Tandem hemiketal formation-intramolecular Friedel-Crafts alkylation: A facile route to hetero-atom-substituted benzo-fused bicyclo[3.3.1]nonanes

Article abstract of DOI:10.1002/1522-2675(20010131)84:1<163::AID-HLCA163>3.0.CO;2-B

A previously unknown intramolecular Friedel-Crafts alkylation with in situ formed hemiketals as the electrophile is reported.

Full text of DOI:10.1002/1522-2675(20010131)84:1<163::AID-HLCA163>3.0.CO;2-B

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Tandem Hemiketal Formation-Intramolecular Friedel-Crafts Alkylation:
A Facile Route to Hetero-Atom-Substituted Benzo-Fused
Bicyclo[3.3.1]nonanes
by Yikang Wu*, Yan Li1), and Yu-Lin Wu
State Key Laboratory of Bio-Organic Chemistry and Natural Products Chemistry, and Shanghai-Hong Kong
Joint Laboratory in Chemical Synthesis, Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, 354 Fenglin Road, Shanghai 200032, China
(e-mail: yikangwu@pub.sioc.ac.cn)
A previously unknown intramolecular Friedel-Crafts alkylation with in situ formed hemiketals as the
electrophile is reported.
In the 120 years history of the Friedel-Crafts (F-C) reaction, ketones [1], either in
the free carbonyl form or after being masked as ketals, have never been mainstay
alkylating agents. This is presumably because, in the presence of a strong acid (a pre-
requisite for most F-C reactions), ketones often undergo extensive side reactions
leading to polymeric by-products. Also, as shown [2] by the examples available in the
literature, alkylation of aromatics with ketones are normally difficult to stop at the
monarylation (i.e., with only one aromatic group attached to the carbonyl C-atom)
stage. In most cases, the hydroxy compound formed in the first arylation reacts further
with the aromatics to give diarylated products (Scheme 1). As for the F-C reactions of
ketals, no case of preparative significance (to our knowledge) was known until recently,
when we showed [3] that spiroketals may undergo intramolecular F-C alkylation in the
presence of a Brùnsted or Lewis acid. In this contribution, we wish to report on the first
examples of synthetically significant F-C reactions with in situ formed hemiketals as
alkylating agents. These results further extend the limits and scope of the well-
established F-C reaction and exemplify new facile entries to the otherwise not easily
accessible hetero-substituted benzo-fused bicyclo[3.3.1]nonane ring system.
Scheme 1
The precursors (open-chain hydroxy ketones) of cyclic hemiketals are prepared
from corresponding aromatic aldehydes 1 in four steps as shown in Scheme 2. The aldol
condensation of cyclopentanone with the aromatic aldehyde followed by elimination of
H2O gave the intermediate a,b-unsaturated ketones, which were directly hydrogenated
1
)
On leave from Faculty of Chemistry and Material Science, Hubei University, Wuhan 430062, China.

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Helvetica Chimica Acta ± Vol. 84 (2001)
over 10% Pd/C to afford ketones 2. The yields were generally good (60 ± 86%), except
for 2c (39%; not optimized). The isolated ketones 2a ± e were subjected to Bayer-
Villiger oxidation with 70% m-chloroperbenzoic acid (MCPBA) in CH2Cl2 with
NaHCO3 as buffer to give the corresponding lactones 3a ± e in 75 ± 88% yields.
Scheme 2
a) 1) 1n NaOH, cyclopentanone, 24 h, r.t.; 2) H2, Pd/C, EtOH; 39 ± 86% over two steps. b) MCPBA, NaHCO3,
r.t., CH2Cl2; 75 ± 88%. c) BuLi (or PhLi), Me3SiC1, THF, 1008; 44 ± 76%. d) TsOH, PhH, reflux, 12 ± 36 h or
BF3 ´ OEt2, THF, reflux, 12 ± 36 h; 57 ± 98%.
The lactone ring of 3a ± e was then opened with the most readily available
organolithium, either BuLi or PhLi. To minimize the addition of a second alkyl group to
the intermediate ketone, Cookeꢀs procedure [4] was applied. Thus, at 1008, with an
excess Me3SiCl to intercept the intermediate hemiketal, the desired ketones could be
obtained in good yields after removal of the termporary silyl-ether protecting group.
Because of the existence of an equilibrium between the open-chain hydroxy ketone
form 4a ± f and the cyclic hemiketal form 5a ± f, the isolated yields were sometimes
lower than the genuine yields. This problem was particularly evident with 4f/5f, where
the hemiketal OH group was in a benzylic position; a substantial fraction of the product
underwent a facile elimination of H2O to yield the corresponding cyclic enol ether. The
unexpected enol ether, however, served equally well in the F-C cyclization as shown by
subsequent experiments (see below).
The ensuing F-C reaction to give (Æ)-6 presumably proceeds through the hemiketal
5 rather than the open-chain form 4, although the 1H-NMR experiments clearly show
that 4 represents, in most cases, the predominant form in solution. This is because the
alternative route would involve an unfavorable eight-membered transition state

Helvetica Chimica Acta ± Vol. 84 (2001)
165
(Scheme 3). It is interesting to note that the OH group at the homobenzylic position
plays a dual role in the F-C reaction. On one hand, it activates the ketone carbonyl
group by forming a hemiketal (the OH may easily leave in the presence of an acid to
generate an oxonium ion), and, on the other hand, the oxy ꢁbridgeꢀ effectively reduces
the degree of rotational freedom of the side chain so that the unfavorable eight-
membered transition state now becomes a favorable six-membered one.
Scheme 3
The F-C reaction of the hemiketals was probed with 5a under several conditions.
Apart from the previously employed HCl/MeOH and BF3 ´ OEt2/THF recipes, we
found that TsOH/PhH also worked well. Due to the convenience of handling the solid
TsOH (monohydrate), the TsOH/PhH combination became the first choice. In fact,
the new conditions often gave better yields. The results of the F-C cyclization are listed
in the Table. As reported earlier for the spiroketals, the presence of an electron-
donating group at the position para to the cyclization site facilitates the intramolecular
F-C reaction. The best results were obtained with those compounds that contained an
alkoxy group at the para-position. Replacing the alkoxy group with Me (weaker
electron-donating group) reduced the yield significantly. The substitution position is
also important. The same MeO group at the meta- instead of para-position had no
facilitating effect at all; the reaction gave a complex product mixture.
