Transformation of Methylene Acetals to Bromoformates with a Combination of Trimethyl(phenylthio)silane and N-Bromosuccinimide

Article abstract of DOI:10.1021/acs.joc.7b00776

A novel transformation reaction of methylene acetals, using a combination of trimethyl(phenylthio)silane (PhSTMS) and N-bromosuccinimide (NBS) under mild reaction conditions, is described. Various methylene acetals were converted to their corresponding br

Full text of DOI:10.1021/acs.joc.7b00776

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Note
Transformation of Methylene Acetals to Bromoformates with a
Combination of Trimethyl(phenylthio)silane and N-Bromosuccinimide
Tomohiro Maegawa, Misa Nogata, Yuuka Hirose, Shun Ohgami,
Akira Nakamura, Yasuyoshi Miki, and Hiromichi Fujioka
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 22 Jun 2017
Downloaded from http://pubs.acs.org on June 23, 2017
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Transformation of Methylene Acetals to Bromoformates
with a Combination of Trimethyl(phenylthio)silane and
NꢀBromosuccinimide
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Tomohiro Maegawa,*,† Misa Nogata,† Yuuka Hirose,† Shun Ohgami,† Akira Nakamura,† Yasuyoshi Miki‡
and Hiromichi Fujioka*,§
†School of Pharmaceutical Sciences, Kindai University, HigashiꢀOsaka, Osaka 577ꢀ8502, Japan
‡Research Organization of Science and Technology, Research Center for Drug Discovery and Pharmaceutical
Science, Nojihigashi, Kusatsu, Shiga 525ꢀ8577, Japan
§Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka 565ꢀ0871, Japan
ABSTRACT: A novel transformation reaction of methylene acetals, using
a combination of
trimethyl(phenylthio)silane (PhSTMS) and Nꢀbromosuccinimide (NBS) under mild reaction conditions, is
described. Various methylene acetals were converted to their corresponding bromoformates in good to high
yields. Under the given conditions, the reaction proceeded via a radical pathway. Further transformation of
bromoformates to their corresponding epoxides was achieved by treatment with NaOMe.
Protective groups are essential in organic syntheses and numerous such groups have been developed.1
Methylene acetal is one among the most popular protective group for diols and is stable under basic to
medium acidic conditions.1 This stability, however, can make deprotection difficult, often requiring strongly
acidic conditions.1,2 We have developed novel deprotection methods for various acetalꢀtype protective groups,
including methylene acetal.3 A combination of silyl triflate and pyridines will react with acetals to form the
corresponding pyridinium salts, which are easily hydrolyzed to give the deprotected products. This method is
applicable to the deprotection of methylene acetals and amenable to further transformation into various types
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of protected diols (Scheme 1ꢀa).3f,g
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Scheme 1. Our studies of methylene acetals
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a) Deprotection and transformation of methylene acetal (previous study)
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OH
K2CO3
OH
1N HCl
MeOH
OTES
TESOTf
2,2'-bipyridyl
TMSOTf
2,2'-bipyridyl
OH
R
R
R
O
O
CH2Cl2
CH2Cl2
R
OMOM
OTES
OMOM
OH
MeOH
Et3N
R
mild conditions
b) Protection of diol with methylene acetal (previous study)
OH
Br
N
tBu
tBu
i) PhSCH2OMe
ii) DBDMH
O
OH OH
O
O
n
N
R1
R2
n
R1
R2
iii) BHT
Br
Me
O
CH3CN, rt
(n = 0,1)
DBDMH
BHT
c) Unexpected reaction of methylene acetal (this work)
O
PhS
DBDMH
OMe
OH
O
O
H
+
Br
O
Br
CH3CN, rt
9
9
9
38%
55%
Note that the protection of diols as methylene acetals also requires harsh reaction conditions, such as strongly
acidic or basic conditions.1 To address this limitation, we developed a novel method to protect diols as
methylene acetals using PhSCH2OMe and 1,3ꢀdibromoꢀ5,5ꢀdimethylhydantoin (DBDMH) in the presence of
diꢀtertꢀbutylhydroxytoluene (BHT)4 (Scheme 1ꢀb). During the course of that study, we found that protection
of simple aliphatic diols as methylene acetals, using our method and without BHT, afforded poor yields of the
corresponding methylene acetal and fair amounts of bromoformate and bromohydrin, which were generated
from methylene acetal under the same reaction conditions (Scheme 1ꢀc).
As described above, methylene acetal is generally considered a robust protective group. We were therefore
surprised to observe cleavage of the methylene acetal under such mild reaction conditions, prompting further
study. And also, halohydrin and vicinal haloester like bromohydrin and bromoformate are not only seen in
partial structure of bioactive compounds5 but also used as useful synthetic intermediate.6 In addition,
conversion of methylene acetal to bromoformate will offer new synthetic strategy using diols, which makes
easy to keep the protection of reactive structure such as bromo and ester group during synthetic process then
reveals reactive structure at late stage. Therefore, the develop of new conversion method from methylene
acetal to bromoformate and related structure is useful.
