An improved synthesis of benzocycloalkanone derivatives

Article abstract of DOI:10.1248/cpb.52.132

A convenient and improved annulation method for the synthesis of bicyclic ketones was developed. A 2,2-dimethyl-6-(2-phenylsulfonyl)ethylcyclohexanone was converted into a sulfonylester by the addition of ethyl acetate and subsequent dehydration. A Dieckm

Full text of DOI:10.1248/cpb.52.132

132
Notes
Chem. Pharm. Bull. 52(1) 132—135 (2004)
Vol. 52, No. 1
An Improved Synthesis of Benzocycloalkanone Derivatives1)
Akimori WADA,* Kyoko SAWADA, Naomi ONO, and Masayoshi ITO
Kobe Pharmaceutical University; 4–19–1 Motoyamakita-machi, Higashinada-ku, Kobe 658–8558, Japan.
Received July 22, 2003; accepted October 10, 2003
A convenient and improved annulation method for the synthesis of bicyclic ketones was developed. A 2,2-di-
methyl-6-(2-phenylsulfonyl)ethylcyclohexanone was converted into a sulfonylester by the addition of ethyl acetate
and subsequent dehydration. A Dieckmann type condensation of the sulfonylester followed by desulfonylation af-
forded the 8,8-dimethyl-1,2,3,4,5,6,7,8-octahydronaphthalene-2-one in good yield. This annulation method was
also applicable for the synthesis of the benzocyclooctanone derivative.
Key words annulation; sulfonylester; bicyclic ketone; retinal anlog
It is well known that (11Z)-retinal (1) and its (all-E)-iso- to afford the b-keto sulfone (8), while this crude product was
mer are a chromophore of protein pigments such as used for the next reaction without a further purification.
rhodopsin, bacteriorhodopsin, phoborhodopsin and so on.2—6) Desulfonylation of 8 was accomplished by treatment with ex-
These proteins exhibit the significant functions in respective cess tributyltin hydride and azobisiisobutylnitrile (AIBN) in
vital cells, in which the conformation of retinal chromophore toluene at 140 °C20) to produce the desired bicyclic ketone
plays an important role. In the past two decades, a number (5a) and the tetrahydronaphthalene derivative (9) in 67% and
of reports have appeared on dealing with the synthesis of 20% yields, respectively (Chart 2). The latter compound
retinal analogs for examining the retinal-structure and pro- would be produced from the initially formed 5a by air oxida-
tein environment around the retinal chromophore in the pig- tion under the reaction conditions. These structures were de-
ments.7—17) In order to investigate the conformation around termined by comparison with the authentic specimens we
the cyclohexene ring of chromophore in rhodopsin, espe- had previously reported.1) It is remarkable that, from the
cially to clarify the torsional angle around the C6—7 single viewpoint of the 6—6 comparable ring annulation, a cycliza-
bond, we have synthesized the bicyclic retinals (2), and from tion using the sulfonylester is more superior than that of the
their binding experiments it was strongly supported that the Dieckmann condensation of the corresponding diester.
tortional angle around the C6—7 single bond of the retinal is
Next we focused our attention on the synthesis of the 6—8
about 60—70° in the protein.1,18) In the preparation of bi- bicyclic ketone (5c). The precursor (12) of the ring closure
cyclic retinals (2), we used the bicyclic ketones (5) as the key reaction was derived from the keto ester (4b), prepared from
intermediates and these ketones were prepared by the Dieck- 3 by alkylation and subsequent demethoxycarbonylation.17)
mann condensation of the diesters (4) derived from the keto Reduction of 4b with LiAlH4 followed by the successive pro-
ester (3).1,17) However, the yields of these cyclization were tection of primary alcohol and PDC oxidation of secondary
very low except for the 6—7 ring system because of a side alcohol, produced the silyloxy ketone (10) in a 62% yield.
reaction such as aromatization, therefore, this methodology After desilylation with tetrabutylammonium floride (TBAF),
is not suitable in the large scale preparation for supply in the the resulting alcohol was treated with carbon tetrabromide
extended research of the investigation on the interaction be- and triphenylphosphine to give the keto bromide, which was
tween the chromophore and proteins (Chart 1). To circum- converted to the solfonylketone (11) by the reaction with
vent this problem, in this paper, we wish to describe a conve- sodium phenylsulfinylamide in the presence of a phase trans-
nient and improved synthesis of the bicyclic ketones (5a, 5c) fer catalyst in a 64% yield. The sulfonylketone (11) was
from the sulfonylesters and subsequent desulfonylation.
