An efficient partial reduction of α,β-unsaturated esters using DIBAL-H in flow

Article abstract of DOI:10.1002/ejoc.201402675

The partial reduction of α,β-unsaturated esters and benzoate derivatives to form the corresponding aldehydes was achieved using a flow reactor system within 1 s at a high flow rate (18 mL min^-1) under cryogenic conditions (-97°C). Commercially available diisobutylaluminium hydride (DIBAL-H) was used as the reductant. The desired enals and benzaldehyde derivatives, except for 4-methoxycinnamate and 4-methoxybenzoate, were formed selectively and redox economically in moderate to high yields.

Full text of DOI:10.1002/ejoc.201402675

FULL PAPER
DOI: 10.1002/ejoc.201402675
An Efficient Partial Reduction of α,β-Unsaturated Esters Using DIBAL-H in
Flow
Masahito Yoshida,[a] Hiroyuki Otaka,[a] and Takayuki Doi*[a]
Keywords: Flow synthesis / Reduction / Chemoselectivity / Aldehydes / Esters
The partial reduction of α,β-unsaturated esters and benzoate
derivatives to form the corresponding aldehydes was
achieved using a flow reactor system within 1 s at a high flow
rate (18 mLmin–1) under cryogenic conditions (–97 °C). Com-
mercially available diisobutylaluminium hydride (DIBAL-H)
was used as the reductant. The desired enals and benzalde-
hyde derivatives, except for 4-methoxycinnamate and 4-
methoxybenzoate, were formed selectively and redox eco-
nomically in moderate to high yields.
ate derivatives using readily available DIBAL-H is still to
be developed. In this paper, we report the efficient partial
reduction of conjugated esters such as α,β-unsaturated es-
ters and benzoate derivatives to give the corresponding al-
dehydes using DIBAL-H in a continuous flow system.
Introduction
Reduction is an important transformation in organic
synthesis, and numerous valuable protocols have been de-
veloped in recent decades. The partial reduction of esters is
a valuable method for providing the corresponding alde-
hydes.[1] However, over-reduction of the aldehydes is often
observed in conventional batch systems, even when the re-
ductant, such as diisobutylaluminum hydride (DIBAL-H),
is added slowly under cryogenic conditions. Therefore, con-
ventional synthetic approaches to synthesizing aldehydes
from esters often involve multiple steps, such as reducing
the esters to the corresponding alcohols, followed by oxi-
dation of the alcohol. Recently, continuous-flow systems
have been developed for use in synthetic organic chemis-
try.[2] Using such a system, reactive and unstable species can
be released from a reactor immediately after their formation
to provide kinetically favored products.[3] The partial re-
duction of saturated aliphatic esters under the conditions
of flow chemistry has been achieved, and has been used in
the synthesis of complex molecules.[4] The single-step syn-
thesis of enals by partial reduction of the corresponding
esters would also be attractive, because conjugated esters
are less susceptible than saturated esters to nucleophilic ad-
dition, such as by hydride or carbon nucleophiles. The par-
tial reduction of cinnamate to cinnamaldehyde in a flow
system has recently been achieved[5] using lithium di-
isobutyl-tert-butoxyaluminum hydride (LDBBA),[6] which
is known to selectively reduce esters to the corresponding
aldehydes in solution-phase synthesis. However, a partial re-
duction of not only α,β-unsaturated esters but also benzo-
Results and Discussion
The flow reactor system that we used for the partial re-
duction of α,β-unsaturated esters is shown in Figure 1. The
reactor (Comet X-01-SS)[7] and tubing, made of stainless
steel, were used because of the good thermal conductivity
of this material. The reagents, i.e., the substrates and
DIBAL-H, were introduced into the reactor at the desired
flow rate independently using rotary piston pumps. A T-
shaped mixer was connected to the outlet of the flow reac-
tor, and the reaction was quenched with EtOH in this
mixer.[8] The reaction was carried out under cryogenic con-
ditions, which were achieved by immersing the system in a
[a] Graduate School of Pharmaceutical Sciences, Tohoku
University,
6-3 Aza-Aoba, Aramaki, Aoba-ku, Sendai 980-8578, Japan
E-mail: doi_taka@mail.pharm.tohoku.ac.jp
http://www.pharm.tohoku.ac.jp/~hannou
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402675.
Figure 1. Flow synthesis for the partial reduction of α,β-unsatu-
rated esters.
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Partial Reduction Using DIBAL-H under Flow Conditions
cooling bath (dry ice/acetone for –78 °C or liquid N2/ cryogenic conditions such as –97 °C were required to
MeOH for –97 °C).
achieve the partial reduction of 2a with high selectivity.
The reduction of ester 2a in flow was investigated, and
Having optimized the reaction conditions, we investi-
the results are summarized in Table 1. The reduction of 2a gated the scope of substrates that could be partially reduced
was initially attempted at –78 °C using a solution of DI- by DIBAL-H using this system. The results are summarized
BAL-H in toluene (0.2 m) and a solution of the substrate 2a in Table 2. The reduction of methyl ester 2aЈ occurred
in toluene (0.1 m) with a flow rates of 1, 3, or 9 mLmin–1, smoothly, but the selectivity of the reduction was only mod-
corresponding to a residence time (tr) of 9, 3, or 1 s, respec- erate (1a:3a = 80:20), and the corresponding aldehyde (i.e.,
tively. Higher conversion for 2a was observed using a 1a) was formed in 71% yield (Table 2, entry 1). In contrast,
shorter residence time (Ͻ3 s), but the selectivity of the reac- the reduction of sterically hindered isopropyl ester 2aЈЈ gave
tion for aldehyde 1a was found to be quite low (Table 1, 1a in good yield and with good selectivity (84% yield, 1a:3a
entries 1–3). The ratio of 1a and 3a increased to 82:18 when = 90:10; Table 2, entry 2). Methyl ester 2aЈ is less hindered
the concentration of DIBAL-H in toluene was decreased than ethyl ester 2a, so the reduction of 2aЈ should proceed
to 0.1 m, although the conversion of 2a decreased (Table 1, more quickly than that of 2a. As a result, the corresponding
entry 4). The reaction was carried out at a lower tempera- aldehyde (i.e., 1a) that was generated in the flow reactor
ture in an attempt to improve both the conversion and the would have been further reduced before the reaction was
selectivity of the DIBAL-H reduction of 2a. When the reac- quenched with EtOH. According to the results described
tion was carried out at –97 °C using a flow rate of above, the ethyl ester prepared using commercially available
18 mLmin–1, the partial reduction of 2a gave a higher con- ethyl diethylphosphonoacetate would be a suitable substrate
version and selectivity (89%, 1a:3a = 93:7; Table 1, entry 5). for partial reduction with DIBAL-H under flow conditions.
