Convenient synthesis of meso-cyclohexa-1,3-dienes by one-pot two-step deoxygenation of 7-oxabicyclo[2.2.1]hept-2-enes

Article abstract of DOI:10.1055/S-0029-1218618

Iron(III) hydroxide oxide was found to be an efficient catalyst for the ring-opening reaction of 5,6-cis-disubstituted 7-oxabicyclo[2.2.1]hept-2-enes with acetyl bromide in dichloromethane at room temperature to give cyclohexene derivatives with leaving groups (acetoxy or bromo groups) disposed on each allylic position. A successive one-pot treatment of the reaction mixture with zinc powder and tetrahydrofuran successfully induced reductive 1,4-elimination to afford synthetically useful 5,6-disubstituted mesocyclohexa-1,3-dienes in good-to-high yields. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/S-0029-1218618

818
PAPER
Convenient Synthesis of meso-Cyclohexa-1,3-dienes by One-Pot Two-Step
Deoxygenation of 7-Oxabicyclo[2.2.1]hept-2-enes
C
onvenientSyn
o
thesisof
m
es
m
o
-Cyclohexa-1,3-di
oenes tsugu Yano, Takashi Fujishima, Ryo Irie*
Department of Chemistry, Graduate School of Science and Technology, Kumamoto University, 2-39-1 Kurokami, Kumamoto 860-8555,
Japan
Fax +81(96)3423379; E-mail: irie@sci.kumamoto-u.ac.jp
Received 15 October 2009; revised 18 November 2009
groups, respectively, disposed at each allylic carbon.7
Abstract: Iron(III) hydroxide oxide was found to be an efficient
These transformations prompted us to seek further refine-
ments, because the reaction products are considered to be
catalyst for the ring-opening reaction of 5,6-cis-disubstituted 7-oxa-
bicyclo[2.2.1]hept-2-enes with acetyl bromide in dichloromethane
at room temperature to give cyclohexene derivatives with leaving
masked cyclohexa-1,3-dienes that could be unmasked by
groups (acetoxy or bromo groups) disposed on each allylic position. reductive elimination of the allylic functional groups.8
A successive one-pot treatment of the reaction mixture with zinc
Here we report a convenient one-pot synthesis of cyclo-
powder and tetrahydrofuran successfully induced reductive 1,4-
hexa-1,3-dienes 1 from 7-oxabicyclo[2.2.1]hept-2-enes 2
elimination to afford synthetically useful 5,6-disubstituted meso-
actuated by iron(III) hydroxide oxide-catalyzed cleavage
of the 2,5-dihydrofuran ring with acetyl bromide, fol-
lowed by zinc-mediated reductive 1,4-elimination
(Scheme 1).
cyclohexa-1,3-dienes in good-to-high yields.
Key words: catalysis, ring opening, furans, reductions, elimina-
tions, cyclohexadienes
R
Alka-1,3-dienes are versatile substrates in organic synthe-
sis, as they are readily available and they undergo asym-
metric functionalization reactions at the double bonds to
produce useful chiral building blocks.1 Dienes in the
meso-form are more valuable because they undergo asym-
metric desymmetrization to give optically active products
with a simultaneous increase in the number of stereogenic
centers.2 In this respect, s-symmetric 5,6-cis-disubstitut-
ed cyclohexa-1,3-dienes 1 are of particular interest as pre-
cursors of densely functionalized chiral cyclohexane
derivatives, such as cyclitols or carbasugars (Scheme 1).3
This is well illustrated by the synthesis of conduritol E
from cyclohexa-3,5-diene-1,2-diol (1, R = OH).4 Further-
more, Toste et al.5 recently demonstrated a catalytic asym-
metric Kornblum DeLaMare rearrangement of
endoperoxides derived from the cyclohexa-1,3-diene 1
(R = CH2OBn) and analogous dienes to give optically ac-
tive 4-hydroxy enones, which should be useful as chiral
building blocks. Accordingly, an efficient method is re-
quired for the synthesis of cyclohexa-1,3-dienes 1.
