An improved synthetic route to angularly functionalized hydrofluorene derivatives through Pd(0)-catalyzed heck reaction

Article abstract of DOI:10.1055/s-2006-926408

4a-Substituted 1,1-dimethyl or 1-carbomethoxy-1-methyl hydrofluorenes carrying various substituents in the aromatic ring could be conveniently synthesized by Pd(0)-catalyzed Heck reaction. The required bromobenzyl- substituted ethylidene cyclohexane subst

Full text of DOI:10.1055/s-2006-926408

PAPER
1263
An Improved Synthetic Route to Angularly Functionalized Hydrofluorene
Derivatives through Pd(0)-Catalyzed Heck Reaction
Synthesisof
A
ngularly
a
Functiona
i
lized
H
n
ydrofluorene
a
D
erivative
k
s
Banerjee, Ranjan Mukhopadhyay, Basudeb Achari, Asish K. Banerjee*
Medicinal Chemistry Division, Indian Institute of Chemical Biology, 4 Raja S. C. Mullick Road, Kolkata 700032, India
Fax +91(33)24735197; E-mail: ashisbanerjee@iicb.res.in
Received 9 September 2005
now describe a simple, generalized and high-yielding
method using Pd(0)-catalyzed intramolecular cyclization
to produce a series of functionalized hydrofluorenes with
substituents at C-1, C-4a and the aromatic ring. Easy
Abstract: 4a-Substituted 1,1-dimethyl or 1-carbomethoxy-1-meth-
yl hydrofluorenes carrying various substituents in the aromatic ring
could be conveniently synthesized by Pd(0)-catalyzed Heck reac-
tion. The required bromobenzyl-substituted ethylidene cyclohexane
substrates were derived from Hagemann’s ester (methyl analogue) transformations of the vinyl group to many other function-
via condensation with appropriate benzyl bromide, hydrolytic de-
alities are also demonstrated.
carboxylation of the ester, 1,4-addition of methyl or cyano group
followed by necessary functional group manipulation, and Wittig
The retrosynthetic plan is described in Scheme 1. The re-
quired 2-(2-bromobenzyl)-1-ethylidenecyclohexane in-
termediates were obtainable from the respective
cyclohexanones. The latter could in turn be prepared
through alkylation of suitably substituted benzyl bro-
mides with the methyl analogue of Hagemann’s ester,
easy decarboxylation to the cyclohexenones, and subse-
quent introduction of a methyl or carbomethoxy group at
the b-position of the conjugated carbonyl system.
olefination. Simple organic transformations converted the vinyl
group to carboxy, formyl or hydroxymethyl. The ring juncture ste-
reochemistry of the products could be ascertained by correlation ap-
proach.
Key words: 4a-substituted hydrofluorenes, Heck reaction, Wittig
reaction, Hagemann’s ester
Hydrofluorenes constitute the basic skeleton of a large
number of highly functionalized diterpenoids of the gib-
berellin and rearranged abietane groups, but synthetic
methodologies for these important and apparently simple
molecules have been scant. Though there are few reports
on the syntheses of 4a-substituted hydrofluorenes,1,2 only
a single methodology established by Ghatak and co-
workers2 is available, to our knowledge, for the synthesis
of 4a-(carboxyl)-substituted hydrofluorenes carrying sub-
stituents at C-1 position; the corresponding position in
gibberellins usually carry a methyl and a carboxyl group.
As these products are expected to serve as putative inter-
mediates to C-10 functionalized gibberellins, we became
interested to develop an improved synthetic methodology
for 1,1-disubstituted hydrofluorenes with diverse func-
tional groups at the 4a-position.
R2
R2
R1
R1
X
R3
R3
H
H
Me
Me
R
R
X = CHO, COOH, CH2OH
R1
Br
Me
R1
Br
O
R2
R3
R2
R3
Me
R
Me R
O
O
R3
R3
R2
Br
+
R2
Br
Br
R1
Inserting a vinyl group at the angular position of hydro-
fluorenes appeared to us as particularly promising, as it
can be easily transformed to other functional groups.
Trost et al. first reported3 the synthesis of hydrofluorenes
with a 4a-vinyl substituent by palladium-catalyzed reduc-
tive cyclization. Although the yields achieved were mod-
erate to good, the methodology involves a complex
reagent system and only C-1 unsubstituted hydrofluo-
renes were synthesized. We have recently reported the re-
sults of our fruitful venture in harnessing the Pd(0)-
catalyzed Heck reaction for the synthesis of several com-
plex diterpenoids.4 In continuation of that exercise we
R1
COOMe
Scheme 1 Retrosynthetic plan
O
i
Br
O
Br
Me
Br
Me
CO2Me Me
3
1
Me
CO2Me
2
Me
Br
O
ii
SYNTHESIS 2006, No. 8, pp 1263–1272
Advanced online publication: 27.03.2006
x
x
.
x
x
.2
0
0
6
Me
4a
DOI: 10.1055/s-2006-926408; Art ID: P14005SS
© Georg Thieme Verlag Stuttgart · New York
Scheme 2 Reagents and conditions: i) t-BuOK, NaI, t-BuOH, re-
flux, 6 h, 65%; ii) KOH, EtOH, reflux, 12 h, 66%.

1264
M. Banerjee et al.
PAPER
Thus, the freshly prepared 2-bromobenzyl bromide 15 was For the preparation of 7a and 7b, the substrates 4a and 4b
reacted6 (Scheme 2) with the methyl analogue (2) of required to be subjected (Scheme 4) to 1,4-addition of a
Hagemann’s ester in the presence of potassium tert-bu- methyl group.4a,8 This was conveniently carried out by
toxide and sodium iodide to afford 3. The ester 3 was hy- treatment with an excess of Gilman’s reagent (Me2CuLi)
drolyzed and decarboxylated in one pot by refluxing with in the presence of a large excess of BF3·Et2O. Conversion
potassium hydroxide in aqueous ethanol to furnish the cy- of 4c to the known substrate 7c was performed by the
clohexenone 4a. The other bromide 57 (easily derived published6 procedure, while the synthesis of 7d has been
from vanillin) afforded the ester 6 after alkylation with 2 described in our earlier communication.4a For preparing
using the above procedure. For decarboxylation of 6, a substrates carrying a carbomethoxy group, addition of a
two-step procedure4a was adopted from our earlier experi- cyano group9 to the cyclohexenone substrates was fol-
ence, as similar catechol derivatives produce a complex lowed by hydrolysis with potassium hydroxide and ester-
mixture of products when refluxed with strong alkali pre- ification with dimethyl sulfate in presence of lithium
sumably due to oxidative degradation. Thus, hydrolysis of hydroxide.10 By this method, 4a, 4b and 4d afforded dia-
6 with lithium hydroxide in methanol–water and subse- stereomeric mixtures of the 2-(2-bromobenzyl)cyclohex-
quent decarboxylation by heating a silica gel slurry of the anones 8a, 8b and 8d (Scheme 4), respectively. Synthesis
resulting acid afforded the cyclohexenone 4b (Scheme 3). of 8c was carried out following the known procedure.6
Syntheses of the other cyclohexenones 4c6 and 4d4a
(Scheme 4) were reported earlier.
The ketones 7a–d or 8a–d were smoothly transformed
(Scheme 5) to the corresponding olefins 9a–d or 10a–d in
excellent yields (85–95%) by Wittig reaction with an ex-
cess of ethylenetriphenylphosphorane.11 The reactions
with 8a–d appeared to produce stereoisomeric mixtures of
olefins when carried out at room temperature. However,
adding the substrates to the ylide at 80–90 °C and then re-
fluxing for three hours afforded a single diastereomer of
each ethylidene derivative (10a–d).
OBn
O
OMe
OBn
OMe
i
O
Me
Br
Br
CO2Me
Br
5
6
COOMe
2
R1
R1
Me
Br
Br
Br
R2
R3
O
R2
R3
O
OBn
OMe
ii
i
Me
Me
Me
Me
7a–d
Me
Me
9a–d
4b
R1
R1
Me
Br
Scheme 3 Reagents and conditions: i) t-BuOK, NaI, t-BuOH, re-
flux, 3 h, 85%; ii) a) LiOH, MeOH–H2O (9:1), r.t., 12 h; b) SiO2, 90
°C, 4 h, 71%.
Br
R2
R3
O
R2
R3
ii
Me
COOMe
COOMe
8a–d
10a–d
O
a: R1 = Me; R2, R3 = H b: R1 = H; R2 = OBn; R3 = OMe
c: R1, R2, R3 = H d: R1 = OMe; R2 = OBn; R3 = H
R3
R2
Scheme 5 Reagents and conditions: i) EtPPh3I, t-BuOK, r.t., 12 h,
85–95%; ii) EtPPh3I, t-BuOK, reflux, 3 h, 85–90%.
Br
R1
4a–d
i
ii
The olefins 9a–d and 10a–d were then subjected to Pd(0)-
catalyzed Heck cyclization12 (Scheme 6). Experiments
were carried out by varying the reaction parameters to get
the best yields of the 4a-vinyl hydrofluorenes as shown in
Table 1. The results reveal that the olefinic substrates
without any substituent at the position ortho to the bromo
group (other than the one occupied by the cyclohexyl-
methyl group) produced the corresponding 4a-vinyl sub-
stituted hydrofluorenes (the cis-stereochemistry was
established as discussed later) in excellent yields, while an
ortho-substituent reduced the yield of the cyclized prod-
uct a considerable extent. Only the olefin 10d (entry 8)
failed to produce any cyclized product even after a long
time; an intractable product resulted instead. These re-
sults, taken together with previous reports from other lab-
R1
R1
Br
Br
R2
R3
O
R2
R3
O
H
Me
Me Me
COOMe
8a–d
7a–d
a: R1 = Me; R2, R3 = H b: R1 = H; R2 = OBn; R3 = OMe
c: R1, R2, R3 = H d: R1 = OMe; R2 = OBn; R3 = H
Scheme 4 Reagents and conditions: i) Me2CuLi, BF3·Et2O, Et2O,
–30 °C to 0 °C, 1 h, 85–90%; ii) a) KCN, EtOH, H2O, reflux, 14 h; b)
KOH, H2O, reflux, 96 h; c) LiOH, Me2SO4, THF, reflux, 4 h, 60–
80%.
Synthesis 2006, No. 8, 1263–1272 © Thieme Stuttgart · New York

PAPER
Synthesis of Angularly Functionalized Hydrofluorene Derivatives
1265
oratories,3 serve in addition to underline the relevance of
Heck reaction in synthesizing angularly substituted poly-
cyclic systems.
