR (300MHz,
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Page 18 of 21
CDCl3): δ 7.32ꢀ7.19 (5H, m), 3.61 (2H, t, J = 6.9 Hz), 3.45ꢀ3.39 (4H, m), 2.71 (2H, t, J = 7.9 Hz), 1.93ꢀ1.88 (2H, m),
1.60ꢀ1.50 (4H, m), 1.29 (16H, m), 0.91 (9H, s), 0.06 (6H, s).; 13C NMR (100 MHz, CDCl3): δ 142.1, 128.5, 128.3, 125.7,
71.0, 69.9, 63.3, 32.9, 32.4, 31.3, 29.8, 29.6, 29.5, 29.4, 26.2, 26.0, 25.8, 18.4, 5.3.; HRMS (MALDIꢀTOF) m/z: [M +
Na]+ calcd for C27H50O2NaSi 457.3476, found 457.3472.
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((12ꢀ(3ꢀPhenylpropoxy)dodecyl)oxy)methanetriyltribenzene (17e). According to the general procedure A, 16e (55.2
mg, 0.0931 mmol), 2,4,6ꢀcollidine (74 ꢁL, 0.559 mmol), TMSOTf (67 ꢁL, 0.372 mmol), and NaBH4 (21.1 mg, 0.559
1
mmol) gave 17e (49.3 mg, 0.0875 mmol, 94%). Eluent: nꢀhexane/EtOAc = 30/1. Colorless oil; H NMR (300 MHz,
CDCl3): δ 7.39ꢀ7.08 (20H, m), 3.34 (2H, t, J = 6.2 Hz), 3.32 (2H, t, J = 6.5 Hz), 2.96 (2H, t, J = 6.9 Hz), 2.62 (2H, t, J =
7.9 Hz), 1.87ꢀ1.77 (2H, m), 1.58ꢀ1.45 (4H, m), 1.26ꢀ1.11 (18H, m).; 13C NMR (100 MHz, CDCl3): δ 144.5, 128.7, 128.5,
128.3, 127.7, 126.8, 125.7, 86.2, 71.0, 69.9, 63.7, 32.4, 31.3, 30.0, 29.8, 29.6, 29.58, 29.5, 26.3, 26.2.; HRMS
(MALDIꢀTOF) m/z: [M + Na]+ calcd for C40H50O2Na 585.3709, found 585.3703.
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3ꢀ((12ꢀChlorododecyl)oxy)propylbenzene (17f). According to the general procedure B, 16f (74.0 mg, 0.201 mmol),
2,4,6ꢀcollidine (79 ꢁL, 0.602 mmol), TMSOTf (73 ꢁL, 0.401 mmol), and NaBH4 (22.8 mg, 0.602 mmol) gave 17f (49.7
mg, 0.147 mmol, 73%). Eluent: nꢀhexane/benzene = 3/1. Colorless oil; 1H NMR (400 MHz, CDCl3): δ 7.30ꢀ7.18 (5H,
m), 3.53 (2H, t, J = 6.8 Hz), 3.42 (2H, t, J = 6.0 Hz), 3.40 (2H, t, J = 6.4 Hz), 2.69 (2H, t, J = 7.8 Hz), 1.92ꢀ1.84 (2H, m),
1.80ꢀ1.73 (2H, m), 1.67ꢀ1.54 (2H, m), 1.43ꢀ1.41 (2H, m), 1.35ꢀ1.27 (14H, m).; 13C NMR (100 MHz, CDCl3): δ 142.1,
128.5, 128.3, 125.7, 71.0, 69.9, 45.2, 32.6, 32.4, 31.3, 29.8, 29.6, 29.54, 29.51, 29.48, 29.45, 28.879, 28.877, 26.2.;
HRMS (FAB) m/z: [M + H]+ calcd for C21H36OCl 339.2455, found 339.2455.