We have also made a brief examination on the generation of the [3.2.1] system to
see whether the procedure is applicable to five-membered hemiketals. Starting from
the easily available levulinic acid (7), aldehyde 8 [5] was readily prepared in four
steps (esterification in MeOH catalyzed by H2SO4, ketalization with ethylene glycol,

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Table. F-C Cyclization under Different Conditions
Starting
Material
R1
R2
Main product
Isolated Yield [%]
Method Aa)
Method Bb)
4a/5a
4b/5b
4c/5c
4d/5d
4e/5e
4f/5f
OCH2O
6a
6b
6c
6d
6e
6f
93
63
73
98
±c)
88
93
Me
H
MeO
H
±c)
73
MeO
MeO
H
88
MeO
±c)
57
OCH2O
a) Method A: cat. TsOH, PhH, reflux. b) Method B: cat. BF3 ´ OEt2, THF, reflux. c) A complex product mixture
was obtained.
reduction with LiAlH4, and Swern oxidation; Scheme 4). Treatment of 8 with
dimethyloxosulfonium methylide [6] (Me2S(O)CH2) gave the corresponding epoxide
9 (20% yield for the Swern oxidation and the epoxidation; not optimized). Ring
opening of the epoxide was realized in 66% yield with the aryllithium prepared from 5-
bromo-1,3-benzodioxole [7] by lithium/halogen exchange with BuLi at 408. The
product 10 was often contaminated by small amounts of 11 (10/11 50 20 :1). In the
presence of an acidic catalyst, the content of 11 increased significantly, reflecting their
relative stability.
Scheme 4
a) 1) MeOH, H2SO4; 60%; 2) HOCH2CH2OH, TsOH; 99%; 3) LiAlH4; 90%; 4) Swern oxidation. b) DMSO/
Me2S(O)CH2; 20% over two steps. c) 788, ArLi, THF; 65%. d) HCl/MeOH, reflux, 12 h; 70%.
In an initial attempt to hydrolyze the ethylene glycol protecting group of 10, it was
noticed that some F-C product was already formed even before the starting ketal was

Helvetica Chimica Acta ± Vol. 84 (2001)
167
fully deprotected. With this insight, we reverted to the original HCl/MeOH procedure,
which effectively combined the deprotection and the F-C reaction into one single step
and gave the final F-C product (Æ)-12 in 70% yield after reaction at reflux temperature
for 12 h.
To examine whether thiohemiketals behave similarly, we next made an effort to
prepare the thiol counterpart of 4a by converting the OH group to mercapto group
(Scheme 5). First, we tried to introduce the S-atom via reaction of the mesylate 13 of 4a
with potassium thioacetate [8]. None of the expected product was obtained, although
formation of the mesylate did occur. Then, we tried to use the anion of benzene-
methanethiol in place of the thioacetate. The substitution went well this time. However,
removal of the benzyl protecting group to release the SH group encountered serious
difficulties. Neither the Na/liq. NH3 [9] nor the Li/naphthalene [10] procedure cleanly
cleaved the benzyl group without yielding by-products. Finally, the problem was
circumvented by using NaSH [11] as the nucleophile. The resulting mercapto ketone
underwent facile thioacetalization, and the intermediate thiohemiketal easily lost one
molecule of H2O to give the enthiol ether 14 as the product. In the subsequent F-C
reaction, a major difference between the O- and S-substrate was observed. Unlike the
enol ethers mentioned above (which undergo F-C cyclization as easily as the
hemiketals), no cyclization took place with the S-analogue 14 under all the conditions
so far employed. The desired cyclization to (Æ)-15, however, could be realized at 408 in
CHCl3 in nearly quantitative yields in the presence of trifluoromethanesulfonic acid (a
stronger acid than TsOH, etc.).
Scheme 5
a) MsCl, CH2Cl2, Et3N; 85%. b) NaSH, DMF; 91%. c) CF3SO3H, CHCl3, 408, 4 h; ca. 100%.
In brief, we have demonstrated a new sub-type of F-C reaction with hemiketals
(formed in situ from the corresponding open-chain hydroxy ketones) acting as
electrophiles. The reaction occurs easily when the para-position (with respect to the
cyclization position) of the aromatic ring carries a strong electron-donating group. The
reaction opens up a facile route to the interesting benzo-fused oxabicyclo[3.3.1]nonane
system, which is otherwise not readily accessible. The corresponding oxabicy-
clo[3.2.1]octanes can also be prepared similarly. The S-analogues appear to need
stronger acid to undergo the desired cyclization.

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Experimental Part
General. M.p.: Flash column chromatography (FC): silica gel H (10 ± 40 mm), elution with petroleum ether
(b.p. 60 ± 908) AcOEt. 1H-NMR Spectra: CDCl3 solns. at 300 MHz, unless stated otherwise. Microanalyses were
carried out in the Microanalytical Laboratory at the Shanghai Institute of Organic Chemistry.
Aldol Condensation: General Procedure. At r.t. aq. 1n NaOH (30 ml) was added to a mixture of the arom.
aldehyde 1 (10 mmol) and cyclopentanone (15 mmol) with stirring. Stirring was continued for 24 h at r.t. Then,
the mixture was extracted with Et2O (5 Â 50 ml) and the combined org. extracts washed with brine (4 Â 30 ml),
dried (MgSO4), and evaporated. The residue was dissolved in EtOH (99.5%; 100 ml) and hydrogenated under
stirring over 10% Pd/C (50 mg) at 1 atm of H2 for 12 ± 24 h. The catalyst was filtered off, the filtrate evaporated,
and the residue submitted to FC (hexanes/AcOEt 8 :1): ketone 2.