HO
OH
ii
i
H
H
R2
Me
Me
R
R1
R1
R
Me
Br
13a: R = Me
b: R = COOMe
R2
R3
11c: R = Me
12c: R = COOMe
R3
i
OHC
H
Me
HOOC
R
Me
R
9a–d: R = Me
10a–d: R = COOMe
iii
11a–d: R = Me
12a–c: R = COOMe
H
H
Me
R
Me
R
a: R1 = Me; R2, R3 = H b: R1 = H; R2 = OBn; R3 = OMe
c: R1, R2, R3 = H d: R1 = OMe; R2 = OBn; R3 = H
14a: R = Me
b: R = COOMe
15a: R = Me
b: R = COOMe
HO
Scheme 6 Reagents and conditions: i) Pd(OAc)2 (5 mol%), PPh3
(20 mol%), K2CO3 (4 equiv), DMF, D.
iv
Table 1 Heck Cyclization of 9a–d and 10a–d
H
Me
R
16a: R = Me
b: R = COOMe
Entry
Olefin
Temp (°C) Time (h)
Cyclized prod-
uct and yield (%)
Scheme 7 Reagents and conditions: i) OsO4 (2 mol%), NMO (5
equiv, 50% in H2O), acetone–t-BuOH (1:1), r.t., 8–10 h, 85–95%; ii)
NaIO4 (1.2 equiv), MeOH–H2O, 0 °C, 2 h, > 95%; iii) NaClO2,
NaH2PO4, DMSO–H2O, r.t., 3 h, > 95%; iv) NaBH4, MeOH, 0 °C,
1 h, 95–98%.
1
2
3
4
5
6
7
8
9a
9b
130
100
100
140
140
130
100
160
40
24
24
48
48
36
24
30
11a (82)
11b (96)
11c (95)
11d (62)
12a (61)
12b (86)
12c (87)
–
9c
9d
fluxing with lithium hydroxide and dimethyl sulfate
(Scheme 9). The melting point of the synthetic compound
and its spectral data are in accordance with the literature2
values for 19. This clearly disclosed the cis stereochemis-
try of the ring juncture for hydrofluorenes 12a–c and also
established the relative orientation of the 4a-vinyl and the
1-carbomethoxy substituents.
10a
10b
10c
10d
Taking one example from each series (11c and 12c) the
angular vinyl group was converted to other functional-
ities, e.g. CH2OH, CHO or COOH by simple organic
transformations (Scheme 7). Thus, dihydroxylation13 by
treatment with N-methyl morpholine oxide and a catalytic
amount of osmium tetraoxide in acetone–tert-butanol
(1:1) afforded the 1,2-dihydroxy hydrofluorenes 13a,b as
diastereomeric mixtures in excellent yields. Cleavage of
the diols by stirring with sodium periodate13 in aqueous
methanol to afford 14a and 14b also proved equally suc-
cessful. Oxidation of 14a,b to the corresponding acids
(15a,b) was effected by treatment with an aqueous solu-
tion of sodium chlorite14 in dimethyl sulfoxide in the pres-
ence of sodium dihydrogen phosphate buffer, while
reduction to the corresponding alcohols 16a and 16b was
carried out with sodium borohydride in methanol; the
yields achieved in all cases were >95%.
Br
HO
i
H
H
16a
17
Me
ii
H
18
Scheme 8 Reagents and conditions: i) CBr4, PPh3, CH2Cl2, –10 °C,
30 min; ii) TBTH, AIBN, benzene, reflux, 4 h. Overall yield: 26%.
MeOOC
HOOC
i
H
H
Me
Me
COOMe
COOMe
The cis stereochemistry at the ring junctures of the com-
pounds 11a–d was established by converting 16a to the
known15 4a-methyl analogue through bromination (with
CBr4 and PPh316) to 17 followed by reduction using
TBTH17 to furnish 18 (Scheme 8). Similarly, to establish
the ring juncture stereochemistry along with the relative
disposition of C-1 carbomethoxy and C-4a vinyl groups
for 12a–c, the acid 15b was converted to the diester by re-
19
15b
Scheme 9 Reagents and conditions: i) LiOH, Me2SO4, THF, reflux,
4 h, 90%.
In conclusion, an efficient and high-yielding methodology
based on Pd(0)-mediated Heck cyclization has been de-
veloped for the synthesis of 4a-vinyl-1-substituted hy-
Synthesis 2006, No. 8, 1263–1272 © Thieme Stuttgart · New York

1266
M. Banerjee et al.
PAPER
13C NMR: d = 21.6 (CH3), 22.1 (CH2), 23.8 (CH3), 31.5 (CH2), 32.7
(CH2), 37.4 (CH2), 125.3 (CH), 126.6 (CH), 127.2 (C), 128.0 (CH),
133.3 (C), 138.0 (C), 139.1 (C), 158.6 (C), 198.0 (C).
MS (EI): m/z (%) = 295, 293 (87) [M+ + 1, Br isotopes], 213 (100),
123.
drofluorenes, which are models used towards
gibberellins. Easy transformation of the vinyl moiety to
other functional groups could be realized. The stereo-
chemistry of the products was established through corre-
lation approach. The utility of Pd(0)-catalyzed Heck
reaction for the construction of angularly vinyl-substitut-
ed structures has also been demonstrated.
Anal. Calcd for C15H17BrO: C, 61.45; H, 5.84. Found: C, 61.38; H,
5.72.
3-(4-Benzyloxy-2-bromo-5-methoxybenzyl)-2-methyl-4-oxo-
cyclohex-2-enecarboxylic Acid Methyl Ester (6)
The same procedure as that described for 3 was followed to synthe-
size 6 (85%) from 5 and 2 as a colorless viscous liquid.
Melting points recorded for the compounds were measured on a
REMCO melting-point apparatus (India) and are uncorrected. H
1
and 13C NMR spectra of the compounds were recorded in CDCl3 so-
lutions with a Bruker DPX-300 spectrometer at 300 MHz and 75
MHz, respectively. In all cases, chemical shifts are in d relative to
TMS as internal standard. Protonation levels of the carbons indicat-
ed in 13C NMR (75 MHz) data were derived from DEPT spectra.
Mass spectra were recorded using a JEOL AX-500 or Q-Tof Mi-
croTM (Waters) mass spectrometer. IR spectra were recorded using
a JASCO FT/IR-410 spectrometer. Microanalyses were performed
on a Perkin-Elmer 2400 Series II CHN Analyzer.
IR (neat): 2951, 1730, 1668, 1502, 1201, 1163 cm–1.
1H NMR: d = 1.89 (s, 3 H), 2.27–2.35 (m, 2 H), 2.43–2.51 (m, 1 H),
2.58–2.67 (m, 1 H), 3.40 (t, J = 4.2 Hz, 1 H), 3.52 (d, J = 16.2 Hz,
1 H), 3.76 (s, 3 H), 3.80 (s, 3 H), 3.87 (d, J = 16.2 Hz, 1 H), 5.07 (s,
2 H), 6.59 (s, 1 H), 7.06 (s, 1 H), 7.30–7.43 (m, 5 H).
MS (EI): m/z (%) = 474, 472 (53) [M+, Br isotopes], 394 (100), 393
(100), 307, 305, 243, 91.
All reagents were of commercial grade and were used from freshly
opened containers without purification. Organic solvents were dried
by standard methods and were distilled before use. All the reactions
were performed under nitrogen atmosphere. Reaction progress was
monitored by TLC on precoated aluminum-backed plates (Merck
Kieselgel 60F254) and the spots were visualized by UV light. Anhy-
drous Na2SO4 was used as drying agent for extracts. Silica gel was
usually employed for column chromatography. Petroleum ether
used was of boiling range 60–80 °C.
2-(4-Benzyloxy-2-bromo-5-methoxybenzyl)-3-methyl-
cyclohex-2-enone (4b)
To a stirred solution of 6 (22.3 g, 0.047 mol) in MeOH (180 mL)
was added a solution of LiOH·H2O (5.94 g, 0.141 mol) in H2O (20
mL) and the mixture was stirred for 16 h. The solvent was removed,
the solid was dissolved in a minimum volume of H2O and the solu-
tion was acidified with dilute HCl. The aqueous part was extracted
with EtOAc (3 × 50 mL); the organic layer was washed with brine
and dried over anhyd Na2SO4. EtOAc was removed; the residue was
added as a CH2Cl2 solution to silica gel to form a slurry which was
heated at 90 °C for 4 h. The slurry was then purified by column
chromatography to obtain 4b (13.8 g, 71%) as a white solid; mp 88–
90 °C.
3-(2-Bromo-3-methylbenzyl)-2-methyl-4-oxocyclohex-2-ene-
carboxylic Acid Methyl Ester (3)
To a stirred solution of t-BuOK (3.57 g, 31.8 mmol) in anhyd t-
BuOH (30 mL) was added a solution of the methyl analogue of
Hagemann’s ester 2 (5.6 g, 33 mmol, in 20 mL of anhyd t-BuOH)
slowly over 30 min and the mixture was allowed to stir for another
hour. The freshly prepared benzyl bromide 1 (7 g, 27 mmol) and
NaI (1.6 g, 10.6 mmol) were then added followed by t-BuOH (30
mL), and the reaction mixture was refluxed for 6 h. After cooling, it
was decomposed by addition of sat. NH4Cl solution. The organic
part was separated out and the aqueous part was extracted with
EtOAc (2 × 30 mL). The combined organic part was washed with
brine, dried and concentrated. The residue was purified by column
chromatography to afford 3 (6.2 g, 65%) as a colorless liquid.
IR (KBr): 2936, 1668, 1501, 1256 cm–1.
1H NMR: d = 1.89 (s, 3 H), 1.96–2.05 (m, 2 H), 2.41–2.50 (m, 4 H),
3.68 (s, 2 H), 3.75 (s, 3 H), 5.07 (s, 2 H), 6.50 (s, 1 H), 7.04 (s, 1 H),
7.30–7.43 (m, 5 H).
13C NMR: d = 21.7 (CH3), 22.0 (CH2), 30.0 (CH2), 32.8 (CH2), 37.4
(CH2), 55.9 (CH3), 71.0 (CH2), 112.5 (CH), 113.9 (C), 117.7 (CH),
127.1 (2 × CH), 127.7 (CH), 128.3 (2 × CH), 131.9 (C), 133.6 (C),
136.4 (C), 146.7 (C), 148.8 (C), 158.6 (C), 198.2 (C).
MS (EI): m/z (%) = 416, 414 (22) [M+, Br isotopes], 335, 128, 115
(100).
IR (neat): 2951, 1733, 1668, 1201, 1162 cm–1.
1H NMR: d = 1.88 (s, 3 H), 2.42 (s, 3 H), 2.27–2.52 (overlap. m, 3
H), 2.59–2.70 (m, 1 H), 3.41 (t, J = 4.5 Hz, 1 H), 3.78 (s, 3 H), 3.69–
3.89 (overlap. m, 2 H), 6.74–6.77 (m, 1 H), 7.06–7.10 (m, 2 H).
Anal. Calcd for C22H23BrO3: C, 63.62; H, 5.58. Found: C, 63.46; H,
5.70.