Lautens et al.6 devised an elegant SN2¢ displacement–
Peterson elimination cascade for the direct conversion of
7-oxabicyclo[2.2.1]hept-2-enes 2 into cyclohexa-1,3-
dienes 1 with dimethyl(phenyl)silyllithium or lithium
dimethyl(phenyl)silylcuprate (Scheme 1). On the other
hand, 7-oxabicyclo[2.2.1]hept-2-enes 2 undergo a neigh-
boring group-induced diastereoselective nucleophilic C–
O displacement with acetyl bromide or acetyl chloride in
the presence of sulfuric acid as a catalyst to afford cyclo-
hexene derivatives with acetoxy and bromo or chloro
Si
R
Peterson
elimination
PhMe2SiM
OM
(ref. 6)
R
R
R
M = Li or Cu⋅LiCN
O
R
AcBr
FeO(OH)
Zn
2
1
OAc
R
(one-pot)
(this work)
asymmetric
functionalization
R
cyclitols,
carbasugars
Br
Scheme 1 Strategies for the synthesis of s-symmetric 5,6-cis-di-
substituted cyclohexa-1,3-dienes 1, useful as chiral building blocks
for densely functionalized cyclohexane derivatives
The starting materials, the 5,6-cis-disubstituted 7-oxabi-
cyclo[2.2.1]hept-2-enes 2, are readily accessible from fu-
ran and maleic anhydride, which undergo an exo-selective
Diels–Alder reaction followed by reduction with lithium
aluminum hydride to give the diol 2a9; its derivatives 2b–
h are obtained after appropriate protection of the hydroxy
groups of 2a (Scheme 2).
O
c
a, b
OR
OR
OH
OH
+
O
O
2b–h
2a
O
O
O
Scheme 2 Synthesis of 5,6-cis-disubstituted 7-oxabicyclo[2.2.1]hept-
2-enes 2a–h. Reagents and conditions: a) Et2O, r.t., 48 h, 91%; b)
LAH, THF, r.t., 24 h, 97%; c) for details, see the experimental section.
The alphabetical suffixes for compounds 2 represent the various sub-
stituents: b, R = Bz; c, R = Ac; d, R = Ms; e, R = CO2Me; f,
R = CONMe2; g, R = Me; h, R = Bn.
SYNTHESIS 2010, No. 5, pp 0818–0822
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Advanced online publication: 22.12.2009
DOI: 10.1055/s-0029-1218618; Art ID: F20009SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Convenient Synthesis of meso-Cyclohexa-1,3-dienes
819
AcBr
By using 2b as a test substrate, we first optimized the con-
ditions for cleavage of the 2,5-dihydrofuran ring. It has
been reported that 2,5-dihydrofuran itself reacts with
acetyl bromide at room temperature in the absence of a
catalyst to give (2Z)-4-bromobut-2-en-1-yl acetate.10 In
fact, treatment of 2b with acetyl bromide under the report-
ed conditions occasionally afforded the desired 3-acet-
oxy-6-bromocyclohexene 3 (Table 1), but the reaction
was not readily reproducible. When sulfuric acid was em-
ployed either catalytically, or even stoichiometrically ac-
cording to the literature,7 significant amounts of the
starting material were recovered and some unidentified
byproducts were obtained. In contrast, the analogous
compound 2 (R = OAc) underwent a clean conversion
into the corresponding ring-opened product. After many
unsuccessful trials, we eventually observed that rust on
the needle attached to the syringe accelerated the reaction.
Careful experiments showed that 2b on its own did not, in
fact, react with acetyl bromide (Table 1, entry 1), whereas
iron(III) hydroxide oxide [FeO(OH), 5 mol%], the main
component of rust, produced a remarkable rate accelera-
tion to give 3 as a diastereomeric mixture (entry 2).11
Acetyl bromide probably transforms iron(III) hydroxide
oxide into an iron(III) salt of sufficient Lewis acidity12 to
assist the C–O displacement reaction of 2b with the bro-
mide anion through a carbenium-ion intermediate13 by co-
ordination to the furan oxygen (Scheme 3, path a).
Alternatively, the acetyl cation, as the actual Lewis acid,
FeIII
(yellow powder)
(dark red solution)
FeO(OH)
Br
CH2Cl2
(path a)
OFeIII
OFeIII
R
R
R
R
FeIII
FeIII
Br
AcBr
FeIII
Br
2
3
O
R
R
Br
Br
Br
(path b)
AcBr
FeIII
Ac
+
[Br-FeIII]
OAc
R
R
[Br-FeIII]
Ac
2
3
O
Ac
R
R
FeIII
Scheme 3 Plausible mechanisms for the ring-opening reaction
We next examined the 1,4-reductive elimination reaction
with zinc and acetic acid in tetrahydrofuran, and found
that the reaction gave the cyclohexa-1,3-diene 1b quanti-
tatively (Scheme 4).8b
Zn (10 equiv), AcOH (0.1 equiv), THF, r.t., 0.5 h
quant
OBz
OBz
3
1b
could be generated by the reaction between acetyl bro- Scheme 4 Reductive elimination reaction of 3 with Zn and AcOH
in THF to give cyclohexa-1,3-diene 1b
mide and an iron(III) salt (Scheme 3 path b). In fact,
iron(III) bromide was found to be similarly effective to
the hydroxide oxide (Table 1, entry 3). The use of acetyl
bromide is more critical, as neither acetyl chloride nor
acetic anhydride caused the reaction under the same con-
ditions. Because it is readily available and stable in air,
iron(III) hydroxide oxide was used throughout the re-
mainder of the study.