Baeyer-Villiger Oxidation: General Procedure. To ketone 2 (10 mmol) in CH2Cl2 (150 ml), 70% MCPBA
(4.949 g; ca. 20 mmol) and powdered NaHCO3 (ca. 29 mmol) were added in small portions. Then, the mixture
was stirred at r.t. for 24 h. The solids were filtered off through Celite (washing with CH2Cl2). The filtrate and
washings were washed twice with aq. sat. NaHCO3 soln., dried (MgSO4), and evaporated. The residue was
submitted to FC: lactone 3.
Lactone Opening by Butyllithium: General Procedure. To a soln. of 3 (3.5 mmol) in dry THF (50 ml) at
1008 under N2, Me3SiCl (1.78 g, 16.5 mmol) was added with stirring, followed by 1.6m/BuLi in hexanes (ca.
7.0 ml, added dropwise). The mixture was then stirred at 1008 for another 20 min and at 788 for 30 min
before the temp. was allowed to increase to 08. EtOH (99.5%, ca. 0.5 ml) was added. After stirring for 5 min, the
excess Me3SiCl and most of the THF were evaporated. H2O (2.0 ml) and 4m dil. HCl (4.0 ml) were added. The
mixture was stirred for 10 min and then extracted with Et2O (4 Â 30 ml). The extract was washed with sat. aq.
NaHCO3 soln. (2 Â 15 ml) and brine (2 Â 20 ml), dried (Na2SO4), and evaporated, and the residue was
submitted to FC: ketone 4, often contaminated with some ring-closed product 5.
Intramolecular F-C Reaction. Method A: A soln. of the precursor 4 (20 mg) and TsOH (1 ± 2 mg) in
benzene (10 ml) was heated under reflux and N2 for 12 ± 36 h. After consumption of the starting material (TLC
monitoring), the mixture was cooled to r.t. and diluted with Et2O (80 ml), the soln. washed with sat. aq.
NaHCO3 soln. (2 Â 5 ml) and brine (2 Â 10 ml), dried (Na2SO4), and evaporated, and the residue was submitted
to FC: F-C product (Æ)-6.
Method B: As described in Method A, except that THF (10 ml) and BF3 ´ OEt2 (1 small drop) were used in
place of benzene and TsOH, resp.
2-[(1,3-Benzodioxol-5-yl)methyl]cyclopentanone (2a): M.p. 41.3 ± 41.78. Yield 63%. IR (KBr): 1740s,
1600w, 1580s, 1440s, 1240s, 1038s, 925m, 810m. 1H-NMR: 1.49 ± 1.64 (m, 1 H); 1.69 ± 1.83 (m, 1 H); 1.91 ± 2.03
(m, 1 H); 2.04 ± 2.19 (m, 2 H); 2.25 ± 2.41 (m, 2 H); 2.50 (dd, J ˆ 14, 8.2, 1 H); 3.06 (dd, J ˆ 14, 4.3, 1 H); 5.94
‡
(s, 2 H); 6.67 (d, J ˆ 7.8, 1 H); 6.67 (br. s, 1 H); 6.73 (d, J ˆ 7.8, 1 H). EI-MS: 218 (40, M ), 162 (6), 135 (100),
136 (12), 122 (6), 77 (14). Anal. calc. for C13H14O3: C 71.54, H 6.46; found: C 71.62, H 6.54.
2-[(3-Methylphenyl)methyl]cyclopentanone (2b): Yield 60%. IR (film): 1740s, 1605m, 1580w, 1150m, 780m,
740m, 695m. 1H-NMR: 1.49 ± 1.64 (m, 1 H); 1.68 ± 1.83 (m, 1 H); 1.92 ± 2.04 (m, 1 H); 2.04 ± 2.20 (m, 2 H);
2.28 ± 2.42 (m, 2 H); 2.34 (s, 1 H); 2.50 (dd, J ˆ 14, 9.5, 1 H); 3.13 (dd, J ˆ 14, 3.8, 1 H); 6.97 ± 7.04 (m, 3 H); 7.18
‡
(t, J ˆ 7.4, 1 H). EI-MS: 188 (36, M ), 145 (15), 117 (43), 105 (100), 91 (31), 77 (23), 65 (12). Anal. calc. for
C13H16O: C 82.94, H 8.66; found: C 83.12, H 8.51.
2-[(3,4-Dimethoxyphenyl)methyl]cyclopentanone (2c): Yield 39%. IR (film): 1735s, 1605m, 1590s, 1515s,
1260s, 1240s, 1050s, 1025s, 810m, 765m. 1H-NMR: 1.50 ± 1.64 (m, 1 H); 1.65 ± 1.81 (m, 1 H); 1.90 ± 2.20 (m, 1 H);
2.03 ± 2.18 (m, 2 H); 2.26 ± 2.40 (m, 2 H); 2.53 (dd, J ˆ 14, 9.1, 1 H); 3.06 (dd, J ˆ 14, 4.3, 1 H); 3.859 (s, 3 H);
‡
3.862 (s, 3 H); 6.67 ± 6.72 (m, 2 H); 6.78 (d, J ˆ 8.5, 1 H). EI-MS: 234 (29, M ), 235 (5), 152 (11), 151 (100), 107
(8), 91 (7), 77 (6). Anal. calc. for C14H18O3: C 71.77, H 7.74; found: C 71.85, H 7.84.
2-[(3-Methylphenyl)methyl]cyclopentanone (2d):Yield 86%. IR (film): 1735s, 1605s, 1590s, 1515m, 1260m,
1240s, 1050m, 1025m, 810m, 765m. 1H-NMR: 1.49 ± 1.64 (m, 1 H); 1.67 ± 1.80 (m, 1 H); 1.91 ± 2.03 (m, 1 H);
2.05 ± 2.19 (m, 2 H); 2.29 ± 2.42 (m, 2 H); 2.52 (dd, J ˆ 14, 9.3, 1 H); 3.14 (dd, J ˆ 14, 4.0, 1 H); 3.81 (s, 3 H); 6.73
‡
(s, 1 H); 6.75 (d, J ˆ 7.7, 1 H); 6.73 ± 6.78 (m, 3 H); 7.21 (t, J ˆ 7.7, 1 H). EI-MS: 204 (99, M ), 148 (100), 147
(52), 121 (72), 91 (45), 77 (27). Anal. calc. for C13H16O2: C 76.44, H 7.90; found: C 76.47, H 7.97.