First, the effects of various solvents were investigated. CH3CN proved to be a good choice of solvent, giving
bromoformate (2) and a small amount of bromohydrin (3) for a total yield of 92% (Table 1, Entry 1). In
contrast, CH2Cl2 gave 2 and 3 in a combined yield of 68%. Other solvents gave the cleaved products in low
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yields (see Table S1). We next examined the effects of a variety of sulfurꢀcontaining compounds using CH3CN
as the solvent (Table 1, Entries 2 to 7). When the reaction was conducted in the absence of PhSCH2OMe, no
cleaved products were obtained (Table 1, Entry 2). This indicated that a sulfurꢀcontaining compound was
essential for the reaction progress. Diphenyl disulfide was effective for the transformation of methylene acetal
and the bromoformate was obtained in 73% yield, while the use of diphenyl sulfide resulted in low yields
(Table 1, Entries 3 and 4). Me2S+Br Br,7 a bromine equivalent, gave bromoformate and bromohydrin but in
low yields (Table 1, Entry 5). Finally, we examined thiophenol and trimethyl(phenylthio)silane (PhSTMS),
with PhSTMS giving the highest yields (84%) for this reaction (Table 1, Entries 6 and 7). The use of
Nꢀbromosuccinimide (NBS) afforded better yields (92%) than the use of DBDMH (84%) (Table 1, Entry 8 vs.
Entry 7). Regarding the molar equivalence of reagents, decreasing the amount of NBS from 3.0 to 1.5
equivalents caused a reduction in yield (Table 1, Entry 9). However, decreasing the relative amounts of both
NBS and PhSTMS to 2.4 and 1.2 equivalents (Entry 10) and 2.0 and 1.0 equivalents (Entry 11) was effective,
resulting in 89% and 91% yields, respectively. The use of 0.5 equivalents of PhSTMS and 2.0 equivalents of
NBS decreased the yield (60%) (Table 1, Entry 12). Therefore, in further investigations, we employed 1.0
equivalent of PhSTMS and 2.0 equivalents of NBS as optimized reaction conditions.
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Table 1. Effect of Reagent
Entry
Reagent
Time
(h)
Yield (%)
2aa
3a
1
2
3
4
5
6
7
8
9
PhSCH2OMe
DBDMH
(1.5)
3
59
33
(1.5)
ꢀ
DBDMH
(1.5)
1
ꢀ
ꢀ
PhSPh
(1.5)
DBDMH
(1.5)
24
1.5
24
1.5
1.5
1
24
73
30b
68
84
92
44
ꢀ
PhSSPh
(1.5)
DBDMH
(1.5)
ꢀ
Me2S+Br Brꢀ
14a
(1.5)
PhSH
DBDMH
(1.5)
ꢀ
ꢀ
ꢀ
ꢀ
(1.5)
PhSTMS
(1.5)
DBDMH
(1.5)
PhSTMS
(1.5)
NBS
(3.0)
PhSTMS
NBS
7.5
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(1.5)
(1.5)
NBS
(2.4)
3
4
5
10
PhSTMS (1.2)
1.5
89
ꢀ
ꢀ
6
7
8
9
11
12
PhSTMS (1.0)
PhSTMS (0.5)
NBS
(2.0)
NBS
(2.0)
1.5
2
91
61
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a) Inseparable byproducts were included.
The optimized reaction yielding compound (2a) also resulted in a small amount of byproduct (Table 1), which
was identified as follows. Under optimized conditions, the substrate having a benzoyl group (1b) yielded the
bromoformate (2b). A small amount of byproduct (2’b) (9%) was also produced and separated from 2b (68%).
1
The H NMR spectrum of 2’b was very similar to that of the compound produced alongside 2a. Thus, the
byproduct listed in Table 1 was identified as regioisomer (2’b) (See Scheme 2).
A variety of substrates were amenable to this transformation reaction giving bromoformates (2), most of
which included regioisomers (2’). Isolation of these regioisomers was difficult and their relative quantities
1
were estimated from H NMR spectra (Scheme 2). The result of Entry 1 of Table 1 is included in Scheme 2.
Substrates bearing ester, ether and halogen functionalities underwent transformation via their methylene
acetal,8 to give their corresponding bromoformates in good to high yields with a regioisomer ratio of roughly
10:1. Substrates bearing aromatic rings yielded two isomers in high yield, while the substrate with an aromatic
ring connected directly to the methylene acetal group (1g) afforded only one regioisomer, (2’g), in moderate
yields. The methylene acetals of internal diols (1h and 1i) also reacted with PhSTMS and NBS to give their
corresponding bromoformates. In the case of 1h, the ratio of regioisomer (2’h) increased slightly compared to
that of compounds 1a to 1f because the steric hindrance of the methyl group affected the degree of selectivity.
The reaction of methylene acetal derived from tertiary alcohol (1j) was examined and the corresponding
bromoformate was obtained, but the product was contaminated with some inseparable byproducts after
purifications, and the starting material was remained even increasing the amounts of reagents under the reflux
conditions. The acetaldehyde acetal (1k) was also reacted under the conditions to give the corresponding
bromoacetate in 79% yield. The same reaction with the methylene acetal of 1,3ꢀdiol (1l) proceeded slowly at
room temperature. Increasing the amounts of both reagents and proceeding under reflux conditions improved
the yield of products to 80% with 1:1 selectivity of regioisomers. Conversely, the reaction with 1m proceeded
only marginally, even under reflux conditions. The reaction of the methylene acetal derived from 1,4ꢀdiol (1n)
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proceeded but unidentified product was obtained.