We then assumed that the iron(III) species would not in-
terfere with the action of zinc, and that acetic acid could
be supplied by hydrolysis of acetyl bromide used in a
slight excess, so that a one-pot preparation of 1b from 2b
without isolation of 3 should be possible. In fact, after we
had confirmed by thin-layer chromatography that 2b was
completely converted into 3 by acetyl bromide (1.2 equiv)
in the presence of iron hydroxide oxide (5 mol%), we add-
ed tetrahydrofuran and zinc dust successively to the mix-
ture and obtained cyclohexa-1,3-diene 1b quantitatively
(Table 2, entry 1).14 Other substrates 2c–h bearing various
hydroxy protecting groups were also examined to deter-
mine whether carboxylic acid ester (entries 1 and 2), sul-
fonic acid ester (entry 3), carbonate (entry 4), carbamate
(entry 5), and methyl ether groups (entry 6) were compat-
ible with the reaction conditions. The reaction of 2f was
slower, presumably because the carbamoyl group coordi-
nated strongly to an iron(III) species, reducing the catalyt-
ic activity of the latter. The lower yields obtained with 2h
were attributed to partial detachment of the benzyl group
(entry 7) during the iron(III)-catalyzed ring-opening step.
Protecting groups that are more sensitive to acids, such as
tert-butyl(dimethyl)silyl or methoxymethyl, were not
suitable, as deprotection and acetylation by acetyl bro-
mide occurred to give cyclohexa-3,5-diene-1,2-diyl-
bis(methylene) diacetate (1c; data not shown). In fact, 1c
was obtained directly from 2a by treatment with an excess
of acetyl bromide (Scheme 5).
Table 1 Ring-Opening Reaction of 7-Oxabicyclo[2.2.1]hept-2-ene
(2b) with Acetyl Bromide Catalyzed by Iron(III) Hydroxide Oxide
OAc
AcBr, catalyst, CH2Cl2, r.t.
OBz
OBz
OBz
OBz
O
2b
Br
3
Entry Catalysta
AcBr
(equiv)
Time
(h)
Conversion
(%)b
1
2
3
none
1
8
trace
>99
92
FeO(OH) (5 mol%)c
FeBr3 (5 mol%)
1
1
0.5
0.5
a For the reaction conditions, see the experimental section.
b Determined by 1H NMR analysis.
c The FeO(OH) was pretreated with AcBr for 30 min before addition
of 2b.
Synthesis 2010, No. 5, 818–822 © Thieme Stuttgart · New York

820
T. Yano et al.
PAPER
Table 2 One-Pot Diene Synthesis from Various 2,5-Dihydrofurans
matrix. Column chromatography was conducted on silica gel 60N
(spherical, neutral), 63–210 mm, obtained from Kanto Chemical
Co., Inc. TLC was performed on Merck silica gel plate (60 F-254).
FeO(OH) and AcBr were purchased from Kanto Chemical Co., Inc.
and from Nacalai Tesque, Inc., respectively, and were used as re-
ceived. Zn powder was purchased from Tokyo Chemical Industry
Co., Ltd. and was activated before use by washing with 1 M aq HCl.
CH2Cl2 was purchased from Wako Pure Chemical Industries, Ltd.
and freshly distilled over CaH2 before use. THF was used as re-
ceived from Wako Pure Chemical Industries, Ltd. Compound 2a
was prepared as previously reported.9
1) FeO(OH) (5 mol%), AcBr (1.2 equiv),
OR
OR
OR
OR
CH2Cl2, r.t.
O
2) Zn (3 equiv), THF, r.t., 0.5 h
2b–h
1b–h
Entry
Substratea (R)
2b (Bz)
Time (h)b
Yield (%)c
1
2
3
4
5
6
7
1
99
99
99
99
80
92
52
2c (Ac)
1
2d (Ms)
2.5
2.5
14
1
1,3-Dienes (1b–h); General Procedure
A Schlenk flask was charged with diene 2 (0.5 mmol), FeO(OH)
(2.2 mg, 25 mmol), and CH2Cl2 (2 mL) under argon. AcBr (44 mL,
0.6 mmol) was added to the resulting suspension, and the mixture
was stirred at r.t. for the time shown in Table 2 until the starting ma-
terial was completely consumed (TLC). Zn powder (0.10 g, 1.5
mmol) was added and the mixture was stirred for 5 min, and then
THF (1 mL) was added and the mixture was stirred for a further 30
min. The mixture was treated with sat. aq. NaHCO3 then filtered
through a pad of Celite to remove unreacted Zn powder. The filtrate
was extracted with CH2Cl2 (2 × 20 mL), and the organic layer was
washed with brine, dried (Na2SO4), and concentrated in vacuo. The
crude product was purified by column chromatography (silica gel).