2-(2-Bromo-3-methylbenzyl)-3,3-dimethylcyclohexanone (7a)
To a stirred suspension of CuI (2.6 g, 13.8 mmol) in anhyd Et2O (20
mL) under nitrogen atmosphere was added MeLi (13.8 mL, 1.2 M)
slowly at –25 °C over 30 min and the mixture was allowed to stir for
another 30 min. Then the temperature was lowered to –50 °C,
BF3·Et2O (1.75 mL, 13.8) was added dropwise, and the solution was
stirred for 5 min. The temperature was raised to –30 °C, an ethereal
solution of 4a (810 mg, 2.76 mmol in 5 mL of Et2O) was added
slowly over 15 min, and the mixture was stirred for another 30 min.
Another lot of BF3·Et2O (1.75 mL) was added slowly and the stir-
ring was continued for 1 h. The temperature was brought up to 0 °C
and the reaction mixture was decomposed by adding sat. NH4Cl so-
lution. The Et2O layer was separated out and the aqueous part was
extracted with Et2O (2 × 50 mL). The combined organic part was
washed with 5% Na2S2O3 and brine, dried and concentrated. Col-
umn chromatography of the residue gave 7b (750 mg, 88%) as a
colorless liquid.
MS (ESI): m/z (%) = 375, 373 (100) [M+ + Na, Br isotopes], 353,
351 (47) [M+ + 1, Br isotopes].
2-(2-Bromo-3-methylbenzyl)-3-methylcyclohex-2-enone (4a)
To a stirred solution of 3 (5.3 g, 0.015 mol) in rectified spirit (50
mL) was added a solution of KOH (5 g, 0.09 mol) in H2O (7 mL).
The reaction mixture was refluxed for 12 h, and was then cooled
down. EtOH was removed under reduced pressure, the mixture was
diluted with H2O and extracted with EtOAc (3 × 20 mL). The organ-
ic extract was washed with H2O (until neutral) and brine, and dried.
It was then concentrated and the residue was purified by column
chromatography to give enone 4a (2.9 g, 66%) as a colorless liquid.
IR (neat): 2951, 1652, 1027, 727 cm–1.
1H NMR: d = 1.85 (s, 3 H), 2.03 (quint, J = 6.3 Hz, 2 H), 2.42 (s, 3
H), 2.42–2.50 (overlap. m, 4 H), 3.76 (s, 2 H), 6.66 (app t, J = 4.9,
4.3 Hz, 1 H), 7.04 (app d, J = 5.2 Hz, 2 H).
Synthesis 2006, No. 8, 1263–1272 © Thieme Stuttgart · New York

PAPER
Synthesis of Angularly Functionalized Hydrofluorene Derivatives
1267
IR (neat): 2964, 1708, 1458, 769 cm–1.
13C NMR: d = 16.2 (CH3), 23.1 (CH2), 24.0 (CH3), 32.2 (CH2), 36.1
(CH2), 41.8 (CH2), 50.7 (C), 51.9 (CH3), 54.9 (CH), 126.3 (CH),
127.3 (C), 128.6 (CH), 129.3 (CH), 138.2 (C), 139.3 (C), 175.2 (C),
209.8 (C).
1H NMR: d = 0.88 (s, 3 H), 1.27 (s, 3 H), 1.58–1.66 (m, 1 H), 1.70–
1.95 (m, 3 H), 2.17–2.35 (m, 2 H), 2.39 (s, 3 H), 2.75 (dd, J = 1.5,
10.5 Hz, 1 H), 2.86 (dd, J = 2.1, 13.6 Hz, 1 H), 3.09 (dd, J = 10.6,
13.6 Hz, 1 H), 7.03–7.10 (m, 2 H), 7.26–2.28 (m, 1 H).
MS (EI): m/z (%) = 354, 352 (12) [M+, Br isotopes], 295, 293, 273,
213 (100), 185, 183, 123.
13C NMR: d = 21.1 (CH3), 23.4 (CH2), 23.9 (CH3), 29.7 (CH3), 30.8
(CH2), 39.9 (CH2), 40.9 (C), 41.8 (CH2), 60.0 (CH), 126.3 (CH),
126.9 (C), 128.3 (CH), 129.9 (CH), 137.9 (C), 140.5 (C), 211.8 (C).
Anal. Calcd for C17H21BrO3: C, 57.80; H, 5.99. Found: C, 58.08; H,
6.16.
MS (FAB): m/z (%) = 311, 309 (61) [M+, Br isotopes], 229 (100),
185, 183.
More Polar, Minor Diastereomer
Colorless crystals; yield: 28%; mp 65–66 °C.
IR (KBr): 2952, 1735, 1205, 1142, 764 cm–1.
Anal. Calcd for C16H21BrO: C, 62.14; H, 6.84. Found: C, 62.39; H,
6.73.
1H NMR: d = 1.47 (s, 3 H), 1.82–1.93 (m, 3 H), 2.14–2.26 (m, 2 H),
2.38 (s, 3 H), 2.38–2.52 (overlap. m, 1 H), 2.74 (dd, J = 2.3, 9.3 Hz,
1 H), 2.84 (dd, J = 2.9, 14.0 Hz, 1 H), 3.34 (dd, J = 9.5, 14.0 Hz, 1
H), 3.71 (s, 3 H), 7.04–7.11 (m, 2 H), 7.25 (d, J = 7.0 Hz, 1 H).
13C NMR: d = 22.4 (CH2), 24.0 (CH3), 24.6 (CH3), 32.7 (CH2), 35.4
(CH2), 40.2 (CH2), 51.5 (C), 51.8 (CH3), 57.8 (CH), 126.4 (CH),
126.8 (C), 128.6 (CH), 129.7 (CH), 138.1 (C), 139.9 (C), 175.2 (C),
208.5 (C).
2-(4-Benzyloxy-2-bromo-5-methoxybenzyl)-3,3-dimethylcyclo-
hexanone (7b)
The same procedure as that described for 7a was followed to syn-
thesize 7b (81%) from 4b as a white solid; mp 83–84 °C.
IR (KBr): 2954, 1700, 1506, 1256, 1165 cm–1.
1H NMR: d = 0.84 (s, 3 H), 1.28 (s, 3 H), 1.58–1.60 (m, 1 H), 1.64–
1.91 (m, 3 H), 2.18–2.28 (m, 2 H), 2.66 (d, J = 10.3 Hz, 1 H), 2.73
(d, J = 13.5 Hz, 1 H), 2.97 (dd, J = 11.0, 13.2 Hz, 1 H), 3.87 (s, 3
H), 5.06 (s, 2 H), 6.97 (s, 1 H), 7.08 (s, 1 H), 7.30–7.43 (m, 5 H).
MS (EI): m/z (%) = 354, 352 (16) [M+, Br isotopes], 295, 293, 273,
213 (100), 185, 183, 121, 81.
13C NMR: d = 20.8 (CH3), 23.4 (CH2), 29.6 (CH2), 29.7 (CH3), 40.1
(CH2), 40.9 (C), 42.0 (CH2), 55.8 (CH3), 60.5 (CH), 71.0 (CH2),
113.5 (C), 116.0 (CH), 117.5 (CH), 127.1 (2 × CH), 127.7 (CH),
128.3 (2 × CH), 132.9 (C), 136.5 (C), 146.8 (C), 148.3 (C), 211.9
(C).
MS (EI): m/z (%) = 432, 430 (58) [M+, Br isotopes], 341, 339, 217,
215, 91 (100).
Anal. Calcd for C17H21BrO3: C, 57.80; H, 5.99. Found: C, 57.97; H,
6.09.
2-(4-Benzyloxy-2-bromo-5-methoxybenzyl)-1-methyl-3-oxo-
cyclohexanecarboxylic Acid Methyl Ester (8b)
Less Polar, Major Diastereomer
White solid; yield: 38%; mp 98–100 °C.
IR (KBr): 2950, 1719, 1503, 1234, 1167, 1001 cm–1.
1H NMR: d = 1.15 (s, 3 H), 1.69–1.75 (m, 1 H), 1.81–1.94 (m, 1 H),
2.00–2.07 (m, 1 H), 2.28–2.44 (m, 4 H), 3.14 (dd, J = 8.6, 14.1 Hz,
1 H), 3.32 (dd, J = 4.2, 8.6 Hz, 1 H), 3.55 (s, 3 H), 3.86 (s, 3 H), 5.07
(s, 2 H), 6.93 (s, 1 H), 6.98 (s, 1 H), 7.28–7.42 (m, 5 H).
13C NMR: d = 16.0 (CH3), 23.1 (CH2), 31.0 (CH2), 35.9 (CH2), 41.8
(CH2), 50.8 (C), 51.9 (CH3), 55.5 (CH), 55.9 (CH3), 70.9 (CH2),
113.8 (C), 115.5 (CH), 117.7 (CH), 127.2 (2 × CH), 127.8 (CH),
128.3 (2 × CH), 131.5 (C), 136.4 (C), 146.8 (C), 148.3 (C), 175.1
(C), 209.8 (C).
Anal. Calcd for C23H27BrO3: C, 64.04; H, 6.31. Found: C, 64.41; H,
6.23.
Synthesis of 8a,8b,8d; General Procedure
To a stirred solution of 4a,b, or 4d (10 mmol) in 95% EtOH (60 mL)
was added a solution of KCN (37 mmol) in H2O (5.6 mL). The mix-
ture was gently refluxed for 14 h. After cooling, an aq KOH solution
(2.5 N, 28 mL) was added and the refluxing was continued for 96 h.
The alcohol was removed under reduced pressure and the reaction
mixture was acidified with 6 N HCl in cold. The solid acid was tak-
en up in EtOAc and the aqueous part was extracted with EtOAc
(2 × 30 mL). The combined organic extract was washed with brine
and dried. Removal of the solvent afforded the crude keto-acid as a
brownish solid, which was dissolved in anhyd THF (30 mL) and
treated with LiOH·H2O (13.3 mmol). After stirring at r.t. for 30 min,
dimethyl sulfate (25 mmol) was added and the mixture was refluxed
for 6 h. THF was removed and the residue was partitioned between
H2O (80 mL) and EtOAc (40 mL). The organic part was separated
and the aqueous part was extracted with EtOAc (2 × 20 mL). The
pooled organic extract was washed with brine and dried. The sol-
vent was evaporated to dryness and the oily residue was purified by
column chromatography to afford the two diastereomeric esters in
pure form.
MS (FAB): m/z (%) = 476, 474 (44) [M+, Br isotopes], 395, 335,
325, 323, 243, 91 (100).
Anal. Calcd for C24H27BrO5: C, 60.64; H, 5.72. Found: C, 60.38; H,
5.85.
More Polar, Minor Diastereomer
Colorless liquid; yield: 20%.
IR (neat): 2945, 1721, 1505, 1256, 1208 cm–1.