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Scheme 2. Scope of Substrate
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1
The ratio of 2 and 2’ was determined by H NMR, which indicated in the parenthesis. a) Inseparable
byproduct was detected in the reaction. b) 1.5 Equiv of PhSTMS and 3.0 equiv of NBS were used under reflux
conditions. c) The yield could not determined.
This reaction was suppressed by the addition of BHT (a radical scavenger). Therefore, the reaction likely
proceeds via a radical pathway. A similar reaction employing benzylidene acetal was reported as a
HanessianꢀHüllar reaction, which features a radical mechanism.9 Generation of a radical on the methylene
carbon of methylene acetal has also been reported.10 A plausible reaction mechanism for the cleavage of
methylene acetal under our optimized conditions is illustrated in Scheme 3. First, the hydrogen on the acetal
carbon is extracted by a bromine radical to generate the radical intermediate A. The bromine radical then
reacts with A to afford intermediate B. An oxonium ion C was generated by the elimination of bromide ion
from B, followed by an attack of bromide ion on the carbon adjacent to the oxygen atom, yielding
bromoformates (2 and 2’). While the bromide ion can attack both carbon atoms adjacent to oxygen (routes a
and b), the less hindered carbon is preferred, resulting in a 10:1 ratio of regioisomer. In the case of 1h, the
methyl group affects the approach of bromide ion to the carbon, leading to a decrease in the ratio of 2h to 2’h
(ca. 7:3).
In the reaction with 1g, benzyl cation was generated from oxonium ion C and subsequently attacked by
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bromide ion to form 2’g exclusively. The reason for the necessity of a sulfur compound is not clear, but we
speculate the generation of PhSBr11 as a reactive intermediate from the reaction of PhSTMS and NBS. The
reaction using PhSSPh or PhSH instead of PhSTMS afforded the corresponding bromoformate in good yields
but the reaction using PhSPh resulted in poor yield since PhSPh could not generate PhSBr by the reaction with
NBS. PhSBr could generate the bromine radical by the homolysis, which might promote the reaction. Or the
disproportionation of PhSBr was occurred and Br2 could be generated in situ and cause the conversion
reaction to bromoformate. But the reaction with Br2 instead of PhSTMS and NBS led to the significant
decrease of the yield of bromoformate, therefore, we presumed that PhSBr is the real reactive intermediate.
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Scheme 3. Plausible Reaction Mechanism
We next investigated the further transformation of bromoformate to epoxide (Scheme 4). Bromoformates
obtained from the transformation reaction were treated with 2.4 equivalents of NaOMe, affording the
corresponding epoxide in good to high yields within 5 min. The epoxides were generated as a single product
although, with the exception of compound (2i), the precursor bromoformates were a mixture of 2 and
regioisomer (2’). The bromoformates bearing benzoyl groups (2b/2’b) proceeded without significant
hydrolysis of the benzoyl group to give the epoxide (4b) in 80% yield. Benzyloxy and aromatic groups were
tolerated under the reaction conditions to give the corresponding epoxides (4d and 4f), respectively.
Bromoformate (2i), derived from an internal methylene acetal, was also converted to its epoxide (4i) in high
yields. We also attempted the reaction of the bromoformate derived from the methylene acetal of 1,3ꢀdiol (1l)
but the corresponding oxetane was not obtained.
Scheme 4. Conversion of Bromoformates to Epoxides
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In addition, a oneꢀpot conversion of methylene acetal to epoxide was achieved by the successive addition of
CH3OH and 4.4 equiv of NaOMe after the generation of bromoformate (Scheme 5).
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Scheme 5. One-pot Conversion of Methylene Acetal to Epoxide
In conclusion, we developed a novel reaction for the transformation of methylene acetals to bromoformates
using PhSTMS and NBS under mild reaction conditions. This is the first report detailing the cleavage of
methylene acetals, via a radical mechanism, by a combination of sulfurꢀcontaining compound and NBS. A
variety of functional groups, including esters, benzyl ethers and halogens, were tolerated under the optimized
reaction conditions. Further transformation of bromoformate to epoxide was achieved by the stepwise addition
of NaOMe in a oneꢀpot procedure.
Experimental Section
General Information
1H NMR and 13C NMR spectra were recorded on a 400ꢀMHz spectrometer in CDCl3 with tetramethylsilane as
an internal standard. Data are reported as follows: chemical shift in ppm (δ), multiplicity (s = singlet, d =
doublet, t = triplet, q = quartet, m = multiplet, brs = broad singlet), coupling constant (Hz) and integration.
HRMS was measured in ESI and FAB modes, and the mass analyzer of the HRMS was orbitrap for ESI and
doubleꢀfocusing for FAB. Unless otherwise noted, all reagents and solvents were purchased from commercial
suppliers and used without further purification. Each regioisomer exhibited similar Rf values on thinꢀlayer
chromatography (TLC) plates run with various solvents. Some could not be separated from the primary
reaction product and remained as a mixture. In mixed samples, the ratio of regioisomer was determined by 1H
NMR; pure data were obtained for those regioisomers that could be isolated.