2-[(4-Methoxyphenyl)methyl]cyclopentanone (2e): Yield 63%. IR (film): 1735s, 1605m, 1590w, 1515s,
1240s, 1050m, 1025m, 810m. 1H-NMR: 1.49 ± 1.63 (m, 1 H); 1.67 ± 1.81 (m, 1 H); 1.89 ± 2.02 (m, 1 H); 2.03 ± 2.17
(m, 2 H); 2.26 ± 2.40 (m, 2 H); 2.52 (dd, J ˆ 14, 9.3, 1 H); 3.07 (dd, J ˆ 14, 4.1, 1 H); 3.79 (s, 3 H); 6.83 (d, J ˆ 8.7,
‡
2 H); 7.09 (t, J ˆ 8.7, 2 H). EI-MS: 204 (13, M ), 147 (4), 122 (11), 121 (100), 91 (7), 77 (8). Anal. calc. for
C13H16O2: C 76.44, H 7.90; found: C 76.49, H 7.96.

Helvetica Chimica Acta ± Vol. 84 (2001)
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6-[(1,3-Benzodioxol-5-yl)methyl]tetrahydro-2H-pyran-2-one (3a): M.p. 61.3 ± 61.78. Yield 83%. IR (KBr):
1730s, 1600w, 1500s, 1490s, 1240s, 1040s, 925s, 805m. 1H-NMR: 1.70 ± 1.95 (m, 3 H); 2.36 ± 2.49 (m, 1 H); 2.51 ±
2.63 (m, 1 H); 2.79 (dd, J ˆ 13.7, 6.7, 1 H); 2.99 (dd, J ˆ 13.7, 5.8, 1 H); 4.38 ± 4.49 (m, 1 H); 5.93 (s, 2 H); 6.67
‡
(dd, J ˆ 8.0, 1.6, 1 H); 6.72 (d, J ˆ 1.6, 1 H); 6.75 (d, J ˆ 8.0, 1 H). EI-MS: 234 (52, M ), 135 (100), 99 (30), 77
(17), 71 (31), 55 (12), 43 (12). Anal. calc. for C13H14O4: C 60.66, H 6.02; found: C 66.73, H 5.94.
Tetrahydro-6-[(3-methylphenyl)methyl]-2H-pyran-2-one (3b): Yield 88%. IR (film): 1730s, 1605m, 1584w,
1240s, 1040s, 925m, 780m. 1H-NMR: 1.46 ± 1.58 (m, 1 H); 1.70 ± 1.95 (m, 3 H); 2.33 (s, 3 H); 2.30 ± 2.48 (m, 1 H);
2.51 ± 2.62 (m, 1 H); 2.81 (dd, J ˆ 13.7, 7.1, 1 H); 3.06 (dd, J ˆ 13.7, 5.8, 1 H); 4.42 ± 4.58 (m, 1 H); 7.01 (br. d, J ˆ
‡
7.7, 1 H); 7.02 (br. s, 1 H); 7.04 (br. d, J ˆ 7.7, 1 H). EI-MS: 204 (26, M ), 187 (11), 105 (45), 99 (100), 91 (14), 77
(20), 71 (100), 55 (26), 43 (27). Anal. calc. for C13H16O2: C 76.44, H 7.90; found: C 76.34, H 7.92.
6-[(3,4-Dimethoxyphenyl)methyl]tetrahydro-2H-pyran-2-one (3c): M.p. 89.1 ± 89.68. IR (KBr): 1720s,
1
1600w, 1585m, 1240s, 1040s, 930w, 860w, 810w. Yield 75%. H-NMR: 1.40 ± 1.58 (m, 1 H); 1.70 ± 1.95 (m, 3 H);
2.34 ± 2.47 (m, 1 H); 2.51 ± 2.63 (m, 1 H); 2.31 (dd, J ˆ 14.0, 6.6, 1 H); 3.01 (dd, J ˆ 14.0, 5.5, 1 H); 3.86 (s, 3 H);
‡
3.88 (s, 3 H); 4.42 ± 4.53 (m, 1 H); 6.74 ± 6.79 (m, 3 H); 6.81 (d, J ˆ 8.5, 1 H). EI-MS: 250 (33, M ), 233 (3), 151
(100), 109 (19), 99 (8), 91 (6), 71 (16). Anal. calc. for C14H18O4: C 67.18, H 7.25; found: C 66.90, H 7.25.
Tetrahydro-6-[(3-methoxyphenyl)methyl]-2H-pyran-2-one (3d): M.p. 35.5 ± 36.18. IR (KBr): 1730s, 1600m,
1585m, 1250s, 1040s, 935w, 780w. Yield 80%. 1H-NMR: 1.43 ± 1.62 (m, 1 H); 1.70 ± 1.96 (m, 3 H); 2.35 ± 2.48
(m, 1 H); 2.51 ± 2.62 (m, 1 H); 2.83 (dd, J ˆ 13.7, 7.1, 1 H); 3.06 (dd, J ˆ 13.7, 5.8, 1 H); 3.79 (s, 3 H); 4.42 ± 4.58
‡
(m, 1 H); 6.80 (d, J ˆ 7.7, 1 H); 6.78 (d, J ˆ 7.7, 1 H); 6.76 (s, 1 H); 7.21 (t, J ˆ 7.7, 1 H). EI-MS: 204 (26, M ), 203
‡
(20), 121 (31), 99 (81), 91 (27), 77 (21), 77 (100), 55 (27), 43 (30). HR-MS: 220.1095 (C13H16O3 ; calc. 220.1099).