3ꢀ((12ꢀBromododecyl)oxy)propylbenzene (17g). According to the general procedure B, 16g (99.2 mg, 0.240 mmol),
2,4,6ꢀcollidine (95 ꢁL, 0.720 mmol), TMSOTf (87 ꢁL, 0.480 mmol), and NaBH4 (27.2 mg, 0.720 mmol) gave 17g (59.3
mg, 0.146 mmol, 61%). Eluent: nꢀhexane/EtOAc = 15/1. Colorless oil; 1H NMR (500MHz, CDCl3): δ 7.18ꢀ7.07 (5H, m),
3.31ꢀ3.27 (6H, m), 2.58 (2H, t, J = 7.7 Hz), 1.81ꢀ1.70 (4H, m), 1.47ꢀ1.44 (2H, m), 1.37ꢀ1.16 (16H, m).; 13C NMR (125
MHz, CDCl3): δ 142.1, 128.5, 128.4, 128.3, 125.7, 71.0, 69.9, 34.1, 32.8, 32.4, 31.3, 29.8, 29.57, 29.53, 29.50, 29.49,
29.42, 28.8, 28.2, 26.2.; HRMS (MALDIꢀTOF) m/z: [M + Na]+ calcd for C21H35ONaBr 405.1769, found 405.1764.
Methyl 12ꢀ(3ꢀphenylpropoxy)dodecanoate (17h). According to the general procedure A, 16h (83.6 mg, 0.221 mmol),
2,4,6ꢀcollidine (174 ꢁL, 1.33 mmol), TMSOTf (160 ꢁL, 0.883 mmol), and NaBH4 (25.1 mg, 0.663 mmol) gave 17h (79.8
mg, 0.199 mmol, 90%). Eluent: nꢀhexane/EtOAc = 15/1. Colorless oil; 1H NMR (500 MHz, CDCl3): δ 7.30ꢀ7.17 (5H,
m), 3.67 (3H, s), 3.42 (2H, t, J = 6.3 Hz), 3.41 (2H, t, J = 6.9 Hz), 2.70 (2H, t, J = 7.4 Hz), 2.31 (2H, t, J = 7.5 Hz),
1.93ꢀ1.86 (2H, m), 1.64ꢀ1.55 (4H, m), 1.34ꢀ1.27 (14H, m). ; 13C NMR (125 MHz, CDCl3): δ 174.3, 142.1, 128.5, 128.3,
125.7, 71.0, 69.9, 51.4, 34.1, 32.4, 31.3, 29.8, 29.6, 29.51, 29.48, 29.41, 29.2, 29.1, 26.2, 24.9.; HRMS (MALDIꢀTOF)
m/z: [M + Na]+ calcd for C22H36O3Na 371.2562, found 371.2557.
3ꢀ(Dodecyloxy)butylbenzene (17i). According to the general procedure B, 16i (43.0 mg, 0.119 mmol),
2ꢀmethoxypyridine (37 ꢁL, 0.356 mmol), TMSOTf (42 ꢁL, 0.237 mmol), and NaBH4 (13.0 mg, 0.356 mmol) gave 17i
1
(24.6 mg, 0.077 mmol, 65%). Eluent: nꢀhexane/EtOAc = 2/1. Colorless oil; H NMR (400 MHz, CDCl3): δ 7.22ꢀ7.08
(5H, m), 3.45ꢀ3.39 (1H, m), 3.32ꢀ3.21 (2H, m), 2.70ꢀ2.53 (2H, m), 1.84ꢀ1.72 (1H, m), 1.67ꢀ1.58 (1H, m), 1.53ꢀ1.46 (2H,
m), 1.30ꢀ1.19 (18H, m), 1.08 (3H, d, J = 6.0 Hz), 0.81 (3H, t, J = 7.3 Hz).; 13C NMR (100 MHz, CDC l3): δ 142.5, 128.4,
128.2, 125.6, 74.4, 68.5, 38.4, 31.9, 31.8, 30.2, 29.66, 29.62, 29.5, 29.3, 26.3, 22.7, 19.7, 14.1.; HRMS (MALDIꢀTOF)
m/z: [M + Na]+ calcd for C22H38ONa 341.2820, found 341.2815.