General procedure for the cleavage of methylene acetal with PhSTMS and NBS (Scheme 2)
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Typical procedure from 1a to 2a and 2’a: To a solution of methylene acetal 1a (30 mg, 0.14 mmol) in
CH3CN (0.7 mL) were added PhSTMS (27.0 ml, 0.14 mmol) and NBS (49.8 mg, 0.28 mmol), successively.
The resulting solution was stirred at room temperature using CaCl2 tube connected with a flask under open air.
After completion of the reaction (monitored by TLC), saturated aqueous NaHCO3 and saturated aqueous
Na2S2O3 were added and the mixture was extracted with EtOAc. The organic layer was dried over Na2SO4 and
evaporated in vacuo. The residue was purified by column chromatography on silica gel (nꢀhexane/CH2Cl2 =
2/1) to give 2a and 2’a (37.4 mg, 0.13 mmol, 91%, obtained as a 92:8 mixture).
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1-Bromododecan-2-yl formate (2a)
Colorless oil; 1H NMR (400 MHz, CDCl3) δ: 8.11 (s, 1H), 5.17ꢀ5.15 (m, 1H), 3.55ꢀ3.44 (m, 2H), 1.74ꢀ1.69 (m, 2H),
1.32ꢀ1.26 (m, 16H), 0.88 (t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ: 160.3, 72.4, 33.7, 32.5, 31.9, 29.54,
29.47, 29.4, 29.3, 29.2, 24.9, 22.7, 14.1; HRMS (FAB) calcd for C13H24O279Br [MꢀH]+ 291.0960, found 291.0933.
2-Bromododecyl formate (2’a
)
Colorless oil; 1H NMR (400 MHz, CDCl3) δ: 8.11 (s, 1H), 4.45ꢀ4.36 (m, 2H), 4.16ꢀ4.10 (m, 1H), 1.93ꢀ1.75 (m, 2H),
1.46ꢀ1.27 (m, 16H), 0.88 (t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ: 160.3, 67.2, 51.0, 35.1, 31.9, 29.54,
29.51, 29.4, 29.3, 28.9, 27.1, 22.7, 14.1; HRMS (FAB) calcd for C13H24O279Br [MꢀH]+ 291.0960, found 291.0959.
Bromoformates 2b and 2’b (47.6 mg, 0.12 mmol, 85%) were obtained as 89:11 mixture from 1b (44.9 mg, 0.14
mmol) after purification by silica gel column chromatography with nꢀhexane/CHCl3 = 2/1 as an eluent.
11-Bromo-10-formyloxyundecyl benzoate (2b)
Yellow oil; 1H NMR (400 MHz, CDCl3) δ: 8.11 (s, 1H), 8.05 (d, J = 7.6 Hz, 2H), 7.58ꢀ7.54 (m, 1H), 7.46ꢀ7.42 (m,
2H), 5.16ꢀ5.11 (m, 1H), 4.32 (t, J = 6.8 Hz, 2H), 3.55ꢀ3.43 (m, 2H), 1.80ꢀ1.71 (m, 4H), 1.47ꢀ1.26 (m, 12H); 13C
NMR (125 MHz, CDCl3) δ: 166.7, 160.3, 132.8, 130.5, 129.5, 128.3, 72.3, 65.1, 33.7, 32.4, 29.31, 29.26, 29.17,
29.15, 28.7, 26.0, 24.9; HRMS (FAB) calcd for C19H28O479Br [M+H]+ 399.1171, found 399.1160.
10-Bromo-11-formyloxyundecyl benzoate (2’b
)
Yellow oil; 1H NMR (400 MHz, CDCl3) δ: 8.11 (s, 1H), 8.05 (d, J = 8.4 Hz, 2H), 7.58ꢀ7.54 (m, 1H), 7.46ꢀ7.43 (m,
2H), 4.45ꢀ4.36 (m, 2H), 4.32 (t, J = 6.6 Hz, 2H), 4.16ꢀ4.09 (m, 1H), 1.92ꢀ1.74 (m, 4H), 1.45ꢀ1.26 (m, 12H); 13C
NMR (125 MHz, CDCl3) δ: 166.7, 160.3, 132.8, 130.5, 129.5, 128.3, 67.2, 65.1, 50.9, 35.1, 29.4, 29.3, 29.2, 28.9,
28.7, 27.1, 26.0; HRMS (ESI) calcd for C19H27O479BrNa [M+Na]+ 421.0990, found 421.0988.
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Bromoformates 2c and 2’c (117 mg, 0.35 mmol, 88%) were obtained as 89:11 mixture from 1c (100 mg, 0.39
mmol) after purification by silica gel column chromatography with nꢀhexane/CH2Cl2 = 1/1 to 1/2 as an eluent.
