Diastereoselective synthesis of 2-arylmethylene-6-hydroxyspiro[4.5]deca-7-ones via FeCl3·6H2O-catalyzed spiroannulation/hydride transfer of 6-(5-arylpent-4-yn-1-yl)-7-oxabicyclo[4.1.0]heptan-2-ols

Article abstract of DOI:10.1021/jo5023266

In the presence of a catalytic amount of FeCl₃·6H₂O, 6-(5-arylpent-4-yn-1-yl)-7-oxabicyclo[4.1.0]heptan-2-ols underwent attack of the pendant acetylene at the iron-activated oxirane to give a vinylic carbocation. Hydride transfer from the carbinol carbon to the newly formed cation center furnished 2-arylmethylene-6-hydroxyspiro[4.5]deca-7-ones in excellent stereoselectivity and good yields.

Full text of DOI:10.1021/jo5023266

Note
pubs.acs.org/joc
Diastereoselective Synthesis of 2‑Arylmethylene-6-
hydroxyspiro[4.5]deca-7-ones via FeCl3·6H2O‑Catalyzed
Spiroannulation/Hydride Transfer of 6‑(5-Arylpent-4-yn-1-yl)-7-
oxabicyclo[4.1.0]heptan-2-ols
Hsin-Hui Lin, Kuan-Yi Lee, Yin-An Chen, Chi-Fan Liu, and Ming-Chang P. Yeh*
Department of Chemistry, National Taiwan Normal University, 88 Ding-Jou Road, Section 4, Taipei 11677, Taiwan, Republic of
China
S
* Supporting Information
ABSTRACT: In the presence of a catalytic amount of FeCl3·6H2O, 6-(5-arylpent-4-yn-1-yl)-7-oxabicyclo[4.1.0]heptan-2-ols
underwent attack of the pendant acetylene at the iron-activated oxirane to give a vinylic carbocation. Hydride transfer from the
carbinol carbon to the newly formed cation center furnished 2-arylmethylene-6-hydroxyspiro[4.5]deca-7-ones in excellent
stereoselectivity and good yields.
he spirocarbocyclic skeleton is present in many natural
report a FeCl3·6H2O-catalyzed spiroannulation/hydride trans-
Tproducts. Due to the existence of spirocycles possessing fer of 6-alkynylalkyl-tethered 7-oxabicyclo[4.1.0]-heptan-2-ols,
affording 2-arylmethylene-6-hydroxyspiro[4.5]deca-7-ones in
good yields and excellent stereoselectivity under air at room
temperature. The spiroannulation may start from attack of the
acetylene at the FeCl3·6H2O-activated oxirane to form a
carbocation, followed by intramolecular hydride transfer from
the carbinol carbon to the newly formed cation center, which
furnished 2-arylmethylene-6-hydroxyspiro[4.5]deca-7-ones.
The cyclic syn epoxy alcohols 1 tethering a 5-arylpent-4-ynyl
moiety at the C-6 position of the ring were prepared from
epoxidation of the corresponding 3-(5-arylpent-4-yn-1-yl)-
cyclohex-2-enols16 with 1.2 equiv of m-chloroperoxybenzoic
acid (m-CPBA). To select an optimum reaction protocol for
the cycloisomerization of 1a, various parameters, such as
Brønsted and Lewis acids, solvents, and temperatures, were
investigated. With acids such as HOTf and ZnBr2 in DCM, 1a
decomposed to give an unidentified crude mixture (Table 1,
entries 1 and 2). When reacted with 0.1 equiv of BF3·OEt2 in
DCM (0.1 M) at room temperature under air for 10 min, 1a
generated the α-hydroxy spirocyclic ketone 2a as a single
stereoisomer in 27% yield (Table 1, entry 3), and none of the
semipinacol rearrangement product was obtained. NMR studies
have provided the initial evidence for the structural assignment
of 2a. The 1H NMR spectrum of 2a showed a triplet, centered
at δ 6.41, assigned to the vinyl proton; a doublet of doublets,
centered at δ 4.39, assigned to the proton at the carbinol
carbon; and a doublet, centered at δ 3.60, assigned to the
useful biological properties, the development of effective
methods to all carbon spirocycles has been actively pursued.1
Many synthetic methods for the construction of such
spirocycles involved alkylation via direct substitution2 or
Michael addition,3 base-induced vinylcyclo-propanol and
-butanol rearrangement,4 pinacol-type rearrangement of cyclic
allylic alcohols bearing an aldehyde,5 or cyclic 2,3-epoxyols,6
rearrangement of bridged cycles,7 Nazarov-type spiroannulation
of dienones,8 Diels−Alder cycloaddition of dienes and cyclic
enones,9 transition-metal-based cycloaddition,10 ene reaction,11
radical cyclization,12 and ring closing metathesis of gem-
dialkenyl molecules.13 As part of our ongoing investigations
on Lewis acid assisted cyclization of cyclic enynols, we recently
reported an example of TfOH-catalyzed cycloisomerization of
C-3-arylpropargylsulfonamide-tethered 2,3-epoxycyclohexanols
at 50 °C in dichloroethane (DCE) for 40 min, producing
spiropiperidines in good yields (Scheme 1, eq 1).14 The
reaction started with the TfOH-assisted semipinacol rearrange-
ment to give the ring contraction 2-arylpropargylsulfonamide-
tethered cyclopentanecarbaldehyde, which underwent a TfOH-
promoted alkyne-aldehyde metathesis via [2 + 2] cyclo-
addition/[2 + 2] cycloreversion to furnish the spiropiperidines.
Surprisingly, when the N-tosylpropargyl tether was replaced by
an alkynylalkyl group, the Lewis acid catalyzed cycloisomeriza-
tion reaction of alkynylalkyl-tethered 2,3-epoxycyclohexanols
proceeded via a different reaction path (Scheme 1, eq 2).
Although intramolecular coupling reaction of alkynes and
epoxides has been studied, the reaction required NiBr2·3H2O,
PhMe2P, and reducing agent i-PrOH at 60 °C.15 Herein, we
Received: October 11, 2014
© XXXX American Chemical Society
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Note
Scheme 1. Acid-Catalyzed Cycloisomerization Reaction of C-6-Alkynylalkyl-Tethered 7-Oxabicyclo[4.1.0]heptan-2-ols
a
Table 1. Optimization of the Reaction Conditions
entry
Lewis acid
TfOH
equiv
solvent
time
yield (%)
b
1
2
0.1
0.5
0.1
0.5
2.0
0.3
0.5
0.5
0.1
0.3
0.1
0.1
0.1
0.05
0.5
0.1
0.5
0.3
0.2 M DCM
0.1 M DCM
0.1 M DCM
0.1 M DCM
0.1 M DCM
0.1 M THF
0.1 M DBE
0.5 h
26 h
n.d.
n.d.
27
b
ZnBr2
3
BF3·OEt2
FeCl3
10 min
0.5 h
0.5 h
4.0 h
24 h
4
37
5
FeCl3
21
6
FeCl3
trace
trace
31
7
FeCl3
8
FeCl3
0.1 M DCE
0.1 M DCM
0.01 M DCM
0.01 M DCM
0.01 M THF
0.01 M MeCN
0.1 M DCM
0.1 M DCM
0.1 M DCM
0.1 M DCM
0.1 M DCM
0.01 M DCM
3.0 h
3.0 h
1.0 h
3.5 h
24 h
9
FeCl3·6H2O
FeCl3·6H2O
FeCl3·6H2O
FeCl3·6H2O
FeCl3·6H2O
AuCl(PPh3)/AgOTf
InCl3
31
10
11
12
13
14
15
16
17
18
19
50
57
c
n.r.
c
24 h
n.r.
3 min
22 h
8
21
5
AgOTf
4.0 h
3.0 h
2.0 h
25 h
SnCl4
29
10
TMSCl
c
Fe(NO3)3·9H2O
0.1
n.r.
a
b
c
All reactions were carried out under air at room temperature. Not detected. No reaction.
hydroxyl proton. The 13C NMR spectrum exhibited a signal at
δ 211.1 assigned to the carbonyl carbon; a signal at δ 150.8
assigned to the olefinic quaternary carbon; a signal at δ 126.2
assigned to the other olefinic carbon; and a signal at δ 81.3
assigned to the carbinol carbon. The relative stereochemistry of
2a was proved by NOESY (nuclear Overhauser enhancement
spectroscopy) measurements and further secured by X-ray
diffraction analysis.17
Next, we focused our efforts toward the use of other Lewis
acids (SnCl4, AuCl(PPh3)/AgOTf, InCl3, SnCl4, AgOTf,
TMSCl, FeCl3, and FeCl3·6H2O), solvents (DCM, DCE,
DBE, THF, MeCN, and MeOH), and temperatures. Results of
the study are summarized in Table 1. As can be seen from
Table 1, subjection of 0.1 equiv of FeCl3·6H2O to 1a in DCM
at 0.01 M concentration under air at room temperature for 3.5
h produced 2a in a best isolated yield of 57% (Table 1, entry
11).