3ꢀ(Dodecyloxy)ꢀ3ꢀmethylbutylbenzene (17j). According to the general procedure B, 16j (90.0 mg, 0.248 mmol),
2ꢀmethoxypyridine (78 ꢁL, 0.745 mmol), TMSOTf (104 ꢁL, 0.496 mmol), and NaBH4 (28.2 mg, 0.745 mmol) gave 17j
1
(57.7 mg, 0.174 mmol, 70%). Eluent: nꢀhexane/EtOAc = 1/1. Colorless oil; H NMR (400 MHz, CDCl3): δ 7.31ꢀ7.16
(5H, m), 3.36 (2H, t, J = 6.4 Hz), 2.67ꢀ2.63 (2H, m), 1.78ꢀ1.76 (2H, m), 1.57ꢀ1.53 (2H, m), 1.35ꢀ1.26 (18H, m), 1.22 (6H,
s), 0.88 (3H, t, J = 6.9 Hz).; 13C NMR (100 MHz, CDCl3): δ 143.1, 128.30, 128.29, 125.6, 73.9, 61.2, 42.1, 31.9, 30.7,
30.3, 29.7, 29.64, 29.58, 29.4, 26.4, 25.8, 22.7, 14.1.; HRMS (FAB) m/z: [M + H]+ calcd for C23H41O 333.3157, found
333.3156.
1ꢀ(Dodecyloxy)adamantine (17k). According to the general procedure B, 16k (90.1 mg, 0.257 mmol),
2ꢀmethoxypyridine (82 ꢁL, 0.771 mmol), TMSOTf (93 ꢁL, 0.514 mmol), and NaBH4 (29.0 mg, 0.771 mmol) gave 17k
(62.6 mg, 0.195 mmol, 76%). Eluent: nꢀhexane/EtOAc = 4/1. Colorless oil; 1H NMR (300 MHz, CDCl3): δ 3.39 (2H, t, J
= 6.8 Hz), 2.06 (2H, brs), 1.54ꢀ1.46 (10H, s), 1.46ꢀ1.41 (2H, m), 1.36ꢀ1.12 (21H, m), 0.89 (3H, t, J = 7.2 Hz).; 13C NMR
(125 MHz, CDCl3): δ 71.6, 59.8, 41.6, 36.5, 31.9, 30.8, 30.5, 29.7, 29.63, 29.61, 29.5, 29.4, 26.3, 22.7, 14.1.; HRMS
(MALDIꢀTOF) m/z: [M + Na]+ calcd for C22H40ONa 343.2977, found 343.2971.
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ASSOCIATED CONTENT
The Supporting Information is available free of charge on the ACS Publications website at DOI:
1H and 13C NMR spectra of new compounds, and 1H NMR study of Tables 1, 4, 5 and Xꢀray crystallographic data for
compounds (PDF)
Crystal data for TMSOTf/2,4,6ꢀcollidine complex (CIF)
Crystal data for TMSOTf/pyridine complex (CIF)
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AUTHOR INFORMATION
Corresponding Author
*fujioka@phs.osakaꢀu.ac.jp
Present Addresses
†School of Pharmaceutical Sciences, Kindai University, 3ꢀ4ꢀ1 Kowakae, HigashiꢀOsaka 577ꢀ8502, Japan
ORCID
Reiya Ohta: 0000ꢀ0003ꢀ4932ꢀ9440
Hiroshi Aoyama: 0000ꢀ0001ꢀ7915ꢀ8975
Mitsuhiro Arisawa: 0000ꢀ0002ꢀ7937ꢀ670X
Tomohiro Maegawa: 0000ꢀ0003ꢀ1580ꢀ1110
Hiromichi Fujioka: 0000ꢀ0002ꢀ9970ꢀ4248
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This work was financially supported by GrantꢀinꢀAid for Scientific Research (B) (15H04632) from JSPS and Platform
for Drug Discovery, Informatics, and Structural Life Science from MEXT. The authors would like to thank H. Yashiro, T.
Matsumoto and A. Yamano of Rigaku Corporation for their singleꢀcrystalꢀXꢀray data measurements with XtaLAB PRO
MM007. We thank Mr. Ramon Francisco Bernardino Avena for calibration of this manuscript.
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