Finally, we found that the use of a 0.3 m DIBAL-H solution Z-Alkenoate 2b and alkynoate 2c were also reduced under
resulted in the partial reduction of 2a to give 1a with a high the same reaction conditions that were used to reduce 2a,
conversion (Ͼ95%), and the desired product 1a was iso- to give 1b (97% yield; Table 2, entry 3) and 1c (84% yield;
lated in 88% yield (Table 1, entry 6). It should be noted that Table 2, entry 4), respectively. Cinnamate derivatives 2d–2f,
vigorous mixing would have occurred in the micromixer at were reduced in the flow system, and ethyl cinnamate (2d)
a high flow rate, leading to the rapid consumption of 2a and its 4-bromo derivative 2e were found to be selectively
within 1 s. It was necessary to terminate the reaction converted into the corresponding aldehydes (i.e., 1d and 1e)
promptly to prevent over-reduction by excess DIBAL-H in high yields (Table 2, entries 5 and 6). In contrast, the re-
that was present.[9] On the other hand, the partial reduction duction of 4-methoxy derivative 2f gave a poor result
of 2a was also investigated with a short residence time (Table 2, entry 7; 20% isolated yield, 1f:3f = 21:79). It is
(0.5 s) at –78 °C, however the reaction was not complete conceivable that the reduction of 2f would proceed more
and the selectivity decreased to 1a:3a = 65:35 (Table 1, en- slowly than the reduction of ethyl cinnamate (2d) due to the
try 7). In addition, alcohol 3a was predominantly obtained decrease in the electrophilicity as a result of the presence of
when the reaction was carried out with a short residence the electron-donating methoxy group. This means that over-
time and a fast flow rate at 0 °C (Table 1, entry 8). Thus, reduction of the generated aldehyde rather than reduction
Table 1. Investigation of the reaction conditions for the reduction of 2a with DIBAL-H under flow conditions.
Entry
Concentration of 2a [m] Concentration of DIBAL-
H [m]
Flow rate
T
Z
tr
Conversion
[%][a]
Ratio
X
Y
W
[s]
1a/3a[b]
1
2
3
4
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.2
0.2
0.2
0.1
0.2
0.3
0.3
0.3
2
6
–78
–78
–78
–78
–97
–97
–78
0
9
3
1
1
1
1
0.5
0.5
49
94
Ͼ 95
86
89
Ͼ 95
90
Ͼ 95
50:50
60:40
62:38
82:18
93:7
93:7
65:35
Ͻ 5:95
18
18
18
18
18
18
5
6[c]
7
8
1
1
[a] The conversion of 2a was determined by crude H NMR spectroscopy. [b] The ratio of 1a and 3a was determined by crude H NMR
spectroscopy. [c] 1a was isolated in 88% yield.
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M. Yoshida, H. Otaka, T. Doi
FULL PAPER
of the substrate (i.e., 2f), could readily occur, even in the under the same reaction conditions (Table 2, entries 8–10).
flow reactor. Benzoate derivatives 2g–2i were also reduced Ethyl benzoate (2g) and its 4-bromo derivative 2h were ef-
ficiently converted into the corresponding aldehydes (i.e.,
1g and 1h, respectively) in good yields. However, alcohol 3i
was the major product when 4-methoxy derivative 2i was
reduced. Similarly to the reduction of cinnamate derivative
2f, the substituent on the benzene ring in a benzoate deriva-
tive was found to significantly affect the selectivity of the
partial reduction.
Table 2. Scope and limitation of a partial DIBAL-H reduction of
conjugated esters.
Saturated ester 4 was also selectively reduced at –78 °C
to give aldehyde 5 in high yield, as has been reported pre-
viously[9] (Scheme 1). Therefore, it is noteworthy that the
flow system we developed is compatible with the partial re-
duction using DIBAL-H of both saturated esters and α,β-
unsaturated esters with benzoate derivatives, except for 4-
methoxycinnamate and 4-methoxybenzoate.
A variety of α,β-unsaturated esters were efficiently re-
duced to the corresponding enals by partial reduction with
DIBAL-H under flow conditions. We next attempted to
synthesize aldehyde 8, which is the key intermediate in the
synthesis of cyclodepsipetide spiruchostatins A and B, and
largazole.[10] Aldehyde 8 has previously been prepared using
Simon’s procedure involving the reduction of α,β-unsatu-
rated ester 7 and oxidation of the resulting alcohol (i.e.,
9),[11,12] although the yield of 8 was moderate (67%) be-
cause the thiol moiety would be oxidized under the reaction
conditions (Table 3, entry 1).[13] In our attempt, the re-
duction of 7 by the slow addition of DIBAL-H at –97 °C
in a batch system provided 8 in only 33% yield because
of over-reduction of 8 (Table 3, entry 2). In contrast, the
continuous-flow reduction of 7 gave desired aldehyde 8 se-
Table 3. Comparison of a flow system with a conventional method
for the preparation of 8. Trt = trityl (triphenylmethyl).
Entry Conditions
Conversion Ratio Yield of 8
[%][a]
8/9[b]
[%][c]
67[d]
1
2
3
Batch: 1) DIBAL-H, 2) oxi-
dation
–
–
Batch: slow addition
(1.1 equiv.)
75
45:55
89:11
33
82
Flow: –97 °C, 18 mLmin–1
1 s
,
Ͼ95
[a] The conversion of 2 was determined by crude 1H NMR spec-
1
troscopy. [b] The ratio of 1 and 3 was was determined by crude H
[a] The conversion of 2 was determined by crude 1H NMR spec-
troscopy. [b] The ratio of 8 and 9 was determined by crude 1H
NMR spectroscopy. [c] Isolated yield. [d] See ref.[12]
NMR spectroscopy. [c] Isolated yield. [d] Isolated as a 2,4-dini-
trophenylhydrazine adduct.
Scheme 1. Partial reduction of ethyl 5-phenylvalerate under flow conditions.
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Eur. J. Org. Chem. 2014, 6010–6016

Partial Reduction Using DIBAL-H under Flow Conditions
singlet), br. d (broad doublet), J (coupling constants in Hertz).