Tetrahydro-6-[(4-Methoxyphenyl)methyl]-2H-pyran-2-one (3e): M.p. 86.5 ± 86.78. Yield 83%. IR (KBr):
1720s, 1610m, 1580w, 1230s, 1160m, 1020s, 915m, 805m. 1H-NMR: 1.45 ± 1.59 (m, 1 H); 1.70 ± 1.95 (m, 4 H);
2.36 ± 2.48 (m, 1 H); 2.52 ± 2.64 (m, 1 H); 2.84 (dd, J ˆ 14, 6.9, 1 H); 3.04 (dd, J ˆ 14, 5.6, 1 H); 3.81 (s, 3 H);
‡
4.49 ± 4.52 (m, 1 H); 6.86 (d, J ˆ 8.7, 2 H); 7.16 (d, J ˆ 8.7, 2 H). EI-MS: 220 (22, M ), 121 (100), 99 (13), 77 (8),
71 (17), 55 (8), 43 (8). Anal. calc. for C13H16O3: C 70.89, H 7.23; found: C 70.67, H 7.00.
10-(1,3-Benzodioxol-5-yl)-9-hydroxydecan-5-one (4a): M.p. 50.8 ± 51.48. Yield 76%. IR (KBr): 3350m,
1715s, 1600w, 1240s, 930s, 800m. 1H-NMR: 0.92 (t, J ˆ 7.3, 3 H); 1.20 ± 1.90 (m, 10 H); 2.20 ± 2.50 (m, 2 H); 2.54 ±
2.65 (m, 1 H); 2.68 ± 2.77 (m, 1 H); 3.78 ± 3.82 (m, 1 H); 5.94 (s, 2 H); 6.66 (dd, J ˆ 8.0, 1.7, 1 H); 6.72 (d, J ˆ 1.7,
‡
1 H); 6.76 (d, J ˆ 8.0, 1 H). EI-MS: 292 (1, M ), 157 (42), 135 (100), 113 (27), 57 (55), 41 (43).
9-Hydroxy-10-(3-methylphenyl)decan-5-one (4b): Yield 76%. IR (film): 3400m, 1715s, 1610m, 1590m,
1040m, 980m, 780m, 740m. 1H-NMR: 0.90 (t, J ˆ 8.4, 3 H); 1.20 ± 1.85 (m, 10 H); 2.33 (s, 3 H); 2.23 ± 2.48
(m, 2 H); 2.56 ± 2.68 (m, 1 H); 2.71 ± 2.84 (m, 1 H); 3.72 ± 3.86 (m, 1 H); 6.92 ± 7.10 (m, 3 H); 7.19 (t, J ˆ 8.0,
‡
1 H). EI-MS: 263 (2, M ), 157 (77), 113 (48), 105 (100), 91 (66), 57 (73), 41 (54).
10-(3,4-Dimethoxyphenyl)-9-hydroxydecan-5-one (4c): Yield 51%. IR (film): 3400m, 1715s, 1600w, 1520s,
1260s, 1240s, 1030s, 770w. 1H-NMR: 0.89 (t, J ˆ 7.4, 3 H); 1.18 ± 1.82 (m, 10 H); 2.30 ± 2.50 (m, 2 H); 2.50 ± 2.62
(m, 1 H); 2.70 ± 2.81 (m, 1 H); 3.70 ± 3.82 (m, 1 H); 3.85 (s, 3 H); 3.87 (s, 3 H); 6.72 ± 6.73 (m, 2 H); 6.80 (d, J ˆ
‡
5.2, 1 H). EI-MS: 308 (5, M ), 157 (35), 151 (100), 113 (21), 57 (47), 41 (43).
9-Hydroxy-10-(3-methoxyphenyl)decan-5-one (4d): Yield 55%. IR (film): 3450m, 1715s, 1600m, 1580m,
1260s, 1140s, 780m. 1H-NMR: 0.89 (t, J ˆ 7.3, 3 H); 1.20 ± 1.82 (m, 10 H); 2.30 ± 2.48 (m, 2 H); 2.55 ± 2.70
(m, 1 H); 2.70 ± 2.85 (m, 1 H); 3.79 (s, 3 H); 3.70 ± 3.86 (m, 1 H); 6.72 ± 6.85 (m, 3 H); 7.21 (br. t, J ˆ 8.0, 1 H).
‡
EI-MS: 278 (0.4, M ), 157 (75), 122 (100), 121 (77), 113 (47), 57 (73), 41 (50).
9-Hydroxy-10-(4-methoxyphenyl)decan-5-one (4e): M.p. 51.3 ± 51.88. Yield 68%. IR (KBr): 3450s, 1715s,
1600m, 1580w, 1260m, 1140m, 780m. 1H-NMR: 0.89 (t, J ˆ 7.4, 3 H); 1.20 ± 1.80 (m, 10 H); 2.30 ± 2.50 (m, 2 H);
2.50 ± 2.64 (m, 1 H); 2.70 ± 2.81 (m, 1 H); 3.70 ± 3.82 (m, 1 H); 3.79 (s, 3 H); 6.84 (d, J ˆ 8.5, 2 H); 7.12 (d, J ˆ 8.5,
‡
2 H). EI-MS: 278 (0.4, M ), 157 (75), 122 (100), 121 (77), 113 (47), 57 (73), 41 (50).
5-Butyl-5,6,7,8,9,10-hexahydro-5,9-epoxycycloocta[f]-1,3-benzodioxole ((Æ)-6a): Yield 93% (Method A,
reflux 12 h; or Method B, 8 h). IR (film): 2980s, 1500s, 1481s, 1240s, 1220s, 1040s, 940m, 850m, 830m, 800m.
1H-NMR: 0.87 (t, J ˆ 7.1, 3 H); 1.08 ± 1.58 (m, 8 H); 1.62 ± 1.78 (m, 2 H); 1.82 ± 2.00 (m, 2 H); 2.42 (d, J ˆ 17,
1 H); 3.28 (dd, J ˆ 17, 7.5, 1 H); 4.36 (t, J ˆ 6.7, 1 H); 5.90 (d, J ˆ 1.4, 1 H); 5.89 (d, J ˆ 1.4, 1 H); 6.50 (s, 1 H);
‡
6.56 (s, 1 H). EI-MS: 274 (10, M ), 231 (100), 189 (12), 131 (7), 103 (6), 77 (5), 41 (6). Anal. calc. for C17H23O3:
C 74.42, H 8.08; found: C 74.58, H 8.19.