2e (CO2Me)
2f (CONMe2)
2g (Me)
2h (Bn)
1.5
a See the experimental section for typical reaction conditions.
b Reaction time for the iron-catalyzed ring-opening step.
c Isolated yields.
1) FeO(OH) (5 mol%), AcBr (4 equiv),
CH2Cl2, r.t., 3 h
OH
OH
OAc
OAc
(1R*,2S*)-Cyclohexa-3,5-diene-1,2-diylbis(methylene) Diben-
zoate (1b)
Column chromatography: hexane–EtOAc, 5:1; yield: 99%; Rf = 0.6
(hexane–EtOAc, 5:1).
O
2) Zn (3 equiv), THF, r.t., 0.5 h
99% (3 steps, 1 pot)
2a
1c
IR (KBr): 1717, 1273, 1111, 710 cm–1.
Scheme 5 Conversion of 7-oxabicyclo[2.2.1]hept-2-ene 2a into cy-
clohexa-1,3-diene 1c by one-pot acetylation, furan ring opening, and
reductive elimination
1H NMR (300 MHz, CDCl3): d = 7.97 (d, J = 7.3 Hz, 4 H), 7.52 (t,
J = 7.3 Hz, 2 H), 7.37 (t, J = 7.7 Hz, 4 H), 6.10–6.06 (m, 2 H), 5.84–
5.81 (m, 2 H), 4.47 (d, J = 6.6 Hz, 4 H), 3.12–3.04 (m, 2 H).
Finally, we successfully performed the reaction with 2b
on a larger scale (26 mmol) to demonstrate the synthetic
benefits of the present method (Scheme 6).15
13C NMR (75 MHz, CDCl3): d = 166.5, 132.9, 130.0, 129.5, 128.3,
126.3, 125.6, 63.5, 35.2.
HRMS-FAB: m/z [M + H]+ calcd for C20H20O4: 349.1440; found:
349.1451.
1) FeO(OH) (5 mol%), AcBr (1.2 equiv),
CH2Cl2, r.t., 2.5 h
The synthesis of 1b was also carried out in a 26 mmol scale under
almost the same conditions as described in the general procedure,
except for a prolonged reaction time at the Fe-catalyzed ring-open-
ing reaction step and a lower reaction temperature at the Zn-medi-
ated reductive elimination step (Scheme 6). Safety note: When
scaled up, the second step of the one-pot protocol should be per-
formed at 0 °C because it is significantly exothermic.
OBz
OBz
OBz
OBz
O
2) Zn (3 equiv), THF, 0 °C, 0.5 h
quant (2 steps, 1 pot)
2b
9.4 g
1b
9.0 g
Scheme 6 Large-scale synthesis of 7-oxabicyclo[2.2.1]hept-2-ene
2b
(1R*,2S*)-Cyclohexa-3,5-diene-1,2-diylbis(methylene) Diace-
tate (1c)
Column chromatography: hexane–EtOAc, 4:1; yield: 99%; Rf = 0.4
(hexane–EtOAc, 3:1).
IR (KBr): 1744, 1242, 1231 cm–1.
1H NMR (300 MHz, CDCl3): d = 6.02–5.99 (m, 2 H), 5.72–5.67 (m,
2 H), 4.19–4.06 (m, 4 H,), 2.87–2.77 (m, 2 H), 2.05 (s, 6 H).
In summary, we have developed a convenient synthesis of
5,6-cis-disubstituted cyclohexa-1,3-dienes, which are
useful as starting materials for the synthesis of densely
functionalized cyclohexane derivatives such as cyclitols
or carbasugars, by means of a one-pot, two-step deoxy-
genation of 7-oxabicyclo[2.2.1]hept-2-enes. The method
is readily scalable without any experimental difficulties.
13C NMR (75 MHz, CDCl3): d = 171.0, 126.3, 125.4, 63.0, 34.9,
20.9.
HRMS-FAB: m/z [M + H]+ calcd for C12H16O4: 225.1127; found:
225.1131.