11-Bromo-10-formyloxyundecyl acetate (2c)
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Colorless oil; 1H NMR (400 MHz, CDCl3) δ: 8.12 (s, 1H), 5.17ꢀ5.11 (m, 1H), 4.05 (t, J = 6.8 Hz, 2H), 3.55ꢀ3.44 (m,
2H), 2.05 (s, 3H), 1.74ꢀ1.69 (m, 2H), 1.65ꢀ1.29 (m, 14H); 13C NMR (100 MHz, CDCl3) δ: 171.2, 160.3, 72.3, 64.6,
33.6, 32.4, 29.3, 29.2, 29.1, 28.5, 25.8, 24.9, 21.0; HRMS (FAB) calcd for C14H26O479Br [M+H]+ 337.1015, found
337.1029.
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10-Bromo-11-formyloxyundecyl acetate (2’c
)
Colorless oil; 1H NMR (400 MHz, CDCl3) δ: 8.11 (s, 1H), 4.45ꢀ4.36 (m, 2H), 4.16ꢀ4.10 (m, 1H), 4.05 (t, J = 6.8 Hz,
2H), 2.05 (s, 3H), 1.93ꢀ1.75 (m, 2H), 1.64ꢀ1.25 (m, 14H); 13C NMR (100 MHz, CDCl3) δ: 171.3, 160.3, 67.2, 64.6,
50.9, 35.1, 29.33, 29.26, 29.15, 28.9, 28.6, 27.1, 25.9, 21.0; HRMS (FAB) calcd for C14H26O481Br [M+H]+
339.0994, found 339.0979.
Bromoformates 2d and 2’d (41.5 mg, 0.11 mmol, 77%) were obtained as 95:5 mixture from 1d (42.9 mg, 0.14
mmol) after purification by silica gel column chromatography with nꢀhexane/CHCl3 = 3/1 as an eluent.
11-Benzyloxy-1-bromoundecan-2-yl formate (2d)
1
Colorless oil; H NMR (400 MHz, CDCl3) δ: 8.11 (s, 1H), 7.35ꢀ7.27 (m, 5H), 5.16ꢀ5.10 (m, 1H), 4.50 (s, 2H),
3.54ꢀ3.43 (m, 4H), 1.74ꢀ1.69 (m, 2H), 1.64ꢀ1.57 (m, 2H), 1.37ꢀ1.28 (m, 12H); 13C NMR (100 MHz, CDCl3) δ:
160.3, 138.7, 128.3, 127.6, 127.4, 72.8, 72.4, 70.5, 33.6, 32.4, 29.7, 29.4, 29.3, 29.2, 26.1, 24.9; HRMS (FAB)
calcd for C19H30O381Br [M+H]+ 387.1358, found 387.1369.
11-Benzyloxy-2-bromoundecyl formate (2’d
)
1
Colorless oil; H NMR (400 MHz, CDCl3) δ: 8.10 (s, 1H), 7.35ꢀ7.28 (m, 5H), 4.50 (s, 2H), 4.45ꢀ4.36 (m, 2H),
4.16ꢀ4.09 (m, 1H), 3.46 (t, J = 6.6 Hz, 2H), 1.92ꢀ1.75 (m, 2H), 1.65ꢀ1.29 (m, 14H); 13C NMR (100 MHz, CDCl3) δ:
160.3, 138.7, 128.3, 127.6, 127.5, 72.9, 70.5, 67.2, 50.9, 35.1, 29.7, 29.42, 29.39, 29.28, 28.9, 27.1, 26.2; HRMS
(FAB) calcd for C19H30O381Br [M+H]+ 387.1358, found 387.1339.
Bromoformates 2e and 2’e (35.5 mg, 0.11 mmol, 81%) were obtained as 88:12 mixture from 1e (32.9 mg, 0.14
mmol) after purification by silica gel column chromatography with nꢀhexane/EtOAc = 30/1 as an eluent.
1-Bromo-11-chloroundecan-2-yl formate (2e)
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Yellow oil; 1H NMR (400 MHz, CDCl3) δ: 8.12 (s, 1H), 5.16ꢀ5.11 (m, 1H), 3.55ꢀ3.44 (m, 4H), 1.80ꢀ1.71 (m, 4H),
1.44ꢀ1.29 (m, 12H); 13C NMR (100 MHz, CDCl3) δ: 160.3, 77.2, 72.3, 45.1, 33.6, 32.6, 32.4, 29.24, 29.22, 29.1,
28.8, 26.8, 24.9; HRMS (FAB) calcd for C12H23O237Cl81Br [M+H]+ 317.0520, found 317.0532.
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)
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Yellow oil; 1H NMR (400 MHz, CDCl3) δ: 8.11 (s, 1H), 4.45ꢀ4.36 (m, 2H), 4.16−4.10 (m, 1H), 3.54 (t, J = 6.6 Hz,
2H), 1.93ꢀ1.23 (m, 16H); 13C NMR (100 MHz, CDCl3) δ: 160.3, 77.2, 67.2, 50.9, 45.2, 35.0, 32.6, 29.3, 29.2, 28.84,
28.80, 27.1, 26.8; HRMS (FAB) calcd for C12H21O237Cl81Br [MꢀH]+ 315.0363, found 315.0389.
Bromoformates 2f and 2’f (39.2 mg, 0.15 mmol, 85%) were obtained as 91:9 mixture from 1f (32.0 mg, 0.18
mmol) after purification by silica gel column chromatography with nꢀhexane/CH2Cl2 = 4/1 to 1/1 as an eluent.