5-Butyl-5,6,7,8,9,10-hexahydro-2-methyl-5,9-epoxybenzocyclooctene ((Æ)-6b): Yield 63% (Method A, 12 h;
Method B resulted in a complex mixture in this case). IR (film): 2930s, 1600w, 1500m, 1440m, 1080m, 1038s,
810s. 1H-NMR: 0.85 (t, J ˆ 7.2, 3 H); 1.10 ± 1.60 (m, 8 H); 1.65 ± 185 (m, 2 H); 1.85 ± 2.05 (m, 2 H); 2.30 (s, 3 H);
2.49 (d, J ˆ 17, 1 H); 3.33 (dd, J ˆ 17, 7.8, 1 H); 4.39 (t, J ˆ 6.5, 1 H); 6.90 (d, J ꢀ 8, 1 H); 6.90 (s, 1 H); 7.20

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Helvetica Chimica Acta ± Vol. 84 (2001)
‡
(d, J ꢀ 8, 1 H). EI-MS: 244 (13, M ), 201 (100), 159 (24), 149 (26), 105 (15), 71 (21), 57 (37), 43 (22), 41 (22).
Anal. calc. for C17H23O3: C 74.42, H 8.08; found: C 74.58, H 8.19.
5-Butyl-5,6,7,8,9,10-hexahydro-2,3-dimethoxy-5,9-epoxybenzocyclooctene ((Æ)-6c): Yield 73% (Method A
or B, 12 h). IR (film): 2850s, 1610w, 1515s, 1250s, 1030m, 850w, 760w. 1H-NMR: 0.86 (t, J ˆ 7.1, 3 H); 1.10 ± 1.60
(m, 8 H); 1.62 ± 1.70 (m, 2 H); 1.72 ± 2.00 (m, 2 H); 2.44 (d, J ˆ 17, 1 H); 3.31 (dd, J ˆ 17, 7.8, 1 H); 3.83 (s, 3 H);
‡
3.85 (s, 3 H); 4.38 (t, J ˆ 6.5, 1 H); 6.49 (s, 1 H); 6.58 (s, 1 H). EI-MS: 290 (20, M ), 247 (100), 205 (15), 43 (6),
41 (10). Anal. calc. for C18H26O3: C 74.45, H 9.02; found: C 74.37, H 9.17.
5-Butyl-5,6,7,8,9,10-hexahydro-2-methoxy-5,9-epoxybenzocyclooctene ((Æ)-6d): Yield 98% (Method A, 12 h)
or 88% (Method B, 10 h). IR (film): 2930s, 1610m, 1580w, 1500s, 1270m, 1240m, 1030m, 840m, 800m. 1H-NMR:
0.86 (t, J ˆ 7.1, 3 H); 1.10 ± 1.58 (m, 8 H); 1.85 ± 2.00 (m, 2 H); 2.50 (d, J ˆ 17, 1 H); 3.35 (dd, J ˆ 17, 7.7, 1 H); 3.78
‡
(s, 3 H); 4.39 (t, J ˆ 6.6, 1 H); 6.61 (br. s, 1 H); 6.70 (d, J ˆ 8, 1 H); 6.91 (d, J ˆ 8, 1 H). EI-MS: 260 (11, M ), 217
(100), 175 (22), 147 (8), 91 (6), 41 (7). Anal. calc. for C17H24O2: C 78.42, H 9.29; found: C 78.23, H 9.58.
5,6,7,8,9,10-Hexahydro-5-phenyl-5,9-epoxycycloocta[f]-1,3-benzodioxole ((Æ)-6f): Yield 88% (Method A,
24 h) or 57% (Method B, 36 h). IR (film): 2980m, 1505m, 1488s, 1235s, 1040m, 1020w, 930w, 830m, 760m.
1H-NMR: 1.40 ± 1.78 (m, 2 H); 1.98 ± 2.30 (m, 4 H); 2.58 (d, J ˆ 17, 1 H); 3.52 (dd, J ˆ 17, 7.7, 1 H); 4.54 (t, J ˆ 7.0,
‡
1 H); 5.85 (d, J ˆ 1.4, 1 H); 5.83 (d, J ˆ 1.4, 1 H); 6.00 (s, 1 H); 6.60 (s, 1 H). EI-MS: 294 (10, M ), 215 (100), 189
‡
(6), 165 (6), 152 (5), 77 (13). HR-MS: 294.1252 (C19H18O3 ; calc. 294.1256).
5-Butyl-6,7,8,9-tetrahydro-5,8-epoxy-5H-cycloocta[f]-1,3-benzodioxole ((Æ)-12). Methyl levulinate (13.0 g;
prepared from technical levulinic acid (7) by reaction with MeOH in the presence of H2SO4 in ca. 60% yield),
ethylene glycol (9.3 g, 0.15 mmol), and TsOH (0.1 g) were stirred with heating in benzene with a Dean-Stark
trap to remove the H2O formed in the reaction. When the distillate became clear, the mixture was cooled to r.t.,
poured into ice-water containing Na2CO3, extracted with Et2O, washed with H2O (2 Â 20 ml) and brine (2 Â
20 ml), dried (Na2SO4), and evaporated: crude ketal (1H-NMR homogeneous) in essentially quant. yield. The
crude ketal was dissolved in dry THF (60 ml). With cooling (ice-water bath) and stirring, LiAlH4 (1.63 g) was
added within 15 min. The mixture was stirred at the same temp. for 30 min and then at r.t. for 3 h. A sufficient
amount of Na2SO4 ´ n H2O was added in small portions to decompose the excess LiAlH4. The solids were filtered
off, and the filter cake was washed with Et2O. The combined filtrate and washing were washed with brine
(20 ml), dried (Na2SO4), and evaporated: intermediate alcohol (5.80 g, 92%).