All melting points were measured on a Yanaco Micro Melting Point
Apparatus MP-J3 and are uncorrected. H NMR spectra were re-
1
corded at 300 MHz or 400 MHz on a JEOL JNM-AL-300 or a JEOL
JNM-AL-400 instrument, respectively. 13C NMR spectra were re-
corded at 75 MHz on a JEOL JNM-AL-300 instrument. IR spectra
were recorded on a SHIMADZU FTIR-8400 instrument. High-
resolution mass (HR-FABMS) spectra were recorded on a JEOL
JMS-HX-110 mass spectrometer with 3-nitrobenzyl alcohol as the
1c was also synthesized from 2a by following the general proce-
dure, except for the use of an excess (4 equiv) of AcBr and a pro-
longed reaction time (3 h) before the reductive elimination step
(Scheme 5).
Synthesis 2010, No. 5, 818–822 © Thieme Stuttgart · New York

PAPER
Convenient Synthesis of meso-Cyclohexa-1,3-dienes
821
(1R*,2S*)-Cyclohexa-3,5-diene-1,2-diylbis(methylene)
Dimethanesulfonate (1d)
Column chromatography: hexane–EtOAc, 1:2; yield: 99%; Rf = 0.5
(hexane–EtOAc, 1:3).
(3 × 100 mL). The combined organic layers were washed with brine
(50 mL), dried (Na2SO4), and concentrated in vacuo. The crude
product was recrystallized [CH2Cl2–hexane (2:1; 30 mL)] to give
2b as crystals; yield: 7.3 g (81%); mp 165–166 °C; Rf = 0.4 (hex-
ane–EtOAc, 5:1).
Because 1d gradually decomposed upon standing at r.t., only the 1H
and 13C NMR spectra are presented here.
IR (KBr): 1717, 1279, 1269, 1119, 712 cm–1.
1H NMR (400 MHz, CDCl3): d = 6.10–6.07 (m, 2 H), 5.74–5.70 (m,
2 H), 4.34 (dd, J = 7.8 and 9.8 Hz, 2 H), 4.23 (dd, J = 5.9 and 9.8
Hz, 2 H), 3.04 (s, 6 H), 3.01–2.95 (m, 2 H).
13C NMR (75 MHz, CDCl3): d = 126.3, 124.7, 67.4, 37.5, 35.3.
1H NMR (300 MHz, CDCl3): d = 8.08 (d, J = 7.2 Hz, 4 H), 7.59 (t,
J = 7.2 Hz, 2 H), 7.47 (t, J = 7.2 Hz, 4 H), 6.44 (s, 2 H), 4.98 (s, 2
H,), 4.65 (dd, J = 5.7 and 10.8 Hz, 2 H), 4.39 (dd, J = 9.2 and 10.8
Hz, 2 H), 2.28–2.22 (m, 2 H).
13C NMR (75 MHz, CDCl3): d = 166.3, 135.7, 133.1, 130.0, 129.6,
128.5, 80.6, 64.4, 39.5.
(1R*,2S*)-Cyclohexa-3,5-diene-1,2-diylbis(methylene) Dimeth-
yl Biscarbonate (1e)
Column chromatography: hexane–EtOAc, 3:1; yield: 99%; mp 58–
59 °C; Rf = 0.4 (hexane–EtOAc, 3:1).
HRMS-FAB: m/z [M + H]+ calcd for C22H20O5: 365.1389; found:
365.1419.
IR (KBr): 1755, 1454, 1443, 1275, 961, 937 cm–1.
1H NMR (300 MHz, CDCl3): d = 6.04–6.00 (m, 2 H), 5.73–5.68 (m,
2 H), 4.28–4.12 (m, 4 H,), 3.77 (s, 6 H), 2.90–2.83 (m, 2 H).
13C NMR (75 MHz, CDCl3): d = 155.6, 125.8, 125.6, 66.3, 54.7,
34.8.
HRMS-FAB: m/z [M + H]+ calcd for C12H16O6: 257.1025; found:
257.1017.
(1R*,2S*,3R*,4S*)-7-Oxabicyclo[2.2.1]hept-5-ene-2,3-diyl-
bis(methylene) Diacetate (2c)
This compound was prepared by a slight modification of the litera-
ture procedure.16
The 1H and 13C NMR spectra are consistent with those reported.
1H NMR (300 MHz, CDCl3): d = 6.40 (s, 2 H), 4.82 (s, 2 H), 4.28
(dd, J = 5.1 and 11.0 Hz, 2 H), 4.07–3.97 (m, 2 H), 2.09 (s, 6 H),
2.07–1.88 (m, 2 H).