transformed into the sulfonylester (12) by the addition of the
Grimm and co-workers reported the construction of the bi- lithium salt of ethyl acetate followed by dehydration with
cyclo[6,4,0]dodecane ring system, the medium ring which thionyl chloride in an 89% yield. The ring closure of 12 and
was difficult to prepare by the usual Dieckmann condensa-
tion of the diester, by an intramolecular cyclization of sul-
fone stabilized carbanion in good yield.19) Applying for this
methodology, we initially tried to prepare the 6—6 bicyclic
ketone (5a). A Michael addition of the sodium salt of 2-
methoxycarbonyl-6,6-dimethylcyclohxanone (3)17) to the
phenyl vinyl sulfone smoothly proceeded to give the corre-
sponding adduct in excellent yield. Treatment of this adduct
with concentrated HCl in EtOH under relfux afforded the
sulfonylketone (6) in a 74% yield by two steps from 3. After
the addition of the lithium salt of ethyl acetate to 6, the re-
sulting hydroxy sulfone was dehydrated with thionyl chloride
to give the sulfonylester (7) in excellent yield. An intramole-
cular cyclization of 7 was achieved using a 2.2 eq of lithium
Chart 1
bis(trimethylsilyl)amide according to the Grimm’s procedure
To whom correspondence should be addressed. e-mail: a-wada@kobepharma-u.ac.jp
© 2004 Pharmaceutical Society of Japan

January 2004
133
Chart 2
Chart 3
subsequent desulfonylation were performed by the same benzene (3ϫ80 ml), followed by a standard workup. The residue was puri-
fied by CC (dichloromethane–ether, 19 : 1) to afford methyl 3,3-dimethyl-1-
manner as described for the case of 7 to produce the desired
6—8 bicyclic ketone (5c) and its isomer of the double bond
(14) in 32% and 30% yields, respectively (Chart 3).
In summary, we were able to demonstrate that the ring an-
nulation using an intramolecular cyclization of the sulfone
stabilized carbanion is an efficient and convenient route for
the preparation of the bicyclic ketones (5), and this method-
ology is very useful for supplying the bicyclic retinals in
large scale (g scale order) for the research field of the confor-
mational analysis of retinal proteins.
(2-phenylsulfonyl)ethyl-2-oxo-cyclohexanecarboxylate (8.9 g, 92%) as a
1
pale yellow oil. [IR (CHCl3) cmϪ1: 2951, 1735, 1705, 1305, 1135; H-NMR
d: 1.00 (3H, s, Me), 1.13 (3H, s, Me), 1.5—2.6 (10H, m, CH2ϫ5), 3.60 (3H,
s, CO2CH3), 7.5—7.9 (5H, m, ArH)].
A mixture of this keto ester (7.2 g, 20 mmol), EtOH (30 ml) and c.HCl
(70 ml) was refluxed for 18 h. After cooling, water (150 ml) was added, and
the organics were extracted with dichloromethane (3ϫ80 ml), followed by a
standard workup. The residue was purified by CC (Et2O–dichloromethane,
1 : 49) to afford the keto sulfone 6 (4.8 g, 80%) as a pale yellow oil. IR
1
(CHCl3) cmϪ1; 2935, 1702, 1313, 1154; H-NMR d: 1.00 (3H, s, Me), 1.14
(3H, s, Me), 1.2—1.8 (6H, m, CH2ϫ3), 1.9—2.1 (2H, m, CH2), 2.6—2.8
(1H, m, CH), 2.3—3.5 (2H, m, CH2) 7.5—7.7 (3H, m, ArH), 7.91 (2H, d,
Jϭ8 Hz, ArH); HR-MS m/z: 294.1289 (Calcd for C16H22O3S: Mϩ 294.1289).
