Intramolecular [2+2] cycloaddition of homoallylketenes to bicyclo[2.1.1]hexan-5-ones

Article abstract of DOI:10.1248/cpb.60.548

Intramolecular [2+2] cycloaddition of γ,δ-unsaturated ketenes derived from hex-5-enoyl chloride derivatives gave bicyclo[2.1.1]hexan-5-ones with complete regioselectivity.

Full text of DOI:10.1248/cpb.60.548

548
Note
Chem. Pharm. Bull. 60(4) 548–553 (2012)
Vol. 60, No. 4
Intramolecular [2+2] Cycloaddition of Homoallylketenes to
Bicyclo[2.1.1]hexan-5-ones
Takaya Hoshikawa, Kei Tanji, Jun-ichi Matsuo,* and Hiroyuki Ishibashi
School of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University;
Kakuma-machi, Kanazawa 920–1192, Japan.
Received December 2, 2011; accepted January 23, 2012; published online January 24, 2012
Intramolecular [2+2] cycloaddition of γ,δ-unsaturated ketenes derived from hex-5-enoyl chloride deriva-
tives gave bicyclo[2.1.1]hexan-5-ones with complete regioselectivity.
Key words intramolecular [2+2] cycloaddition; ketene; alkene; bicyclo[2.1.1]hexan-5-one; regioselective
Intramolecular [2+2] cycloaddition of ketenes to olefins is cycloaddition regioselectivity opposite to that was expected
a powerful tool for stereo- and regioselective construction of by electronic consideration.12,13) Thus, intramolecular [2+2]
polycyclic cyclobutanones.1) It is known that the tether length cycloaddition of ketene with a longer-tethered terminal alkene
between ketenes and alkenes influences the yield of the intra- usually gives a fused compound 9 rather than a bridged com-
molecular cycloaddition, and many examples of three-atom pound 10 since the more nucleophilic terminal alkenyl carbon
tethers have been reported.1–4) Intramolecular cycloaddition attacks the electrophilic ketene carbon (Chart 3). In fact, intra-
reactions of alkenylketenes with a longer tether have been molecular cycloaddition of a three-carbon-tethered ketene 12
achieved with reactive ketenes (keteniminium salts5) and alk- afforded 13 as the major product with normal regioselectivity
oxyketenes6)) or ketenes having conformationally restricted (Chart 4).9,14)
tethers.7) On the other hand, reactions of alkenylketenes with
Effects of substituents on ketenes derived from carboxylic
a tether of less than three atoms are very rare. An allylketene acid chlorides 15a–j were studied to clarify the scope and
2, which had a one-atom tether did not give a [2+2] adduct limitations of the present intramolecular [2+2] cycloaddition
but gave cyclopentenone 3 in 79% yield (Chart 1).8,9) To the of homoallylketenes (Table 1). The carboxylic acid chlorides
best of our knowledge, successful [2+2] cycloaddition of two- 15a–j were prepared from the corresponding carboxylic acids
atom tethered homoallylketenes has not been reported to date by using oxalyl chloride in dichloromethane. After evapora-
except chromium–ketene complex.10) We want to report here tion of volatiles, a carboxylic acid chloride was dissolved
intramolecular [2+2] cycloaddition of homoallylketenes free in acetonitrile and diisopropylethylamine was added. The
from chromium complexation.
resulting reaction mixture was stirred at reflux for 11h. A
monosubstituted ketene formed from hex-5-enoyl chloride 15a
did not give the desired product 16a because dimerization
Results and Discussion
We first investigated the reaction of homoallylketene 5, or oligomerization of the ketene proceeded faster (entry 1).
and it was found that bicyclo[2.1.1]hexan-5-one 7 was isolated Similar low efficiency of a monoalkylketene was reported in
in 71% yield by treatment of carboxylic acid chloride 4 with
diisopropylethylamine in acetonitrile at reflux (Chart 2).9) The
bicyclo[2.1.1]hexan-5-one structure of 7 was unambiguously
determined by X-ray crystallographic analysis.11) The other
regioisomer 6 was not obtained at all. This result showed a
Chart 3. Intramolecular [2+2] Cycloaddition of
Terminal Alkene
a Ketene with a
Chart 1
Chart 2
Chart 4
*To whom correspondence should be addressed. e-mail: jimatsuo@p.kanazawa-u.ac.jp
© 2012 The Pharmaceutical Society of Japan

April 2012
549
Table 1. Intramolecular [2+2] Cycloaddition of Homoallylketenes to Bicyclo[2.1.1]hexan-5-ones 16a–j
Entry
15
R
16
Yield (%)a)
1
2
15a
15b
15c
15d
15e
15f
15g
15h
15i
H
16a
16b
16c
16d
16e
16f
16g
16h
16i
0
63
69
40
79
67
70
0
Bu
Bn
3
4
1-Naphthylmethyl
5
Cy
6
t-Bu
Ph
7
8
MeO
BnO
PhS
9
20
31
10
15j
16j
a) Isolated yield.9)
three-carbon-tethered ketenes.14) Intramolecular cycloaddition m, multiplet; br, broad. 13C-NMR spectra were recorded on
of alkylhomoallylketenes gave the corresponding cycloadducts a JOEL JNM ECA600 (150MHz) or a JOEL JNM ECS400
16b–f in moderate to good yields (entries 2–6). Cycloaddition (100MHz) spectrometer with complete proton decoupling.