(1R*,2S*)-Cyclohexa-3,5-diene-1,2-diylbis(methylene) Bis(di-
methylcarbamate) (1f)
Column chromatography: hexane–EtOAc, 1:3; yield: 80%; Rf = 0.5
(hexane–EtOAc, 1:4).
13C NMR (75 MHz, CDCl3): d = 170.9, 135.6, 80.4, 63.8, 39.2, 21.0.
(1R*,2S*,3R*,4S*)-7-Oxabicyclo[2.2.1]hept-5-ene-2,3-diyl-
bis(methylene) Dimethanesulfonate (2d)
The compound was prepared by a slight modification of the litera-
IR (KBr): 1705, 1497, 1456, 1402, 1360, 1194, 1057, 770 cm–1.
1H NMR (300 MHz, CDCl3): d = 6.00–5.97 (m, 2 H), 5.74–5.69 (m,
2 H), 4.20–4.09 (m, 4 H,), 2.90 (s, 12 H), 2.90–2.80 (m, 2 H).
13C NMR (75 MHz, CDCl3): d = 156.3, 126.4, 125.0, 63.8, 36.2,
35.7, 35.3.
HRMS-FAB: m/z [M + H]+ calcd for C14H22N2O4: 283.1658; found:
283.1659.
ture procedure.17
The 1H and 13C NMR spectra were consistent with those reported.
1H NMR (300 MHz, CDCl3): d = 6.43 (t, J = 0.9 Hz, 2 H), 4.89 (t,
J = 0.9 Hz, 2 H), 4.37 (dd, J = 5.7 and 9.7 Hz, 2 H), 4.25–4.19 (m,
2 H,), 3.07 (s, 6 H), 2.24–2.16 (m, 2 H).
13C NMR (75 MHz, CDCl3): d = 135.6, 80.2, 68.8, 40.2, 37.6.
(1R*,2S*,3R*,4S*)-7-Oxabicyclo[2.2.1]hept-5-ene-2,3-diyl-
bis(methylene) Dimethyl Biscarbonate (2e)
(5R*,6S*)-5,6-Bis(methoxymethyl)cyclohexa-1,3-diene (1g)
Column chromatography: CH2Cl2; yield: 92%.
MeO2CCl (0.4 mL, 6.5 mmol) was added to a soln of 2a (0.17 g, 1.1
mmol), DMAP (6 mg, 50 mmol), and pyridine (0.4 mL, 5 mmol) in
CH2Cl2 (4 mL) at 0 °C under argon, and the mixture was allowed to
warm to r.t. with stirring for 3 h. The mixture was treated with sat.
aq NaHCO3 (2 mL) and extracted with CH2Cl2 (3 × 10 mL). The
combined organic layers were washed with brine (5 mL), dried
(Na2SO4), and concentrated in vacuo. The crude product was puri-
fied by column chromatography [silica gel, hexane–EtOAc (2:1)] to
give 2e as an oil; yield: 0.25 g (88%); mp 57–58 °C; Rf = 0.5 (hex-
ane–EtOAc, 1:1).
The 1H and 13C NMR spectra were consistent with those reported in
the literature.6
1H NMR (300 MHz, CDCl3): d = 5.96–5.92 (m, 2 H), 5.74–5.70 (m,
2 H), 3.51–3.46 (m, 2 H), 3.38–3.32 (m, 2 H), 3.32 (s, 6 H), 2.78–
2.68 (m, 2 H).
13C NMR (75 MHz, CDCl3): d = 127.9, 124.5, 71.8, 58.6, 35.8.
(5R*,6S*)-5,6-Bis(benzyloxymethyl)cyclohexa-1,3-diene (1h)
Column chromatography: hexane–CH2Cl2, 1:1; yield: 52%.
IR (KBr): 1744, 1445, 1323, 1263, 949, 901, 840, 795 cm–1.
The 1H and 13C NMR spectra were consistent with those reported in
1H NMR (300 MHz, CDCl3): d = 6.38 (s, 2 H), 4.86 (s, 2 H), 4.32
(dd, J = 7.9 and 10.3 Hz, 2 H), 4.16–4.05 (m, 2 H), 3.81 (s, 6 H),
2.12–2.03 (m, 2 H).
13C NMR (75 MHz, CDCl3): d = 155.4, 135.5, 80.3, 67.3, 54.9, 39.3.
HRMS-FAB: m/z [M + H]+ calcd for C12H16O7: 273.0974; found:
273.0989.
the literature.6
1H NMR (300 MHz, CDCl3): d = 7.37–7.24 (m, 10 H), 5.96–5.92
(m, 2 H), 5.78–5.73 (m, 2 H), 4.46 (s, 4 H), 3.61–3.56 (m, 2 H,),
3.48–3.43 (m, 2 H), 2.86–2.76 (m, 2 H).