1-Bromo-4-phenylbutan-2-yl formate (2f)
Yellow oil; 1H NMR (400 MHz, CDCl3) δ: 8.13 (s, 1H), 7.32ꢀ7.17 (m, 5H), 5.18ꢀ5.12 (m, 1H), 3.56ꢀ3.45 (m, 2H),
2.75ꢀ2.60 (m, 2H), 2.13ꢀ2.01 (m, 2H); 13C NMR (100 MHz, CDCl3) δ: 160.2, 140.4, 128.6, 128.3, 126.3, 71.7, 34.1,
33.5, 31.2; HRMS (FAB) calcd for C11H14O281Br [M+H]+ 259.0157, found 259.0150.
2-Bromo-4-phenylbutyl formate (2’f
)
Yellow oil; 1H NMR (400 MHz, CDCl3) δ: 8.09 (s, 1H), 7.33ꢀ7.20 (m, 5H), 4.47ꢀ4.36 (m, 2H), 4.10ꢀ4.04 (m, 1H),
2.97ꢀ2.73 (m, 2H), 2.22ꢀ2.09 (m, 2H); 13C NMR (100 MHz, CDCl3) δ: 160.2, 140.2, 128.6, 128.5, 126.4, 67.1, 50.0,
36.7, 33.2; HRMS (ESI) calcd for C11H13O281Br [M]+ 258.0078, found 258.0060.
Bromoformate 2’g (26.9 mg, 0.12 mmol, 58%) was obtained as a single isomer from 1g (30.0 mg, 0.20 mmol)
after purification by silica gel column chromatography with nꢀhexane/CH2Cl2 = 5/1 as an eluent.
2-Bromo-2-phenylethyl formate (2’g
)
Colorless oil; 1H NMR (400 MHz, CDCl3) δ: 8.03 (s, 1H), 7.44ꢀ7.32 (m, 5H), 5.13 (t, J = 7.2 Hz, 1H), 4.73ꢀ4.60 (m,
2H); 13C NMR (100 MHz, CDCl3) δ: 160.0, 137.7, 129.2, 128.9, 127.8, 66.7, 49.1; HRMS (FAB) calcd for
C9H8O279Br [MꢀH]+ 226.9708, found 226.9692.
Bromoformates 2h and 2’h (38.3 mg, 0.13 mmol, 93%) were obtained as 73:27 mixture from 1h (30.0 mg, 0.14
mmol) after purification by silica gel column chromatography with nꢀhexane/CH2Cl2 = 6/1 as an eluent.
2-Bromododecan-3-yl formate (2h) and 3-Bromododecan-2-yl formate (2’h) (inseparable mixture)
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Yellow oil; 1H NMR (400 MHz, CDCl3) δ: 8.16 (s, 0.3H), 8.09 (s, 0.7H), 5.22ꢀ5.17 (m, 0.7H), 5.06ꢀ5.02 (m, 0.3H),
4.23ꢀ4.17 (m, 0.3H), 4.02ꢀ3.97 (m, 0.7H), 1.84ꢀ1.55 (m, 4H), 1.40ꢀ1.27 (m, 15H), 0.88 (t, J = 6.6 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ: 160.4, 160.1, 75.8, 71.8, 57.6, 49.8, 34.5, 31.8, 29.5, 29.42, 29.36, 29.2, 28.9, 27.5,
25.2, 22.6, 22.0, 17.7, 14.1.
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Bromoformate 2i (40.0 mg, 0.10 mmol, 82%) was obtained as a single isomer from 1i (40.0 mg, 0.12 mmol) after
purification by silica gel column chromatography with nꢀhexane/CH2Cl2 = 10/1 as an eluent.
11-Bromoicosan-10-yl formate (2i)
Yellow oil; 1H NMR (400 MHz, CDCl3) δ: 8.15 (s, 1H), 5.12ꢀ5.08 (m, 1H), 4.06–4.02 (m, 1H), 1.82ꢀ1.26 (m, 32H),
0.88 (t, J = 6.6 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ: 160.4, 74.9, 57.0, 35.0, 32.1, 31.8, 29.46, 29.45, 29.39,
29.37, 29.25, 28.9, 27.6, 25.2, 22.7, 14.1; HRMS (FAB) calcd for C21H41O279Br [MꢀH]+ 403.2212, found 403.2220.
Bromoformate 2k (56.6 mg, 0.22 mmol, 79%) was obtained as a single isomer from 1k (49.8 mg, 0.28 mmol) after
purification by silica gel column chromatography with nꢀhexane to nꢀhexane/EtOAc = 20/1 as an eluent and
preparative TLC with nꢀhexane/EtOAc = 10/1 as developing solvent.
1-Bromo-3-phenylpropan-2-yl acetate (2k)12
Colorless oil; 1H NMR (400 MHz, CDCl3) δ: 7.33ꢀ7.23 (m, 5H), 5.21ꢀ5.15 (m, 1H), 3.50 (dd, J = 10.8 Hz, 4.8Hz,
1H), 3.37 (dd, 11.6 Hz, 4.8Hz, 2H), 3.07 (s, 3H).