Mass spectra and high-resolution mass spectra were measured with
JEOL JMS-DX303 (EI), MS-AX500 (FAB), or BRUKER micro-
TOF-II (ESI) instruments. IR spectra were recorded with a Shim-
adzu FTIR-8400 instrument, and data given in cm–1. Only the
strongest and/or structurally important absorptions are reported.
Melting points were measured using a Round Science Inc. RFS-
10instrument.
lectively (8:9 = 89:11) in 82% yield (Table 3, entry 3). This
system could provide a sufficient amount of enal 8 in a
single step (264 mgmin–1), so this method would be a useful
and redox-economical[14] way to make the desired enals
from the corresponding α,β-unsaturated esters on a gram
scale.
General Procedure for the Synthesis of α,β-Unsaturated Esters: A
solution of the appropriate phosphonate (1.4 equiv.) in THF
(3 mL/mmol) was added dropwise to a solution of NaH (1.3 equiv.)
in THF (0.5 mL/mmol) at 0 °C. After addition was complete, the
reaction mixture was stirred at 0 °C for 30 min, then a solution of
the appropriate aldehyde (1.0 equiv.) in THF (0.5 mL/mmol) was
added dropwise at 0 °C. The mixture was stirred for 30 min at room
temperature, then it was quenched with H2O. The aqueous layer
was extracted with ethyl acetate. The organic layer was washed with
brine, dried with MgSO4, filtered, and concentrated in vacuo. The
Conclusions
In conclusion, we have demonstrated the partial re-
duction of α,β-unsaturated esters using commercially avail-
able DIBAL-H in a continuous-flow system. The reaction
conditions established using the flow reactor enabled us to
readily and reproducibly produce the desired enals in mod-
erate to high yields. It should be noted that the flow rate
and reagent concentrations are crucial for achieving high
conversion of the substrate under cryogenic conditions, and residue was purified by column chromatography on silica gel (elut-
ing with EtOAc/hexane, 2:98) to give the α,β-unsaturated esters.
the prompt termination of the reaction using EtOH is es-
sential for preventing the enals from being over-reduced by
excess DIBAL-H. The reaction temperature can be strictly
regulated by using a smaller flow reactor rather than a
larger coventional batch system, thus conjugated esters can
be readily reduced to aldehydes at low temperatures such as
–97 °C. No special reductants are required to achieve the
partial reduction of α,β-unsaturated esters and benzoate de-
rivatives, so the method we have developed would be a con-
venient and useful way of producing enals. We are currently
applying this method to a part of a natural product synthe-
sis, and the results of our investigations will be reported in
due course.
Ethyl (E)-5-Phenyl-2-pentenoate (2a):[15] Yield quant., colorless oil.
1H NMR (400 MHz, CDCl3): δ = 7.32–7.28 (m, 2 H), 7.27–7.22
(m, 3 H), 7.00 (dt, J = 15.6, 6.8 Hz, 1 H), 5.84 (dt, J = 15.6, 2.0 Hz,
1 H), 4.17 (q, J = 7.2 Hz, 2 H), 2.77 (t, J = 8.0 Hz, 2 H), 2.53–2.48
(m, 2 H), 1.27 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 166.5, 147.9, 140.7, 128.4, 128.2, 126.1, 121.8, 60.1,
34.2, 33.8, 14.2 ppm. IR (neat): ν = 2981, 2936, 2905, 1721, 1654,
˜
1316, 1267, 1198, 1149, 1041, 700 cm–1. HRMS (EI): calcd. for
C13H16O2 204.1150; found 204.1141.
Methyl (E)-5-Phenyl-2-pentenoate (2aЈ):[16] Yield 91%, colorless oil.
1H NMR (400 MHz, CDCl3): δ = 7.33–7.27 (m, 2 H), 7.24–7.15
(m, 3 H), 7.00 (dt, J = 15.6, 6.8 Hz, 1 H), 5.84 (dt, J = 15.6, 1.6 Hz,
1 H), 3.72 (s, 3 H), 2.77 (t, J = 8.0 Hz, 2 H), 2.54–2.49 (m, 2 H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 166.9, 148.2, 140.6, 128.4,
128.2, 126.1, 121.3, 51.3, 34.2, 33.8 ppm. IR (neat): ν = 3027, 2949,
˜
1725, 1658, 1436, 1319, 1272, 1203, 1174, 1150, 700 cm–1. HRMS
(EI): calcd. for C12H14O2 190.0994; found 190.1001.
Experimental Section
General Methods: All commercially available reagents, including
substrates 2d, 2g, and 2h, were used as received. Dry THF and
dichloromethane (Kanto Chemical Co.) were obtained by passing
commercially available pre-dried, oxygen-free formulations through
activated alumina columns. MeOH was distilled from iodine and
magnesium turnings. DMF was purchased from Wako (for peptide
synthesis, grade: 99.5%). All reactions in solution phase were moni-
tored by thin-layer chromatography on Merck silica gel plates
(0.2 mm, 60F-254), which were visualized with UV light, and devel-
oped with anisaldehyde, or ethanolic phosphomolybdic acid (10%).
Silica gel 60N (Kanto Chemical Co. 100–210 μm) was used for col-
umn chromatography, and Merck silica gel plates (2.0 mm, 60F-
254) were used for preparative thin-layer chromatography. 1H
(400 MHz) and 13C (100 MHz) NMR spectra were recorded with
JEOL JNM-AL400 spectrometers in the indicated solvent. Chemi-
cal shifts (δ) are reported in parts per million (ppm) relative to the
signal for internal tetramethylsilane (δ = 0 ppm for 1H) for solu-
tions in CDCl3. NMR spectroscopic data were calibrated as fol-
lows: chloroform (δ = 7.26 ppm for 1H) or [D]chloroform (δ =
77.0 ppm for 13C), [D5]dimethyl sulfoxide (δ = 2.50 ppm for 1H)
or [D6]dimethyl sulfoxide (δ = 39.5 ppm for 13C) when an internal
standard is not indicated. Multiplicities are reported using the fol-
lowing abbreviations: s (singlet), d (doublet), t (triplet), q (quartet),
m (multiplet), dd (doublet of doublets), dt (doublet of triplets), ddd
(doublet of doublet of doublets), ddt (doublet of doublet of trip-
lets), dddd (doublet of doublet of doublet of doublets), br. s (broad
Ethyl (E)-3-(4-Bromophenyl)-2-propenoate (2e):[17] Yield quant.,
colorless oil. 1H NMR (400 MHz, CDCl3): δ = 7.60 (d, J =
16.0 Hz, 1 H), 7.50 (d, J = 8.6 Hz, 2 H), 7.37 (d, J = 8.6 Hz, 2 H),
6.41 (d, J = 16.0 Hz, 1 H), 4.26 (q, J = 7.0 Hz, 2 H), 1.33 (t, J =
7.0 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 166.6, 143.1,
133.3, 132.0, 129.3, 124.3, 118.9, 60.5, 14.2 ppm. IR (neat): ν =
˜
2980, 2937, 1712, 1637, 1489, 1310, 1202, 1175, 1073 cm–1. HRMS
(EI): calcd. for C11H11BrO2 253.9942; found 253.9945.