With optimized reaction conditions in hand, we next
explored the generality of the spiroannulation/hydride transfer
reaction conditions with various substituents on the phenyl
ring, and results are shown in Table 2. The phenyl rings bearing
one or two methyl groups at the C-3 or C-4 position of the
phenyl ring, 2b−d, were smoothly cyclized to give the desired
spirocyclic ketones 2b−d in 70−80% yields. A phenyl group at
the C-4 position of the phenyl group, 1e, was also efficient,
providing a 77% yield of the desired spirocyclic ketone 2e.17
Sterically hindered naphthalenyl- or phenanthrenyl-substituted
alkynes, 1f and 1g, resulted in lower yields of the corresponding
products 2f (46%) and 2g (45%). Substrate 1h, with an
electron-donating methoxy group at C-3 of the phenyl ring,
afforded 2h17 in 59% yield. Moving this electron-donating
group to C-4, 1i gave a significant increase in the yield of the
desired product 2i (86%). On the basis of higher yields
obtained with a methyl or methoxy group at C-4 of the phenyl
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Table 2. Synthesis of 2-Arylmethylene-6-hydroxyspiro[4.5]deca-7-ones from 6-(5-Arylpent-4-yn-1-yl)-7-
a b c
, ,
oxabicyclo[4.1.0]heptan-2-ols and FeCl3·6H2O
a
b
c
Reaction conditions: 1 (1.0 equiv), FeCl3·6H2O (10 mol %), air, room temperature. Structures were confirmed by X-ray diffraction analysis. No
reaction.
ring, it may be stated that an electron-donating substituent at
the C-4 of the phenyl ring increased the nucleophilicity of the
acetylene, which attacked at the iron-activated oxirane more
efficiently to give a higher yield of the spirocyclic ketone (see
Scheme 2). Moreover, the presence of a bromine atom on the
phenyl ring, for example, 1j and 1k, was also tolerated and
produced the corresponding spirocyclic ketones 2j and 2k,
albeit in only 13 and 17% yield, respectively. Incorporation of
an arylalkynyl moiety at the C-4 position of the phenyl ring,
1l−n, was also effective and generated the desired spirocyclic
ketones 2l−n in moderate yields (46−62%). Unfortunately,
compound 1o bearing an electron-withdrawing ester group at
the C-3 position of the phenyl ring delivered the spirocyclic
ketone 2o in only 10% yield. Moreover, compound 1p, carrying
an amino group at C-4 of the phenyl ring, was recovered
C
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Note
group in the alkynylalkyl tether (Scheme 1, eq 1) may reduce
the nucleophilicity of the acetylene, and thereby prevented the
acetylene from attacking the activated oxirane. Instead, the
reaction underwent the acid-promoted semipinacol rearrange-
ment/alkyne-aldehyde metathesis to afford the spiro-
piperidines.
Scheme 2. Suggested Reaction Mechanism for the
Formation of 1 to 2
To provide further insight into the reaction mechanism, a
deuterium-labeling experiment was conducted. The deuterated
substrate 1c-d, with 86% d-incorporation (relative to one
proton) at the carbinol carbon, was subjected to the opitimized
reaction conditions (Scheme 3). The desired compound 2c-d
was isolated in 81% yield with 86% d-incorporation at the
vinylic carbon. Moreover, the deuterium NMR of 2c-d verified
the existence of deuterium incorporation at the vinylic position
(see the NMR spectra in the Supporting Information for
details). Thus, the deuterium-labeling study provided strong
evidence to support the hydride transfer mechanism, as
suggested above.
However, no desired spiro hydroxyketone was observed
when substrate 9, having a terminal alkyne, was treated with 0.1
equiv of FeCl3·6H2O under the same reaction conditions.
Instead, carbochlorination of 9 occurred,16 generating 8-
chlorospiro[5.5]undec-7-ene-1,2-diol (10)17 as a single stereo-
isomer in 34% yield (Scheme 4). Compound 9 failed to
Scheme 4. Carbochlorination of 9
quantitatively when treated with FeCl3·6H2O under the
standard reaction conditions.
The reaction path for the formation of 2a from 1a is
suggested in Scheme 2. Attack of the pendant acetylene at the
iron-activated oxirane 7 gave the vinylic cation 8. Transfer of
the hydride from the carbinol carbon to the proximal cation
center led to the spirocyclic ketone 2 after protonation. A
similar 1,5-hydride shift in a vinylic cation intermediate has
been reported.18 Moreover, treatment of the diastereomer of 1i,
anti-1i (Figure 1), with 0.1 equiv of FeCl3·6H2O resulted in
undergo the usual spiroannulation/hydride transfer process,
which may be due to the unfavorable formation of a terminal
vinylic carbocation. Unfortunately, the use of 1.0 equiv of
FeCl3·6H2O did not improve the yield, and 9 gave 10 in only
23% yield. Moreover, subjection of the methyl-terminated
alkyne substrate, 11, to FeCl3·6H2O under the standard
reaction conditions led to a 24% yield of the spirodiendiol 12
and a 20% yield of the desired spirocyclic ketone 13 (Scheme
5). The formation of 12 may start from attack of the acetylene
Figure 1. Structure of anti-1i.
recovering of the starting substrate quantitatively under the
standard reaction conditions. Therefore, it is reasonable to state
that chelation of both hydroxyl and oxirane oxygens to the iron
center to form intermediates 7 and 8 is critical for the
spiroannulation/hydride transfer reaction path. It is important
to note that the electron-withdrawing effect of the N-tosyl
Scheme 3. Deuterium-Labeling Study
D
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Note
(3 × 13 cm, 10% ethyl acetate/hexanes) to afforded 3-(5-phenylpent-
4-yn-1-yl)cyclohex-2-enone as a light yellow oil (1.220 g, 66%). To a
solution of 3-(5-phenylpent-4-yn-1-yl)cyclohex-2-enone (0.370 g, 1.55
mmol) in methanol (15.5 mL) were added NaBH4 (0.070 g, 1.80
mmol) and CeCl3·7H2O (0.870 g, 2.32 mmol) at 0 °C under air. After
the reaction was stirred at room temperature for 30 min, the methanol
was removed under reduced pressure. To the reaction mixture were
added water and ethyl acetate (1/1). The aqueous phase was extracted
with ethyl acetate (3 × 30 mL) and washed with brine (30 mL). The
combined organic layers were dried over MgSO4, filtered, and
concentrated under reduced pressure to give a crude oil. To the
crude product in DCM (15.5 mL) at 0 °C was added mCPBA (0.395
g, 2.33 mmol, 70%) portionwise, and the reaction mixture was stirred
at 0 °C for 10 min. The reaction mixture was allowed to warm up to
room temperature. After being stirred for 3 h, the mixture was
quenched with saturated NaHCO3(aq). The resulting mixture was
stirred at rt for 30 min. The mixture was extracted with DCM (3 × 30
mL) and washed with brine. The organic layer was dried over MgSO4.
The drying agent was removed by filtration, and the resulting solution
was concentrated under reduced pressure. The residue was purified by
flash chromatography over silica gel (3 × 13 cm, 10% ethyl acetate/
hexanes), providing (1S*,2S*,6R*)-6-(5-phenylpent-4-ynyl)-7-
oxabicyclo[4.1.0]heptan-2-ol (1a) (0.278 g, 1.09 mmol, 70%) as a
yellow oil: 1H NMR (400 MHz, CDCl3) δ 7.39−7.31 (m, 2H), 7.28−
7.26 (m, 3H), 4.00 (s, 1H), 3.19 (d, J = 2.9 Hz, 1H), 2.45−2.43 (m,
2H), 1.99 (s, 1H), 1.88−1.81 (m, 1H), 1.76−1.68 (m, 5H), 1.58−
1.43(m, 3H), 1.30−1.22 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3)
δ 131.5, 128.2, 127.6, 29.4, 81.2, 66.8, 63.9, 61.2, 36.5, 29.2, 26.8, 24.0,
19.4, 18.1; IR (CH2Cl2) 3412, 2942, 2856, 1491, 1442, 848, 758, 693
cm−1; MS (EI) m/e (%) 256.1 ([M]+, 8), 238.1 (31), 210.1 (22),
128.1 (100), 115.1 (70); HRMS (EI) m/e calcd for C17H20O2 [M]+
256.1463, found 256.1466.
Scheme 5. Cycloisomerization of 11
at the iron-activated oxirane to form the cation intermediate 14.
Deprotonation of the methyl group gave the spiroallene 15,
which underwent double bond migration to afford the
spirodiendiol 12. The (Z)-configuration of the exo double
bond was confirmed by NOSEY NMR spectroscopy.
In conclusion, this report describes a general stereoselective
synthesis of 2-arylmethylene-6-hydroxyspiro[4.5]deca-7-ones
through FeCl3·6H2O-catalyzed spiroannulation/hydride trans-
fer of 6-(5-arylpent-4-yn-1-yl)-7-oxabicyclo[4.1.0]-heptan-2-ols.
A variety of spiro α-hydroxyketones were available stereo-
selectively using a catalytic amount of the inexpensive, efficient,
and environmentally friendly FeCl3·6H2O at room temperature
in the open air.
(1S*,2S*,6R*)-6-(5-m-Tolylpent-4-ynyl)-7-oxabicyclo[4.1.0]-
heptan-2-ol (1b). (0.561 g, 0.21 mmol, 81% from 0.821 g, 3.26 mmol
1
of 3-(5-(m-tolyl)pent-4-yn-1-yl)cyclohex-2-enone). A yellow oil: H
NMR (400 MHz, CDCl3) δ 7.21−7.15 (m, 3H), 7.08 (d, J = 6.9 Hz,
1H), 4.01−3.98 (m, 1H), 3.19 (d, J = 3.1 Hz, 1H), 2.44−2.41 (m,
2H), 2.31 (s, 3H), 2.08 (br s, 1H), 1.87−1.80 (m, 1H), 1.75−1.67 (m,
5H), 1.58−1.42 (m, 3H), 1.30−1.24 (m, 1H); 13C{1H} NMR (100
MHz, CDCl3) δ 137.9, 132.2, 128.6, 128.6, 128.1, 123.6, 89.0, 81.3,
66.9, 64.0, 61.3, 36.6, 29.1, 26.8, 24.0, 21.2, 19.4, 18.2; IR (CH2Cl2)
3421, 2940, 2864, 1715, 1600, 1448, 784, 692 cm−1; MS (ESI) m/e
(%) 293.1 ([M + Na]+, 100), 288.2 (18); HRMS (ESI) m/e calcd for
C18H22NaO2 [M + Na]+ 293.1517, found 293.1519.
EXPERIMENTAL SECTION
■
General Considerations. All FeCl3·H2O-catalyzed cycloisomeri-
zation reactions were performed in the open air at ambient
temperature. Anhydrous solvents or reaction mixtures were transferred
via an oven-dried syringe or cannula. Solvents were predried by
molecular sieves and then by passing through an Al2O3 column. 6-(5-
Arylpent-4-yn-1-yl)-7-oxabicyclo[4.1.0]heptan-2-ols 1 were synthe-
sized by oxidation of 6-(5-arylpent-4-yn)cyclohex-2-enol15 with
MCPBA. Column chromatography was conducted with silica gel 60,
(1S*,2S*,6R*)-6-(5-p-Tolylpent-4-ynyl)-7-oxabicyclo[4.1.0]-
heptan-2-ol (1c). (0.662 g, 2.45 mmol, 67% from 0.920 g, 3.66 mmol
1
of 3-(5-(p-tolyl)pent-4-yn-1-yl)cyclohex-2-enon). A colorless oil: H
NMR (400 MHz, CDCl3) δ 7.27 (d, J = 7.9 Hz, 2H), 7.08 (d, J = 7.9
Hz, 2H), 3.99 (br s, 1H), 3.18 (d, J = 3.0 Hz, 1H), 2.44−2.41 (m, 2H),
2.33 (s, 3H), 2.04 (d, J = 8.3 Hz, 1H), 1.87−1.80 (m, 1H), 1.75−1.67
(m, 5H), 1.59−1.42 (m, 3H), 1.30−1.21 (m, 1H); 13C{1H} NMR
(100 MHz, CDCl3) δ 137.6, 131.4, 128.9, 120.7, 88.5, 81.2, 66.8, 63.6,
61.2, 36.5, 29.1, 26.8, 24.0, 21.4, 19.4, 18.1; IR (CH2Cl2) 3419, 2942,
2863, 1444, 1037, 817 cm−1; MS (EI) m/e (%) 270.1 ([M]+, 8), 252.2
(18), 237.2 (17), 165.1 (18), 142.1 (100); HRMS (EI) m/e calcd for
C18H22O2 [M]+ 270.1620, found 270.1619.