1H NMR: d = 1.52 (s, 3 H), 1.82–1.91 (m, 3 H), 2.13–2.25 (m, 2 H),
2.43–2.49 (m, 1 H), 2.61 (dd, J = 1.8, 9.5 Hz, 1 H), 2.72 (dd, J = 2.6,
13.9 Hz, 1 H), 3.20 (dd, J = 9.7, 13.9 Hz, 1 H), 3.70 (s, 3 H), 3.87
(s, 3 H), 5.07 (s, 2 H), 6.96 (s, 1 H), 7.12 (s, 1 H), 7.28–7.43 (m, 5
H).
13C NMR: d = 22.5 (CH2), 24.9 (CH3), 31.4 (CH2), 36.1 (CH2), 40.5
(CH2), 51.7 (C), 51.8 (CH3), 56.0 (CH3), 58.2 (CH), 71.1 (CH2),
113.5 (C), 116.1 (CH), 117.6 (CH), 127.3 (2 × CH), 127.9 (CH),
128.5 (2 × CH), 132.4 (C), 136.5 (C), 147.1 (C), 148.5 (C), 175.2
(C), 208.7 (C).
2-(2-Bromo-3-methylbenzyl)-1-methyl-3-oxo-cyclohexane-
carboxylic Acid Methyl Ester (8a)
Less Polar, Major Diastereomer
White solid; yield: 50%; mp 70–71 °C.
IR (KBr): 2973, 1715, 1228, 762 cm–1.
1H NMR: d = 1.18 (s, 3 H), 1.71–1.76 (m, 1 H), 1.87–1.91 (m, 1 H),
2.01–2.04 (m, 1 H), 2.39 (s, 3 H), 2.28–2.57 (m, 4 H), 3.27 (dd, J =
8.2, 14.4 Hz, 1 H), 3.51 (s, 3 H), 3.45–3.50 (overlap. m, 1 H), 7.04–
7.12 (m, 3 H).
MS (EI): m/z (%) = 476, 474 (27) [M+, Br isotopes], 395 (100), 385,
383, 325, 323, 215.
Anal. Calcd for C24H27BrO5: C, 60.64; H, 5.72. Found: C, 60.52; H,
5.81.
Synthesis 2006, No. 8, 1263–1272 © Thieme Stuttgart · New York

1268
M. Banerjee et al.
PAPER
2-(4-Benzyloxy-2-bromo-3-methoxybenzyl)-1-methyl-3-oxo-
cyclohexanecarboxylic Acid Methyl Ester (8d)
Less Polar, Major Diastereomer
Colorless liquid; yield: 38%.
IR (neat): 2948, 1727, 1483, 1269, 1034 cm–1.
1H NMR: d = 1.16 (s, 3 H), 1.63–1.75 (m, 1 H), 1.81–1.92 (m, 1 H),
1.99–2.06 (m, 1 H), 2.27–2.49 (m, 4 H), 3.18 (dd, J = 8.4, 14.3 Hz,
1 H), 3.38–3.43 (m, 1 H), 3.51 (s, 3 H), 3.86 (s, 3 H), 5.08 (s, 2 H),
6.79 (d, J = 8.6 Hz, 1 H), 6.98 (d, J = 8.6 Hz, 1 H), 7.28–7.43 (m, 5
H).
13C NMR: d = 16.1 (CH3), 23.1 (CH2), 31.1 (CH2), 36.0 (CH2), 41.8
(CH2), 50.7 (C), 51.9 (CH3), 55.0 (CH), 60.2 (CH3), 70.8 (CH2),
112.8 (CH), 120.4 (C), 126.5 (CH), 127.1 (2 × CH), 127.8 (CH),
128.4 (2 × CH), 132.3 (C), 136.7 (C), 146.6 (C), 150.7 (C), 175.2
(C), 209.9 (C).
Anal. Calcd for C18H25Br: C, 67.29; H, 7.84. Found: C, 67.37; H,
7.73.
1-Benzyloxy-5-bromo-4-(6-ethylidene-2,2-dimethylcyclohexyl-
methyl)-2-methoxybenzene (9b)
White solid; yield: 94%; mp 88–90 °C.
IR (KBr): 2940, 1506, 1254, 1211, 1003 cm–1.
1H NMR: d = 0.92 (s, 3 H), 1.05 (s, 3 H), 1.25–1.30 (m, 2 H), 1.41
(d, J = 6.5 Hz, 3 H), 1.47–1.63 (m, 2 H), 1.95–1.98 (m, 2 H), 2.37
(bd, J = 13.9 Hz, 1 H), 2.63 (m, 1 H), 2.95 (dd, J = 3.2, 13.5 Hz, 1
H), 3.78 (s, 3 H), 4.64 (q, J = 6.5 Hz, 1 H), 5.06 (s, 2 H), 6.50 (s, 1
H), 7.01 (s, 1 H), 7.28–7.44 (m, 5 H).
13C NMR: d = 12.6 (CH3), 22.6 (CH2), 24.0 (CH2), 28.1 (CH3), 28.2
(CH3), 33.4 (CH2), 34.8 (C), 35.4 (CH2), 55.7 (CH), 56.1 (CH3),
71.3 (CH2), 114.2 (C), 114.8 (CH), 118.0 (C), 119.4 (CH), 127.5 (2
× CH), 127.9 (CH), 128.5 (2 × CH), 134.1 (C), 136.7 (C), 137.2 (C),
146.6 (C), 148.3 (C).
MS (FAB): m/z (%) = 477, 475 (26) [M+ + 1, Br isotopes], 476, 474
(41) [M+, Br isotopes], 395, 335, 307, 305 (100), 215, 183.
MS (EI): m/z (%) = 444, 442 (68) [M+, Br isotopes], 364, 362, 307
(100), 305, 227.
Anal. Calcd for C24H27BrO5: C, 60.64; H, 5.72. Found: C, 60.56; H,
5.78.
Anal. Calcd for C25H31BrO2: C, 67.72; H, 7.05. Found: C, 67.88; H,
7.03.
More Polar, Minor Diastereomer
Colorless liquid; yield: 21%.
1-Bromo-2-(6-ethylidene-2,2-dimethylcyclohexylmethyl)-
benzene (9c)
Colorless liquid; yield: 82%.
IR (neat): 2950, 1468, 1441, 1025, 750 cm–1.
1H NMR: d = 0.93 (s, 3 H), 1.05 (s, 3 H), 1.36 (d, J = 6.7 Hz, 3 H),
1.26–1.31 (m, 1 H), 1.43–1.66 (m, 3 H), 1.93–2.08 (m, 2 H), 2.32–
2.37 (m, 1 H), 2.71 (dd, J = 12.0, 13.4 Hz, 1 H), 3.04 (dd, J = 3.3,
13.4 Hz, 1 H), 4.58 (q, J = 6.3 Hz, 1 H), 6.95–7.00 (m, 2 H), 7.12
(app t, J = 7.3 Hz, 1 H), 7.47 (d, J = 7.7 Hz, 1 H).
13C NMR: d = 12.5 (CH3), 22.6 (CH2), 24.1 (CH2), 28.0 (CH3), 28.1
(CH3), 33.9 (CH2), 34.8 (C), 35.6 (CH2), 55.3 (CH), 119.3 (CH),
124.5 (CH), 126.4 (C), 127.0 (CH), 131.3 (CH), 132.4 (C), 137.0
(C), 141.4 (C).
IR (neat): 2943, 1727, 1484, 1270, 1034 cm–1.
1H NMR: d = 1.49 (s, 3 H), 1.82–1.92 (m, 3 H), 2.12–2.28 (m, 2 H),
2.43–2.49 (m, 1 H,), 2.65–2.79 (m, 2 H), 3.26 (dd, J = 9.6, 14.1 Hz,
1 H), 3.70 (s, 3 H), 3.86 (s, 3 H), 5.08 (s, 2 H), 6.82 (d, J = 8.5 Hz,
1 H), 7.15 (d, J = 8.5 Hz, 1 H), 7.31–7.43 (m, 5 H).
13C NMR: d = 22.4 (CH2), 24.7 (CH3), 31.6 (CH2), 35.6 (CH2), 40.3
(CH2), 51.5 (C), 51.7 (CH3), 57.8 (CH), 60.3 (CH3), 70.8 (CH2),
112.9 (CH), 120.0 (C), 127.1 (3 × CH), 127.8 (CH), 128.4 (2 × CH),
132.9 (C), 136.7 (C), 146.4 (C), 150.7 (C), 175.1 (C), 208.7 (C).
MS (FAB): m/z (%) = 477, 475 (31) [M+ + 1, Br isotopes], 476, 474
(38) [M+, Br isotopes], 395 (100), 385, 383, 307, 305, 215, 136.
Anal. Calcd for C24H27BrO5: C, 60.64; H, 5.72. Found: C, 60.72; H,
5.83.
MS (EI): m/z (%) = 308, 306 (10) [M+, Br isotopes], 293, 291, 227
(100), 138, 137, 89, 79.
Wittig Olefination of 7; General Procedure
To a stirred suspension of ethyl triphenyl phosphonium iodide (17.5
mmol) in anhyd toluene (30 mL) was added solid t-BuOK (15.0
mmol) and the mixture was stirred at r.t. for 2 h. Then, a solution of
the ketone (5 mmol) in anhyd toluene (10 mL) was added slowly
and the stirring was continued for another 12 h. The reaction was
quenched with sat. NH4Cl solution and extracted with Et2O (2 × 50
mL). The organic extract was washed with brine and dried. The sol-
vent was removed and the residue was purified by column chroma-
tography to give the product.
Anal. Calcd for C17H23Br: C, 66.45; H, 7.54. Found: C, 66.58; H,
7.69.
1-Benzyloxy-3-bromo-4-(6-ethylidene-2,2-dimethylcyclohexyl-
methyl)-2-methoxybenzene (9d)
Colorless liquid; yield: 91%.
IR (neat): 2932, 1483, 1290, 1038 cm–1.
1H NMR: d = 0.92 (s, 3 H), 1.04 (s, 3 H), 1.35 (d, J = 6.6 Hz, 3 H),
1.25–1.63 (m, 4 H), 1.90–2.05 (m, 2 H), 2.28–2.33 (m, 1 H), 2.62–
2.71 (app t, J = 12.7 Hz, 1 H), 3.00 (dd, J = 3.2, 13.6 Hz, 1 H), 3.87
(s, 3 H), 4.58 (q, J = 6.6 Hz, 1 H), 5.08 (s, 2 H), 6.63 (d, J = 8.5 Hz,
1 H), 6.74 (d, J = 8.5 Hz, 1 H), 7.31–7.43 (m, 5 H).
2-Bromo-1-(6-ethylidene-2,2-dimethylcyclohexylmethyl)-3-
methylbenzene (9a)
Colorless liquid; yield: 84%.