Ethyl (6,6-dimethyl-2-((2-phenylsulfonyl)ethyl)cyclohexen-1-yl)acetate
Experimental
IR spectra were recorded on a Perkin-Elmer FT-IR Paragon 1000 spec-
1
trometer. H-NMR spectra were obtained on a Varian Gemini-200 or Gem- (7) To a stirred solution of LDA, prepared from n-BuLi (1.6 M hexane so-
ini-300 NMR spectrometer in deuteriochloroform. 13C-NMR spectra were lution, 13 ml, 20.8 mmol) and diisopropylamine (2.1 g, 21 mmol) in THF
obtained on a Gemini-300 NMR spectrometer in deuteriochloroform. Mass (30 ml), was added a solution of ethyl acetate (1.8 ml, 21 mmol) in THF
spectra were determined on a Hitachi M-4100 instrument. Column chro- (7 ml) at Ϫ70 °C, and the resulting mixture was stirred for an additional
matography (CC) was performed using Merck silica gel 60. All reactions 30 min. A solution of the sulfonylketone 6 (2.2 g, 7.5 mmol) in THF (10 ml)
were carried out under a nitrogen atmosphere. THF and ether were purified was added at Ϫ70 °C and the mixture was further stirred for 2 h. The reac-
by distillation from benzophenone-sodium ketyl under nitrogen. Commer- tion was quenched with saturated aqueous NH4Cl (40 ml), and after the re-
cially available chemicals were used without further purification except moval of THF in vacuo, the organics were extracted with dichloromethane
when otherwise noted. Diisopropylamine was purified by distillation from (3ϫ70 ml), followed by a standard workup. The residue was purified by CC
CaH2. Standard workup means that the organic layers were finally washed (dichloromethane–hexane, 3 : 97) to give the hydoxyester (2.65 g, 93%) as a
with brine, dried over anhydrous sodium sulfate (Na2SO4), filtered, and con- mixture of diastereoisomer. [1H-NMR d: 0.88 (3H, s, Me), 1.29 (3H, t,
centrated in vacuo below 30 °C using a rotary evaporator.
Jϭ7 Hz, CO2CH2CH3), 1.2—2.1 (9H, m, CH2ϫ4 and CH), 2.34 (1H, d,
2,2-Dimethyl-6-(2-phenylsulfonyl)ethylcyclohexanone (6) To a stirred Jϭ16 Hz, CH2COO), 2.54 (1H, d, Jϭ16 Hz, CH2COO), 3.0—3.3 (2H, m,
solution of the keto ester 3 (5.04 g, 27 mmol) in benzene (100 ml) and CH2SO2), 4.16 (2H, q, Jϭ7 Hz, CO2CH2CH3), 4.38 (H, s, OH, disappeared
NaOMe (0.55 g, 8.2 mmol) was added a solution of phenyl vinyl sulfone with D2O), 7.5—7.7 (3H, m, ArH), 7.88 (2H, d, Jϭ8 Hz, ArH)].
(5.4 g, 54 mmol) in benzene (25 ml) at 0 °C under nitrogen, and the resulting
To a solution of the hydroxy ester (2.6 g, 6.8 mmol) in pyridine (24 ml)
mixture was stirred for an additional 3 h. The reaction was quenched with was added thionyl chloride (1.3 ml, 18 mmol) at 0 °C, and the resulting mix-
saturated aqueous NH4Cl (60 ml) and then the organics were extracted with ture was stirred for 10 min. The reaction was quenched with 5% HCl (50 ml)

134
Vol. 52, No. 1
in an ice bath, and the organics were extracted with dichhoromethane 0 °C under nitrogen, and the resulting mixture was stirred for an additional
(3ϫ50 ml), followed by a standard workup. The residue was purified by CC 4 h. The reaction was quenched with saturated aqueous NH4Cl (30 ml) and
(dichloromethane–hexane, 1 : 49) to give the sulfonylester 7 (2.18 g, 88%) as
a colorless oil. NMR analysis indicated that the endo and exo isomers of the
double bond were present in a ratio of 5 : 1. Analytical samples were ob-
tained respectively by further CC using the same eluent.
then the organics were extracted with ether (3ϫ50 ml), followed by a stan-
dard workup. The residue was purified by CC (ether–hexane, 1 : 1) to give the
hydroxyketone (928 mg, 98%).