(1S*,2S*,6R*)-6-(5-p-Tolylpent-4-ynyl)-7-oxabicyclo[4.1.0]-
heptan-2-ol (1c-d). (0.133 g, 0.49 mmol, 71% from 0.174 g, 0.69
mmol of 3-(5-(p-tolyl)pent-4-yn-1-yl)cyclohex-2-enone). A colorless
oil: 1H NMR (400 MHz, CDCl3) δ 7.27 (d, J = 8.2 Hz, 2H), 7.08 (d, J
= 8.0 Hz, 2H), 4.00 (s, 86% D), 3.18 (s, 1H), 2.44−2.41 (m, 2H), 2.33
(s, 3H), 2.00 (br s, 1H), 1.87−1.81 (m, 1H), 1.76−1.67 (m, 5H),
1.58−1.43 (m, 3H), 1.29−1.24 (m, 1H); 13C{1H} NMR (100 MHz,
CDCl3) δ 137.6, 131.4, 128.9, 120.7, 88.5, 81.2, 66.4 (t, JCD = 21.7 Hz,
1C), 63.9, 61.2, 36.5, 29.0, 26.7, 24.0, 21.4, 19.4, 18.1; 2H NMR (76.8
MHz, CDCl3) δ 4.00 (s, 12H); IR (CH2Cl2) 3430, 3027, 2941, 2863,
1510, 1167, 818 cm−1; MS (FAB) m/e (%) 272.1 ([M + H]+, 37),
254.1 (60), 142.1 (84), 119.1 (74); HRMS (FAB) m/e calcd for
C18H222HO2 [M + H]+ 272.1761, found 272.1761.
1
hexanes, and ethyl acetate. H NMR were recorded at 400 or 500
MHz in CDCl3 with CHCl3 (δ 7.24 ppm) or (CH3)4Si (δ 0.00 ppm)
as internal standard. 13C NMR spectra were obtained at 100 or 125
MHz in CDCl3 with CHCl3 as internal standard (δ 77.00 ppm).
Melting points are uncorrected. Mass spectra were acquired on a
spectrometer at an ionization potential of 70 eV and were reported as
mass/charge (m/e) with percent relative abundance. High-resolution
mass spectra were obtained with a double-focusing mass spectrometer.
General Procedure for the Synthesis of 1a. To a solution of t-
butyllithium (15 mmol, 1.6 M in pentane) was added slowly a solution
of (5-iodopent-1-yn-1-yl)benzene (2.538 g, 9.4 mmol) in ether (20
mL) over a period of 30 min at −78 °C under N2. After the reaction
mixture was stirring at this temperature for 30 min, 3-ethoxycyclohex-
2-en-1-one (1.10 g, 7.85 mmol) in ether (15 mL) was added dropwise
at −78 °C under N2. After 0.5 h, the reaction mixture was allowed to
warm to room temperature. The reaction was monitored by TLC,
until no trace of enone could be detected. The mixture was quenched
with HCl(aq) (35 mL, 2.0 M) at 0 °C for 30 min, followed by stirring at
rt for 2 h. The aqueous phase was extracted with ether (3 × 30 mL)
and washed with brine (30 mL). The combined organic layers were
dried over MgSO4, filtered, and concentrated under reduced pressure
to give a crude oil. The oil was purified by flash column over silica gel
E
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Note
(1S*,2S*,6R*)-6-(5-(3,4-Dimethylphenyl)pent-4-yn-1-yl)-7-
oxabicyclo[4.1.0]heptan-2-ol (1d). (0.600 g, 2.12 mmol, 75% from
0.750 g, 2.82 mmol of 3-(5-(3,4-dimethylphenyl)pent-4-yn-1-yl)-
cyclohex-2-enone). A yellow oil: 1H NMR (400 MHz, CDCl3) δ
7.17 (s, 1H), 7.12 (d, J = 7.8 Hz, 1H), 7.04 (d, J = 7.7 Hz, 1H), 4.00
(br s, 1H), 3.19 (d, J = 3.1 Hz, 1H), 2.44−2.41 (m, 2H), 2.24 (s, 3H),
2.22 (s, 3H), 1.94 (br s, 1H), 1.88−1.81 (m, 1H), 1.76−1.67 (m, 5H),
1.58−1.42 (m, 3H), 1.29−1.24 (m, 1H); 13C{1H} NMR (100 MHz,
CDCl3) δ 136. 136.4, 132.6, 129.5, 128.9, 121.0, 88.3, 81.3, 66.8, 64.0,
61.2, 36.5, 29.1, 26.8, 24.0, 19.6, 19.5, 19.4, 18.1; IR (CH2Cl2) 3421,
2940, 2864, 1499, 1489, 1037, 820 cm−1; MS (ESI) m/e (%) 307.2
([M + Na]+, 100); HRMS (ESI) m/e calcd for C19H24NaO2 [M +
Na]+ 307.1674, found 307.1677.
(1S*,2S*,6R*)-6-(5-(Biphenyl-4-yl)pent-4-ynyl)-7-oxabicyclo-
[4.1.0]heptan-2-ol (1e). (0.417 g, 1.25 mmol, 84% from 0.470 g, 1.5
mmol of 3-(5-([1,1′-biphenyl]-4-yl)pent-4-yn-1-yl)cyclohex-2-enon).
A yellow solid; mp 100−101 °C; 1H NMR (400 MHz, CDCl3) δ 7.56
(d, J = 7.3 Hz, 2H), 7.51 (d, J = 8.3 Hz, 2H), 7.45 (d, J = 8.4 Hz, 2H),
7.41 (d, J = 7.8 Hz, 2H), 7.33 (t, J = 7.3 Hz, 1H), 4.02 (br s, 1H), 3.18
(d, J = 2.9 Hz, 1H), 2.46−2.43 (m, 2H), 2.32 (d, J = 7.1 Hz, 1H),
1.86−1.79 (m, 1H), 1.76−1.68 (m, 5H), 1.59−1.42 (m, 3H), 1.28−
1.20 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 140.3, 140.3,
131.9, 128.7, 127.4, 126.9, 126.8, 122.7, 90.1, 81.0, 66.9, 63.8, 61.3,
36.5, 28.9, 26.7, 24.9, 19.4, 18.3; IR (CH2Cl2) 2421, 3031, 2941, 1446,
842, 765 cm−1; MS (EI) m/e (%) 332.1 ([M]+, 7), 314.2 (10), 204.1
(100), 191.1 (28); HRMS (EI) m/e calcd for C23H24O2 [M]+
332.1776, found 332.1782.
mmol of 3-(5-(4-methoxyphenyl)pent-4-yn-1-yl)cyclohex-2-enone). A
yellow oil: 1H NMR (400 MHz, CDCl3) δ 7.33−7.30 (m, 2H), 6.82−
6.79 (m, 2H), 3.99 (br s, 1H), 3.79 (s, 3H), 3.18 (d, J = 3.0 Hz, 1H),
2.43−2.40 (m, 2H), 2.21 (br s, 1H), 1.86−1.79 (m, 1H), 1.75−1.66
(m. 5H), 1.50−1.42 (m, 3H), 1.30−1.21 (m, 1H); 13C{1H} NMR
(100 MHz, CDCl3) δ 159.0, 132.8, 115.9, 113.8, 87.7, 80.8, 66.9, 63.9,
61.2, 55.2, 36.5, 28.9, 26.7, 24.0, 19.3, 18.2; IR (CH2Cl2) 3406, 3032,
2942, 2863, 1487, 842, 764, 698 cm−1; MS (FAB) m/e (%) 287.2 ([M
+ H]+, 10), 219.2 (18), 204.1 (100), 181.1 (50), 167.1 (49); HRMS
(FAB) m/e calcd for C18H23O3 [M + H]+ 287.1647, found 287.1649.
(1R*,2S*,6S*)-6-(5-(4-Methoxyphenyl)pent-4-ynyl)-7-oxabicyclo-
[4.1.0]heptan-2-ol (anti-1i). To a solution of 3-(5-(4-methoxy-
phenyl)pent-4-yn-1-yl)cyclohex-2-enone and NaOH (2 M, 0.050
mL, 0.1 mmol) in methanol was added H2O2 (35%, 0.388 g, 4
mmol) at 0 °C, and the reaction mixture was stirred at 0 °C until the
starting material is consumed (TLC). The reaction mixture was
purified by flash chromatography (silica gel, 10% ethyl acetate/
hexanes) affording (1S*,6S*)-6-(5-(4-methoxyphenyl)-pent-4-yn-1-
yl)-7-oxabicyclo[4.1.0]heptan-2-one as a light yellow oil (0.270 g,
0.95 mmol, 95%). To a solution of (1S*,6S*)-6-(5-(4-methoxy-
phenyl)pent-4-yn-1- yl)-7-oxabicyclo[4.1.0]heptan-2-one (0.227 g,
0.80 mmol) in methanol (8.0 mL) were added NaBH4 (0.036 g,
0.96 mmol) and CeCl3·7H2O (0.417 g, 1.12 mmol) at 0 °C under air.