13C NMR: d = 12.5 (CH3), 22.6 (CH2), 24.1 (CH2), 27.9 (CH3), 28.1
(CH3), 33.4 (CH2), 34.7 (C), 35.6 (CH2), 55.2 (CH), 60.4 (CH3),
71.1 (CH2), 112.9 (CH), 119.1 (CH), 120.2 (C), 125.7 (CH), 127.2
(2 × CH), 127.8 (CH), 128.4 (2 × CH), 135.0 (C), 136.9 (C), 137.0
(C), 146.7 (C), 150.1 (C).
MS (EI): m/z (%) = 444, 442 (23) [M+, Br isotopes], 363, 307, 305,
137, 91 (100).
IR (neat): 2950, 1451, 1024, 772 cm–1.
1H NMR: d = 0.93 (s, 3 H), 1.06 (s, 3 H), 1.26–1.35 (m, 1 H), 1.37
(dd, J = 1.0, 6.6 Hz, 3 H), 1.44–1.66 (m, 3 H), 1.94–2.10 (m, 2 H),
2.30–2.37 (dt, J = 3.3, 13.9 Hz, 1 H), 2.40 (s, 3 H), 2.73 (dd, J =
12.0, 13.5 Hz, 1 H), 3.09 (dd, J = 3.3, 13.5 Hz, 1 H), 4.57 (q, J = 6.6
Hz, 1 H), 6.77–6.80 (m, 1 H), 7.01 (d, J = 4.9 Hz, 2 H).
13C NMR: d = 12.5 (CH3), 22.6 (CH2), 24.1 (CH2), 24.2 (CH3), 27.9
(CH3), 28.2 (CH3), 34.5 (CH2), 34.8 (C), 35.7 (CH2), 55.0 (CH),
119.2 (CH), 125.7 (CH), 127.2 (C), 127.9 (CH), 128.7 (CH), 137.0
(C), 137.8 (C), 141.5 (C).
Anal. Calcd for C25H31BrO2: C, 67.72; H, 7.05; found C, 67.61; H,
7.19.
Wittig Olefination of 8; General Procedure
To a suspension of ethyl triphenyl phosphonium iodide (12 mmol)
in anhyd toluene (20 mL) was added t-BuOK (10.62 mmol) and the
MS (EI): m/z (%) = 322, 320 (72) [M+, Br isotopes], 241, 197, 185
(98), 183 (100), 81, 69.
Synthesis 2006, No. 8, 1263–1272 © Thieme Stuttgart · New York

PAPER
Synthesis of Angularly Functionalized Hydrofluorene Derivatives
1269
mixture was stirred at r.t. for 1 h. The suspension was heated to 80
°C and a solution of the ketone (3.54 mmol) in toluene (5 mL) was
added slowly over 15 min. The reaction mixture was heated under
reflux for 3 h. After cooling to r.t., it was quenched with sat. NH4Cl
solution and the organic part was separated. The aqueous part was
extracted with Et2O (2 × 20 mL); the combined organic extract was
washed with brine and dried. After removal of the solvent, the resi-
due was purified by column chromatography to give the product.
2-(4-Benzyloxy-2-bromo-3-methoxybenzyl)-3-ethylidene-1-
methylcyclohexanecarboxylic Acid Methyl Ester (10d)
Colorless liquid; yield: 88%.
IR (neat): 2941, 2865, 1727, 1483, 1269, 1036 cm–1.
1H NMR: d = 1.23 (s, 3 H), 1.40 (d, J = 6.6 Hz, 3 H), 1.44–1.62 (m,
3 H), 2.02–2.14 (m, 3 H), 2.78 (, d, J = 7.2 Hz, 2 H), 3.00 (t, J = 7.2
Hz, 1 H), 3.57 (s, 3 H), 3.88 (s, 3 H), 4.83 (q, J = 6.6 Hz, 1 H), 5.09
(s, 2 H), 6.73 (d, J = 8.5 Hz, 1 H), 6.78 (d, J = 8.5 Hz, 1 H), 7.29–
7.43 (m, 5 H).
13C NMR: d = 12.6 (CH3), 21.4 (CH3), 23.4 (CH2), 24.9 (CH2), 32.8
(CH2), 33.3 (CH2), 48.6 (C), 49.1 (CH), 51.4 (CH3), 60.2 (CH3),
70.9 (CH2), 112.8 (CH), 119.4 (CH), 120.4 (C), 125.3 (CH), 127.1
(2 × CH), 127.7 (CH), 128.3 (2 × CH), 133.4 (C), 136.2 (C), 136.7
(C), 146.6 (C), 150.3 (C), 177.4 (C).
2-(2-Bromo-3-methylbenzyl)-3-ethylidene-1-methylcyclo-
hexanecarboxylic Acid Methyl Ester (10a)
White solid; yield: 81%; mp 55–56 °C.
IR (KBr): 2938, 1718, 1253, 1108 cm–1.
1H NMR: d = 1.26 (s, 3 H), 1.41 (d, J = 6.6 Hz, 3 H), 1.55–1.58 (m,
3 H), 1.98–2.07 (m, 1 H), 2.13–2.27 (m, 2 H), 2.41 (s, 3 H), 2.85 (d,
J = 7.3 Hz, 2 H), 3.06 (t, J = 7.3 Hz, 1 H), 3.58 (s, 3 H), 4.81 (q, J =
6.6 Hz, 1 H), 6.87–6.90 (m, 1 H), 7.03–7.04 (m, 2 H).
MS (EI): m/z (%) = 489, 487 (11) [M+ + 1, Br isotopes], 488, 486
(8) [M+, Br isotopes], 407, 307, 305, 215, 121 (100).
13C NMR: d = 12.7 (CH3), 21.5 (CH3), 23.5 (CH2), 24.1 (CH3), 24.9
(CH2), 33.4 (CH2), 33.9 (CH2), 48.8 (C), 49.0 (CH), 51.5 (CH3),
119.5 (CH), 126.0 (CH), 127.4 (C), 128.1 (CH), 128.2 (CH), 136.2
(C), 138.0 (C), 140.1 (C), 177.5 (C).
Anal. Calcd for C26H31BrO4: C, 64.07; H, 6.41. Found: C, 64.33; H,
6.34.
Heck Cyclization of 9 and 10; General Procedure
A stirred suspension of olefin (3.58 mmol), Pd(OAc)2 (0.19 mmol),
triphenyl phosphine (0.76 mmol) and anhyd K2CO3 (14.4 mmol) in
anhyd DMF (20 mL) was refluxed for several hours (details in
Table 1). After cooling, H2O (50 mL) was added to the reaction
mixture and the solution was extracted with EtOAc (3 × 25 mL).
The organic extract was washed with brine, dried and concentrated.
Column chromatography of the crude product afforded the 4a-vinyl
substituted hydrofluorenes.
MS (EI): m/z (%) = 366, 364 (9) [M+, Br isotopes], 307, 305, 285,
181 (100), 121.
Anal. Calcd for C19H25BrO2: C, 62.47; H, 6.90. Found: C, 62.22; H,
6.83.
2-(4-Benzyloxy-2-bromo-5-methoxybenzyl)-3-ethylidene-1-
methylcyclohexanecarboxylic Acid Methyl Ester (10b)
Colorless liquid; yield: 86%.
1,1,5-Trimethyl-4a-vinyl-2,3,4,4a,9,9a-hexahydro-1H-fluorene
(11a)
Colorless liquid; yield: 82%.
IR (neat): 2933, 1458, 910, 766 cm–1.
1H NMR: d = 0.94 (s, 3 H), 1.03 (s, 3 H), 1.13–1.26 (m, 2 H), 1.36–
1.47 (m, 2 H), 1.56–1.79 (m, 2 H), 2.04–2.10 (m, 1 H), 2.23 (s, 3 H),
2.70–2.87 (m, 2 H), 5.15–5.24 (m, 2 H), 6.10 (dd, J = 10.8, 17.6 Hz,
1 H), 6.85–6.87 (m, 1 H), 7.00–7.03 (m, 2 H).
13C NMR: d = 18.5 (CH2), 19.7 (CH3), 29.0 (CH3), 29.7 (CH2), 31.2
(CH3), 32.6 (C), 33.8 (CH2), 34.3 (CH2), 52.3 (C), 57.5 (CH), 113.8
(CH2), 122.1 (CH), 126.3 (CH), 129.1 (CH), 134.1 (C), 141.8 (C),
146.7 (CH), 149.4 (C).
IR (neat): 2944, 1727, 1503, 1253, 1166 cm–1.
1H NMR: d = 1.24 (s, 3 H), 1.44 (d, J = 6.7 Hz, 3 H), 1.54–1.64 (m,
3 H), 1.98–2.07 (m, 1 H), 2.16–2.18 (m, 2 H), 2.68–2.79 (m, 2 H),
2.95 (dd, J = 4.8, 9.8 Hz, 1 H), 3.58 (s, 3 H), 3.80 (s, 3 H), 4.88 (q,
J = 6.7 Hz, 1 H), 5.07 (s, 2 H), 6.60 (s, 1 H), 7.02 (s, 1 H), 7.28–7.44
(m, 5 H).
13C NMR: d = 12.7 (CH3), 21.9 (CH3), 23.5 (CH2), 24.6 (CH2), 32.6
(CH2), 33.0 (CH2), 48.6 (C), 49.7 (CH), 51.5 (CH3), 56.0 (CH3),
71.1 (CH2), 114.3 (CH), 117.7 (CH), 119.7 (CH), 127.3 (2 × CH),
127.8 (CH), 128.4 (2 × CH), 132.5 (C), 136.2 (C), 136.6 (C), 146.7
(C), 148.3 (C), 177.4 (C); one carbon peak remained undistin-
guished due to overlap.
MS (EI): m/z (%) = 488, 486 (19) [M+, Br isotopes], 407, 307, 305,
MS (EI): m/z (%) = 241 [M+ + 1], 240 (100) [M+], 213, 156, 143, 69.
121, 91 (100).
Anal. Calcd for C18H24: C, 89.94; H, 10.06. Found: C, 89.79; H,
10.08.
Anal. Calcd for C26H31BrO4: C, 64.07; H, 6.41. Found: C, 64.41; H,
6.54.
6-Benzyloxy-7-methoxy-1,1-dimethyl-4a-vinyl-2,3,4,4a,9,9a-
hexahydro-1H-fluorene (11b)
White solid; yield: 96%; mp 76–78 °C.
2-(2-Bromobenzyl)-3-ethylidene-1-methylcyclohexane-
carboxylic Acid Methyl Ester (10c)
Colorless liquid; yield: 86%.
IR (neat): 2946, 1730, 1442, 1234, 752 cm–1.
1H NMR: d = 1.25 (s, 3 H), 1.40 (d, J = 6.6 Hz, 3 H), 1.53–1.68 (m,
3 H), 2.01–2.09 (m, 1 H), 2.18–2.19 (m, 2 H), 2.82 (d, J = 7.4 Hz, 2
H), 3.05 (t, J = 7.4 Hz, 1 H), 3.59 (s, 3 H), 4.83 (q, J = 6.6 Hz, 1 H),
6.97–7.18 (m, 3 H), 7.49 (d, J = 7.0 Hz, 1 H).