of a phenylketene derived from 15g also proceeded to afford Chemical shifts are reported in parts per million relative to
an adduct 16g in 70% yield (entry 7). However, intramolecu- tetramethylsilane with the solvent resonance as the internal
lar cycloaddition of alkoxyketenes generated from 15h,i did standard CDCl3. Analytical TLC was performed on Merck
not proceed smoothly (entries 8 and 9). These results were in precoated TLC plates (silica gel 60 GF254, 0.25mm). Silica-
contrast with the efficient [2+2] cycloaddition of alkoxyketene gel column chromatography was carried out on silica gel
derived from chromium–carbene complex.10) It is assumed 60N (Kanto Kagaku Co., Ltd., spherical, neutral, 63–210μm).
that problematic generation of ketenes from 15h,i under the Preparative thin-layer chromatography (PTLC) was carried
basic conditions would cause the low conversion to 16h,i. out on silica gel Wakogel B-5F. All reactions were carried
An α-phenylsulfany derivative 15j gave the corresponding out under nitrogen in dried glassware with magnetic stirring.
bicyclo[2.1.1]hexan-5-one 16j in 31% yield (entry 10). In all of Diisopropylamine was used after distillation from CaH2.
the experiments described above, a small amount of the cor-
responding carboxylic acid anhydrides was formed,15) but the Cycloaddition. 2-Tritylhex-5-enoic Acid (a Substrate of
other regioisomers, [2.2.0]hexan-2-ones, were not obtained. 4) To a stirred solution of sodium hydride (60% oil suspen-
Preparation of Substrates for Intramolecular [2+2]
The unusual regioselectivity observed in cycloaddition of sion, 71.2mg, 1.78mmol) in tetrahydrofuran (THF) (8mL) was
homoallylketene 8 (n=0) was explained by high ring strain added 3,3,3-triphenylpropionic acid (500.0mg, 1.65mmol),
of fused [2.2.0]hexan-2-one 9 (n=0).16) Even if [2.2.0]hexan- and the mixture was refluxed for 15min and the mixture was
°
2-one 9 (n=0) was formed, reversibility of ketene cycloaddi- cooled to 0 C. n-Butyllithium (1.65M in hexane, 1.20mL,
tion1) would lead to the more stable bridged regioisomer 10 1.98mmol) was added and the mixture was stirred for 5min.
(n=0).
4-Bromo-1-butene (0.201mL, 1.98mmol) was added and the
°
In summary, intramolecular [2+2] cycloaddition of homoal- mixture was stirred at 30 C for 23h. The reaction mixture
lylketenes derived from hex-5-enoyl chlorides with diisopro- was quenched with 5% hydrochloric acid and extracted with
pylethylamine gave bicyclo[2.1.1]hexan-5-ones.17,18) These com- ethyl acetate. The combined organic extracts were washed
pounds have been prepared by photolysis of γ,δ-unsaturated with brine, dried over anhydrous sodium sulfate, filtered, and
chromium–carbene complexes,10) intramolecular alkylation concentrated. The crude product was purified by column chro-
of 2-tosyloxymethylcyclopentanones19,20) and β′-silyloxy enol matography on silica gel (25g, hexane–ethyl acetate=3:1) to
triflate,21) or oxidative rearrangement of bicyclo[2.2.0]hexan- afford 2-tritylhex-5-enoic acid (85.2mg, 0.239mmol, 14%) as
2-ol.22) The present method would offer an another useful a colorless crystal: mp 138.0–139.0 C (hexane, ethyl acetate);
°
method for synthesis of bicyclo[2.1.1]hexan-5-ones.23)
1H-NMR (600MHz, CDCl3) δ: 1.31–1.37 (m, 1H), 1.69 (dt,
J=14.4, 8.2Hz, 1H), 2.04–2.17 (m, 2H), 4.21 (d, J=11.0Hz,
1H), 5.01–5.05 (m, 2H), 5.78 (ddt, J=17.2, 10.3, 7.6Hz, 1H),
Experimental
General All melting points were determined on 7.14–7.17 (m, 3H), 7.19–7.22 (m, 6H), 7.30–7.31 (m, 6H);
Yanagimoto micro melting point apparatus and are uncor- 13C-NMR (150MHz, CDCl3) δ: 29.9, 32.1, 50.9, 60.1, 116.0,
rected. Infrared spectra (IR) were recorded on Horiba IR-710. 126.1, 126.1, 127.4, 129.9, 137.2, 145.0, 180.1; IR (CHCl3) cm−1:
1H-NMR spectra were recorded on a JOEL JNM ECA600 1709, 1495, 1446, 706; Anal. Calcd for C25H24O2: C, 84.24; H,
(600MHz) or a JOEL JNM ECS400 (400MHz) spectrometer 6.79. Found: C, 84.27; H, 6.78.
at room temperature; chemical shifts (δ) are reported in parts
2-Tritylhept-6-enoic Acid (a Substrate of 11) To a
per million relative to tetramethylsilane. Splitting pattern stirred solution of sodium hydride (60% oil suspension,
are designated as s, singlet; d, doublet; t, triplet; q, quartet; 65.8mg, 1.65mmol) in THF (8mL) was added 3,3,3-triphen-

550
Vol. 60, No. 4
ylpropionic acid (499.9mg, 1.65mmol), and the mixture was a colorless oil.