After the reaction was stirred at room temperature for 30 min, the
methanol was removed under reduced pressure. To the reaction
mixture were added water and ethyl acetate (1/1). The aqueous phase
was extracted with ethyl acetate (3 × 30 mL) and washed with brine
(30 mL). The combined organic layers were dried over MgSO4,
filtered, and concentrated under reduced pressure and purified by flash
chromatography (silica gel, 9% ethyl acetate/hexanes) to give
(1R*,2S*,6S*)-6-(5-(4-methoxyphenyl)pent-4-ynyl)-7-oxabicyclo-
(1S*,2S*,6R*)-6-(5-(Naphthalen-1-yl)pent-4-ynyl)-7-oxabicyclo-
[4.1.0]heptan-2-ol (1f). (0.400 g, 1.31 mmol, 83% from 0.455 g, 1.57
mmol of 3-(5-(naphthalen-1-yl)pent-4-yn-1-yl)cyclohex-2-enone). A
1
yellow oil: H NMR (400 MHz, CDCl3) δ 8.31 (d, J = 8.2 Hz, 1H),
1
7.82 (d, J = 8.0 Hz, 1H), 7.77 (d, J = 8.2 Hz, 1H), 7.61 (d, J = 7.1 Hz,
1H), 7.57−7.53 (m, 1H), 7.51−7.47 (m, 1H), 7.38 (t, J = 7.7 Hz, 1H),
3.99 (br s, 1H), 3.20 (d, J = 3.0 Hz, 1H), 2.61−2.55 (m, 2H), 2.21 (br
s, 1H), 1.88−1.69 (m, 6H), 1.58−1.42 (m, 3H), 1.27−1.22 (m, 1H);
13C{1H} NMR (100 MHz, CDCl3) δ 133.3, 133.0, 129.9, 128.1, 127.9,
126.4, 126.1, 126.0, 125.4, 121.4, 94.4, 79.0, 66.9, 63.8, 61.3, 36.5, 28.7,
26.5, 24.0, 19.6, 18.3; IR (CH2Cl2) 3406, 2942, 2862, 2223, 1586,
1396, 801, 775 cm−1; MS (EI) m/e (%) 306.1 ([M]+, 8), 178.1 (100),
165.1 (60), 141.1 (36); HRMS (EI) m/e calcd for C21H22O2 [M]+
306.1620, found 306.1625.
[4.1.0]heptan-2-ol as a colorless oil (0.110 g, 0.38 mmol, 48%). H
NMR (400 MHz, CDCl3) δ 7.36−7.32 (m, 2H), 6.85−6.82 (m, 2H),
4.08−4.03 (m, 1H), 3.82 (s, 3H), 2.98 (s, 1H), 2.46−2.43 (m, 2H),
1.98−1.87 (m, 2H), 1.79−1.68 (m. 6H), 1.55−1.47 (m, 1H), 1.36−
1.28 (m, 1H), 1.24−1.16 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3)
δ 159.1, 132.9, 116.0, 113.8, 87.9, 80.8, 66.7, 62.1, 61.0, 55.3, 36.1,
30.0, 27.5, 24.1, 19.4, 15.5.
(1S*,2S*,6R*)-6-(5-(2-Bromophenyl)pent-4-ynyl)-7-oxabicyclo-
[4.1.0]heptan-2-ol (1j). (0.215 g, 0.64 mmol, 65% from 0.313 g, 0.99
mmol of 3-(5-(2-bromophenyl)pent-4-yn-1-yl)cyclohex-2-enone). A
1
yellow oil: H NMR (400 MHz, CDCl3) δ 7.56 (dd, J = 7.9, 1.3 Hz,
(1S*,2S*,6R*)-6-(5-Phenanthren-9-yl)pent-4-ynyl)-7-oxabicyclo-
[4.1.0]heptan-2-ol (1g). (0.468 g, 1.31 mmol, 66% from 0.340 g, 1.01
mmol of 3-(5-(phenanthren-9-yl)pent-4-yn-1-yl)cyclohex-2-enone). A
1H), 7.41 (dd, J = 7.7, 1.8 Hz, 1H), 7.24 (td, J = 7.9, 1.3 Hz, 1H), 7.12
(td, J = 7.7, 1.7 Hz, 1H), 4.00 (br s, 1H), 3.20 (d, J = 3.2 Hz, 1H),
2.51−2.48 (m, 2H), 2.01−1.95 (m, 1 H), 1.89−1.70 (m, 6H), 1.59−
1.43 (m, 3H), 1.31−1.21 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3)
δ 133.3, 132.3, 128.1, 126.9, 125.8, 125.4, 94.5, 80.0, 66.8, 63.9, 61.2,
36.4, 29.1, 26.8, 23.8, 19.5, 18.1 IR (CH2Cl2) 3398, 2939, 2864, 1465,
1026, 755 cm−1; MS (ESI) m/e (%) 359.0 ([M + 2 + Na]+, 95), 357.0
([M + Na]+, 100); HRMS (ESI) m/e calcd for C17H19BrNaO279 [M +
Na]+ 357.0466, found 357.0462.
(1S*,2S*,6R*)-6-(5-(4-Bromophenyl)pent-4-ynyl)-7-oxabicyclo-
[4.1.0]heptan-2-ol (1k). (0.372 g, 1.11 mmol, 74% from 0.432 g, 1.50
mmol of 3-(5-(4-bromophenyl)pent-4-yn-1-yl)cyclohex-2-enone). A
yellow solid; mp 54−55 °C; 1H NMR (400 MHz, CDCl3) δ 7.41 (, J =
8.5 Hz, 2H), 7.24 (d, J = 8.4 Hz, 2H), 4.02−3.96 (m, 1H), 3.18 (d, J =
3.1 Hz, 1H), 2.43−2.40 (m, 2H), 2.03−1.99 (m, 1H), 1.88−1.81 (m,
1H), 1.75−1.65 (m, 5H), 1.58−1.42 (m, 3H), 1.31−1.22 (m, 1H);
13C{1H} NMR (100 MHz, CDCl3) δ 130.0, 131.4, 122.7, 121.7, 90.7,
1
yellow oil: H NMR (400 MHz, CDCl3) δ 8.68−8.66 (m, 1H), 8.63
(d, J = 8.2 Hz, 1H), 8.44−8.41 (m, 1H), 7.93 (s, 1H), 7.83 (dd, J = 7.8,
1.1 Hz, 1H), 7.68−7.55 (m, 4H), 4.03−4.00 (m, 1H), 3.23 (d, J = 3.1
Hz, 1H), 2.64−2.62 (m, 2H), 2.04 (br s, 1H), 1.92−1.72 (m, 6H),
1.59−1.44 (m, 3H),1.30−1.25 (m, 1H); 13C{1H} NMR (100 MHz,
CDCl3) δ 131.4, 131.3, 131.3, 130.0, 130.0, 128.3 (3C), 127.1, 126.9,
126.8, 122.7, 122.5, 120.1, 94.1, 79.3, 66.9, 63.9, 61.3, 36.7, 29.0, 26.8,
24.1, 19.7, 18.1; IR (CH2Cl2) 3405, 3061, 2943, 2863, 2221, 1492,
1040, 892 cm−1; MS (EI) m/e (%) 356.2 ([M]+, 16), 228.1 (100),
205.1 (15), 177.1 (11); HRMS (EI) m/e calcd for C25H24O2 [M]+
356.1776, found 356.1781.
(1S*,2S*,6R*)-6-(5-(3-Methoxyphenyl)pent-4-yn-1-yl)-7-oxabi-
cyclo[4.1.0]heptan-2-ol (1h). (0.39 g, 1.36 mmol, 73% from 0.500 g,
1.86 mmol of 3-(5-(3-methoxyphenyl)pent-4-yn-1-yl)cyclohex-2-
1
enone). A yellow oil: H NMR (400 MHz, CDCl3) δ 7.19 (t, J =
7.9 Hz, 1H), 6.98 (td, J = 7.9, 1.0 Hz, 1H), 6.92−6.91 (m, 1H), 6.85−
6.82 (m, 1H), 4.01−3.98 (m, 1H), 3.79 (s, 3H), 3.19 (d, J = 3.1 Hz,
1H), 2.45−2.42 (m, 2H), 1.94 (br s, 1H), 1.88−1.80 (m, 1H), 1.76−
1.67 (m, 5H), 1.53−1.43 (m, 3H), 1.31−1.25 (m, 1H); 13C{1H} NMR
(100 MHz, CDCl3) δ 159.2, 129.2, 124.7, 124.0, 116.4, 114.1, 89.3,
81.0, 66.9, 63.9, 61.2, 55.2, 36.5, 29.0, 36.7, 23.9, 19.3, 18.2; IR
(CH2Cl2) 3402, 2940, 1578, 1288, 1044, 853 cm−1; MS (ESI) m/e
(%) 309.1 ([M + Na]+, 100), 244.6 (5); HRMS (ESI) m/e calcd for
C18H22NaO3 [M + Na]+ 309.1467, found 309.1471.
80.2, 66.8, 63.8, 61.2, 36.5, 29.1, 26.8, 23.8, 19.4, 18.1; IR (CH2Cl2)
3406, 2942, 2863, 1711, 1486, 1070, 1010, 823 cm−1; MS (FAB) m/e
(%) 335.1 ([M + H]+, 35), 317.0 (60), 182.9 (85), 154.0 (100), 136.0
79
(72), 107.1 (39); HRMS (FAB) m/e calcd for C17H20BrO2 [M +
H]+ 335.0647, found 335.0647.
(1S*,2S*,6R*)-6-(5-(4-(Phenylethynyl)phenyl)pent-4-ynyl)-7-oxa-
bicyclo[4.1.0]heptan-2-ol (1l). (0.844 g, 2.37 mmol, 79% from 1.014
g, 3.00 mmol of 3-(5-(4-(phenylethynyl)phenyl)pent-4-yn-1-yl)-
cyclohex-2-enone). A yellow oil; 1H NMR (400 MHz, CDCl3) δ
7.53−7.51 (m, 2H), 7.45−7.43 (m, 2H), 7.37−7.33 (m, 5H), 4.00 (br
s, 1H), 3.19 (d, J = 3.0 Hz, 1H), 2.46−2.43 (m, 2H), 2.08 (br s, 1H),
(1S*,2S*,6R*)-6-(5-(4-Methoxyphenyl)pent-4-ynyl)-7-oxabicyclo-
[4.1.0]heptan-2-ol (1i). (0.117 g, 0.41 mmol, 45% from 0.243 g, 0.91
F
dx.doi.org/10.1021/jo5023266 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
1.88−1.84 (m, 1H), 1.75−1.67 (m, 5H), 1.59−1.43 (m, 3H), 1.31−
1.22 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 131.6, 131.5,
131.4, 128.4, 128.3, 123.7, 123.1, 122.5, 91.4, 90.8, 89.1, 81.0, 66.9,
63.9, 61.2, 36.5, 29.1, 26.7, 23.9, 19.5, 18.1; IR (CH2Cl2) 3473, 2947,
1715, 1509, 1108, 826, 757, 692 cm−1; MS (EI) m/e (%) 356.2 ([M]+,
7), 228.1 (100), 193.1 (11), 142.1 (23); HRMS (EI) m/e calcd for
C25H24O2 [M]+ 356.1766, found 356.1776.