Ethyl (E)-3-(4-Methoxyphenyl)-2-propenoate (2f):[17] Yield 91%,
1
white solid, m.p. 48–49 °C. H NMR (400 MHz, CDCl3): δ = 7.64
(d, J = 16.0 Hz, 1 H), 7.46 (d, J = 9.0 Hz, 2 H), 6.89 (d, J = 9.0 Hz,
2 H), 6.30 (d, J = 16.0 Hz, 1 H), 4.25 (q, J = 7.0 Hz, 2 H), 3.82 (s,
3 H), 1.32 (t, J = 7.0 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 167.2, 161.2, 144.1, 129.6, 127.1, 115.7, 114.2, 60.2, 55.2,
14.3 ppm. IR (neat): ν = 2980, 2937, 1709, 1634, 1605, 1513, 1253,
˜
1172 cm–1. HRMS (EI): calcd. for C12H14O3 206.0943; found
206.0938.
Ethyl (E)-5-(Triphenylmethylthio)-2-pentenoate (7):[12] Acrolein
(1.31 mL, 17.6 mmol, 1.4 equiv.) was added to a solution of trityl-
thiol (3.5 g, 12.6 mmol, 1.0 equiv.) and triethylamine (2.46 mL,
17.6 mmol, 1.4 equiv.) in dichloromethane (25.2 mL, 2.0 mL/mmol)
at room temperature under argon. The mixture was stirred at the
same temperature for 2 h, then it was concentrated in vacuo. The
residue was used for the next reaction without further purification.
Eur. J. Org. Chem. 2014, 6010–6016
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M. Yoshida, H. Otaka, T. Doi
FULL PAPER
Sodium hydride (0.563 g, 11.7 mmol, 1.3 equiv.) was added to a
solution of triethyl phosphonoacetate (2.68 mL, 13.5 mmol,
1.5 equiv.) in THF (18.0 mL, 1.43 mL/mmol) at 0 °C under argon.
The mixture was stirred at the same temperature for 30 min, then
it was cooled to 0 °C. A solution in THF (18 mL, 1.43 mL/mmol)
of crude residue prepared as described above was added to the
reaction mixture. The mixture was stirred at the same temperature
for 25 min, then it was quenched with H2O, and the aqueous layer
was extracted with ethyl acetate. The organic layer was washed with
brine, dried with MgSO4, filtered, and concentrated in vacuo. The
residue was purified by column chromatography on silica gel (elut-
ing with EtOAc/hexane, 2:98) to give unsaturated ester 7 (2.59 g,
a
solution of 5-phenyl-2-pentynoic acid (1.71 g, 9.82 mmol,
1.0 equiv.) in DMF (20 mL, 2 mL/mmol) at 0 °C under argon. The
mixture was stirred at room temperature for 16 h, then it was
quenched with NH4Cl (aq.), and the aqueous layer was extracted
with ethyl acetate. The organic layer was washed with Na2S2O3
(aq.), H2O, and brine, dried with MgSO4, filtered, and concen-
trated in vacuo. The residue was purified by column chromatog-
raphy on silica gel (eluting with EtOAc/hexane, 2:98) to give 2c
(1.70 g, 8.41 mmol, 86%) as a colorless oil. 1H NMR (400 MHz,
CDCl3): δ = 7.38–7.28 (m, 2 H), 7.26–7.18 (m, 3 H), 4.16 (q, J =
7.2 Hz, 2 H), 2.89 (t, J = 7.6 Hz, 2 H), 2.61 (t, J = 7.6 Hz, 2 H),
1.30 (t, J = 7.6 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
6.44 mmol, 51% over two steps) as a white solid, m.p. 81–82 °C. 153.7, 139.5, 128.5, 128.2, 126.6, 88.2, 73.6, 61.8, 33.8, 20.8,
1H NMR (400 MHz, CDCl3): δ = 7.41–7.19 (m, 15 H), 6.75 (dt, J
= 16.0, 6.8 Hz, 1 H), 5.69 (d, J = 16.0 Hz, 1 H), 4.15 (q, J = 7.6 Hz,
2 H), 2.28 (t, J = 7.2 Hz, 2 H), 2.18 (dt, J = 7.2, 6.8 Hz, 2 H), 1.26
(t, J = 7.6 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 166.3,
146.5, 144.6, 129.5, 127.9, 126.6, 122.3, 66.8, 60.2, 31.3, 30.2,
13.9 ppm. IR (CHCl ): ν = 3029, 2983, 2937, 2235, 1710, 1455,
˜
3
1366, 1252, 1070, 751, 699 cm–1. HRMS (EI): calcd. for C13H14O2
202.0994; found 202.0987.
Ethyl 5-Phenylpentanoate (4):[22] Palladium on carbon (10%;
500 mg, 10 wt.-%) was added to a solution of the ethyl (E)-5-
phenyl-2-pentenoate (5.00 g, 24.5 mmol, 1.0 equiv.) in ethyl acetate
(98.0 mL, 4 mL/mmol). The reaction vessel was purged with
hydrogen (5ϫ). The mixture was stirred at room temperature for
2 h, then it was filtered a pad of Celite®. The filtrate was concen-
trated in vacuo, and the resulting residue was purified by column
chromatography on silica gel (eluting with EtOAc/hexane, 2:98) to
give 4 (4.63 g, 22.4 mmol, 91%) as a colorless oil. 1H NMR
(400 MHz, CDCl3): δ = 7.32–7.23 (m, 2 H), 7.22–7.12 (m, 3 H),
4.11 (q, J = 6.8 Hz, 2 H), 2.62 (t, J = 7.6 Hz, 2 H), 2.31 (t, J =
7.2 Hz, 2 H), 1.66 (m, 4 H), 1.23 (t, J = 6.8 Hz, 3 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 173.5, 142.6, 128.3, 128.2, 125.6,
14.2 ppm. IR (CHCl ): ν = 3056, 3030, 2980, 1719, 1654, 1594,
˜
3
1489, 1444, 1367, 1335, 1309, 1270, 1196, 1143, 1035, 743, 701,
622 cm–1. HRMS (ESI): calcd. for C24H22NaOS [M + Na]+
425.1551; found 425.1526.