To a stirred solution of PPh3 (1.04 g, 4.0 mmol) and CBr4 (1.09 g,
endo-Isomer: IR (CHCl3) cmϪ1; 2936, 1727, 1315, 1142; 1H-NMR d: 0.92 3.3 mmol) in dichloromethane, a solution of the hydroxyketone (519 mg,
(6H, s, Meϫ2), 1.25 (3H, t, Jϭ7 Hz, CO2CH2CH3), 1.3—1.6 (4H, m, 2.6 mmol) in dichloromethane (25 ml) was added at 0 °C. The resulting mix-
CH2ϫ2) , 1.91 (2H, t, Jϭ7 Hz, CH2), 2.3—2.5 (2H, m, CH2), 2.97 (2H, s, ture was stirred for an additional 10 min, and after the removal of
CH2CO), 3.1—3.3 (2H, m, CH2SO2), 4.08 (2H, q, Jϭ7 Hz, CO2CH2CH3), dichloromethane in vacuo, ether was added and the precipitate was filtered
7.5—7.7 (3H, m, ArH), 7.91 (2H, d, Jϭ8 Hz, ArH); HR-MS m/z: 364.1702.
off using Celite. The filtrate was concentrated in vacuo to give the crude
bromoketone (1.65 g), which was used in the next reaction without purifica-
(Calcd for C20H28O4S: Mϩ 364.1707).
1
exo-Isomer: H-NMR d: 0.98 (3H, s, Me), 1.03 (3H, s, Me), 1.25 (3H, t, tion.
Jϭ7 Hz, CO2CH2CH3), 1.3—1.9 (9H, m, CH2ϫ4, CH), 3.1—3.3 (2H, m,
The above bromoketone was dissolved in H2O–acetone–benzene
CH2SO2), 4.08 (2H, q, Jϭ7 Hz, CO2CH2CH3), 5.78 (1H, s, ϭCH), 7.5—7.7 (120 : 90 : 90, 50 ml), and to this solution were added PhSO2Na (820 mg,
(3H, m, ArH), 7.91 (2H, d, Jϭ8 Hz, ArH). 5.0 mmol) and TBAI (360 mg, 1.0 mmol). The resulting mixture was heated
8,8-Dimethyl-1,2,3,4,5,6,7,8-octahydronaphthalene-2-one (5a) and 8,8- at 110 °C for 14 h. After cooling, the organics were extracted with
Dimethyl-5,6,7,8-tetrahydro-2-naphthol (9) To a stirred solution of LiH- dichloromethane (3ϫ70 ml), followed by a standard workup. The residue
MDS, prepared from n-BuLi (1.6 M hexane solution, 7.6 ml, 12.1 mmol) and
was purified by CC (dichloromethane–hexane, 3 : 97) to give the sulfonylke-
hexamethyldisilazane (1.9 g, 11.9 mmol) in THF (20 ml), was added a solu- tone 11 (960 mg, 65%) as a pale yellow oil. IR (CHCl3) cmϪ1; 2934, 1700,
1
tion of sulfonylester 7 (2.0 g, 5.5 mmol) in THF (40 ml) at Ϫ70 °C, and the 1307, 1149; H-NMR d: 1.02 (3H, s, Me), 1.14 (3H, s Me), 1.2—2.1 (12H,
resulting mixture was stirred for an additional 2 h. The reaction was m, CH2ϫ6), 2.42 (1H, quint, Jϭ7 Hz, CH), 3.0—3.2 (2H, m, CH2SO2),
quenched with saturated aqueous NH4Cl (40 ml) and after the removal of 7.5—7.7 (3H, m, ArH), 7.89 (2H, d, Jϭ8 Hz, ArH); HR-MS m/z: 322.1592.
THF in vacuo, the organics were extracted with dichloromethane (3ϫ70 ml), (Calcd for C18H26O3S: Mϩ 322.1601).
followed by a standard workup to give the crude cyclized product 8 (1.9 g)
Ethyl (6,6-dimethyl-2-((4-phenylsulfonyl)butyl)cyclohexen-1-yl)acetate
as a pale yellow oil.
(12) This was prepared from the ketone 11 (517 mg, 1.6 mmol) by the ad-
To a stirred solution of the cyclized sulfone 8 (1.9 g) and (n-Bu)3SnH dition of ethyl acetate (0.42 ml, 4.4 mmol) and subsequent dehydration with
(7.0 g, 22 mmol, 4 eq of 8) in toluene (60 ml) was added dropwise a solution thionylcloride (0.53 g, 4.4 mmol) by the same manner as described for the
of azobisisobutylnitrile (0.66 g, 4.0 mmol) in toluene (15 ml) under reflux.