(1S*,2S*,6R*)-6-(5-(4-(p-Tolylethynyl)phenyl)pent-4-yn-1-yl)-7-
oxabicyclo[4.1.0]heptan-2-ol (1m). (0.126 g, 0.34 mmol, 71% from
0.168 g, 0.477 mmol of 3-(5-(4-(p-tolylethynyl)phenyl)pent-4-yn-1-
yl)cyclohex-2-enone). A light yellow solid: mp 108−110 °C; 1H NMR
(400 MHz, CDCl3) δ 7.44−7.40 (m, 4H), 7.34 (d, J = 8.2 Hz, 2H),
7.15 (d, J = 8.0 Hz, 2H), 4.00 (br s, 1H), 3.19 (d, J = 3.1 Hz, 1H),
2.47−2.44 (m, 2H), 2.37 (s, 3H), 1.94−1.82 (m, 2H), 1.76−1.70 (m,
5H), 1.56−1.46 (m, 3H), 1.29−1.26 (m, 1H); 13C{1H} NMR (100
MHz, CDCl3) δ 138.6, 131.5, 131.5, 131.3, 129.1, 123.5, 122.7, 120.0,
91.3, 91.1, 88.5, 81.0, 66.8, 63.9, 61.2, 36.5, 29.2, 26.8, 23.9, 21.5, 19.5,
18.0 ; IR (CH2Cl2) 3358, 2938, 2857, 1516, 1434, 1036, 839 cm−1; MS
(ESI) m/e (%) 393.2 ([M + Na]+, 100), 367.2 (42), 363.2 (24), 279.1
(12); HRMS (ESI) m/e calcd for C26H26NaO2 [M + Na]+ 393.1831,
found 393.1834.
(APCI) m/e (%) 195.1 ([M + H]+, 100), 177.1 (18); HRMS (APCI)
m/e calcd for C12H19O2 [M + H]+ 195.1385, found 195.1383.
General Experimental Procedure for FeCl3·6H2O-Catalyzed
Cycloisomerization of 6-(5-Arylpent-4-yn-1-yl)-7-oxabicyclo-
[4.1.0]-heptan-2-ols. Synthesis of (5R*,6R*,E)-1-Benzylidene-6-
hydroxyspiro[4.5]decan-7-one (2a). To a solution of 6-(5-phenyl-
pent-4-yn-1-yl)-7-oxabicyclo[4.1.0]heptan-2-ol (1a) (0.17 g, 0.67
mmol) in DCM (67 mL) was added FeCl3·6H2O (18 mg, 0.067
mmol) at room temperature under air. After complete consumption of
the starting material (3.5 h), the reaction mixture was quenched with
H2O (50 mL). The resulting mixture was extracted with ether (3 × 30
mL). The organic phase was dried over MgSO4, filtered, and
concentrated under reduced pressure. Purification of the residue by
flash column chromatography (7% ethyl acetate/hexanes) over silica
gel gave 2a (98 mg, 0.38 mmol, 57%) as a white solid: mp 116−117
1
°C; H NMR (500 MHz, CDCl3) δ 7.36−7.31 (m, 4H), 7.18 (tt, J =
13.9, 1.7 Hz, 1H), 6.41 (t, J = 2.5 Hz, 1H), 4.39 (dd, J = 3.7, 1.2 Hz,
1H), 3.60 (d, J = 3.9 Hz, 1H), 2.71−2.67 (m, 2H), 2.59−2.55 (m,
1H), 2.51−2.44 (m, 1H), 2.06−2.01 (m, 1H), 1.92−1.60 (m, 6H),
1.40−1.35 (m, 1H); 13C{1H} NMR (125 MHz, CDCl3) δ 211.1,
150.8, 138.2, 128.5, 128.1, 126.2, 121.2, 81.3, 57.1, 39.0, 36.5, 32.3,
29.4, 24.2, 23.3; IR (CH2Cl2) 3475, 2946, 2831, 1714, 1108, 874, 697
cm−1; MS (EI) m/e (%) 256.2 ([M]+, 65), 238.2 (46), 183.1 (100),
141.1 (68), 129.1 (28); HRMS (EI) m/e calcd for C17H20O2 [M]+
256.1463, found 256.1465. Crystals suitable for X-ray diffraction
analysis were grown from CH2Cl2 and hexanes.17
(1S*,2S*,6R*)-6-(5-(4-((4-Methoxyphenyl)ethynyl)phenyl)pent-4-
yn-1-yl)-7-oxabicyclo[4.1.0]heptan-2-ol (1n). (0.280 g, 0.73 mmol,
61% from 0.438 g, 1.19 mmol of 3-(5-(4-((4-methoxyphenyl)ethynyl)-
phenyl)pent-4-yn-1-yl)cyclohex-2-enone). A light yellow solid: mp
1
108−110 °C; H NMR (400 MHz, CDCl3) δ 7.47−7.45 (m, 2H),
(5R*,6R*,E)-6-Hydroxy-1-(3-methylbenzylidene)spiro[4.5]decan-
7-one (2b). The crude residue obtained from the reaction of 1b (0.28
g, 1 mmol) with FeCl3·6H2O (28 mg, 0.1 mmol) was purified by flash
column chromatography to give 2b (0.19 g, 0.70 mmol, 70%) as a
7.42 (d, J = 8.3 Hz, 2H), 7.34 (d, J = 8.3 Hz, 2H), 6.89−6.74 (m, 2H),
4.02−3.98 (m, 1H), 3.82 (s, 1H), 3.19 (d, J = 3.0 Hz, 1H), 2.46−2.43
(m, 2H), 2.09 (br s, 1H), 1.88−1.81 (m, 1H), 1.75−1.69 (m, 5H),
1.58−1.43 (m, 3H), 1.31−1.24 (m, 1H); 13C{1H} NMR (100 MHz,
CDCl3) δ 159.7, 133.0, 131.4, 131.2, 123.3, 122.8, 115.2, 114.0, 91.2,
90.9, 87.8, 81.0, 66.8, 63.9, 61.2, 55.3, 36.5, 29.1, 26.8, 23.9, 19.5, 18.1;
IR (CH2Cl2) 3402, 2941, 2862, 1654, 1517, 1247, 1031, 833 cm−1; MS
(ESI) m/e (%) 409.2 ([M + Na]+, 100), 387.2 (11); HRMS (ESI) m/e
calcd for C26H26O3Na [M + Na]+ 409.1780, found 409.1773.
Ethyl 3-(5-((1R*,5S*,6S*)-5-Hydroxy-7-oxabicyclo[4.1.0]heptan-
1-yl)pent-1-yn-1-yl)benzoate (1o). (0.416 g, 1.27 mmol, 82% from
0.435 g, 1.40 mmol of ethyl 3-(5-(3-oxocyclohex-1-en-1-yl)pent-1-yn-
1-yl)benzoate). A light yellow oil: 1H NMR (400 MHz, CDCl3) δ 8.06
(t, J = 1.4 Hz, 1H), 7.94 (dt, J = 7.9, 1.3 Hz, 1H), 7.55 (dt, J = 7.9, 1.3
Hz, 1H), 7.36 (t, J = 7.8 Hz, 1H), 4.38 (q, J = 7.1 Hz, 2H), 4.03−3.97
(m, 1H), 3.19 (d, J = 3.1 Hz, 1H), 2.46−2.43 (m, 2H), 2.02 (d, J = 9.6
Hz, 1H),1.89−1.82 (m, 1H), 1.78−1.68 (m, 5H), 1.59−1.43 (m, 3H),
1.40 (t, J = 7.1 Hz, 3H), 1.32−1.23 (m, 1H); 13C{1H} NMR (100
MHz, CDCl3) δ 166.0, 135.6, 132.6, 130.6, 128.6, 128.3, 124.1, 90.4,
80.3, 66.8, 63.8, 61.2, 61.1, 36.5, 29.1, 26.8, 23.8, 19.4, 18.1, 14.3; IR
(CH2Cl2) 3424, 2941, 2863, 1720, 1295, 1227, 1105, 755 cm−1; MS
(FAB) m/e (%) 329.1 ([M + H]+, 43), 311.1 (100), 283.1 (97), 265.1
(53), 177.0 (65); HRMS (FAB) m/e calcd for C20H25O4 [M + H]+
329.1753, found 329.1751.
1
yellow oil: H NMR (400 MHz, CDCl3) δ 7.22−7.15 (m, 3H), 7.00
(d, J = 7.4 Hz, 1H), 6.38 (t, J = 2.4 Hz, 1H), 4.38 (d, J = 2.4 Hz, 1H),
3.60 (d, J = 3.7 Hz, 1H), 2.71−2.67 (m, 2H), 2.59−2.54 (m, 1H),
2.52−2.46 (m, 1H), 2.34 (s, 3H), 2.07−2.00 (m, 1H), 1.95−1.60 (m,
6H), 1.40−1.36 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 211.1,
150.5, 138.1, 137.6, 129.3, 128.0, 127.0, 125.5, 121.2, 81.3, 57.1, 39.0,
36.5, 32.3, 29.4, 24.4, 23.3, 21.5; IR (CH2Cl2) 3455, 2949, 2875, 1717,
144.1, 1104 cm−1; MS (APCI) m/e (%) 271.2 ([M + H]+, 100), 253.2
(13); HRMS (APCI) m/e calcd for [M + H]+ C18H23O2 271.1698,
found 271.1692.