Isopropyl (E)-5-Phenyl-2-pentenoate (2aЈЈ):[18] DMF (66 μL,
0.85 mmol, 0.1 equiv.) was added dropwise to a solution of acid
(1.50 g, 8.52 mmol, 1.0 equiv.) and oxalyl chloride (805 μL,
9.37 mmol, 1.1 equiv.) in CH2Cl2 at 0 °C, and the mixture was
stirred at the same temperature for 10 min. The mixture was then
stirred at room temperature for 30 min, and then it was quenched
with iPrOH, and stirred for a further 30 min. The mixture was then
concentrated, and the residue was purified by column chromatog-
raphy on silica gel (eluting with EtOAc/hexane, 2:98) to give iso-
propyl ester 2aЈЈ (1.52 g, 6.99 mmol, 82%) as a colorless oil. 1H
NMR (400 MHz, CDCl3): δ = 7.32–7.27 (m, 2 H), 7.22–7.17 (m, 3
H), 6.98 (dt, J = 16.0, 6.8 Hz, 1 H), 5.83 (dt, J = 16.0, 1.6 Hz, 1
H), 5.05 (m, 1 H), 2.77 (t, J = 8.4 Hz, 2 H), 2.53–2.48 (m, 2 H),
1.25 (d, J = 6.4 Hz, 6 H) ppm. 13C NMR (100 MHz, CDCl3): δ
= 166.1, 147.6, 140.8, 128.4, 128.2, 126.1, 122.2, 67.4, 34.3, 33.8,
60.1, 35.5, 34.1, 30.8, 24.5, 14.1 ppm. IR (CHCl ): ν = 2937, 2860,
˜
3
1735, 1453, 1373, 1238, 1180, 1030, 748, 699 cm–1. HRMS (EI):
calcd. for C13H18O2 206.1307; found 206.1315.
Ethyl 4-Methoxybenzoate (2i):[23] SOCl2 (2.02 mL, 27.7 mmol,
2.1 equiv.) was added to a solution of 4-methoxybenzoic acid
(2.0 g, 13.2 mmol) in EtOH (3 mL/mmol) at 0 °C under argon. The
mixture was stirred at 40 °C for 14 h, then it was concentrated in
vacuo. The residue was dissolved in ethyl acetate and H2O. The
organic layer was washed with NaHCO3 (aq.) and brine, dried with
MgSO4, filtered, and concentrated in vacuo. The residue was puri-
fied by column chromatography on silica gel (eluting with EtOAc/
hexane, 2:98) to give 2i (2.35 g, 13.1 mmol, quant.) as a colorless
oil. 1H NMR (400 MHz, CDCl3): δ = 7.99 (d, J = 9.2 Hz, 2 H),
6.90 (d, J = 9.2 Hz, 2 H), 4.34 (q, J = 7.2 Hz, 2 H), 3.84 (s, 3 H),
1.37 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
166.3, 163.1, 131.4, 122.8, 113.4, 60.5, 55.3, 14.3 ppm. IR (CHCl3):
21.8 ppm. IR (neat): ν = 2980, 1716, 1654, 1312, 1271, 1201, 1180,
˜
1109, 699 cm–1. HRMS (EI): calcd. for C14H18O2 218.1307; found
218.1306.
Ethyl (Z)-5-Phenyl-2-pentenoate (2b):[19] NaH (425 mg, 8.85 mmol,
1.2 equiv.) was added to a solution of ethyl (di-o-tolylphosphono)
acetate[20] (1.2 g, 8.05 mmol, 1.0 equiv.) in THF (35 mL, 4.3 mL/
mmol) at 0 °C. The mixture was stirred at the same temperature
for 30 min, then it was cooled to –78 °C. A solution of 3-phenylpro-
panal was added at –78 °C. The mixture was stirred at the same
temperature for 20 min, then it was quenched with H2O, and the
aqueous layer was extracted with ethyl acetate. The organic layer
was washed with brine, dried with MgSO4, filtered, and concen-
trated in vacuo. The residue was purified by column chromatog-
raphy on silica gel (eluting with EtOAc/hexane, 1:2) to give 2b
(1.25 g, 6.12 mmol, 76%) as a colorless oil. 1H NMR (400 MHz,
CDCl3): δ = 7.34–7.25 (m, 2 H), 7.24–7.14 (m, 3 H), 6.22 (dt, J =
7.2, 11.6 Hz, 1 H), 5.77 (dt, J = 1.4, 11.6 Hz, 1 H), 4.15 (q, J =
7.2 Hz, 2 H), 2.99 (dq, J = 1.4, 7.6 Hz, 2 H), 2.76 (t, J = 7.6 Hz, 2
H), 1.27 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 166.2, 148.9, 141.1, 128.4, 128.3, 125.9, 120.2, 59.8, 35.0, 30.3,
ν = 2980, 2937, 2906, 1711, 1607, 1278, 1257, 1169, 1103 cm–1.
˜
HRMS (EI): calcd. for C10H12O3 180.0786; found 180.0786.
General Procedure for the Flow Synthesis of α,β-Unsaturated Alde-
hydes from Esters: The flow system was established with two rotary
piston pumps (Reglo-CPF Digital/ISM 321 and RH0.CKC-LF/
FMI013, ISMATEC®), a syringe pump (HII-10B, Techno aplica-
tions®), stainless steel tube, teflon tube, the flow reactor (Comet
X-01-SS, Techno applications®) and a methanol/liquid N2 bath or
an acetone/dry-ice bath (see Figure 1). Before use, the flow system
was flushed with dry toluene. A solution of the substrate in toluene
(0.1 m) was then loaded into a stainless steel sample loop (Tube 1),
and a solution of DIBAL-H in toluene (0.3 m) was loaded into
another stainless steel sample loop (Tube 2). The two sample solu-
tions were pumped at a combined flow rate of 18.0 mLmin–1, and
mixed in the reactor (Comet and Tube 3) at –97 °C. The output of
the reactor was connected with a T-shaped mixer to quench the
reaction with EtOH (2 mLmin–1). The resulting mixture was col-
14.2 ppm. IR (CHCl ): ν = 3028, 2981, 2931, 1717, 1644, 1454,
˜
3
1415, 1189, 1161, 1031, 1189, 699 cm–1. HRMS (EI): calcd. for
C13H16O2 204.1150; found 204.1151.