The resulting mixture was further stirred for 10 min under reflux, and then hexane, 1 : 49) to give the sulfonylester 12 (555 mg, 94%) as a pale yellow
cooled to come to room temperature. After the removal of toluene in vacuo, oil. NMR analysis indicated that the endo and exo isomers of double bond
preparation of 6. The crude product was purified by CC (dichloromethane–
the residue was purified by CC (ether–hexane, 15 : 75) to give the bicyclic were present in a ratio of 5 : 2. Analytical samples were obtained respec-
ketone 5a (1.45 g, 67%) and the naphthol 9. (0.19 g, 20%). These com- tively by further CC using the same eluent.
pounds were identical with the authentic specimens obtained by the Dieck-
endo-Isomer: IR (CHCl3) cmϪ1; 2935, 1728, 1306, 1142; 1H-NMR d: 0.93
(6H, s, Meϫ2), 1.22 (3H, t, Jϭ7 Hz, CO2CH2CH3), 1.2—1.8 (10H, m,
mann condensation in the literature.1)
Ketone 5a: IR (CHCl3) cmϪ1; 1705; 1H-NMR d: 0.98 (6H, s, Meϫ2), CH2ϫ5), 1.83 (2H, t, Jϭ6.5 Hz, CH2), 2.97 (2H, s, CH2CO), 3.0—3.2 (2H,
1.4—1.5 (2H, m, CH2), 1.5—1.7 (2H, m, CH2), 1.9—2.0 (2H, m, m, CH2SO2), 4.07 (2H, q, Jϭ7 Hz, CO2CH2CH3), 7.5—7.7 (3H, m, ArH),
[CH2ϫ1/2]ϫ2), 2.2—2.5 (4H, m, CH2 and [CH2ϫ1/2]ϫ2), 2.84 (2H, br s, 7.91 (2H, d, Jϭ8 Hz, ArH); HR-MS m/z: 392.2039. (Calcd for C22H32O4S:
CH2), 13C-NMR d: 19.1, 27.5 (2C), 30.7, 34.2, 39.1, 41.2, 42.0, 128.3, Mϩ 392.2020).
132.8, 212.2. HR-MS m/z: 178.1362. (Calcd for C12H18O: Mϩ 178.1357).
exo-Isomer: H-NMR d: 1.08 (3H, s, Me), 1.10 (3H, s, Me), 1.22 (3H, t,
1
1
Naphthol 9: IR (CHCl3) cmϪ1; 3598, 3343, 2933, 1610; H-NMR d: 1.24 Jϭ7 Hz, CO2CH2CH3), 1.3—2.0 (13H, m, CH2ϫ6, CH), 3.0—3.2 (2H, m,
(6H, s, Meϫ2), 1.5—1.9 (4H, m, CH2ϫ2), 2.71 (2H, t, Jϭ6 Hz, CH2), 4.53 CH2SO2), 4.07 (2H, q, Jϭ7 Hz, CO2CH2CH3), 5,76 (1H, sm ϭCH), 7.5—
(1H, s, OH), 6.62 (1H, dd, Jϭ8, 2.5 Hz, ArH), 6.83 (1H, d, Jϭ2.5 Hz, ArH), 7.7 (3H, m, ArH), 7.91 (2H, d, Jϭ8 Hz, ArH).
6.96 (1H, d, Jϭ8 Hz, ArH), 13C-NMR d: 19.8, 29.9, 31.8 (2C), 33.9, 39.1,
111.8, 112.7, 128.3, 129.9, 147.3, 153.0.