IR (KBr): 2942, 2864, 1496, 1292, 1221 cm–1.
1H NMR: d = 0.94 (s, 3 H), 1.00 (s, 3 H), 1.07–1.26 (m, 2 H), 1.36–
1.45 (m, 2 H), 1.54–1.62 (m, 1 H), 1.89 (br d, J = 13.8 Hz, 1 H), 2.20
(t, J = 9.8 Hz, 1 H), 2.75 (d, J = 9.8 Hz, 2 H), 3.84 (s, 3 H), 5.05 (s,
2 H), 5.10–5.17 (m, 2 H), 5.82 (dd, J = 10.5, 17.8 Hz, 1 H), 6.52 (s,
1 H), 6.78 (s, 1 H), 7.27–7.44 (m, 5 H).
13C NMR: d = 12.5 (CH3), 21.5 (CH3), 23.4 (CH2), 24.8 (CH2), 33.1
(2 × CH2), 48.6 (C), 49.2 (CH), 51.4 (CH3), 119.5 (CH), 124.6 (C),
126.5 (CH), 127.1 (CH), 130.8 (CH), 132.3 (CH), 136.0 (C), 139.8
(C), 177.2 (C).
MS (EI): m/z (%) = 352, 350 (28) [M+, Br isotopes], 293, 291, 271,
211, 181 (100), 171, 169, 121, 93.
13C NMR: d = 18.9 (CH2), 28.5 (CH3), 30.7 (CH3), 31.2 (CH2), 32.4
(C), 33.3 (CH2), 34.8 (CH2), 51.5 (C), 56.2 (CH3), 58.5 (CH), 71.4
(CH2), 108.8 (CH), 109.9 (CH), 111.7 (CH2), 127.6 (2 × CH), 127.6
(CH), 128.3 (2 × CH), 133.7 (C), 137.5 (C), 143.9 (C), 145.7 (CH),
146.9 (C), 148.7 (C).
MS (EI): m/z (%) = 362 (63) [M+], 271, 86 (100).
Anal. Calcd for C18H23BrO2: C, 61.54; H, 6.60. Found: C, 61.69; H,
6.79.
Anal. Calcd for C25H30O2: C, 82.83; H, 8.34. Found: C, 82.72; H,
8.41.
Synthesis 2006, No. 8, 1263–1272 © Thieme Stuttgart · New York

1270
M. Banerjee et al.
PAPER
1,1-Dimethyl-4a-vinyl-2,3,4,4a,9,9a-hexahydro-1H-fluorene
(11c)
1 H), 5.14 (d, J = 10.8 Hz, 1 H), 5.67 (dd, J = 10.8, 17.6 Hz, 1 H),
6.52 (s, 1 H), 6.81 (s, 1 H), 7.27–7.43 (m, 5 H).
Colorless liquid; yield: 95%.
IR (neat): 2938, 1469, 909, 756 cm–1.
13C NMR: d = 20.0 (CH2), 26.7 (CH3), 30.2 (CH2), 30.8 (CH2), 32.2
(CH2), 43.8 (C), 51.4 (CH3), 51.8 (C), 52.7 (CH), 56.3 (CH3), 71.5
(CH2), 109.0 (CH), 109.8 (CH), 113.3 (CH2), 127.6 (2 × CH), 127.7
(CH), 128.0 (2 × CH), 132.7 (C), 138.0 (C), 142.9 (C), 143.8 (C),
147.2 (CH), 148.9 (C), 177.6 (C).
1H NMR: d = 0.96 (s, 3 H), 1.03 (s, 3 H), 1.09–1.19 (m, 1 H), 1.22–
1.29 (m, 1 H), 1.35–1.49 (m, 2 H), 1.58–1.70 (m, 1 H), 1.96 (br d,
J = 13.9 Hz, 1 H), 2.06 (t, J = 9.8 Hz, 1 H), 2.83 (d, J = 9.7 Hz, 2
H), 5.19–5.25 (m, 2 H), 5.88 (dd, J = 10.8, 17.8 Hz, 1 H), 6.92–6.95
(m, 1 H), 7.10–7.13 (m, 2 H), 7.19–7.22 (m, 1 H).
13C NMR: d = 18.9 (CH2), 28.6 (CH3), 30.8 (CH3), 31.1 (CH2), 32.4
(C), 33.4 (CH2), 34.7 (CH2), 51.6 (C), 58.0 (CH), 111.9 (CH2),
122.9 (CH), 124.6 (CH), 126.0 (CH), 126.3 (CH), 141.4 (C), 145.5
(CH), 152.0 (C).
MS (EI): m/z (%) = 407 [M+ + 1], 406 (71) [M+], 315, 255, 91 (100).
Anal. Calcd for C26H30O4: C, 76.82; H, 7.44. Found: C, 76.71; H,
7.38.
1-Methyl-4a-vinyl-2,3,4,4a,9,9a-hexahydro-1H-fluorene-1-
carboxylic Acid Methyl Ester (12c)
Colorless liquid; yield: 87%.
IR (neat): 2942, 1731, 1459, 1227, 1132, 758 cm–1.
MS (EI): m/z (%) = 227 [M+ + 1], 226 (100) [M+], 183, 155, 142,
129.
Anal. Calcd for C17H22: C, 90.20; H, 9.80. Found: C, 90.01; H, 9.89.
1H NMR: d = 1.22 (s, 3 H), 1.13–1.36 (m, 2 H), 1.45–1.50 (m, 1 H),
1.66–1.81 (m, 1 H), 1.92 (br d, J = 14.1 Hz, 1 H), 2.09 (br d, J = 13.5
Hz, 1 H), 2.84–3.05 (m, 3 H), 3.62 (s, 3 H), 5.12–5.22 (m, 2 H), 5.73
(dd, J = 10.8, 17.6 Hz, 1 H), 6.92–6.95 (m, 1 H), 7.12–7.15 (m, 2
H), 7.23–7.25 (m, 1 H).
6-Benzyloxy-5-methoxy-1,1-dimethyl-4a-vinyl-2,3,4,4a,9,9a-
hexahydro-1H-fluorene (11d)
Colorless liquid; yield: 62%.
IR (neat): 2935, 1480, 1266, 1066 cm–1.
13C NMR: d = 19.9 (CH2), 26.7 (CH3), 30.0 (CH2), 30.5 (CH2), 32.2
(CH2), 43.6 (C), 51.3 (CH3), 51.8 (C), 52.2 (CH), 113.5 (CH2),
122.8 (CH), 124.7 (CH), 126.3 (CH), 126.4 (CH), 140.3 (C), 142.6
(CH), 151.7 (C), 177.5 (C).
MS (EI): m/z (%) = 271 [M+ + 1], 270 (68) [M+], 211, 210, 183, 155,
141 (100).
1H NMR: d = 0.90 (s, 3 H), 1.02 (s, 3 H), 1.11–1.47 (m, 4 H), 1.60–
1.71 (m, 1 H), 2.10–2.25 (m, 2 H), 2.25–2.82 (m, 2 H), 3.76 (s, 3 H),
5.04 (s, 2 H), 5.15–5.21 (m, 2 H), 6.16 (dd, J = 10.6, 17.8 Hz, 1 H),
6.75 (d, J = 8.0 Hz, 1 H), 6.82 (d, J = 8.0 Hz, 1 H), 7.29–7.45 (m, 5
H).
13C NMR: d = 18.7 (CH2), 29.3 (CH3), 30.7 (CH3), 31.3 (CH2), 32.6
(C), 33.3 (CH2), 34.8 (CH2), 51.7 (C), 56.9 (CH), 60.6 (CH3), 71.1
(CH2), 112.3 (CH), 113.2 (CH), 119.2 (CH), 127.2 (2 × CH), 127.7
(CH), 128.4 (2 × CH), 135.8 (C), 137.5 (C), 145.2 (C), 146.1 (C),
146.5 (CH), 150.9 (C).
Anal. Calcd for C18H22O2: C, 79.96; H, 8.20. Found: C, 80.13; H,
8.32.
1-(1,1-Dimethyl-1,2,3,4,9,9a-hexahydrofluoren-4a-yl)ethane-
1,2-diol (13a)
To a stirred a solution of 11c (705 mg, 3.12 mmol) in acetone–
t-BuOH (1:1, 3 mL) was added NMO (1.6 mL, 15.4 mmol, 50% so-
lution in H2O) in cold, followed by OsO4 (7.9 mg, 1 mmol%). The
reaction mixture was stirred at r.t. for 8 h. The solvent was evapo-
rated and the residue was dissolved in EtOAc (10 mL). The solution
was washed with 5 M HCl (6.5 mL) and then stirred with 45% so-
dium metabisulfate solution (10 mL) for 20 min. The organic part
was separated, washed with brine and dried. Complete removal of
the solvent followed by column chromatography of the residue gave
the diastereomeric mixture of diols 13a (680 mg, 84%) as a sticky
liquid.
MS (EI): m/z (%) = 363 [M+ + 1], 362 (65) [M+], 271, 201, 91 (100).
Anal. Calcd for C25H30O2: C, 82.83; H, 8.34. Found: C, 82.88; H,
8.43.
1,5-Dimethyl-4a-vinyl-2,3,4,4a,9,9a-hexahydro-1H-fluorene-1-
carboxylic Acid Methyl Ester (12a)
Colorless liquid; yield: 61%.
IR (neat): 2936, 1731, 1458, 1234, 1128, 769 cm–1.
1H NMR: d = 1.20 (s, 3 H), 1.20–1.35 (overlap. m, 3 H), 1.46–1.56
(m, 1 H), 1.82–1.97 (m, 1 H), 2.06 (br d, J = 13.5 Hz, 1 H), 2.22 (s,
3 H), 2.71–2.82 (m, 1 H), 2.88–2.99 (m, 2 H), 3.59 (s, 3 H), 5.13 (d,
J = 17.8 Hz, 1 H), 5.20 (d, J = 10.9 Hz, 1 H), 5.86 (dd, J = 10.9, 17.6
Hz, 1 H), 6.87 (d, J = 6.5 Hz, 1 H), 7.02–7.08 (m, 2 H).
13C NMR: d = 19.3 (CH3), 19.5 (CH2), 26.9 (CH3), 28.5 (CH2), 29.5
(CH2), 32.3 (CH2), 43.0 (C), 51.1 (CH3), 51.6 (CH), 52.1 (C), 114.2
(CH2), 122.1 (CH), 126.3 (CH), 129.1 (CH), 134.0 (C), 140.6 (C),
143.7 (CH), 148.7 (C), 177.5 (C).
IR (neat): 3384, 2941, 1459, 1036 cm–1.