Ethyl 5-Phenyl-2-pentynoate (2c):[21] K2CO3 (2.71 g, 19.6 mmol,
2.0 equiv.) and EtI (1.17 mL, 14.7 mmol, 1.5 equiv.) were added to lected, and the product was isolated by the following procedures.
6014 Eur. J. Org. Chem. 2014, 6010–6016
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Partial Reduction Using DIBAL-H under Flow Conditions
Method A: The collected mixture was diluted with water, and the
mixture was extracted with diethyl ether. The organic layer was
washed with brine, dried with MgSO4, filtered, and concentrated
in vacuo. The residue was purified by column chromatography on
silica gel to give desired aldehyde.
3026, 2932, 2360, 2342, 2219, 1617, 1507, 1138, 669 cm–1. HRMS
(EI): calcd. for C17H14N4O4 338.1015; found 338.1010.
(E)-Cinnamaldehyde (1d):[25] Collection time: 1 min; pale yellow oil
(93.9 mg, 79%). 1H NMR (400 MHz, CDCl3): δ = 9.71 (d, J =
8.0 Hz, 1 H), 7.62–7.54 (m, 2 H), 7.48 (d, J = 16.3 Hz, 1 H), 7.48–
7.40 (m, 3 H), 6.73 (dd, J = 16.3, 8.0 Hz, 1 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 193.5, 152.6, 133.8, 131.1, 128.9, 128.4,
Method B (for a volatile compound): H2O (1.78 mL, 2.0 mL/mmol)
was added to a solution of 2,4-dinitrophenylhydrazine (178.2 mg,
0.9 mmol, 1.0 equiv.) and H2SO4 (0.7 mL) in EtOH (0.7 mL,
0.8 mL/mmol) at room temperature. The mixture was stirred for
10 min at room temperature, then a solution of the crude aldehyde
was added at the same temperature. The mixture was stirred for
30 min at room temperature, then the precipitate was collected by
filtration, and purified by recrystallization (acetone/water) to give
the desired hydrazone.
(E)-5-Phenyl-2-pentenal (1a):[16] Collection time: 1 min; R = Et: col-
orless oil (127.4 mg, 88%); R = Me: colorless oil (101.7 mg, 71%);
R = iPr: colorless oil (120.6 mg, 84%). 1H NMR (400 MHz,
CDCl3): δ = 9.48 (d, J = 7.8 Hz, 1 H), 7.32–7.29 (m, 2 H), 7.18–
7.22 (m, 3 H), 6.85 (dt, J = 15.8, 6.8 Hz, 1 H), 6.13 (ddt, J = 15.8,
7.8, 1.4 Hz, 1 H), 2.83 (t, J = 8.0 Hz, 2 H), 2.67 (ddt, J = 8.0, 6.8,
1.4 Hz, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 193.8, 157.2,
128.3 ppm. IR (neat): ν = 3062, 3029, 2992, 2815, 1677, 1626, 1450,
˜
1124, 972, 747, 688 cm–1. HRMS (EI): calcd. for C9H8O 132.0675;
found 132.0569.
(E)-3-(4-Bromophenyl)-2-propenal (1e):[26] Collection time: 1 min;
1
white solid (148.4 mg, 78%), m.p. 80–81 °C. H NMR (400 MHz,
CDCl3): δ = 9.71 (d, J = 7.8 Hz, 1 H), 7.57 (d, J = 8.6 Hz, 2 H),
7.43 (d, J = 8.6 Hz, 2 H), 7.42 (d, J = 16.2 Hz, 1 H), 6.70 (dd, J =
16.2, 7.8 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 193.3,
151.0, 132.9, 132.4, 129.7, 129.0, 125.6 ppm. IR (neat): ν = 3084,
˜
3048, 2825, 2742, 1678, 1624, 1583, 1490, 1128, 1009, 981,
806 cm–1. HRMS (EI): calcd. for C9H779BrO 209.9680; found
209.9673.
(E)-3-(4-Methoxyphenyl)-2-propenal (1f):[27] Collection time: 1 min;
white solid (28.7 mg, 20%), m.p. 58–59 °C. 1H NMR (400 MHz,
CDCl3): δ = 9.65 (d, J = 7.8 Hz, 1 H), 7.52 (d, J = 9.0 Hz, 2 H),
7.42 (d, J = 15.8 Hz, 1 H), 6.95 (d, J = 9.0 Hz, 2 H), 6.61 (dd, J =
15.8, 7.8 Hz, 1 H), 3.86 (s, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 193.6, 162.2, 152.6, 130.3, 126.7, 126.5, 114.5,
140.1, 133.2, 128.5, 128.2, 126.2, 34.1, 33.9 ppm. IR (neat): ν =
˜
3062, 2929, 2817, 1692, 1637, 1454, 1123, 973, 748, 700 cm–1.
HRMS (EI): calcd. for C11H12O 160.0888; found 160.0890.
(E)-5-Phenyl-2-pentenol (3a):[24] Colorless oil. 1H NMR (400 MHz,
CDCl3): δ = 7.32–7.27 (m, 2 H), 7.21–7.16 (m, 3 H), 5.80–5.60 (m, 55.4 ppm. IR (neat): ν = 3033, 2982, 2955, 2938, 2844, 2765, 1668,
˜
2 H), 4.06 (d, J = 5.6 Hz, 2 H), 2.70 (t, J = 8.4 Hz, 2 H), 2.37 (m, 1604, 1512, 1264, 1250, 1176, 1131 cm–1. HRMS (EI): calcd. for
2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 141.6, 132.1, 129.6,
C10H10O2 162.0681; found 162.0681.