(5R*,6R*,E)-6-Hydroxy-1-(4-methylbenzylidene)spiro[4.5]decan-
7-one (2c). The crude residue obtained from the reaction of 1c (0.14
g, 0.5 mmol) with FeCl3·6H2O (14 mg, 0.050 mmol) was purified by
flash column chromatography to give 2c (0.10 g, 0.36 mmol, 71%) as a
white solid: mp 97−99 °C; 1H NMR (500 MHz, CDCl3) δ 7.25 (d, J
= 8.1 Hz, 2H), 7.13 (d, J = 8.0 Hz, 2H), 6.37 (t, J = 2.4 Hz, 1H), 4.37
(s, 1H), 3.59 (d J = 2.9 Hz, 1H), 2.67−2.65 (m, 2H), 2.58−2.54 (m,
1H), 2.50−2.42 (m, 1H), 2.33 (s, 3H), 2.04−2.00 (m, 1H), 1.90−1.60
(m, 6H), 1.39−1.35 (m, 1H); 13C{1H} NMR (125 MHz, CDCl3) δ
211.1, 149.7, 135.8, 135.4, 128.8, 128.4, 121.0, 81.3, 57.1, 38.9, 36.5,
32.3, 29.4, 24.4, 23.3, 21.1; IR (CH2Cl2) 3477, 2945, 2871, 1714, 1385,
1313, 1108, 876 cm−1; MS (EI) m/e (%) 270.2 ([M]+, 70), 252.2 (21),
197.1 (100), 155.1 (51), 105.4 (68); HRMS (EI) m/e calcd for
C18H22O2 [M]+ 270.1620, found 270.1617. Crystals suitable for X-ray
diffraction analysis were grown from CH2Cl2 and hexanes.17
(1S*,2S*,6R*)-6-(Pent-4-yn-1-yl)-7-oxabicyclo[4.1.0]heptan-2-ol
(9). (0.935 g, 5.19 mmol, 88% from 0.972 g, 6.00 mmol of 3-(pent-4-
yn-1-yl)cyclohex-2-enone). A white oil: 1H NMR (400 MHz, CDCl3)
δ 3.99 (br s, 1H), 3.16 (d, J = 3.0 Hz, 1H), 2.24−2.20 (m, 2H), 2.11
(br s, 1H), 1.97 (t, J = 2.6 Hz, 1H), 1.85−1.78 (m, 1H), 1.75−1.61 (m,
5H), 1.58−1.51 (m, 2H), 1.48−1.42 (m, 1H), 1.30−1.21 (m, 1H);
13C{1H} NMR (100 MHz, CDCl3) δ 83.8, 68.8, 66.9, 63.8, 61.2, 36.3,
29.0, 26.7, 23.6, 18.4, 18.1; IR (CH2Cl2) 3414, 3295, 2942, 2864, 2116,
1037, 635 cm−1; MS (FAB) m/e (%) 181.1 ([M + H]+, 92), 163.1
(100), 123.1 (87), 121.1 (58); HRMS (FAB) m/e calcd for C11H17O2
[M + H]+ 181.1229, found 181.1227.
(5R*,6R*,E)-6-Hydroxy-1-(4-methylbenzylidene)spiro[4.5]decan-
7-one (2c-d). The crude residue obtained from the reaction of 1c-d
(59 mg, 0.22 mmol) with FeCl3·6H2O (5.9 mg, 0.022 mmol) was
purified by flash column chromatography to give 2c-d (48 mg, 0.18
1
mmol, 81%) as a white solid: mp 102−104 °C; H NMR (500 MHz,
CDCl3) δ 7.25 (d, J = 8.1 Hz, 2H), 7.13 (d, J = 7.9 Hz, 2H), 6.37 (t, J
= 2.4 Hz, 86% D), 4.37 (dd, J = 3.8, 1.3 Hz, 1H), 3.59 (d, J = 3.9 Hz,
1H), 2.71−2.65 (m, 2H), 2.56−2.54 (m, 1H), 2.50−2.43 (m, 1H),
2.33 (s, 3H), 2.05−2.01 (m, 1H), 1.90−1.60 (m, 6H), 1.39−1.35 (m,
1H); 13C{1H} NMR (125 MHz, CDCl3) δ 211.2, 149.6, 135.8, 135.4,
128.9, 128.4, 120.7 (t, JC‑D = 23.8 Hz, 1C), 81.3, 57.1, 39.0, 36.5, 32.3,
29.4, 24.5, 23.3, 21.1; IR (CH2Cl2) 3476, 2944, 2871, 1714, 1107, 820
cm−1; MS (EI) m/e (%) 271.1 ([M]+, 86), 253.2 (20), 242.2 (15),
198.1 (100), 156.1 (58), 106.1 (69); HRMS (EI) m/e calcd for
(1S*,2S*,6R*)-6-(Hex-4-yn-1-yl)-7-oxabicyclo[4.1.0]heptan-2-ol
(11). (0.579 g, 2.97 mmol, 74% from 0.705 g, 4.00 mmol of 3-(hex-4-
1
yn-1-yl)cyclohex-2-enone). A light yellow oil: H NMR (400 MHz,
CDCl3) δ 4.01−3.97 (m, 1H), 3.16 (d, J = 3.1 Hz, 1H), 2.17−2.13 (m,
2H), 2.00 (br s, 1H), 1.85−1.79 (m, 1H), 1.77 (t, J = 2.5 Hz, 3H),
1.73−1.64 (m, 3H), 1.61−1.42 (m, 5H), 1.30−1.21 (m, 1H); 13C{1H}
NMR (100 MHz, CDCl3) δ 78.5, 76.1, 66.8, 64.0, 61.2, 36.5, 29.1,
26.7, 24.2; IR (CH2Cl2)3421, 2943, 2863, 1443, 1065, 845 cm−1; MS
1
C18 H212HO2 [M]+ 271.1683, found 271.1685.
G
dx.doi.org/10.1021/jo5023266 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
(5R*,6R*,E)-1-(3,4-Dimethylbenzylidene)-6-hydroxyspiro[4.5]-
decan-7-one (2d). The crude residue obtained from the reaction of 1d
(0.23 g, 0.85 mmol) with FeCl3·6H2O (23 mg, 0.085 mmol) was
purified by flash column chromatography to give 2d (0.19 g, 0.66
3.1 Hz, 1H), 3.81 (s, 3H), 3.61 (d, J = 3.8 Hz, 1H), 2.72−2.68 (m,
2H), 2.60−2.55 (m, 1H), 2.52−2.47 (m, 1H), 2.07−2.02 (m, 1H),
1.92−1.60 (m, 6H), 1.41−1.36 (m, 1H); 13C{1H} NMR (100 MHz,
CDCl3) δ 211.1, 159.4, 151.1, 139.6, 129.0, 121.2, 121.1, 114.0, 111.9,
81.2, 57.1, 55.2, 38.9, 36.5, 32.4, 29.4, 24.4, 23.3; IR (CH2Cl2) 3470,
2946, 2874, 1714, 1596, 1443, 1158, 1107 cm−1; MS (APCI) m/e (%)
287.2 ([M + H]+, 100), 269.2 (30); HRMS (APCI) m/e calcd for
C18H23O3 [M + H]+ 287.1647, found 287.1640. Crystals suitable for
X-ray diffraction analysis were grown from CH2Cl2 and hexanes.17
(5R*,6R*,E)-6-Hydroxy-1-(4-methoxybenzylidene)spiro[4.5]-
decan-7-one (2i). The crude residue obtained from the reaction of 1i
(76 mg, 0.27 mmol) with FeCl3·6H2O (7.0 mg, 0.027 mmol) was
purified by flash column chromatography to give 2i (66 mg, 0.23
1
mmol, 80%) as a white solid: mp 108−110 °C; H NMR (400 MHz,
CDCl3) δ 7.12 (s, 1H), 7.09 (s, 2H), 6.34 (t, J = 2.4 Hz, 1H), 4.37 (dd,
J = 3.8, 1.1 Hz, 1H), 3.58 (d J = 3.8 Hz, 1H), 2.69−2.65 (m, 2H),
2.58−2.53 (m, 1H), 2.50−2.45 (m, 1H), 2.25 (s, 3H), 2.24 (s, 3H),
2.06−1.97 (m, 1H), 1.90−1.58 (m, 6H), 1.39−1.34 (m, 1H); 13C{1H}
NMR (100 MHz, CDCl3) δ 211.2, 149.5, 136.1, 135.8. 134.5. 129.9.
129.4. 125.9. 121.1. 81.3. 57.1. 39.0. 36.5. 32.3. 29.4 24.4. 23.3. 19.8.
19.4; IR (CH2Cl2) 34.75, 29.42, 28.70, 1715, 1443, 1107 cm−1; MS
(APCI) m/e (%) 285.2 ([M + H]+, 100), 267.2 (13); HRMS (APCI)
m/e calcd for C19H25O2 [M + H]+ 285.1855, found 285.1849. Crystals
suitable for X-ray diffraction analysis were grown from CH2Cl2 and
hexanes.17
1
mmol, 86%) as a white solid: mp 90−91 °C; H NMR (400 MHz,
CDCl3) δ 7.30−7.27 (m, 2H), 6.88−6.85 (m, 2H), 6.34 (t, J = 2.3 Hz,,
1H), 4.36 (d, J = 3.7 Hz, 1H), 3.80 (s, 3H), 3.60 (d, J = 3.8 Hz, 1H),
2.67−2.63 (m, 2H), 2.58−2.53 (m, 1H), 2.49−2.41 (m, 1H), 2.04−
1.99 (m, 1H), 1.93−1.60 (m, 6H), 1.38−1.34 (m, 1H); 13C{1H} NMR
(100 MHz, CDCl3) δ 211.1, 157.9, 148.4, 131.0, 129.6, 120.5, 113.5,
81.2, 57.0, 55.2, 38.9, 36.5, 32.1, 29.4, 24.4, 23.2; IR (CH2Cl2) 3473,
2945, 1607, 1510, 1248, 1178, 1107, 1712, 1034, 827 cm−1; MS (EI)
m/e (%) 286.1 ([M]+, 100), 213.1 (72), 171.1 (21), 121.1 (53);
HRMS (EI) m/e calcd for C18H22O3 [M]+ 286.1569, found 286.1574.