°
refluxed for 15min and the mixture was cooled to 0 C. n-
2-[(Naphthalen-1-yl)methyl]hex-5-enoic Acid (a Substrate
Butyllithium (1.65M in hexane, 1.17mL, 1.93mmol) was added of 15d) To a stirred solution of diisopropylamine (4.59mL,
°
and the mixture was stirred for 5min. 5-Bromo-1-pentene 32.8mmol) in THF (100mL) was added dropwise at 0 C n-
(0.23mL, 1.94mmol) was added and the mixture was stirred butyllithium (1.62M in hexane, 20.2mL, 32.7mmol), and the
°
°
at 30 C for 23h. The reaction mixture was quenched with 5% mixture was stirred at 0 C for 15min. 5-Hexenoic acid (1.50g,
hydrochloric acid and extracted with ethyl acetate. The com- 13.1mmol) was added and the mixture was stirred for 20min.
bined organic extracts were washed with brine, dried over an- 1-(Chloromethyl)naphthalene (2.35mL, 15.7mmol) was added
hydrous sodium sulfate, filtered, and concentrated. The crude and the mixture was stirred at room temperature for 22h. The
product was purified by column chromatography on silica gel reaction mixture was quenched with 1N hydrochloric acid and
(13g, hexane–ethyl acetate=7:1) to afford 2-tritylhept-6-enoic extracted with ethyl acetate. The combined organic extracts
acid (273.7mg, 0.739mmol, 45%) as a colorless crystal: mp were washed with brine, dried over anhydrous sodium sulfate,
142.0–143.5 C (hexane, ethyl acetate); 1H-NMR (600MHz, filtered, and concentrated. The crude product was purified
°
CDCl3) δ: 1.19–1.25 (m, 1H), 1.41–1.49 (m, 2H), 1.59–1.65 (m, by column chromatography on silica gel (40g, hexane–ethyl
1H), 1.96–2.02 (m, 2H), 4.12–4.15 (m, 1H), 4.91 (dd, J=10.3, acetate=4:1), and then purified by recrystallization from
1.0Hz, 1H), 4.95 (dq, J=17.2, 2.1Hz, 1H), 5.68–5.76 (m, hexane and dichloromethane to afford 2-[(naphthalen-1-yl)
1H), 7.12–7.14 (m, 3H), 7.17–7.19 (m, 6H), 7.27–7.29 (m, 6H); methyl]hex-5-enoic acid (1.47g, 5.78mmol, 44%) as a colorless
1
13C-NMR (150MHz, CDCl3) δ: 27.5, 30.4, 33.5, 52.0, 60.2, crystal: mp 75.5–76.0 C (hexane, dichloromethane); H-NMR
°
114.7, 126.1, 127.4, 129.9, 138.2, 145.1, 180.2; IR (CHCl3) cm−1: (600MHz, CDCl3) δ: 1.64–1.69 (m, 1H), 1.86 (ddt, J=14.8, 9.3,
1708, 1495, 1446, 706; Anal. Calcd for C26H26O2: C, 84.29; H, 5.5Hz, 1H), 2.03–2.09 (m, 1H), 2.14–2.20 (m, 1H), 2.90 (ddt,
7.07. Found: C, 84.29; H, 7.20.
J=9.3, 7.6, 4.8Hz, 1H), 3.19 (dd, J=14.1, 7.2Hz, 1H), 3.49 (dd,
2-Butylhex-5-enoic Acid (a Substrate of 15b) To a J=14.1, 7.2Hz, 1H), 4.94 (dd, J=10.3, 1.4Hz, 1H), 4.99 (dq,
stirred solution of sodium hydride (60% oil suspension, J=17.2, 1.7Hz, 1H), 5.73 (ddt, J=16.8, 10.0, 6.5Hz, 1H), 7.32–
89.6mg, 2.24mmol) in THF (18mL) was added 5-hexenoic 7.34 (m, 1H), 7.36–7.39 (m, 1H), 7.47–7.49 (m, 1H), 7.51–7.54
acid (253.5mg, 2.22mmol), and the mixture was refluxed for (m, 1H), 7.74 (d, J=7.9Hz, 1H), 7.86 (d, J=7.2Hz, 1H), 8.02
10min and then cooled to 0 C. A solution of lithium diisopro- (d, J=8.2Hz, 1H); 13C-NMR (150MHz, CDCl3) δ: 31.1, 31.4,
°
pylamide which was prepared by adding n-butyllithium (1.67M 35.4, 45.8, 115.4, 123.5, 125.4, 125.6, 126.1, 127.2, 127.4, 128.9,
in hexane, 1.33mL, 2.22mmol) to a solution of diisopropyl- 131.8, 133.9, 134.8, 137.5, 181.8; IR (CHCl3) cm−1: 1709, 1703,
amine (0.373mL, 2.66mmol) in THF (8mL) was cannulated 918, 798; Anal. Calcd for C17H18O2: C, 80.28; H, 7.13. Found:
and the mixture was stirred few minutes. 4-Bromo-1-butane C, 80.11; H, 7.05.