13C NMR (75 MHz, CDCl3): d = 138.5, 128.3, 128.1, 127.6, 127.5,
124.5, 73.0, 69.5, 36.0.
(1R*,2S*,3R*,4S*)-7-Oxabicyclo[2.2.1]hept-5-ene-2,3-diyl-
bis(methylene) Bis(dimethylcarbamate) (2f)
(1R*,2S*,3R*,4S*)-7-Oxabicyclo[2.2.1]hept-5-ene-2,3-diyl-
bis(methylene) Dibenzoate (2b)
A soln of 2a (0.78 g, 5.0 mmol) in THF (20 mL) was cooled to 0 °C,
NaH (60% in mineral oil, 0.39 g, 11 mmol) was slowly added, and
the mixture was stirred for 30 min. Me2NCOCl (1.0 mL, 11 mmol)
was added dropwise and the mixture was allowed to warm to r.t.
with stirring overnight. After treatment with H2O (10 mL), the mix-
BzCl (6.3 mL, 55 mmol) was added dropwise to a soln of 2a (3.8 g,
25 mmol), DMAP (0.3 g, 2.5 mmol), and Et3N (7.6 mL, 55 mmol)
in CH2Cl2 (100 mL) at 0 °C under argon, and the mixture was al-
lowed to warm to r.t. with stirring overnight. The mixture was then
treated with sat. aq. NaHCO3 (50 mL) and extracted with CH2Cl2
Synthesis 2010, No. 5, 818–822 © Thieme Stuttgart · New York

822
T. Yano et al.
PAPER
ture was extracted with EtOAc (3 × 20 mL). The combined organic
layers were washed with brine (10 mL), dried (Na2SO4), and con-
centrated in vacuo. The crude product was purified by column chro-
matography [silica gel, hexane–EtOAc (1:3)] to give 2f as crystals;
yield: 0.85 g (57%); mp 85–86 °C; Rf = 0.3 (hexane–EtOAc, 1:4).
Institute for Materials Chemistry and Engineering, Kyushu Univer-
sity, for HRMS-FAB analysis.
References
IR (KBr): 1697, 1501, 1445, 1400, 1366, 1182, 1059, 768, 679
cm–1.
(1) Catalytic Asymmetric Synthesis, 2nd ed.; Ojima, I., Ed.;
Wiley: New York, 2000.
(2) For selected reviews, see: (a) Rovis, T. In New Frontiers in
Asymmetric Catalysis; Mikami, K.; Lautens, M., Eds.;
Wiley: Hoboken, 2007, 275. (b) Spivey, A. C.; Andrews, B.
I.; Brown, A. D. Recent Res. Dev. Org. Chem. 2002, 6, 147.
(3) Takano, S.; Yoshimitsu, T.; Ogasawara, K. J. Org. Chem.
1994, 59, 54.
(4) Arjona, O.; Gómez, A. M.; López, J. C.; Plumet, J. Chem.
Rev. 2007, 107, 1919.
(5) Staben, S. T.; Xin, L.; Toste, F. D. J. Am. Chem. Soc. 2006,
128, 12658.
(6) Lautens, M.; Ma, S.; Belter, R. K.; Chiu, P.; Leschziner, A.
J. Org. Chem. 1992, 57, 4065.
(7) (a) Baran, A.; Kazaz, C.; Seçen, H. Tetrahedron 2004, 60,
861. (b) Baran, A.; Kazaz, C.; Seçen, H.; Sütbeyaz, Y.
Tetrahedron 2003, 59, 3643.
(8) For reviews on reductive elimination of vicinal heteroatoms,
see: (a) Krebs, A.; Swienty-Busch, J.; Fleming, I. In
Comprehensive Organic Synthesis, Vol. 6; Trost, B. M., Ed.;
Pergamon: Oxford, 1991, Chap. 5.1.3.2. (b) Ham, P. Zinc–
Acetic Acid, In Encyclopedia of Organic Reagents for
Organic Synthesis, Vol. 8; Paquette, L. A., Ed.; Wiley: New
York, 1995, 5531.
(9) Das, J.; Vu, T.; Harris, D. N.; Ogletree, M. L. J. Med. Chem.
1988, 31, 930.
(10) Mitchell, M.; Qaio, L.; Wong, C.-H. Adv. Synth. Catal.
2001, 343, 596.