128.4, 128.3, 125.8, 63.6, 35.5, 33.9 ppm. IR (neat): ν = 3336, 3026,
˜
(E)-2,4-Dinitrophenylhydrazone of Benzaldehyde (1g):[28] Collection
2925, 2856, 1454, 999, 970, 746, 699 cm–1. HRMS (EI): calcd. for
C11H14O 162.1045; found 162.1043.
time for the aldehyde: 1 min; yellow solid (208.0 mg, 81%, as a
1
hydrazone), m.p. 228–229 °C. H NMR (400 MHz, [D6]DMSO): δ
(Z)-5-Phenyl-2-pentenal (1b): Collection time: 1 min; colorless oil
(139.0 mg, 96%). 1H NMR (400 MHz, CDCl3): δ = 9.92 (d, J =
8.0 Hz, 1 H), 7.36–7.26 (m, 2 H), 7.24–7.14 (m, 3 H), 6.62 (dt, J =
11.2, 7.8 Hz, 1 H), 5.95 (ddt, J = 11.2, 8.0, 1.2 Hz, 1 H), 2.92 (m,
2 H), 2.82 (t, J = 7.2 Hz, 2 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 190.5, 151.4, 139.9, 130.5, 128.5, 128.3, 126.3, 35.1, 29.6 ppm.
= 11.6 (s, 1 H), 8.86 (d, J = 2.6 Hz, 1 H), 8.70 (s, 1 H), 8.37 (dd,
J = 2.6, 9.6 Hz, 1 H), 8.10 (d, J = 9.6 Hz, 1 H), 7.83–7.76 (m, 2
H), 7.54–7.44 (m, 3 H) ppm. 13C NMR (100 MHz, [D6]DMSO): δ
= 149.4, 144.5, 137.0, 133.8, 130.5, 129.7, 129.4, 128.9, 127.3, 123.0,
116.7 ppm. IR (neat): ν = 3286, 3116, 3101, 3093, 2362, 2341, 1586,
˜
1507, 1315, 1262, 1137, 741 cm–1. HRMS (EI): calcd. for
C13H10N4O4 286.0702; found 286.0708.
IR (neat): ν = 3027, 2926, 2857, 1679, 1497, 1454, 1071, 739,
˜
700 cm–1. HRMS (EI): calcd. for C11H12O 160.0888; found
160.0883.
(E)-2,4-Dinitrophenylhydrazone of 4-Bromobenzaldehyde (1h): Col-
lection time for the aldehyde: 1 min; yellow solid (283.2 mg, 86%,
as a hydrazone), m.p. 259–260 °C [ref, m.p. 258–259 °C].[29] 1H
NMR (400 MHz, [D6]DMSO): δ = 11.6 (s, 1 H), 8.85 (d, J =
2.6 Hz, 1 H), 8.67 (s, 1 H), 8.37 (dd, J = 2.6, 9.6 Hz, 1 H), 8.10 (d,
J = 9.6 Hz, 1 H), 7.39 (d, 2 H), 7.71 (d, 2 H) ppm. 13C NMR
(100 MHz, [D6]DMSO): δ = 148.1, 144.3, 137.2, 133.0, 132.0,
(Z)-2,4-Dinitrophenylhydrazone of 5-Phenyl-2-pentynal (1c): Collec-
tion time for the aldehyde: 1 min; yellow solid (255.2 mg, 84%, as a
E/Z mixture of hydrazones, E/Z = 7:93). The mixture was partially
separated by silica gel column shromatography for the structure
determinsation.
129.7, 129.7, 129.1, 123.8, 122.9, 116.8 ppm. IR (neat): ν = 3300,
˜
Data for the (Z) hydrazone: Yellow solid, m.p. 98–99 °C. 1H NMR
(400 MHz, CDCl3): δ = 11.8 (s, 1 H), 9.02 (dd, J = 0.8, 2.4 Hz, 1
H), 8.22 (dd, J = 2.4, 9.6 Hz, 1 H), 7.82 (dd, J = 0.8, 9.6 Hz, 2 H),
7.30–7.05 (m, 5 H), 6.68 (d, J = 0.8 Hz, 1 H), 2.93 (t, J = 7.2 Hz,
2 H), 2.81 (t, J = 7.2 Hz, 2 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 144.0, 139.4, 138.6, 129.8, 129.7, 128.4, 128.2, 126.5, 126.5,
3287, 3093, 2916, 2849, 2360, 2341, 1616, 1514, 1326, 1314,
1082 cm–1. HRMS (EI): calcd. for C13H979BrN4O4 363.9807; found
363.9810.
4-Methoxybenzaldehyde (1i):[30] Collection time: 1 min; colorless oil
(14.4 mg, 12%). 1H NMR (400 MHz, CDCl3): δ = 9.88 (s, 1 H),
123.1, 116.8, 107.3, 72.0, 34.2, 21.6 ppm. IR (neat): ν = 3264, 3104, 7.83 (d, J = 8.8 Hz, 2 H), 7.00 (d, J = 8.8 Hz, 2 H), 3.88 (s, 3 H)
˜
3029, 2926, 2360, 1617, 1592, 1517, 1333, 1311 cm–1. HRMS (EI): ppm. 13C NMR (100 MHz, CDCl3): δ = 190.7, 164.5, 131.9, 129.8,
calcd. for C17H14N4O4 338.1015; found 338.1034.
114.2, 55.4 ppm. IR (neat): ν = 2937, 2841, 1697, 1685, 1601, 1315,
˜
1261, 1216, 1161, 1025, 834 cm–1. HRMS (EI): calcd. for C8H8O2
136.0524; found 136.0520.
Data for the (E) hydrazone: Yellow solid, m.p. 175–176 °C. 1H
NMR (400 MHz, [D6]DMSO): δ = 11.7 (s, 1 H), 8.83 (d, J =
2.8 Hz, 1 H), 8.36 (dd, J = 2.8, 9.6 Hz, 1 H), 7.95 (s, 1 H), 7.84 (d,
J = 9.6 Hz, 1 H), 7.30–7.05 (m, 5 H), 2.85 (t, J = 7.0 Hz, 2 H),
2.76 (t, J = 7.0 Hz, 2 H) ppm. 13C NMR (100 MHz, [D6]DMSO):
δ = 143.8, 140.0, 137.5, 133.1, 129.8, 128.4, 128.2, 126.2, 122.7,
(E)-2,4-Dinitrophenylhydrazone of 5-Phenylpentanal (5): Collection
time for the aldehyde: 1 min; yellow solid (272.5 mg, 88%, as a
hydrazone), m.p. 96–97 °C [ref, m.p. 97.5–99 °C].[31] 1H NMR
(400 MHz, CDCl3): δ = 11.0 (s, 1 H), 9.10 (d, J = 2.4 Hz, 1 H),
116.7, 97.7, 79.1, 77.1, 33.5, 20.8 ppm. IR (neat): ν = 3287, 3104, 8.28 (dd, J = 2.4, 9.8 Hz, 1 H), 7.86 (d, J = 9.8 Hz, 1 H), 7.51 (dd,
˜
Eur. J. Org. Chem. 2014, 6010–6016
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6015

M. Yoshida, H. Otaka, T. Doi
FULL PAPER
2011, 69, 600–610; c) C. F. Carter, H. Lange, D. Sasaki, I. R.