(0.24mL, 2.24mmol) was added, and the resulting cake was
2-Cyclohexylhex-5-enoic Acid (a Substrate of 15e) To
°
heated at 30 C for 63h. The reaction mixture was quenched a stirred solution of sodium hydride (60% oil suspension,
with 5% hydrochloric acid at room temperature, and the mix- 574.8mg, 14.4mmol) in THF (30mL) was added cyclohexa-
ture was extracted with ether. The combined organic extracts neacetic acid (2.00g, 14.1mmol), and the mixture was refluxed
°
were washed with water, dried over anhydrous sodium sulfate, for 10min and then cooled to 0 C. A solution of lithium di-
filtered, and concentrated. The crude product was purified by isopropylamide which was prepared by adding n-butyllithium
column chromatography on silica gel (6g, hexane–ether=3:1) (1.67M in hexane, 10.1mL, 16.9mmol) to a solution of diiso-
to afford 2-butylhex-5-enoic acid (134.3mg, 0.789mmol, 36%) propylamine (2.40mL, 17.1mmol) in THF (15mL) was can-
1
as a pale yellow oil: H-NMR (600MHz, CDCl3) δ: 0.90 (t, nulated and the mixture was stirred few minutes. 4-Bromo-
J=6.9Hz, 3H), 1.27–1.35 (m, 4H), 1.46–1.52 (m, 1H), 1.54– 1-butene (1.40mL, 13.8mmol) was added, and the resulting
°
1.59 (m, 1H), 1.61–1.67 (m, 1H), 1.72–1.78 (m, 1H), 2.04–2.15 cake was heated at 30 C for 5h. The reaction mixture was
(m, 2H), 2.38 (tt, J=8.9, 5.5Hz, 1H), 4.97 (dd, J=10.0, 1.4Hz, quenched with 5% hydrochloric acid at room temperature,
1H), 5.03 (dq, J=17.2, 1.7Hz, 1H), 5.79 (ddt, J=17.2, 10.3, and the mixture was extracted with ether. The combined or-
6.9Hz, 1H); 13C-NMR (150MHz, CDCl3) δ: 13.9, 22.6, 29.4, ganic extracts were washed with water, dried over anhydrous
31.2, 31.5, 31.8, 44.9, 115.1, 137.8, 182.7; IR (CHCl3) cm−1: sodium sulfate, filtered, and concentrated. The crude product
1705, 918; high resolution (HR)-MS (EI+) Calcd for C10H18O2 was purified by flash column chromatography on silica gel
(m/z) 170.1307, Found 170.1304.
(20g, hexane–ether=7:1) to afford 2-cyclohexylhex-5-enoic
1
2-Benzylhex-5-enoic Acid24) (a Substrate of 15c) To a acid (979.1mg, 4.89mmol, 35%) as a pale yellow oil: H-NMR
stirred solution of diisopropylamine (0.614mL, 4.38mmol) (600MHz, CDCl3) δ: 1.00 (dq, J=12.4, 3.1Hz, 1H), 1.06–1.18
°
in THF (20mL) was added dropwise at 0 C n-butyllithium (m, 2H), 1.20–1.28 (m, 2H), 1.53–1.75 (m, 7H), 1.79–1.81
(1.67M in hexane, 2.62mL, 4.38mmol), and the mixture (m, 1H), 1,98–2.04 (m, 1H), 2.09–2.16 (m, 1H), 2.20 (ddd,
°
was stirred at 0 C for 15min. 5-Hexenoic acid (201.1mg, J=11.0, 7.6–4.1Hz, 1H), 4.97 (ddt, J=10.3, 1.4, 1.4Hz, 1H),
1.76mmol) was added and the mixture was stirred for 15min. 5.03 (dq, J=17.2, 1.7Hz, 1H), 5.79 (ddt, J=17.2, 10.3, 6.9Hz,
Benzyl bromide (0.25mL, 2.10mmol) was added and the mix- 1H); 13C-NMR (150MHz, CDCl3) δ: 26.3, 26.3, 28.2, 30.4,
ture was stirred at room temperature for 15h. The reaction 30.9, 31.9, 40.0, 51.2, 115.1, 137.9, 182.0; IR (CHCl3) cm−1:
mixture was quenched with 5% hydrochloric acid and extract- 1703, 1641, 1450, 910; HR-MS (EI+) Calcd for C12H14O2S (m/z)
ed with ether. The combined organic extracts were washed 196.1463, Found 196.1469.