(11) The present ring-opening reaction is apparently
nonstereospecific in contrast to those reported by Seçen,
which are retentive and directed by a neighboring-group
effect (see ref. 7).
(12) Upon addition of AcBr to a yellow suspension of FeO(OH)
in CH2Cl2, a dark-red homogeneous solution was obtained.
(13) Ferritto, R.; Vogel, P. Synlett 1996, 281.
(14) Water was not intentionally added, but the reductive
elimination was carried out in open air so that the AcBr was
probably hydrolyzed to AcOH.
1H NMR (300 MHz, CDCl3): d = 6.38 (s, 2 H), 4.83 (s, 2 H), 4.35
(dd, J = 12.2 and 15.8 Hz, 2 H), 4.12–4.01 (m, 2 H), 2.93 (s, 12 H),
2.07–1.98 (m, 2 H).
13C NMR (75 MHz, CDCl3): d = 156.3, 135.6, 80.4, 64.7, 39.6, 36.4,
35.9.
HRMS-FAB: m/z [M + H]+ calcd for C14H22N2O5: 299.1607; found:
299.1565.
(1R*,2S*,3R*,4S*)-2,3-Bis(methoxymethyl)-7-oxabicy-
clo[2.2.1]hept-5-ene (2g)
The compound was prepared by a slight modification of the litera-
ture procedure.18
The 1H and 13C NMR spectra were consistent with those reported.
1H NMR (300 MHz, CDCl3): d = 6.35 (t, J = 0.9 Hz, 2 H), 4.83 (t,
J = 0.9 Hz, 2 H), 3.48 (dd, J = 5.1 and 8.8 Hz, 2 H), 3.36 (s, 6 H),
3.34–3.28 (m, 2 H), 1.95–1.86 (m, 2 H).
13C NMR (75 MHz, CDCl3): d = 135.5, 80.5, 72.0, 58.8, 39.8.
(1R*,2S*,3R*,4S*)-2,3-Bis(benzyloxymethyl)-7-oxabicy-
clo[2.2.1]hept-5-ene (2h)
NaH (60% in mineral oil, 0.50 g, 13 mmol) was slowly added to a
soln of 2a (0.71 g, 4.7 mmol) in THF (20 mL) at 0 °C, and the mix-
ture was stirred for 30 min. BnBr (1.5 mL, 13 mmol) was added
dropwise, and the mixture was allowed to warm to r.t. with stirring
overnight. After treatment with H2O (10 mL), the mixture was ex-
tracted with EtOAc (3 × 20 mL). The combined organic layers were
washed with brine (10 mL), dried (Na2SO4), and concentrated in
vacuo. The crude product was purified by column chromatography
[silica gel, hexane–EtOAc (8:1)] to give 2h as an oil; yield: 0.97 g
(62%); Rf = 0.3 (hexane–EtOAc, 8:1).
IR (KBr): 1497, 1454, 1366, 1310, 1028, 907, 737, 696 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.38–7.25 (m, 10 H), 6.35 (s, 2 H),
4.87 (s, 2 H), 4.51 and 4.49 (ABq, J = 12.1 Hz, 4 H), 3.59 (dd,
J = 5.1 and 8.8 Hz, 2 H), 3.42–3.36 (m, 2 H), 2.01–1.92 (m, 2 H).
13C NMR (75 MHz, CDCl3): d = 138.2, 135.5, 128.4, 127.7, 127.7,
80.7, 73.3, 69.8, 40.0.
HRMS-FAB: m/z [M + H]+ calcd for C22H24O3: 337.1804; found:
337.1805.
(15) In large-scale reactions, the second step of the present one-
pot protocol should be performed at 0 °C because it is
significantly exothermic.
(16) Takao, K.; Yasui, H.; Yamamoto, S.; Sasaki, D.; Kawasaki,
S.; Watanabe, G.; Tadano, K. J. Org. Chem. 2004, 69, 8789.
(17) (a) Oishi, T.; Maruyama, M.; Shoji, M.; Maeda, K.;
Kumahara, N.; Tanaka, S.-I.; Hirama, M. Tetrahedron 1999,
55, 7471. (b) Borthwick, S.; Dohle, W.; Hirst, R. P.; Booker-
Milburn, I. K. Tetrahedron Lett. 2006, 47, 7205.
(18) Millward, D. B.; Sammis, G.; Waymouth, R. M. J. Org.
Chem. 2000, 65, 3902.
Acknowledgment
This work was supported by the Asahi Glass Foundation. We are
also grateful to Professor Fumito Tani and Ms. Eri Okazaki at the
Synthesis 2010, No. 5, 818–822 © Thieme Stuttgart · New York