1H NMR [major peaks]: d = 0.50 (s, 3 H), 0.99 (s, 3 H), 1.19–1.35
(m, 3 H), 1.49–1.64 (m, 2 H), 1.99–2.11 (m, 2 H), 2.19 (exchange-
able br s, 2 H), 2.70 (dd, J = 4.8, 16.1 Hz, 1 H), 2.97 (dd, J = 7.3,
16.1 Hz, 1 H), 3.44–3.82 (m, 3 H), 7.10–7.20 (m, 3 H), 7.26–7.28
(m, 1 H).
13C NMR [major peaks]: d = 18.0 (CH2), 25.4 (CH3), 26.1 (CH2),
31.5 (CH3), 32.3 (C), 32.6 (CH2), 37.8 (CH2), 50.7 (CH), 52.8 (C),
62.8 (CH2), 74.8 (CH), 123.6 (CH), 124.5 (CH), 125.7 (CH), 126.5
(CH), 143.9 (C), 147.3 (C).
MS (EI): m/z (%) = 285 [M+ + 1], 284 (70) [M+], 225 (100), 224,
209, 197, 169, 155.
Anal. Calcd for C19H24O2: C, 80.24; H, 8.51. Found: C, 80.38; H,
8.56.
MS (EI): m/z (%) = 260 (22) [M+], 215, 200 (100), 199 (100), 143,
129.
7-Benzyloxy-6-methoxy-1-methyl-4a-vinyl-2,3,4,4a,9,9a-
hexahydro-1H-fluorene-1-carboxylic Acid Methyl Ester (12b)
Colorless liquid; yield: 86%.
IR (neat): 2939, 1728, 1496, 1225 cm–1.
The minor peaks attributed to minor isomers were ignored.
4a-(1,2-Dihydroxyethyl)-1-methyl-2,3,4,4a,9,9a-hexahydro-1H-
fluorene-1-carboxylic Acid Methyl Ester (13b)
The same procedure as described for 13a was followed to synthe-
size 13b (84%) from 12c. A second column chromatography of the
product over 100–200 mesh silica gel could separate a portion of the
major diastereomer in pure form (41%).
1H NMR: d = 1.20 (s, 3 H), 1.08–1.33 (overlap. m, 2 H), 1.42–1.46
(m, 1 H), 1.58–1.75 (m, 1 H), 1.85 (br d, J = 14.1 Hz, 1 H), 2.07 (br
d, J = 13.2 Hz, 1 H), 2.72–2.88 (m, 2 H), 2.98 (dd, J = 7.6, 11.6 Hz,
1 H), 3.61 (s, 3 H), 3.85 (s, 3 H), 5.05 (s, 2 H), 5.10 (d, J = 17.6 Hz,
Synthesis 2006, No. 8, 1263–1272 © Thieme Stuttgart · New York

PAPER
Synthesis of Angularly Functionalized Hydrofluorene Derivatives
1271
Major Diastereomer
1,1-Dimethyl-1,2,3,4,9,9a-hexahydrofluorene-4a-carboxylic
Acid (15a)
White solid; mp 72–73 °C.
To a stirred solution of 14a (80 mg, 0.35 mmol) in DMSO (2 mL)
was added a solution of sodium dihydrogen phosphate dihydrate
(164 mg, 1.05 mmol) in H2O (0.6 mL) and the mixture was cooled
to 0 °C. A solution of sodium chlorite (154 mg, 1.22 mmol) in H2O
(0.4 mL) was added and stirred at r.t. for 3 h. The reaction mixture
was diluted with H2O and extracted with EtOAc (2 × 10 mL). The
extract was washed with brine and dried. Concentration of the ex-
tract gave a residue, which was purified by column chromatography
to furnish 15a (82 mg, 96%) as white crystals; mp 158–160 °C.
IR (KBr): 3342, 2945, 1718, 1231, 740 cm–1.
1H NMR: d = 1.16 (s, 3 H), 1.21–1.36 (m, 2 H), 1.43–1.49 (m, 1 H),
1.55–1.68 (m, 1 H), 2.11–2.25 (m, 4 H, including exchangeable 2
H), 2.74–2.98 (m, 3 H), 3.47 (dd, J = 9.7, 11.2 Hz, 1 H), 3.74 (s, 3
H), 3.77–3.83 (m, 2 H), 7.09–7.20 (m, 3 H), 7.50–7.53 (m, 1 H).
13C NMR: d = 18.6 (CH2), 26.0 (CH3), 29.4 (CH2), 30.3 (CH2), 32.5
(CH2), 44.1 (C), 45.9 (CH), 51.8 (C), 52.1 (CH3), 63.7 (CH2), 73.1
(CH), 124.4 (CH), 124.6 (CH), 126.2 (CH), 126.4 (CH), 140.6 (C),
148.7 (C), 179.0 (C).
IR (KBr): 2950, 1694, 1276, 745 cm–1.
1H NMR: d = 1.00 (s, 3 H), 1.02 (s, 3 H), 1.00–1.13 (overlap. m, 1
H), 1.27–1.49 (m, 3 H), 1.64–1.74 (m, 1 H), 2.37 (br d, J = 13.7 Hz,
1 H), 2.82–2.94 (m, 3 H), 7.06–7.26 (m, 4 H).
13C NMR: d = 19.5 (CH2), 27.9 (CH3), 30.2 (CH3), 31.5 (CH2), 32.2
(C), 33.2 (CH2), 34.1 (CH2), 53.7 (CH), 56.0 (C), 121.5 (CH), 125.0
(CH), 126.6 (CH), 127.2 (CH), 141.4 (C), 149.1 (C), 182.4 (C).
MS (EI): m/z (%) = 304 (59) [M+], 244 (100), 243 (100), 184, 183,
155, 129, 105.
Anal. Calcd for C18H24O4: C, 71.03; H, 7.95; found C, 71.32; H,
7.81.
1,1-Dimethyl-1,2,3,4,9,9a-hexahydrofluorene-4a-carbaldehyde
(14a)
MS (EI): m/z (%) = 244 (39) [M+], 200, 199 (100), 143, 129.
To a solution of 13a (520 mg, 2 mmol) in MeOH (20 mL) was add-
ed a solution of sodium periodate (525 mg, 2.5 mmol) in H2O
(4 mL) dropwise at 0 °C. The mixture was stirred for 2 h and fil-
tered. The residue was washed with MeOH. The combined filtrate
was concentrated. The residue was dissolved using H2O (20 mL)
and Et2O (20 mL). The organic part was separated and the aqueous
part was extracted with Et2O (2 × 10 mL). The combined organic
extract was washed with brine, dried and concentrated. Column
chromatography of the residue furnished 14a (450 mg, 99%) as a
colorless liquid.
Anal. Calcd for C16H20O2: C, 78.65; H, 8.25. Found: C, 78.32; H,
8.17.
1-Methyl-1,2,3,4,9,9a-hexahydrofluorene-1,4a-dicarboxylic
Acid 1-Methyl Ester (15b)
The same procedure as described for 15a was followed to synthe-
size 15b (99%) from 14b as a white solid; mp 144–145 °C.
IR (KBr): 3269, 2947, 1725, 1698, 1231, 1183, 764 cm–1.
1H NMR: d = 1.08–1.19 (m, 1 H), 1.27 (s, 3 H), 1.27–1.39 (overlap.
m, 1 H), 1.49–1.56 (m, 1 H), 1.68–1.77 (m, 1 H), 2.09 (br d, J = 13.5
Hz, 1 H), 2.31 (br d, J = 13.9 Hz, 1 H), 2.86 (dd, J = 12.1, 15.2 Hz,
1 H), 3.02 (dd, J = 8.0, 15.2 Hz, 1 H), 3.56 (dd, J = 8.3, 11.7 Hz, 1
H), 3.65 (s, 3 H), 7.15–7.24 (m, 4 H).
13C NMR: d = 20.4 (CH2), 25.9 (CH3), 30.6 (CH2), 31.6 (CH2), 32.7
(CH2), 43.8 (C), 48.1 (CH), 51.6 (CH3), 56.3 (C), 122.3 (CH), 124.7
(CH), 126.8 (CH), 127.2 (CH), 140.0 (C), 148.3 (C), 177.4 (C),
181.9 (C).
IR (neat): 2945, 1721, 1471, 1458, 754 cm–1.
1H NMR: d = 0.90 (s, 3 H), 1.03 (s, 3 H), 1.24–1.29 (m, 2 H), 1.35–
1.57 (m, 3 H), 2.35 (br d, J = 14.0 Hz, 1 H), 2.52 (app t, J = 9.7 Hz,
1 H), 2.87–3.02 (m, 2 H), 6.85 (d, J = 7.2 Hz, 1 H), 7.11–7.30 (m, 3
H), 9.52 (s, 1 H).
13C NMR: d = 18.9 (CH2), 27.7 (CH3), 28.3 (CH2), 29.9 (CH3), 31.9
(C), 33.5 (CH2), 33.8 (CH2), 52.6 (CH), 61.2 (C), 122.9 (CH), 125.2
(CH), 126.5 (CH), 127.7 (CH), 142.8 (C), 145.0 (C), 202.8 (CH).
MS (EI): m/z (%) = 288 (21) [M+], 270, 244, 242, 229, 184 (100),
183 (100), 130.
MS: m/z (%) = 228 (31) [M+], 200, 199 (100), 129.
Anal. Calcd for C16H20O: C, 84.16; H, 8.83. Found: C, 84.43; H,
8.74.
Anal. Calcd for C17H20O4: C, 70.81; H, 6.99. Found: C, 70.56; H,
7.08.
4a-Formyl-1-methyl-2,3,4,4a,9,9a-hexahydro-1H-fluorene-1-
carboxylic Acid Methyl Ester (14b)
The same procedure as described for 14a was followed to synthe-
(1,1-Dimethyl-1,2,3,4,9,9a-hexahydrofluoren-4a-yl)methanol
(16a)
To a stirred solution of 14a (140 mg, 0.62 mmol) in MeOH (4 mL)
NaBH4 (24 mg, 0.62 mmol) was added portionwise at 0 °C and the
mixture was stirred for 1 h. MeOH was removed and the residue
was dissolved in minimum volume of H2O. Aq AcOH was added
until effervescence ceased and the mixture was extracted with
EtOAc (2 × 10 mL). The extract was washed with brine, dried and
concentrated. Column chromatography of the crude alcohol over
neutral alumina afforded 16a (138 mg, 98%) as a colorless liquid.
size 14b (95%) from 13b as a colorless liquid.
IR (neat): 2929, 1721, 1457, 1167 cm–1.
1H NMR: d = 1.00–1.06 (m, 1 H), 1.30 (s, 3 H), 1.17–1.43 (m, 2 H),
1.50–1.56 (m, 1 H), 2.05 (br d, J= 12.9 Hz, 1 H), 2.38 (d, J = 13.5
Hz, 1 H), 2.87–3.07 (m, 2 H), 3.34 (dd, J = 8.1, 12.0 Hz, 1 H), 3.66
(s, 3 H), 6.86 (d, J = 7.2 Hz, 1 H), 7.14–7.24 (m, 2 H), 7.32 (d, J =
7.2 Hz, 1 H), 9.49 (s, 1 H).
13C NMR: d = 20.4 (CH2), 25.0 (CH3), 27.9 (CH2), 30.8 (CH2), 32.8
(CH2), 44.4 (C), 46.1 (CH), 51.7 (CH3), 60.7 (C), 122.8 (CH), 124.9
(CH), 126.6 (CH), 127.6 (CH), 141.4 (C), 144.8 (C), 177.4 (C),
200.4 (CH).