With stirring and cooling ( 788), DMSO (3.4 ml) was added (over 10 min) to a soln. of oxalyl chloride (2.0 ml)
in dry CH2Cl2 (40 ml). The mixture was stirred for 20 min. A soln. of the intermediate alcohol (2.10 g) in CH2Cl2
(2 ml) was introduced. Stirring was continued at 788 for 1.5 h before Et3N (1.4 ml) was added. The bath was
allowed to warm to r.t. over ca. 1 h, then H2O (30 ml) was added. The mixture was extracted with Et2O (4 Â
40 ml), the combined org. phase washed with H2O (2Â 20 ml) and brine (20 ml), dried (Na2SO4), and evaporated
to give the aldehyde 8 (2.01 g), which was directly used in the reaction with the sulfur ylide to prepare 9.
NaH (0.90 g, 60% suspension in mineral oil) was washed with dry hexanes to remove oil. Dry DMSO
(40 ml) was added, followed by Me3S(O)I (5.04 g) in small portions. After stirring at r.t. for 1 h, the crude
aldehyde 8 (2.01 g) in DMSO (1 ml) was added. The mixture was stirred at r.t. for 5 min, then at 608 for another
3 h. The mixture was partitioned between H2O and Et2O, the Et2O phase washed with brine, dried, and
evaporated, and the residue was chromatographed: 2-methyl-2-[2-(oxiran-2-yl)ethyl]-1,3-dioxole (9; 0.45 g, 20%
1
over 2 steps). Oil which was used immediately in the next step. H-NMR (90 MHz): 1.33 (s, 3 H); 1.50 ± 1.90
‡
(m, 4 H); 2.50 (dd, J ˆ 5, 3, 1 H); 2.77 (t, J ˆ 5, 1 H); 2.97 (m, 1 H); 3.80 ± 4.15 (m, 4 H). EI-MS: 158 (4, M ),
156 (11), 101 (19), 87 (27), 83 (57), 55 (39), 43 (100).
To a soln. of 5-bromo-1,3-benzodioxole (1.6 g, 8 mmol) in dry THF (45 ml) stirred at 788 under N2, 1.6m
BuLi in hexane (5.0 ml) was added. The mixture was stirred at 408 for 1.5 h. The bath temp. was lowered to
788 and BF3 ´ OEt2 (1.42 g, freshly distilled) was added, followed by 9 (0.80 g, 5 mmol) in THF (5 ml). After
another 45 min at 788, aq. NaHCO3 soln. (5 ml) was added. The mixture was extracted with Et2O (3 Â 50 ml),
washed with brine (10 ml), dried (MgSO4), and submitted to FC: 1-(1,3-benzodioxol-5-yl)-4-(2-methyl-1,3-
dioxol-2-yl)butan-2-ol (10, 0.92 g, 65%), containing small amounts of 2-{{5-[(1,3-benzodioxol-5-yl)methyl]te-
trahydro-2-methylfuran-2-yl}oxy}ethanol (11). Oil. 1H-NMR: 1.32 (s, 3 H); 1.50 ± 1.78 (m, 2 H); 1.78 ± 1.92
(m, 2 H); 2.22 (v.br. s, OH); 2.60 (dd, J ˆ 14, 8.2, 1 H); 2.70 (dd, J ˆ 14, 4.7, 1 H); 3.70 ± 3.80 (m, 1 H); 3.88 ± 3.98
(m, 4 H); 5.91 (s, 2 H); 6.64 (dd, J ˆ 8.0, 1.4, 1 H); 6.70 (d, J ˆ 1.4, 1 H); 6.73 (d, J ˆ 8.0, 1 H).
A soln. of 10 (22 mg) in MeOH (5 ml) containing 36% HCl soln. (1 small drop) was heated to reflux for
12 h under N2. The mixture was cooled to r.t., diluted with Et2O (50 ml), washed with aq. NaHCO3 soln. (10 ml)
and brine (10 ml), dried (Na2SO4), and submitted to give 12 (12 mg, 70%). Oil. IR (film): 2850s, 1500m, 1480m,
1230m, 1030m, 930w, 840w. 1H-NMR: 1.69 (s, 3 H); 1.68 ± 1.90 (m, 2 H); 1.98 ± 2.09 (m, 1 H); 2.18 ± 2.31
(m, 1 H); 2.42 (d, J ˆ 16, 1 H); 3.30 (dd, J ˆ 16, 5.2, 1 H); 4.71 (t, J ˆ 6.3, 1 H); 5.90 (s, 2 H); 6.54 (s, 1 H); 6.67

Helvetica Chimica Acta ± Vol. 84 (2001)
171
‡
(s, 1 H). EI-MS: 218 (22, M ), 203 (8), 189 (100), 175 (19), 115 (14), 91 (8), 77 (8). HR-MS: 218.0928
‡
(C13H14O3 ; calc. 218.0943).
10-(1,3-Benzodioxol-5-yl)-9-[(methylsulfonyl)oxy]decan-5-one (13). MsCl (39 mg, 1.5 equiv.) was added
dropwise at 08 to a stirred soln. of 4a (66mg, 0.22 mmol) and Et3N (0.2 ml) in CH2Cl2 (5 ml). Stirring was
continued at r.t. for 6 h. Et2O (50 ml) was added, before the mixture was washed with H2O (2 Â 10 ml) and brine
(15 ml), dried (MgSO4), and evaporated to give the crude product, which was submitted to FC: 13 (71 mg,
85%). Gum. IR (film): 1720s, 1610w, 1500s, 1495s, 1350s, 1170s, 900s, 810m. 1H-NMR: 0.89 (t, J ˆ 7.3, 3 H);
1.18 ± 1.36 (m, 3 H); 1.46 ± 1.62 (m, 3 H); 1.63 ± 1.80 (m, 2 H); 2.37 (t, J ˆ 7.5, 2 H); 2.38 ± 2.48 (m, 2 H); 2.43
(s, 3 H); 2.89 (d, J ˆ 6.3, 2 H); 4.70 ± 4.82 (m, 1 H); 5.93 (s, 2 H); 6.66 (d, J ˆ 8.0, 1.7, 1 H); 6.71 (d, J ˆ 1.7, 1 H);
‡
6.74 (d, J ˆ 8.0, 1 H). EI-MS: 370 (6, M ), 274 (18), 174 (100), 144 (20), 135 (78), 77 (21), 57 (19), 41 (19). Anal.
calc. for C18H36O6S: C 58.36, H 7.07; found: C 58.09, H 7.12.