Bromoformates 2l and 2’l (39.1 mg, 0.14 mmol, 80%) were obtained as 56:44 mixture from 1l (34.6 mg, 0.18
mmol) after purification by silica gel column chromatography with nꢀhexane/CH2Cl2 = 20/1 to 2/1 as an eluent.
1-Bromo-5-phenylpentan-3-yl formate (2l)
Yellow oil; 1H NMR (400 MHz, CDCl3) δ: 8.12 (s, 1H), 7.31ꢀ7.16 (m, 5H), 5.23ꢀ5.17 (m, 1H), 3.44ꢀ3.33 (m, 2H),
2.73ꢀ2.59 (m, 2H), 2.28ꢀ2.10 (m, 2H), 2.03ꢀ1.87 (m, 2H); 13C NMR (100 MHz, CDCl3) δ: 160.6, 140.8, 128.5,
128.2, 126.2, 72.1, 37.2, 35.6, 31.4, 28.2; HRMS (FAB) calcd for C12H16O281Br [M+H]+ 273.0313, found
273.0313.
3-Bromo-5-phenylpentyl formate (2’l)
Yellow oil; 1H NMR (400 MHz, CDCl3) δ: 8.03 (s, 1H), 7.32ꢀ7.20 (m, 5H), 4.44ꢀ4.29 (m, 2H), 4.09ꢀ4.02 (m, 1H),
2.96ꢀ2.74 (m, 2H), 2.26ꢀ2.08 (m, 4H); 13C NMR (100 MHz, CDCl3) δ: 160.8, 140.5, 128.54, 128.50, 126.2, 61.9,
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52.3, 40.8, 37.7, 33.6; HRMS (FAB) calcd for C12H16O279Br [M+H]+ 271.0334, found 271.0320.
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Bromoformate 2’m (4.7 mg, 0.019 mmol, 11%) was obtained as a single isomer from 1m (30.0 mg, 0.18 mmol)
after purification by silica gel column chromatography with nꢀhexane/CH2Cl2 = 3/1 as an eluent.
3-Bromo-3-phenylpropyl formate (2’m)
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Yellow oil; 1H NMR (400 MHz, CDCl3) δ: 8.06 (s, 1H), 7.42ꢀ7.28 (m, 5H), 5.09 (dd, J = 8.8, 6.0Hz, 1H), 4.36ꢀ4.23
(m, 2H), 2.65ꢀ2.42 (m, 2H); 13C NMR (100 MHz, CDCl3) δ: 160.6, 141.1, 128.9, 128.7, 127.2, 61.8, 50.7, 38.5;
HRMS (FAB) calcd for C10H11O279BrNa [M+Na]+ 264.9840, found 264.9825.
1-Bromododecan-2-ol (3a)13
Colorless oil; 1H NMR (400 MHz, CDCl3) δ: 3.81ꢀ3.75 (m, 1H), 3.57ꢀ3.53 (m, 1H), 3.41ꢀ3.37 (m, 1H), 2.10 (d, J =
5.2 Hz, 1H), 1.57ꢀ1.26 (m, 18H), 0.88 (t, J = 6.8 Hz, 3H).
General procedure for the formation of epoxide 4 from bromoformates (Scheme 4)
Typical procedure from 2a and 2’a to 4a: NaOMe (36.2 mg, 0.67 mmol) was added to a solution of
bromoformate 2a and 2’a (82 mg, 0.28 mmol) in CH3OH (1.4 mL) and the resulting solution was stirred until
completion of the reaction (monitored by TLC). Saturated NH4Cl was then added and extracted with CH2Cl2.
The organic layer was dried over Na2SO4 and evaporated in vacuo, and the residues were purified by column
chromatography on silica gel (nꢀhexane/CH2Cl2 = 3/1) to give 4a (47.7 mg, 0.26 mmol, 93%).
2-Decyloxirane (4a)14
Colorless oil ; 1H NMR (400 MHz, CDCl3) δ: 2.93ꢀ2.88 (m, 1H), 2.75 (t, J = 4.6 Hz, 1H), 2.46 (dd, J = 4.8, 2.8 Hz,
1H), 1.55ꢀ1.26 (m, 18H), 0.88 (t, J = 6.8 Hz, 3H).
9-(Oxiran-2-yl)nonyl benzoate (4b)
Epoxide 4b (23.2 mg, 0.080 mmol, 80%) was obtained from 2b and 2’b mixture (39.9 mg, 0.10 mmol) as yellow
oil after purification by silica gel column chromatography with nꢀhexane/CH2Cl2 = 1/1 as an eluent; 1H NMR (400
MHz, CDCl3) δ: 8.04 (d, J = 8.0 Hz, 2H), 7.56 (t, J = 7.4 Hz, 1H), 7.44 (t, J = 7.6 Hz, 2H), 4.32 (t, J = 6.6 Hz, 2H),
2.93ꢀ2.88 (m, 1H), 2.75 (t, J = 4.4 Hz, 1H), 2.46 (dd, J = 5.0, 2.6 Hz, 1H), 1.80ꢀ1.73 (m, 2H), 1.57ꢀ1.26 (m, 14H);
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13C NMR (100 MHz, CDCl3) δ: 166.7, 132.8, 130.5, 129.5, 128.3, 65.1, 52.4, 47.1, 32.5, 29.44, 29.38, 29.2, 28.7,
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26.0, 25.9; HRMS (FAB) calcd for C18H27O3 [M+H]+ 291.1960, found 291.1943.