with brine, dried over anhydrous sodium sulfate, filtered, and
2-tert-Butylhex-5-enoic Acid (a Substrate of 15f) To
concentrated. The crude product was purified by preparative a stirred solution of sodium hydride (60% oil suspension,
thin-layer chromatography on silica gel (hexane–ether=2:1) to 695.6mg, 17.4mmol) in THF (45mL) was added 3,3-dimethyl-
afford 2-benzylhex-5-enoic acid (293.1mg, 1.43mmol, 81%) as butyric acid (2.00g, 17.2mmol), and the mixture was refluxed

April 2012
551
°
for 15min and the mixture was cooled to 0 C. n-Butyllithium mixture of diethyl oxalate (5.0mL, 37.1mmol), THF (45mL)
°
(1.65M in hexane, 12.5mL, 20.6mmol) was added and the and diethyl ether (60mL) at −78 C and the solution stirred
mixture was stirred for 5min. 4-Bromo-1-butene (2.10mL, for 4h, then stirred for 9h at room temperature. The reaction
°
20.7mmol) was added and the mixture was stirred at 30 C for was quenched with saturated ammonium chloride solution
2h. The reaction mixture was quenched with 5% hydrochloric and the mixture was extracted with ether. The combined or-
acid and extracted with ether. The combined organic extracts ganic extracts were washed with brine, dried over anhydrous
were washed with brine, dried over anhydrous sodium sulfate, sodium sulfate, filtered, and concentrated. The crude product
filtered, and concentrated. The crude product was purified was purified by column chromatography on silica gel (80g,
°
by Kugelrohr distillation (100 C/10.5mmHg) and the distil- hexane–ether=11:1) to afford ethyl 2-oxohex-5-enoate (5.45g,
lation residue was purified by column chromatography on 34.7mmol, 94%) as a pale yellow oil.
silica gel (5g, hexane–ether=6:1) to afford 2-tert-butylhex-
Sodium triacetoxyborohydride (6.29g, 39.3mmol) was add-
5-enoic acid (168.4mg, 0.989mmol, 6%) as a yellow oil: ed to a solution of ethyl 2-oxohex-5-enoate (5.45g, 34.7mmol)
1H-NMR (600MHz, CDCl3) δ: 0.10 (s, 9H), 1.54–1.60 (m, 1H), in dichloromethane (150mL). The mixture was stirred at room
1.73–1.80 (m, 1H), 1.95–2.01 (m, 1H), 2.10–2.16 (m, 1H), 2.18 temperature for 1d. Then, sodium triacetoxyborohydride
(dd, J=12.0, 2.4Hz, 1H), 4.98 (dd, J=10.3, 1.4Hz, 1H), 5.04 (5.72g, 35.7mmol) was added to the mixture. The mixture
(dq, J=17.2, 1.7Hz, 1H), 5.79 (ddt, J=17.2, 10.3, 7.2Hz, 1H); was stirred at room temperature for 2d. The solution was
13C-NMR (150MHz, CDCl3) δ: 26.8, 27.8, 32.5, 32.7, 55.6, quenched with saturated aqueous sodium hydrogen carbonate
115.3, 137.8, 181.5; IR (CHCl3) cm−1: 1703, 1369, 918; HR-MS solution and the mixture was extracted with dichloromethane.
(EI+) Calcd for C10H18O2 (m/z) 170.1307, Found 170.1308.
The combined organic extracts were washed with brine, dried
2-Phenylhex-5-enoic Acid (a Substrate of 15g) To a over anhydrous sodium sulfate, filtered, and concentrated.
stirred mixture of potassium hydride (1.66g, 29.6mmol) in The crude product was purified by column chromatography
°
dimethyl sulfoxide (DMSO) (25mL) was added at 0 C tri- on silica gel (60g, hexane–diethyl ether=11:1) to afford ethyl
fluoromethanesulfonic acid (1.12mL, 12.7mmol), and the 2-hydroxyhex-5-enoate (3.53g, 22.2mmol, 64%) as a colorless
resulting mixture was stirred at room temperature for 15min. oil.
4-Bromo-1-butene (1.03mL, 10.1mmol) and diethyl phenyl-
Silver(I) oxide (1.91g, 8.25mmol), benzyl bromide (1.0mL,
malonate (2.00g, 8.47mmol) were added successively at room 5.85mL) and tetrabutylammonium iodine (2.03g, 5.50mmol)
°
temperature, and the reaction mixture was stirred at 50 C for were added to a N,N-dimethylformamide (DMF) (25mL) solu-
12h. The reaction mixture was quenched with 1N hydrochlo- tion of ethyl 2-hydroxyhex-5-enoate (874.8mg, 5.50mmol), the
ric acid and extracted with ether. The combined organic ex- resulting mixture was stirred for 8h at room temperature. The
tracts were washed with brine, dried over anhydrous sodium reaction mixture was filtered and extracted with diethyl ether.
sulfate, filtered, and concentrated. The crude product was The combined organic extracts were washed with brine, dried
purified by column chromatography on silica gel (30g, hex- over anhydrous sodium sulfate, filtered, and concentrated.
ane–ether=8:1) to afford diethyl 2-(butyl-3-enyl)-2-phenyl- The crude product was purified by column chromatography
malonate (2.07g, 7.11mmol, 84%) as a colorless oil.
on silica gel (15g, hexane–diethyl ether=10:1) to afford ethyl
To a stirred solution of diethyl 2-(butyl-3-enyl)-2-phenyl- 2-(benzyloxy)hex-5-enoate (737.5mg, 2.97mmol, 54%) as a
malonate (2.06g, 7.09mmol) in ethanol (13mL) was added a pale yellow oil.