5-(6-Butyl-3,4-dihydro-2H-thiopyran-2-yl)-1,3-benzodioxole (14). To a soln. of 13 (32 mg, 0.09 mmol) in
DMF (5 ml) stirred at 08, NaSH ´ n H2O (220 mg, >5 equiv.) was added. The mixture was stirred at 08 until the
solids were well-dispersed. The mixture was then stirred at 408 for 4 h before being partitioned between H2O
(5 ml) and AcOEt (30 ml). The aq. layer was extracted twice (2 Â 30 ml). The combined org. phases were
washed with H2O (2 Â 10 ml) and brine (2 Â 10 ml), dried (MgSO4), and evaporated to give the crude oil.
MeOH (10 ml) was added, followed by 6n HCl (0.5 ml). The mixture was then stirred at 408 for 30 min. MeOH
was evaporated, the residue diluted with Et3O (50 ml), washed with H2O (10 ml), aq. sat. NaHCO3 soln.
(10 ml), and brine (2 Â 10 ml), (MgSO4), and evaporated, and the residue was submitted to FC: 14 (23 mg,
90%). Oil. IR (film): 1640w, 1600w, 1500s, 1490s, 1440m, 1245s, 1040s, 930m, 770w. 1H-NMR: 0.88 (t, J ˆ 7.2,
3 H); 1.20 ± 1.40 (m, 4 H); 1.40 ± 1.65 (m, 4 H); 1.95 ± 2.30 (m, 4 H); 2.78 (dd, J ˆ 7.4, 3.6, 2 H); 3.18 ± 3.30
(m, 1 H); 5.49 (t, J ˆ 3.7, 1 H); 5.92 (s, 3 H); 6.67 (d, J ˆ 8.0, 1 H); 6.69 (s, 1 H); 6.73 (d, J ˆ 8.0, 1 H). EI-MS:
‡
‡
290 (34, M ), 174 (62), 155 (100), 135 (39), 99 (33), 77 (33), 41 (21). HR-MS: 290.1314 (C17H22O2S ; calc.
290.1340).
5-Butyl-5,6,7,8,9,10-hexahydro-5,9-epithiocycloocta[f]-1,3-benzodioxole ((Æ)-15). To a soln. of 14 (6 mg) in
CH2Cl2 (3 ml), CF3SO3H (1 small drop) was added. The mixture was stirred at 408 for 4 h. Then AcOEt (40 ml)
was added, the soln. washed with H2O (5 ml), aq. sat. NaHCO3 soln. (10 ml), and brine (10 ml), dried (MgSO4),
and evaporated, and the residue was submitted to FC: (Æ)-15 (ca. quant.). Oil. 1H-NMR: 0.92 (t, J ˆ 7.0, 3 H);
1.20 ± 1.80 (m, 10 H); 1.85 ± 2.20 (m, 2 H); 2.84 (d, J ˆ 17, 1 H); 3.19 ± 3.25 (m, 1 H); 3.45 (dd, J ˆ 17, 6.5, 1 H);
‡
5.91 (s, 1 H); 5.92 (s, 1 H); 6.60 (s, 1 H); 6.69 (s, 1 H). EI-MS: 290 (14, M ), 249 (5), 247 (71), 85 (52), 71 (69),
‡
57 (100), 43 (77). HR-MS: 290.1355 (C17H22O2S ; calc. 290.1340).
This work was supported by the Chinese Academy of Sciences (CAS ꢁKnowledge Innovationꢀ Project), the
Life Science Special Fund of CAS Supported by the Ministry of Finance (Stz 98-3-03), the National ꢁ973ꢀ Project
(G2000077502), the Ministry of Science and Technology of China (970211006-06), and the National Natural
Science Foundation of China (29832020, 20025207).
REFERENCES
[1] G. Casiraghi, G. Sartori, G. Casnati, F. Bigi, J. Chem. Soc., Perkin Trans. 1 1983, 1649; S. Fung, N. A.
Abraham, F. Belini, K. Sestanj, Can. J. Chem. 1983, 61, 368; D. Bonnet-Delpon, M. Charpentier-Morize, R.
Jacquot, J. Org. Chem. 1988, 53, 759.
[2] J. E. Hofmann, A. Schriesheim, in ꢁFriedel-Crafts and Related Reactionsꢀ, Ed. G. A. Olah, Interscience
Publishers, New York, 1964, p. 597 ± 640.
[3] J.-F. Fan, Y.-K. Wu, Y.-L. Wu, J. Chem. Soc., Perkin Trans. 1 1999, 1189.
[4] M. P. Cooke, Jr., J. Org. Chem. 1986, 51, 951.
[5] U. P. Dhokte, A. S. Rao, Synth. Commun. 1988, 18, 811; W.-S. Zhou, G.-P. Wei, Synthesis 1990, 822; W. G.
Taylor, J. Org. Chem. 1979, 44, 1020.
[6] E. J. Corey, M. Chaykovsky, J. Am. Chem. Soc. 1965, 87, 1353.
[7] H. Konishi, K. Aritomi, T. Okano, J. Kiji, Bull. Chem. Soc. Jpn. 1989, 62, 591; W. Bouthrone, J. W.
Cornforth, J. Chem. Soc. (C) 1969, 1202.
[8] L. Even, D. Florentin, A. Maryqued, Bull. Soc. Chim. Fr. 1990, 127, 758.
[9] J. E. T. Corrie, J. R. Hlubucek, G. Lowe, J. Chem. Soc., Perkin Trans. 1 1977, 1421.
[10] H.-J. Liu, J. Yip, K.-S. Shia, Tetrahedron Lett. 1997, 38, 2253.
[11] S. Fukuda, Y. Akiyoshi, K. Hori, J. Org. Chem. 1999, 64, 4768.
Received July 28, 2000