IR (neat): 3381, 2932, 1460, 1031, 755 cm–1.
1H NMR: d = 0.88 (s, 3 H), 1.10 (s, 3 H), 1.26–1.58 (m, 6 H), 2.30
(t, J = 8.8 Hz, 1 H), 2.74–2.90 (m, 2 H), 3.91 (s, 2 H), 7.09–7.24 (m,
4 H).
13C NMR: d = 18.9 (CH2), 29.4 (CH3), 29.7 (CH3), 31.9 (CH2, C),
33.4 (CH2), 35.6 (CH2), 48.8 (CH), 50.9 (C), 66.8 (CH2), 121.1
(CH), 124.8 (CH), 126.2 (CH), 126.6 (CH), 143.0 (C), 149.1 (C).
MS (EI): m/z (%) = 272 (32) [M+], 243, 242, 212, 183 (100), 156,
141, 130, 115.
Anal. Calcd for C17H20O3: C, 74.97; H, 7.40. Found: C, 75.16; H,
7.51.
MS (EI): m/z (%) = 230 (12) [M+], 200, 199 (100), 143, 129.
Anal. Calcd for C16H22O: C, 83.43; H, 9.63. Found: C, 83.62; H,
9.57.
Synthesis 2006, No. 8, 1263–1272 © Thieme Stuttgart · New York

1272
M. Banerjee et al.
PAPER
4a-Hydroxymethyl-1-methyl-2,3,4,4a,9,9a-hexahydro-1H-
fluorene-1-carboxylic Acid Methyl Ester (16b)
The same procedure as described for 16a was followed to synthe-
size 16b (92%) from 14b as a colorless liquid.
IR (KBr): 2951, 1725, 1258, 1190, 756 cm–1.
1H NMR: d = 1.04–1.14 (m, 1 H), 1.25 (s, 3 H), 1.25–1.38 (m, 1 H),
1.54–1.74 (m, 2 H), 2.08 (br d, J = 13.6 Hz, 1 H), 2.31 (br d, J = 13.8
Hz, 1 H), 2.81–2.89 (m, 1 H), 3.00 (dd, J = 8.1, 15.2 Hz, 1 H), 3.54
(dd, J = 8.4, 11.6 Hz, 1 H), 3.66 (s, 3 H), 3.71 (s, 3 H), 6.99 (d, J =
7.8 Hz, 1 H), 7.15–7.24 (m, 3 H) [Lit.10 d = 1.23, 3.63, 3.67 (s, 3 ×
3 H)].
13C NMR: d = 20.4 (CH2), 25.9 (CH3), 30.4 (CH2), 31.8 (CH2), 32.5
(CH2), 44.1 (C), 48.2 (CH), 51.7 (CH3), 51.8 (CH3), 56.1 (C), 122.0
(CH), 124.6 (CH), 126.6 (CH), 126.9 (CH), 139.8 (C), 148.9 (C),
175.6 (C), 177.2 (C).
IR (neat): 3537, 2939, 1722, 1460, 1227, 758 cm–1.
1H NMR: d = 1.26 (s, 3 H), 1.20–1.51 (overlap. m, 5 H), 1.90 (ex-
changeable br s, 1 H), 2.15–2.19 (m, 1 H), 2.77–2.96 (m, 2 H), 3.14
(dd, J = 8.0, 11.6 Hz, 1 H), 3.60 (d, J = 12.5 Hz, 1 H), 3.76 (s, 3 H),
3.85 (d, J = 12.5 Hz, 1 H), 7.12–7.23 (m, 4 H).
13C NMR: d = 20.2 (CH2), 26.5 (CH3), 30.1 (CH2), 31.9 (CH2), 32.0
(CH2), 43.6 (CH), 44.1 (C), 50.3 (C), 52.3 (CH3), 63.0 (CH2), 121.2
(CH), 124.7 (CH), 126.4 (CH), 126.5 (CH), 140.7 (C), 149.7 (C),
179.7 (C).
MS (EI): m/z (%) = 302 (38) [M+], 243, 242, 184, 183 (100), 141.
Anal. Calcd for C18H22O4: C, 71.50; H, 7.33. Found: C, 71.77; H,
7.21.
MS (EI): m/z (%) = 274 (14) [M+], 256, 244, 243, 184, 183 (100),
141, 128.
Anal. Calcd for C17H22O3: C, 74.42; H, 8.08. Found: C, 74.59; H,
8.13.
Acknowledgment
We are grateful to Late Prof. U. R. Ghatak of our institute for his va-
luable suggestions and criticism, and CSIR for the award of a Rese-
arch Fellowship to M.B.
1,1,4a-Trimethyl-2,3,4,4a,9,9a-hexahydro-1H-fluorene (18)
To a stirred solution of 16a (175 mg, 0.22 mmol) in anhyd CH2Cl2
(1 mL) at –10 °C was added CBr4 (87.5 mg, 0.26 mmol) and the
mixture was stirred for 10 min. PPh3 (63.5 mg, 0.24 mmol) was add-
ed portionwise and the reaction mixture was stirred at the same tem-
perature for 30 min. The organic layer was washed with H2O and
brine, and then dried. The solvent was evaporated to afford the
crude bromide 17, which readily decomposes at r.t.
References
(1) Parham, W. E.; Czuba, L. J. J. Org. Chem. 1969, 34, 1899.
(2) Ghosh, S.; Ghatak, U. R. J. Org. Chem. 1980, 46, 1486.
(3) Trost, B. M.; Walchli, R. J. Am. Chem. Soc. 1987, 109, 3487.
(4) (a) Banerjee, M.; Mukhopadhyay, R.; Achari, B.; Banerjee,
A. K. Org. Lett. 2003, 5, 3931. (b) Sengupta, S.;
Mukhopadhyay, R.; Achari, B.; Banerjee, A. K. Tetrahedron
Lett. 2005, 46, 1515. (c) Sengupta, S.; Drew, G. B.;
Mukhopadhyay, R.; Achari, B.; Banerjee, A. K. J. Org.
Chem. 2005, 70, 7694.
(5) Miyano, S.; Fukushima, H.; Inagawa, H.; Hashimoto, H.
Bull. Chem. Soc. Jpn. 1986, 59, 3285.
(6) Pal, S.; Mukhopadhyay, J. K.; Ghatak, U. R. J. Org. Chem.
1994, 59, 2687.
(7) Berger, D. M.; Brinberg, G.; DeMorin, F.; Dutia, M.;
Powell, D.; Wang, Y. D. Synthesis 2003, 1712.
(8) Banik, B. K.; Chakraborti, A. K.; Ghatak, U. R. J. Chem.
Res., Synop. 1986, 406; J. Chem. Res., Miniprint 1986, 3391.
(9) Ghatak, U. R.; Chakravarty, J.; Banerjee, A. K. Tetrahedron
1968, 24, 1577.
The crude bromide was immediately dissolved in anhyd benzene
(20 mL) and a solution of TBTH (0.07 mL, 0.26 mmol) and AIBN
(8 mg) in anhyd benzene (10 mL) was added slowly at refluxing
condition over 1 h. Refluxing was continued for another 4 h before
cooling. The solvent was removed and the residue was purified by
column chromatography to give 18 (12 mg, 26%) as a colorless liq-
uid.
IR (neat): 2929, 1474, 754 cm–1.
1H NMR: d = 0.93 (s, 3 H), 1.12 (s, 3 H), 1.17–1.35 (m, 3 H), 1.44
(s, 3 H), 1.39–1.65 (m, 3 H), 1.86 (t, J = 9.5 Hz, 1 H), 2.78 (d, J =
9.5 Hz, 2 H), 7.07–7.20 (m, 4 H); [Lit.3,9 d = 0.93, 1.12, 1.44 (s, 3 ×
3 H)].
13C NMR: d = 18.9 (CH2), 25.6 (CH3), 29.5 (CH3), 30.9 (CH3), 32.1
(C) 33.8 (CH2), 35.1 (CH2), 36.1 (CH2), 45.1 (C), 57.3 (C) 121.3
(CH), 124.4 (CH), 125.9 (CH), 126.0 (CH), 141.3 (C), 154.3 (C).
(10) Chakraborti, A. K.; Basak, A.; Grover, V. J. Org. Chem.
1999, 64, 8014.
(11) (a) Mori, M.; Uozumi, Y.; Kimura, M.; Ban, Y. Tetrahedron
1986, 42, 3793. (b) Maercker, A. Org. React. (N.Y.) 1965,
14, 270.
MS (EI): m/z (%) = 214 (81) [M+], 200, 199 (100), 143, 129.
Anal. Calcd for C16H22: C, 89.65; H, 10.35. Found: C, 89.38; H,
10.27.
1-Methyl-1,2,3,4,9,9a-hexahydrofluorene-1,4a-dicarboxylic
Acid Dimethyl Ester (19)
(12) Link, J. T. Org. React. (N.Y.) 2002, 60, 157; and references
cited therein.
To a stirred solution of 15b (72 mg, 0.25 mmol) in anhyd THF (2
mL) was added LiOH·H2O (12.6 mg, 0.3 mmol) and the reaction
mixture was stirred at r.t. for 30 min. Dimethyl sulfate (48 mL, 0.5
mmol) was added to it and the mixture was heated to reflux for 4 h.
It was cooled and THF was removed. The residue was taken up in
EtOAc (5 mL), washed with H2O and brine, and dried. Removal of
the solvent followed by column chromatography of the residue af-
forded 19 (69 mg, 92%) as a white solid; mp 85–88 °C (Lit.2 mp 89
°C).
(13) Clive, D. L. J.; Wang, J. J. Org. Chem. 2004, 69, 2773.
(14) Konoike, T.; Matsumura, K.; Yorifuji, T.; Shinomoto, S.;
Ide, Y.; Ohya, T. J. Org. Chem. 2002, 67, 7741.
(15) Mukhopadhyaya, J. K.; Pal, S.; Ghatak, U. R. Synth.
Commun. 1995, 25, 1641.
(16) (a) Kocienski, P. J.; Cernigliaro, G.; Feldstein, G. J. Org.
Chem. 1977, 42, 353. (b) Hayashi, H.; Nakanishi, K.;
Brandon, C.; Marmur, J. J. Am. Chem. Soc. 1973, 95, 8749.
(17) Nakamura, E.; Inubushi, T.; Aoki, S.; Machii, D. J. Am.
Chem. Soc. 1991, 113, 8980.
Synthesis 2006, No. 8, 1263–1272 © Thieme Stuttgart · New York