Baxendale, S. V. Ley, Chem. Eur. J. 2011, 17, 3398–3405; d) H.
Lange, C. F. Carter, M. D. Hopkin, A. Burke, J. G. Goode,
I. R. Baxendale, S. V. Ley, Chem. Sci. 2011, 2, 765–769; e) D.
Webb, T. F. Jamison, Org. Lett. 2012, 14, 568–571; f) S. New-
ton, C. F. Carter, C. M. Pearson, L. de C. Alves, H. Lange, P.
Thansandote, S. V. Ley, Angew. Chem. Int. Ed. 2014, 53, 4915–
4920; Angew. Chem. 2014, 126, 5015–5020.
J = 5.4, 5.4 Hz, 1 H), 7.25–7.34 (m, 2 H), 7.14–7.24 (m, 3 H), 2.68
(t, J = 7.6 Hz, 2 H), 2.46 (dt, J = 5.4, 6.8 Hz, 2 H), 1.60–1.80 (m,
4 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 152.2, 145.0, 141.9,
137.7, 129.9, 128.7, 128.3, 125.8, 123.4, 116.4, 35.6, 32.3, 30.8,
25.7 ppm. IR (neat): ν = 3292, 2930, 2858, 1619, 1519, 1592, 1332,
˜
1305, 1264, 743 cm–1. HRMS (EI): calcd. for C17H18N4O4
342.1328; found 342.1335.
Synthesis of (E)-5-(Triphenylmethylthio)-2-pentenal (8)[12]
[5] J. de M. Muñoz, J. Alcázar, A. de la Hoz, A. Díaz-Ortiz, Eur.
J. Org. Chem. 2012, 260–263.
Method 1: One-step flow method (Table 3, entry 3). Collection
time: 4.5 min; white solid (1.19 g, 82%), m.p. 141–142 °C. 1H NMR
(400 MHz, CDCl3): δ = 9.42 (d, J = 8.0 Hz, 1 H), 7.47–7.38 (m, 6
H), 7.32–7.19 (m, 9 H), 6.61 (dt, J = 16.0, 6.4 Hz, 1 H), 6.13 (dd,
J = 16.0, 8.0 Hz, 1 H), 2.34–2.27 (m, 4 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 193.6, 155.6, 144.5, 133.5, 129.4, 127.9,
[6] M. S. Kim, Y. M. Choi, D. K. An, Tetrahedron Lett. 2007, 48,
5061–5064.
[7] The stainless steel reactor (Comet-X01-SS) was purchased
from Techno Applications, Inc., 36-16-204 Denenchofu Hon-
machi, Ota-ku, Tokyo 145-0072, Japan.
[8] EtOH was used to quench the reaction because MeOH was
frozen at –97 °C in a flow reactor.
[9] Recently, Jamison et al. also reported the effect of flow rate on
the partial reduction of saturated esters using DIBAL-H under
flow conditions. Vigorous mixing occurred at the fast flow rate
in a flow reactor, and a short residence time gave high conver-
sion and excellent selectivity (see ref.[4e]).
126.7, 66.9, 31.6, 29.9 ppm. IR (neat): ν = 3056, 3030, 2980, 2929,
˜
1719, 1444, 1269, 1195, 743, 700 cm–1. HRMS (ESI): calcd. for
C24H22NaOS [M + Na]+ 381.1289; found 381.1275.
Method 2: One-step batch method (Table 3, entry 2). DIBAL-H
(1.0 m in toluene; 0.990 mL, 0.990 mmol, 1.1 equiv.) was added
[10] a) Y. Masuoka, A. Nagai, K. Shin-ya, K. Furihata, K. Nagai,
K. Suzuki, Y. Hayakawa, H. Seto, Tetrahedron Lett. 2001, 42,
41–44; b) K. Taori, V. J. Paul, H. Luesch, J. Am. Chem. Soc.
2008, 130, 1806–1807.
over 4 min to
a solution of α,β-unsaturated ester (362 mg,
0.900 mmol, 1.0 equiv.) in toluene (20 mL/mmol) at –97 °C under
argon. The mixture was stirred for 5 min, then it was quenched
with EtOH at –97 °C, and diluted with H2O. The aqueous layer
was extracted with ethyl acetate. The organic layer was washed with
brine, dried with MgSO4, filtered, and concentrated in vacuo. The
residue was purified by column chromatography on silica gel
(EtOAc/hexane, 4:96) to give aldehyde 8 (105 mg, 0.293 mmol,
33%) as a white solid.
[11] K. W. Li, J. Wu, W. Xing, J. A. Simon, J. Am. Chem. Soc. 1996,
118, 7237–7238.
[12] S. Fuse, K. Okada, Y. Iijima, A. Munakata, K. Machida, T.
Takahashi, M. Takagi, K. Shin-ya, T. Doi, Org. Biomol. Chem.
2011, 9, 3825–3833.
[13] An alternative synthesis of aldehyde 8 using a Wittig reaction
was attempted by Janda et al., and aldehyde 8 was formed in
60% yield (over two steps). Y. Chen, C. Gambs, Y. Abe, P.
Wentworth Jr., K. D. Janda, J. Org. Chem. 2003, 68, 8902–
8905.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures for S1–S4, characterization data and
copies of the 1H and 13C NMR spectra for substrates and products.
[14] N. Z. Burns, P. S. Baran, R. W. Hoffmann, Angew. Chem. Int.
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N. J. Race, J. F. Bower, Org. Lett. 2013, 15, 4616–4619.
S. Kamijo, S. Yokosaka, M. Inoue, Tetrahedron 2012, 68, 5290–
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This work was supported by the Japanese Ministry of Education,
Culture, Sports, Science and Technology (MEXT) (Grant-in-Aid
for Scientific Research on Innovative Areas, grant number 2105)
and partially supported by MEXT (Platform for Drug Discovery,
Informatics, and Structural Life Science). Prof. Dr. Hidetoshi Tok-
uyama and Dr. Kentaro Okano (Tohoku University) are thanked
for their kind help with HRMS measurements.
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Received: June 2, 2014
Published Online: August 6, 2014
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