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2-(9-Benzyloxynonyl)oxirane (4d)15
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Epoxide 4d (15.1 mg, 0.055 mmol, 82%) was obtained from 2d and 2’d mixture (25.7 mg, 0.067 mmol) as yellow
oil after purification by silica gel column chromatography with nꢀhexane/CH2Cl2 = 1/1 to 4/5 as an eluent; 1H NMR
(400 MHz, CDCl3) δ: 7.37ꢀ7.25 (m, 5H), 4.50 (s, 2H), 3.46 (t, J = 6.6 Hz, 2H), 2.93ꢀ2.88 (m, 2H), 2.75 (t, J = 4.6
Hz, 1H), 2.46 (dd, J = 5.0, 2.6 Hz, 1H), 1.65ꢀ1.26 (m, 16H).
2-Phenethyloxirane (4f)16
Epoxide 4d (35.9 mg, 0.24 mmol, 87%) was obtained from 2f and 2’f mixture (72.0 mg, 0.28 mmol) as yellow oil
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after purification by silica gel column chromatography with nꢀhexane/CH2Cl2 = 2/1 as an eluent; H NMR (400
MHz, CDCl3) δ: 7.29 (t, J = 7.1 Hz, 2H), 7.22ꢀ7.18 (m, 3H), 2.98ꢀ2.93 (m, 1H), 2.87ꢀ2.72 (m, 3H), 2.48 (dd, J =
4.8, 2.8 Hz, 1H), 1.92ꢀ1.80 (m, 2H).
2,3-Dinonyloxirane (4i)
Epoxide 4i (35.2 mg, 0.12 mmol, 99%) was obtained from 2i (50.6 mg, 0.12 mmol) as yellow solid after
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purification by silica gel column chromatography with nꢀhexane/CH2Cl2 = 3/1 as an eluent; m.p. 37ꢀ38 °C; H
NMR (400 MHz, CDCl3) δ: 2.92ꢀ2.89 (m, 2H), 1.58ꢀ1.27 (m, 32H), 0.88 (t, J = 6.4 Hz, 6H); 13C NMR (100 MHz,
CDCl3) δ: 57.3, 31.9, 29.56, 29.51, 29.3, 27.8, 26.6, 22.7, 14.1; HRMS (FAB) calcd for C20H41O [M+H]+ 297.3158,
found 297.3168.
General procedure for the one-pot conversion of methylene acetal 1a to epoxide 4a (Scheme 5)
To a solution of methylene acetal 1a (60 mg, 0.28 mmol) in CH3CN (1.4 mL) were added PhSTMS (54.0 ml,
0.28 mmol) and NBS (99.7 mg, 0.56 mmol), successively. The resulting solution was stirred at room
temperature. After completion of the reaction (monitored by TLC), CH3OH (1.4 mL) and NaOMe (66.4 mg,
1.23 mmol) were added to the solution and the resulting mixture was stirred for 5 min. Saturated aqueous
NaHCO3 and saturated aqueous Na2S2O3 were then added and the mixture was extracted with CH2Cl2. The
organic layer was dried over Na2SO4 and evaporated in vacuo. The residue was purified by column
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chromatography on silica gel (nꢀhexane/CH2Cl2 = 3/1) to give 4a (44.1 mg, 0.24 mmol, 86%).
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ASSOCIATED CONTENT
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Supporting information
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The Supporting Information is available free of charge on the ACS Publication website at DOI:
1H and 13C NMR spectra.
AUTHOR INFORMATION
Corresponding author
Eꢀmail:maegawa@phar.kindai.ac.jp, fujioka@phs.osakaꢀu.ac.jp
ORCID
Tomohiro Maegawa: 0000ꢀ0003ꢀ1580ꢀ1110
Hiromichi Fujioka: 0000ꢀ0002ꢀ9970ꢀ4248
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was financially supported by JSPS KAKENHI Grant Number JP26460023 and MEXT (Ministry of
Education, Culture, Sports, Sciences, and Technology)ꢀsupported Program for the Strategic Research
Foundation at Private Universities, 2014ꢀ2018 (S1411037).
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Fuji K. Tetrahedron Lett. 1993, 34, 5127 and references also cited in ref. 3g and 3h.
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M. J. Nat. Prod. 2005, 68, 1677.
6) Rodriguez, J.; Dulcère, JꢀP. Synthesis, 1993, 1177.
7) Choudhury, L. H.; Parvin, T.; Khan, A. T. Tetrahedron 2009, 65, 9513.
8) We conducted the cleavage reaction of 2c bearing AcO group using 2N HCl, and AcO group was
hydrolyzed in addition to methylene acetal under the reaction conditions.
9) (a) Hanessian, S. Carbohydr. Res. 1966, 2, 86. (b) Failla, D. L.; Hullar, T. L.; Siskin, S. B. Chem. Commun.
1966, 716.
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