solution of potassium hydroxide (1.19g, 21.2mmol) in water
To a stirred solution of ethyl 2-(benzyloxy)hex-5-enoate
(8mL), and the mixture was refluxed for 6h. After evapora- (344.5mg, 1.39mmol) in ethanol (8mL) was added a solution
tion of the solvent, the residue was extracted with 10% aque- of potassium hydroxide (235.5mg, 4.20mmol) in water (6mL),
ous solution of potassium hydroxide. The water extracts were and the mixture was refluxed for 13h. After evaporation of
acidified to pH 2 with 10% hydrochloric acid, and the mixture the solvent, the residue was acidified to pH 2 with 5% hydro-
were extracted with ether. The combined organic extracts was chloric acid, and the mixture was extracted with ether. The
washed with brine, dried over anhydrous sodium sulfate, fil- combined organic extracts were washed with brine, dried over
tered, and concentrated. The obtained 2-(but-3-enyl)-2-phenyl- anhydrous sodium sulfate, filtered, and concentrated to afford
°
malonic acid was heated at 155 C for 14h. The crude product 2-(benzyloxy)hex-5-enoic acid (270.4mg, 1.23mmol, 88%)
1
was purified by column chromatography on silica gel (13g, as a pale yellow oil: H-NMR (600MHz, CDCl3) δ: 1.92 (dt,
hexane–ethyl acetate=2:1) to afford 2-phenylhex-5-enoic acid J=7.6, 6.2Hz, 2H), 2,17–2.28 (m, 2H), 4.02 (t, J=6.2Hz, 1H),
(984.9mg, 5.18mmol, 73% for 2 steps) as a pale yellow oil: 4.48 (d, J=11.3Hz, 1H), 4.73 (d, J=11.3Hz, 1H), 4.98–5.04
1H-NMR (600MHz, CDCl3) δ: 1.86 (ddt, J=14.8, 7.6, 7.6Hz, (m, 2H), 5.78 (ddt, J=17.2, 10.3, 6.9Hz, 1H), 7.30–7.34 (m,
1H), 2.00 (q, J=6.9Hz, 2H), 2.15 (ddt, J=14.3, 7.6Hz, 1H), 1H), 7.35–7.37 (m, 4H); 13C-NMR (150MHz, CDCl3) δ: 29.2,
3.56 (t, J=7.2Hz, 1H), 4.97–5.01 (m, 2H), 5.75 (ddt, J=16.5, 31.8, 72.6, 76.7, 115.7, 128.1, 128.1, 128.4, 137.0, 137.1, 178.3;
10.3, 6.2Hz, 1H), 7.26–7.28 (m, 1H), 7.30–7.32 (m, 2H); IR (CHCl3) cm−1: 1720, 698; HR-MS (EI+) Calcd for C13H16O3
13C-NMR (150MHz, CDCl3) δ: 31.3, 32.0, 50.8, 115.5, 127.4, (m/z) 220.1099, Found 220.1103.
128.1, 128.6, 137.3, 138.2, 180.5; IR (CHCl3) cm−1: 1709, 918,
700; HR-MS (EI+) Calcd for C12H14O2 (m/z) 190.0994, Found a stirred solution of diisopropylamine (2.10mL, 15.0mmol)
2-(Phenylthio)hex-5-enoic Acid (a Substrate of 15j) To
°
in THF (30mL) was added dropwise at 0 C n-butyllithium
190.0992.
2-(Benzyloxy)hex-5-enoic Acid25) (a Substrate of 15i) To (1.67M in hexane, 8.98mL, 15.0mmol), and the mixture
°
a dry flask containing magnesium (2.52g, 103.7mmol) was stirred at 0 C for 20min. (Phenylthio)acetic acid (1.01g,
was added a solution of the 4-bromo-1-butene (4.51mL, 6.00mmol) was added and the mixture was stirred for 20min.
44.4mmol) in THF (60mL) dropwise with vigorous agita- 4-Bromo-1-butene (1.22mL, 12.0mmol) was added and the
tion. The resultant solution was then added dropwise to a mixture was stirred at room temperature for 24h. The reaction

552
Vol. 60, No. 4
mixture was quenched with 5% hydrochloric acid and extract- (dq, J=7.2, 2.7Hz, 1H), 1.60–1.67 (m, 2H), 1.71–1.76 (m,
ed with ether. The combined organic extracts were washed 1H) 1.83–1.88 (m, 1H), 2.83 (dt, J=3.1, 1.7Hz, 1H), 2.93 (d,
with brine, dried over anhydrous sodium sulfate, filtered, and J=14.1Hz, 1H) 3.02 (d, J=14.4Hz, 1H), 7.20–7.30 (m, 5H);
concentrated. The crude product was purified by column chro- 13C-NMR (150MHz, CDCl3) δ: 21.9, 24.9, 31.3, 34.0, 52.2,
matography on silica gel (25g, hexane–ethyl acetate=2:1) 66.0, 126.1, 128.3, 129.4, 138.0, 201.2; IR (CHCl3) cm−1: 1786,
to afford 2-(phenylthio)hex-5-enoic acid (1.22g, 5.53mmol, 1770, 704; HR-MS (EI+) Calcd for C13H14O (m/z) 186.10447,
1
92%) as a yellow oil: H-NMR (600MHz, CDCl3) δ: 1.86 Found 186.10414.