2,2-Dimethyl-6-((1,1-dimethyl)ethyldimethylsilyloxy)butylcyclohexa-
none (10) A solution of the keto ester 4b (2 g, 8.3 mmol) in dry ether
4,4-Dimethyl-1,2,3,4,7,8,9,10-octahydrobenzocycloocten-6(5H)-one
(5c) and 4,4-Dimethyl-1,2,3,4,8,9,10,10a-octahydrobenzocycloocten-
6(7H)-one (14) These were prepared from the sulfonylester 12 (517 mg,
1.6 mmol) by treatment with LiHMDS, prepared from n-BuLi (1.6 M hexane
(10 ml) was added dropwise to a stirred suspension of LiAlH4 (822 mg, solution, 1.7 ml, 2.5 mmol) and hexamethyldisilazane (0.53 ml, 2.5 mmol) in
21 mmol) in ether (30 ml) at 0 °C under nitrogen, and the resulting mixture THF (10 ml), and subsequent desulfonylation with tributyltinhydride (1.35 g,
was stirred for an additional 15 min. The excess of LiAlH4 was destroyed by 4.6 mmol) and AIBN (80 mg, 0.5 mmol) by the same manner as described
the addition of moist Et2O and water, and the mixture was extracted with for the preparation of 5a. The crude product was purified by CC
Et2O. The extract was washed with brine, dried and concentrated to afford (ether–hexane, 15 : 85) to give the bicyclic ketones 5c (86 mg, 32%) and 14
the crude dialcohol, which was used for the next reaction without further pu- (70 mg, 30%) as pale yellow oils. Endo-isomer 5c was identical with the au-
rification.
A solution of TBDMSCl (1.87 g, 12 mmol) in dichloromethane (10 ml)
thentic specimen obtained by the Dieckmann condensation in the literature.1)
endo-Isomer 5c: IR (CHCl3) cmϪ1; 1690; 1H-NMR d 0.98 (6H, s, Meϫ2),
was added to a stirred mixture of the crude alcohol, DMAP (130 mg, 1.4—1.5 (2H, m, CH2), 1.5—1.8 (6H, m, CH2ϫ3), 2.0—2.1 (4H, m,
1.1 mmol), and Et3N (1.51 ml, 11 mmol) at 0 °C. The resulting mixture was CH2ϫ2), 2.4—2.5 (2H, m, CH2), 3.15 (2H, s, CH2). HR-MS m/z: 206.1690.
stirred for an additional 3 h at room temperature. The reaction was quenched (Calcd for C19H32O4: Mϩ 206.1669).
1
with saturated NH4Cl (50 ml), and the organics were extracted with dich-
exo-Isomer 14: H-NMR d: 1.24 (3H, s, Me), 1.26 (3H, s, Me), 1.3—2.5
horomethane (3ϫ50 ml), followed by a standard workup to give the silyl- (14H, m, CH2ϫ7), 3.1—3.3 (1H, m, CH), 6.55 (1H, m, ϭCH). 13C-NMR d:
oxyalcohol.
21.5, 22.0, 25.2, 27.3, 31.5, 34.1, 38.1, 40.0, 41.4, 44.0, 118.8, 160.2, 212.5.
The silyloxyalcohol was dissolved in dichloromethane (70 ml) and then HR-MS m/z: 206.1678. (Calcd for C19H32O4: Mϩ 206.1669).
PDC (15 g, 39 mmol) was added all at once. The resulting mixture was
stirred for an additional 8 h and then filtered with Celite. The filtrate was
Acknowledgments This work was supported in part by the Kobe Phar-
successively washed with 10% HCl, 10% NaHCO3, brine and then dried maceutical University Collaboration Fund and The Science Research Pro-
over Na2SO4. After removal of the solvent, the residue was purified by CC motion Fund from the Japan Private School Promotion Foundation.
(ether–hexane, 1 : 9) to give the silyloxyketone 10 (1.63 g, 62%, 3 steps) as a
colorless oil. IR (CHCl3) cmϪ1; 2932, 1700; 1H-NMR d: 0.03 (6H, s,
SiMe2), 0.88 (9H, s, SiCMe3), 1.03 (3H, s, Me), 1.17 (3H, s, Me), 1.2—2.2
(12H, m, CH2ϫ6) , 2.50 (1H, quint, Jϭ7 Hz, CH), 3.59 (2H, t, Jϭ6.5 Hz,
OCH2); HR-MS m/z: 312.2481. (Calcd for C18H36O2Si: Mϩ 312.2482).
References and Notes
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stirred solution of the silyloxyketoe 10 (1.49 g, 4.8 mmol) in THF (30 ml)
was added a solution of TBAF (1.0 solution in THF, 1.38 ml, 1.38 mmol) at
(11) To
a
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M

January 2004
135
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