(5R*,6R*,E)-6-Hydroxy-1-(2-bromobenzylidene)spiro[4.5]decan-
7-one (2j). The crude residue obtained from the reaction of 1j (0.21 g,
0.63 mmol) with FeCl3·6H2O (17 mg, 0.063 mmol) was purified by
flash column chromatography to give 2j (27 mg, 0.08 mmol, 13%) as a
(5R*,6R*,E)-1-(Biphenyl-4-ylmethylene)-6-hydroxyspiro[4.5]-
decan-7-one (2e). The crude residue obtained from the reaction of 1e
(0.12 g, 0.35 mmol) with FeCl3·6H2O (10 mg, 0.035 mmol) was
purified by flash column chromatography to give 2e (0.09 g, 0.27
1
mmol, 77%) as a white solid: mp 179−180 °C; H NMR (400 MHz,
CDCl3) δ 7.61−7.56 (m, 4H), 7.44−7.40 (m, 4H), 7.34−7.32 (m,
1H), 6.43 (t, J = 2.2 Hz, 1H), 4.39 (d, J = 3.7 Hz, 1H), 3.62 (d, J = 3.8
Hz, 1H), 2.75−2.70 (m, 2H), 2.58−2.53 (m, 1H), 2.49−2.41 (m, 1H),
2.04−2.02 (m, 1H), 1.91−1.61 (m, 6H), 1.40−1.35 (m, 1H); 13C{1H}
NMR (100 MHz, CDCl3) δ 211.0, 151.1, 140.8, 138.7, 137.3, 128.9,
128.7, 127.1, 126.9, 126.7, 120.7, 81.2, 57.2, 28.9, 36.4, 32.4, 29.4, 24.4,
23.2; IR (CH2Cl2) 3482, 3027, 2944, 1714, 1108, 443, 699 cm−1; MS
(EI) m/e (%) 332.2 ([M]+, 76), 259.1 (45), 181.1 (100), 152.1 (67);
HRMS (EI) m/e calcd for C23H24O2 [M]+ 332.1776, found 332.1774.
Crystals suitable for X-ray diffraction analysis were grown from
CH2Cl2 and hexanes.17
1
yellow oil: H NMR (400 MHz, CDCl3) δ 7.56 (d, J = 7.9 Hz, 1H),
7.40 (dd, J = 76 1.0 Hz, 1H), 7.27 (t, J = 7.4 Hz, 1H), 7.06 (td, J = 7.7,
1.3 Hz, 1H), 6.57 (s, 1H), 4.41 (d, J = 2.8 Hz, 1H), 3.62 (d, J = 3.7 Hz,
1H), 2.60−2.50 (m, 4H), 2.09−1.97 (m, 2H), 1.84−1.17 (m, 4H),
1.60−1.55 (m, 1H), 1.43−1.37 (m, 1H); 13C{1H} NMR (100 MHz,
CDCl3) δ 210.9, 152.8, 137.8, 132.4, 129.9, 127.8, 126.9, 124.3, 120.6,
81.4, 56.8, 38.9, 36.2, 32.0, 29.3, 24.4, 23.4; IR (CH2Cl2) 3429, 2939,
1711, 1430, 1261, 1022, 753 cm−1; MS (APCI) m/e (%) 377.1 ([M +
H +2]+, 95), 335.1 ([M + H]+, 100); HRMS (APCI) m/e calcd for
C17H2079BrO2 [M + H]+ 335.0647, found 335.0648.
(5R*,6R*,E)-6-Hydroxy-1-(naphthalen-1-ylmethylene)spiro[4.5]-
decan-7-one (2f). The crude residue obtained from the reaction of 1f
(0.15 g, 0.5 mmol) with FeCl3·6H2O (14 mg, 0.050 mmol) was
purified by flash column chromatography to give 2f (0.07 g, 0.23
1
mmol, 46%) as a white solid: mp 105−107 °C; H NMR (400 MHz,
CDCl3) δ 8.05−8.03 (m, 1H), 7.84−7.82 (m, 1H), 7.73−7.71 (m,
1H), 7.51−7.45 (m, 2H), 7.44−7.40 (m, 2H), 6.89 (s, 1H), 4.47 (s,
1H), 3.68 (br s, 1H), 2.58−2.51 (m, 1H), 2.50−2.37 (m, 3H), 2.05−
1.97 (m, 2H), 1.84−1.67 (m, 4H), 1.57−1.47 (m, 1H), 1.43−1.36 (m,
1H); 13C{1H} NMR (100 MHz, CDCl3) δ 211.1, 152.8, 135.4, 133.5,
131.7, 128.3, 126.8, 126.0, 125.7, 125.5, 125.2, 124.6, 118.2, 81.4, 56.3,
38.8, 36.5, 32.0, 29.5, 24.1, 23.3; IR (CH2Cl2) 3461, 3047, 2945, 2870,
2369, 1712, 1391, 1107, 782 cm−1; MS (EI) m/e (%) 306.2 ([M]+,
100), 259.2 (13), 233.2 (70), 191.1 (55), 165.1 (61), 141.1 (58);
HRMS (EI) m/e calcd for C21H22O2 [M]+ 306.1620, found 306.1621.
(5R*,6R*,E)-6-Hydroxy-1-(phenanthren-9-ylmethylene)spiro[4.5]-
decan-7-one (2g). The crude residue obtained from the reaction of 1g
(0.34 g, 0.95 mmol) with FeCl3·6H2O (26 mg, 0.095 mmol) was
purified by flash column chromatography to give 2g (0.15 g, 0.42
mmol, 45%) as a yellow oil; 1H NMR (400 MHz, CDCl3) δ 8.72 (d, J
= 7.9 Hz, 1H), 8.67 (d, J = 8.0 Hz, 1H), 8.10 (dd, J = 7.9, 1.0 Hz, 1H),
7.84 (dd, J = 7.8, 1.2 Hz, 1H), 7.67−7.57 (m, 5H), 6.91 (t, J = 2.6 Hz,
1H), 4.56 (d, J = 3.8 Hz, 1H), 3.72 (t, J = 3.9 Hz, 1H), 2.64−2.50 (m,
4H), 2.61−2.08 (m, 2H), 1.94−1.74 (m, 4H), 1.60−1.44 (m, 1H),
1.48−1.42 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 211.1,
153.2, 140.0, 131.7, 131.3, 130.3, 129.7, 128.4, 126.7.126.6, 126.5,
126.3, 126.2, 125.4, 122.9, 122.5, 118.6, 81.5, 56.3, 39.0, 36.6, 32.0,
29.6, 24.2, 23.4; IR (CH2Cl2) 3478, 3061, 2947, 2872, 1715, 1608,
1377, 1108, 898, 746 cm−1; MS (APCI) m/e (%) 357.2 ([M + H]+,
100), 195.2 (57) 163.1 (22), 122.0 (18); HRMS (APCI) m/e calcd for
[M + H]+ C25H25O2 357.1855, found 357.1854.
(5R*,6R*,E)-1-(4-Bromobenzylidene)-6-hydroxyspiro[4.5]decan-
7-one (2k). The crude residue obtained from the reaction of 1k (0.17
g, 0.5 mmol) with FeCl3·6H2O (13 mg, 0.050 mmol) was purified by
flash column chromatography to give 2k (28 mg, 0.08 mmol, 17%) as
a yellow oil: 1H NMR (400 MHz, CDCl3) δ 7.43 (d, J = 8.5 Hz, 2H),
7.20 (d, J = 8.5 Hz, 2H), 6.34 (s, 1H), 4.36 (d, J = 3.8 Hz, 1H), 3.62
(d, J = 3.8 Hz, 1H), 2.65−2.55 (m, 3H), 2.51−2.43 (m, 1H), 2.07−
2.02 (m, 1H), 1.90−1.61 (m, 6H), 1.41−1.36 (m, 1H); 13C{1H} NMR
(100 MHz, CDCl3) δ 210.9, 153.9, 137.2, 131.2, 130.1, 120.2, 119.9,
81.1, 57.2, 38.9, 36.4, 32.3, 29.4, 24.4, 23.2; IR (CH2Cl2) 3457, 2946,
2874, 1714, 1488, 1249, 1108, 1009, 824, 736 cm−1; MS (EI) m/e (%)
334.1 ([M]+, 81), 318.1 (41), 261.1 (98), 182.2 (95), 165.1 (100),
141.1 (60), 128.2 (43); HRMS (EI) m/e calcd for C17H1979BrO2 [M]+
334.0568, found 334.0564.
(5R*,6R*,E)-6-Hydroxy-1-(4-(phenylethynyl)benzylidene)spiro-
[4.5]decan-7-one (2l). The crude residue obtained from the reaction
of 1l (0.14 g, 0.4 mmol) with FeCl3·6H2O (11 mg, 0.040 mmol) was
purified by flash column chromatography to give 2l (66 mg, 0.18
1
mmol, 46%) as a white solid: mp 179−181 °C; H NMR (400 MHz,
CDCl3) δ 7.57−7.50 (m, 4H), 7.37−7.35 (m, 5H), 6.42 (t, J = 2.3 Hz,
1H), 4.40 (d, J = 3.7 Hz, 1H), 3.66 (d, J = 3.8 Hz, 1H), 2.74−2.71 (m,
2H), 2.62−2.53 (m, 1H), 2.54−2.45 (m, 1H), 2.09−2.04 (m, 1H),
1.94−1.70 (m, 6H), 1.44−1.39 (m, 1H); 13C{1H} NMR (100 MHz,
CDCl3) δ 211.0, 152.1, 138.2, 131.5, 131.4, 128.4, 128.3, 128.1, 123.4,
120.8, 120.8, 89.7, 89.4, 81.2, 57.3, 38.9, 36.4, 32.5, 29.4, 24.4, 23.2; IR
(CH2Cl2) 3477, 2945, 1714, 1385, 1313, 2871, 1108, 876 cm−1; MS
(EI) m/e (%) 356.2 ([M]+, 100), 283.2 (36), 241.1 (23), 191.1 (48),
142.1 (32); HRMS (EI) m/e calcd for C25H24O2 [M]+ 356.1776,
found 356.1776.