(ddt, J=14.4, 7.2, 7.2Hz, 1H), 2.00 (ddt, J=15.1, 7.6, 7.6Hz,
1-[(Naphthalen-1-yl)methyl]bicyclo[2.1.1]hexan-5-one
1
1H), 2.25 (q, J=7.2Hz, 2H), 3.64 (t, J=7.6Hz, 1H), 5.02 (dd, (16d) Pale yellow oil: H-NMR (600MHz, CDCl3) δ: 1.32
J=10.3, 1.4Hz, 1H), 5.06 (dq, J=17.2, 1.4Hz, 1H) 5.77 (ddt, (d, J=7.6, 1H), 1.53 (dq, J=7.2, 2.4Hz, 1H), 1.58–1.63 (m,
J=16.8, 10.3, 6.5Hz, 1H), 7.29–7.33 (m, 3H), 7.47–7.49 (m, 1H), 1.66–1.73 (m, 2H), 1.82–1.86 (m, 1H), 2.81–2.82 (m, 1H),
2H); 13C-NMR (150MHz, CDCl3) δ: 30.4, 31.0, 49.9, 116.2, 3.41 (d, J=14.8Hz, 1H), 3.50 (d, J=14.4Hz, 1H), 7.39–7.42
128.2, 129.0, 132.8, 133.0, 136.5, 178.5; IR (CHCl3) cm−1: (m, 2H), 7.46–7.52 (m, 2H), 7.73 (dd, J=6.9, 2.4Hz, 1H), 7.85
1708, 919; HR-MS (EI+) Calcd for C12H14O2S (m/z) 222.0715, (dd, J=7.9, 0.7Hz, 1H), 8.03 (d, J=8.2Hz, 1H); 13C-NMR
Found 222.0709.
(150MHz, CDCl3) δ: 22.0, 25.4, 29.8, 32.0, 52.4, 66.0, 124.0,
Typical Procedure for Intramolecular [2+2] Cyclo- 125.5, 125.7, 127.0, 127.7, 128.7,132.3, 133.8, 134.5, 201.2; IR
addition: Preparation of 1-Tritylbicyclo[2.1.1]hexane-5-one (CHCl3) cm−1: 1776, 1018; HR-MS (DART) Calcd for C17H16O
(7) To a stirred solution of 2-tritylhex-5-enoic acid (32.7mg, (m/z) 236.12011, Found 236.12088.
°
0.0917mmol) in dichloromethane (1.5mL) was added at 0 C
1-Cyclohexylbicyclo[2.1.1]hexan-5-one
(16e) Colorless
oxalyl chloride (0.023mL, 0.272mmol) and the mixture was oil: 1H-NMR (600MHz, CDCl3) δ: 1.04–1.18 (m, 3H),
stirred for 17h. The volatiles were evaporated in vacuo to 1.21–1.29 (m, 2H), 1.35 (d, J=7.2Hz, 1H), 1.57–1.58 (m, 1H),
remove all of excess oxalyl chloride and dichloromethane. 1.64–1.79 (m, 9H), 1.83–1.87 (m, 1H), 2.79–2.80 (m, 1H);
To the resulting acid chloride acetonitrile (0.46mL) and 13C-NMR (150MHz, CDCl3) δ: 21.7, 22.4, 26.2, 26.2, 26.3,
N,N-diisopropylethylamine (0.0188mL, 0.110mmol) were 28.7, 29.2, 29.4, 36.2, 52.3, 69.7, 202.4; IR (CHCl3) cm−1: 2929,
added successively at room temperature, and the mixture was 1766, 1450; HR-MS (EI+) Calcd for C12H18O (m/z) 178.13538,
refluxed for 11h. The reaction mixture was quenched with Found 178.13577.
saturated aqueous sodium hydrogen carbonate solution at
1-tert-Butylbicyclo[2.1.1]hexan-5-one (16f) Pale yellow
room temperature, and the mixture was extracted with ether. oil: 1H-NMR (600MHz, CDCl3) δ: 1.00 (s, 9H), 1.32 (d,
The combined organic extracts were washed with brine, dried J=7.2Hz, 1H), 1.70 (dq, J=5.2, 2.4Hz, 1H), 1.72–1.82 (m,
over anhydrous sodium sulfate, filtered, and concentrated. The 3H), 1.83–1.87 (m, 1H), 2.77 (dt, J=3.1, 1.7Hz, 1H); 13C-NMR
crude product was purified by preparative thin-layer chroma- (150MHz, CDCl3) δ: 21.7, 21.8, 26.4, 28.2, 30.1, 51.9, 72.9,
tography on silica gel (hexane–ethyl acetate=10:1) to afford 202.2; IR (CHCl3) cm−1: 1776, 1769; HR-MS (EI+) Calcd for
1-tritylbicyclo[2.1.1]hexane-5-one 7 (22.0mg, 0.0650mmol, C10H16O (m/z) 152.12012, Found 152.12036.