(5R*,6R*,E)-6-Hydroxy-1-(3-methoxybenzylidene)spiro[4.5]-
decan-7-one (2h). The crude residue obtained from the reaction of 1h
(0.28 g, 0.98 mmol) with FeCl3·6H2O (26 mg, 0.098 mmol) was
purified by flash column chromatography to give 2h (0.16 g, 0.57
(5R*,6R*,E)-6-Hydroxy-1-(4-(p-tolylethynyl)benzylidene)spiro-
[4.5]decan-7-one (2m). The crude residue obtained from the reaction
of 1m (0.11 g, 0.28 mmol) with FeCl3·6H2O (8.0 mg, 0.028 mmol)
was purified by flash column chromatography to give 2m (66 mg, 0.19
1
mmol, 59%) as a white solid: mp 100−102 °C; H NMR (400 MHz,
CDCl3) δ 7.24 (t, J = 8.0 Hz, 1H), 6.95 (d, J = 7.7 Hz, 1H), 6.90 (s, 1
H), 6.75 (dd, J = 8.2, 2.4 Hz, 1H), 6.39 (t, J = 2.2 Hz, 1H), 4.39 (d, J =
H
dx.doi.org/10.1021/jo5023266 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
1
mmol, 62%) as a white solid: mp 170−171 °C; H NMR (400 MHz,
CDCl3) δ 7.48 (d, J = 8.2 Hz, 2H), 7.42 (d, J = 8.0 Hz, 2H),7.33 (d, J
= 8.2 Hz, 2H), 7.15 (d, J = 8.0 Hz, 2H), 6.40 (t, J = 2.5 Hz, 1H), 4.39
(d, J = 3.7 Hz, 1H), 3.63 (d, J = 3.8 Hz, 1H), 2.73−2.68 (m, 2H),
2.61−2.55 (m, 1H), 2.52−2.44 (m, 1H), 2.37 (s, 3H), 2.08−2.03 (m,
1H), 1.92−1.63 (m, 6H), 1.42−1.37 (m, 1H); 13C{1H} NMR (100
MHz, CDCl3) δ 210.9, 152.0, 138.3, 138.1, 131.5, 131.3, 129.1, 128.4,
121.0, 120.9, 120.3, 89.8, 89.0, 81.2, 57.3, 38.9, 36.4, 32.5, 28.4, 24.5,
23.3, 21.5; IR (CH2Cl2) 3455, 2943, 2866, 1712, 1516, 1342, 1107,
817 cm−1;MS (ESI) m/e (%) 393.2 ([M + Na]+, 100), 360.3 (10),
266.2 (10); HRMS (EI) m/e calcd for C26H26NaO2 [M + Na]+
393.1831, found 393.1823.
217.1 ([M + Na]+, 13), 177.1 (3); HRMS (ESI) m/e calcd for
C12H18NaO2 [M + Na ]+ 217.1204, found 217.1200.
(5R*,6R*,E)-1-Ethylidene-6-hydroxyspiro[4.5]decan-7-one (13).
Compound 13 a colorless oil: 1H NMR (400 MHz, CDCl3) δ
5.44−5.38 (m, 1H), 4.23 (dd, J = 3.9, 1.3 Hz, 1H), 3.56 (d, J = 3.9 Hz,
1H), 2.55−2.49 (m, 1H), 2.45−2.30 (m, 3H), 2.00−1.93 (m, 1H),
1.69 (dt, J = 6.6, 1.5 Hz, 3 H), 1.78−1.52 (m, 6H), 1.34−1.29 (m,
1H); 13C{1H} NMR (100 MHz, CDCl3) δ 211.5, 148.4, 114.9, 81.2,
55.5, 39.0, 36.5, 30.0, 29.6, 23.5, 23.2, 14.9; IR (CH2Cl2) 3471, 2942,
2871, 1713, 1641, 1442, 1108, 805 cm−1; MS (APCI) m/e (%) 195.1
([M + H]+,100), 177.1 (11); HRMS (ESI) m/e calcd for C12H19O2
[M + H]+ 195.1385, found 195.1380.
(5R*,6R*,E)-6-Hydroxy-1-(4-((4-methoxyphenyl)ethynyl)benzyl-
idene)spiro[4.5]decan-7-one (2n). The crude residue obtained from
the reaction of 1n (0.15 g, 0.39 mmol) with FeCl3·6H2O (11 mg,
0.039 mmol) was purified by flash column chromatography to give 2n
(91 mg, 0.24 mmol, 60%) as a white solid: mp 173−175 °C; 1H NMR
(400 MHz, CDCl3) δ 7.47 (d, J = 8.6 Hz, 4H), 7.32 (d, J = 8.3 Hz,
2H), 6.89−6.86 (m, 2H), 6.40 (t, J = 2.5 Hz, 1H), 4.39 (d, J = 3.5 Hz,
1H), 3.83 (br s, 3H), 3.63 (d, J = 3.6 Hz, 1H), 2.73−2.68 (m, 2H),
2.60−2.56 (m, 1H), 2.52−2.45 (m, 1H), 2.07−2.02 (m, 1H), 1.92−
1.63 (m, 6H), 1.42−1.37 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3)
δ 211.0, 159.6, 151.9, 137.9, 133.0, 131.2, 128.4, 121.2, 120.9, 115.5,
114.0, 89.6, 88.4, 81.2, 57.3, 55.3, 38.9, 36.4, 32.5, 29.4, 24.5, 23.3; IR
(CH2Cl2) 3451, 2941, 1711, 1599, 1513, 1248, 1026, 832 cm−1;MS
(ESI) m/e (%) 409.2 ([M + Na]+, 700), 334.2 (40), 229.1 (70), 143.1
(60); HRMS (EI) m/e calcd for C26H26NaO3 [M + Na]+ 409.1780,
found 409.1783. Crystals suitable for X-ray diffraction analysis were
grown from CH2Cl2 and hexanes.17
ASSOCIATED CONTENT
* Supporting Information
NMR spectra for compounds 1a−o, 2a−o, 2c-d, and 9−13,
and X-ray crystallographic information files for compounds 2a,
2c−e, 2h, 2n, and 10. This material is available free of charge
via the Internet at http://pubs.acs.org.
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S
AUTHOR INFORMATION
Corresponding Author
*E-mail: cheyeh@ntnu.edu.tw (M.-C.P.Y.).
Notes
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Ethyl 3-((E)-((5R*,6R*)-6-Hydroxy-7-oxospiro[4.5]decan-1-yl-
idene)methyl)-benzoate (2o). The crude residue obtained from the
reaction of 1o (0.11 g, 0.34 mmol) with FeCl3·6H2O (9.0 mg, 0.034
mmol) was purified by flash column chromatography to give 2o (11
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This work has been supported the by Ministry of Science and
Technology (NSC 101-2113-M-003-002-MY3) and National
Taiwan Normal University.
1
mg, 0.03 mmol, 10%) as a yellow oil: H NMR (400 MHz, CDCl3) δ
8.03 (s, 1H), 7.86 (td, J = 7.8, 1.3 Hz, 2H), 7.36 (d, J = 7.7 Hz, 1H),
7.39 (t, J = 7.7 Hz, 1H), 6.43 (t, J = 2.3 Hz, 1H), 4.47−4.35 (m, 3H),
3.64 (d, J = 3.8 Hz, 1H), 2.73−2.69 (m, 2H), 2.61−2.51 (m, 1H),
2.53−2.46 (m, 1H), 1.93−1.64 (m, 6H), 1.42−1.38 (m, 1H), 1.40 (t, J
= 7.7 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 210.9, 166.7,
152.2, 138.4, 132.6, 130.4, 129.6, 128.1, 127.2, 120.4, 81.2, 60.9, 57.2,
38.9, 36.4, 32.3, 29.4, 24.4, 23.3, 14.3; IR (CH2Cl2) 3473, 2946, 2872,
1715, 1282, 1205, 1107, 1025 cm−1; MS (EI) m/e (%) 328.2 ([M]+,
13), 299.2 (36), 253.2 (45), 149.1 (100), 141.1 (18); HRMS (EI) m/e
calcd for C20H24O4 [M]+ 328.1675, found 328.1678.
REFERENCES
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1
solid: H NMR (400 MHz, CDCl3) δ 5.81 (s, 1H), 3.91−3.87 (m,
1H), 3.57 (d, J = 1.8 Hz, 1H), 2.30 (td, J = 6.4, 1.6 Hz, 2H), 2.07 (br s,
1H), 1.86−1.79 (m, 3H), 1.75−1.60 (m, 4H), 1.45−1.49 (m, 2H),
1.43−1.37 (m, 1H), 1.27−1.21 (m, 1H); 13C{1H} NMR (100 MHz,
CDCl3) δ 134.8, 128.2, 74.9, 68.9, 42.1, 33.1, 32.3, 30.2, 28.7, 19.2,
18.6; IR (CH2Cl2) 3421, 3301, 2942, 2866, 1713, 1647, 1449, 1059,
869, 758, 642 cm−1; MS (ESI) m/e (%) 217.1 ([M + 2 − H]−, 31),
215.1 ([M − H]−, 100), 195.0 (11); HRMS (ESI) m/e calcd for
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35
C11H16ClO2 [M − H]− 215.0839, found 215.0832. Crystals suitable
for X-ray diffraction analysis were grown from CH2Cl2 and hexanes.17
(5S*,6R*,7S*,Z)-1-Ethylidenespiro[4.5]dec-2-ene-6,7-diol (12).
The crude residue obtained from the reaction of 11 (0.39 g, 2.0
mmol) with FeCl3·6H2O (54 mg, 0.20 mmol) was purified by flash
column chromatography to give 12 (93 mg, 0.48 mmol, 24%) and 13
1
(76 mg, 0.40 mmol, 20%). Compound 12 a colorless oil: H NMR
(500 MHz, CDCl3) δ 5.70 (ddd, J = 9.9, 5.0, 2.5 Hz, 1H), 5.16−5.13
(m, 1H), 5.12−5.08 (m, 1H), 4.08−4.04 (m, 1H), 3.56 (m, 1H),
2.36−2.3 (m, 4H), 2.15−2.09 (m, 1H), 1.90 (d, J = 7.4 Hz, 1H),
1.81−1.75 (m, 3H), 1.58 (td, J = 6.4, 1.6 Hz, 3H), 1.40−1.33 (m, 1H);
13C{1H} NMR (125 MHz, CDCl3) δ 146.9, 131.8, 124.0, 119.5, 71.5,
66.2, 54.9, 35.3 29.3, 27.8, 21.5, 14.6; IR (CH2Cl2) 3421, 3301, 2942,
2866, 1713, 1647, 1449, 1059, 869, 758, 642 cm−1; MS (ESI) m/e (%)
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I
dx.doi.org/10.1021/jo5023266 | J. Org. Chem. XXXX, XXX, XXX−XXX

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Stambuli, J. P.; Silverman, S. M.; Schworer, U. J. Am. Chem. Soc. 2006,
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dx.doi.org/10.1021/jo5023266 | J. Org. Chem. XXXX, XXX, XXX−XXX