°
71%) as a colorless crystal: mp 168.0–169.0 C (hexane, ethyl
1-Phenylbicyclo[2.1.1]hexane-5-one (16g) Pale yellow
acetate); 1H-NMR (600MHz, CDCl3) δ: 1.27 (td, J=11.7, oil: H-NMR (600MHz, CDCl3) δ: 1.84 (d, J=7.6Hz, 1H),
4.5Hz, 1H), 1.42 (d, J=7.6Hz, 1H), 1.69 (tdd, J=11.7, 3.8, 1.97 (tdd, J =10.7, 5.5, 1.7Hz, 1H), 2.01–2.06 (m, 2H), 2.10–
1.7Hz, 1H), 1.89–1.93 (m, 1H), 2.03–2.07 (m, 1H), 2.14 (dq, 2.18 (m, 2H), 3.03 (dt, J=3.1, 1.7Hz, 1H), 7.25–7.37 (m, 5H);
J=7.6, 2.7Hz, 1H), 2.82 (dt, J=3.4, 1.7Hz, 1H), 7.20–7.26, (m, 13C-NMR (150MHz, CDCl3) δ: 22.1, 27.3, 32.8, 53.1, 67.9,
15H); 13C-NMR (150MHz, CDCl3) δ: 21.6, 26.9, 49.5, 60.1, 127.0, 127.2, 128.4, 136.0, 199.5; IR (CHCl3) cm−1: 1786, 1776,
72.3, 126.1, 127.6, 130.3, 202.9; IR (CHCl3) cm−1: 1772, 706; 1770, 700; HR-MS (EI+) Calcd for C12H12O (m/z) 172.08882,
Anal. Calcd for C25H22O: C, 88.72; H, 6.55. Found: C, 88.89; Found 172.08859.
1
H, 6.64.
1-(Benzyloxy)bicyclo[2.1.1]hexan-5-one (16i) Pale yel-
5-Tritylbicyclo[3.2.0]heptan-6-one (13) Colorless crystal: low oil: 1H-NMR (600MHz, CDCl3) δ: 1.60 (d, J=6.9Hz,
1
°
mp 184.0–186.0 C (hexane, ethyl acetate) H-NMR (600MHz, 1H), 1.78–1.96 (m, 5H), 2.58 (dt, J=2.8, 1.4Hz, 1H), 4.68
CDCl3) δ: 1.69–1.88 (m, 4H), 1.96–2.02 (m, 1H), 2.13 (dd, (d, J=11.3Hz, 1H), 4.88 (d, J=11.3Hz, 1H), 7.29 (tt, J=6.5,
J=12.7, 6.9Hz, 1H), 2.37–2.42 (m, 1H), 3.09–3.15 (m, 2H), 1.7Hz, 1H), 7.33–7.38 (m, 4H); 13C-NMR (150MHz, CDCl3)
7.03–7.34 (m, 15H); 13C-NMR (150MHz, CDCl3) δ: 24.4, 33.1, δ: 21.7, 23.6, 30.2, 45.0, 69.4, 91.9, 127.6, 127.8, 128.4, 137.7,
36.4, 38.7, 50.6, 62.7, 85.4, 126.3, 126.5, 127.2, 127.6, 127.8, 200.2; IR (CHCl3) cm−1: 1793, 1321; HR-MS (EI+) Calcd for
129.5, 130.5, 131.7, 144.7, 145.3, 147.1, 215.1; IR (CHCl3) cm−1: C13H14O2 (m/z) 202.09938, Found 202.0988.
1764, 704; HR-MS (EI+) Calcd for C26H24O (m/z) 352.18272,
Found 352.18242.
1-(Phenylthio)bicycle[2.1.1]hexan-5-one (16j) Colorless
oil: H-NMR (600MHz, CDCl3) δ: 1.61 (d, J=7.6Hz, 1H),
1
1-Butylbicyclo[2.1.1]hexan-5-one (16b) Pale yellow oil: 1.76–1.78 (m, 1H), 1.83–1.96 (m, 4H), 2.89–2.90 (m, 1H),
1H-NMR (600MHz, CDCl3) δ: 0.90 (t, J=7.2Hz, 3H), 1.30– 7.30–7.31 (m, 3H), 7.57–7.59 (m, 2H); 13C-NMR (150MHz,
1.38 (m, 4H), 1.40 (d, J=7.2Hz, 1H), 1.54 (dq, J=7.1, 2.7Hz, CDCl3) δ: 22.5, 26.6, 33.3, 50.7, 66.6, 128.3, 128.8, 131.2,
1H), 1.58–1.75 (m, 4H), 1.79 (tdd, J=11.0, 4.5, 1.7Hz, 1H), 135.0, 197.8; IR (CHCl3) cm−1: 1795; HR-MS (EI+) Calcd for
1.85–1.90 (m, 1H), 2.83 (dt, J=3.1, 1.7Hz, 1H); 13C-NMR C12H12SO (m/z) 204.06089, Found 204.06057.
(150MHz, CDCl3) δ: 13.9, 22.1, 23.2, 25.1, 26.8, 27.7, 31.2,
52.7, 65.9, 202.1; IR (CHCl3) cm−1: 1776, 1765; HR-MS (EI+)
Calcd for C10H16O (m/z) 152.12012, Found 152.11996.
Acknowledgments The authors thank Prof. Shuhei
Fujinami (Kanazawa University) for X-ray crystallographic
1-Benzylbicyclo[2.1.1]hexan-5-one (16c) Colorless oil: analysis. This work was supported by a Grant-in-Aid for
1H-NMR (600MHz, CDCl3) δ: 1.35 (d, J=7.2Hz, 1H), 1.56 Scientific Research from the Ministry of Education, Culture,

April 2012
553
observed in a reaction of alkoxyketene prepared from chromium–
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M. B., Tetrahedron, 46, 8031–8042 (1990).
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