Cyclization of aryllithiums tethered to methylenecycloalkanes: Stereoselective synthesis of 4α-substituted cis-hexahydrofluorenes

Article abstract of DOI:10.1021/jo020593r

The cyclization of an aryllithium tethered to a methylenecycloalkane, generated from 2-(o-bromobenzyl)-1-methylenecycloalkanes 1, 2, and 3 by low-temperature lithium-bromine exchange, has been found to be a kinetically slow but thermodynamically favorable process that proceeds at a convenient rate in an exclusively 5-exo fashion when solutions of the aryllithium in n-heptane-di-n-butyl ether (9:1 v/v) are warmed to 45 °C. The cyclization affords stereoisomerically pure cisfused products (7 and 8) when the methylenecycloalkane is five- or six-membered but it is less stereoselective when the methylenecycloalkane is seven-membered. The ring-closure of the aryllithium derived from 2-(o-bromobenzyl)-1-methylenecyclohexane (2) provides an experimentally convenient route to stereoisomerically pure 4a-substituted cis-hexahydrofluorenes in 60-90% isolated yield.

Full text of DOI:10.1021/jo020593r

Cycliza tion of Ar yllith iu m s Teth er ed to Meth ylen ecycloa lk a n es:
Ster eoselective Syn th esis of 4a -Su bstitu ted
cis-Hexa h yd r oflu or en es
William F. Bailey,* Tahir Daskapan,† and Sriram Rampalli
Department of Chemistry, The University of Connecticut, Storrs, Connecticut 06269-3060
bailey@uconn.edu
Received September 10, 2002
The cyclization of an aryllithium tethered to a methylenecycloalkane, generated from 2-(o-
bromobenzyl)-1-methylenecycloalkanes 1, 2, and 3 by low-temperature lithium-bromine exchange,
has been found to be a kinetically slow but thermodynamically favorable process that proceeds at
a convenient rate in an exclusively 5-exo fashion when solutions of the aryllithium in n-heptane-
di-n-butyl ether (9:1 v/v) are warmed to 45 °C. The cyclization affords stereoisomerically pure cis-
fused products (7 and 8) when the methylenecycloalkane is five- or six-membered but it is less
stereoselective when the methylenecycloalkane is seven-membered. The ring-closure of the
aryllithium derived from 2-(o-bromobenzyl)-1-methylenecyclohexane (2) provides an experimentally
convenient route to stereoisomerically pure 4a-substituted cis-hexahydrofluorenes in 60-90%
isolated yield.
Some time ago, Ghatak and co-workers reported that
cyclization of the aryl radical derived from various 2-(o-
bromobenzyl)-1-methylenecycloalkanes proceeds exclu-
sively in a 6-endo fashion as depicted below.1,2 More
recently, Ishibashi’s group presented convincing evidence
suggesting that formation of the 6-endo products was
actually the result of a rapid 5-exo cyclization followed
by a neophyl rearrangement.3,4 Be that as it may, it
occurred to us that the behavior of the aryllithium
derived from such substrates would provide a rather
stringent test of the scope of the intramolecular cycliza-
tion of olefinic organolithiums.5
It was anticipated that cyclization of an aryllithium
generated from a 2-(o-bromobenzyl)-1-methylenecycloal-
kane would proceed in a 5-exo fashion. What was unclear
at the inception of this study was whether such cycliza-
tion would be more rapid than the myriad of other
processes, such as proton abstraction from solvent or
intramolecular proton transfer, that could consume the
organolithium. Indeed, while quaternary centers have
been constructed by cyclization of various olefinic alky-
llithiums,6 the creation of a quaternary center via cy-
clization of a relatively stable aryllithium to give a less
stable primary alkyllithium appears not to have been
investigated. Herein we report that cyclization of aryl-
lithiums tethered to methylenecycloalkanes is an exclu-
sively 5-exo process that proceeds at a convenient rate
at elevated temperatures. The method provides a expedi-
ent and highly steroselective route to 4a-substituted cis-
hexahydrofluorenes.
Resu lts a n d Discu ssion
The previously reported 2-(o-bromobenzyl)-1-methyl-
enecycloalkanes (1-3)2,3 required for this study were
easily prepared, as illustrated in Scheme 1, by alkylation
of the potassium enolate of the appropriate cycloalkanone
in THF with o-bromobenzyl bromide followed by Wittig
olefination. Authentic samples of the corresponding
2-benzyl-1-methylenecycloalkanes (4-6)2,3 were gener-
† On leave from the Department of Chemistry, Ankara University.
(1) Pal, S.; Mukherjee, M.; Podder, D.; Mukherjee, A. K.; Ghatak,
U. R. J . Chem. Soc., Chem. Commun. 1991, 1591.
(2) Pal, S.; Mukhopadhyaya, J . K.; Ghatak, U. R. J . Org, Chem.
1994, 59, 2687.
(3) Ishibashi, H.; Kobayashi, T.; Nakashima, S.; Tamura, O. J . Org.
Chem. 2000, 65, 9022.
(6) See, for example: (a) Bailey, W. F.; Rossi, K. J . Am. Chem. Soc.
1989, 111, 765. (b) Krief, A.; Barbeaux, P. Synlett 1990, 511. (c) Bailey,
W. F.; Khanolkar, A. D. J . Org. Chem. 1990, 55, 6058. (d) Bailey, W.
F.; Khanolkar, A. D. Tetrahedron 1991, 47, 7727. (e) Bailey, W. F.;
Khanolkar, A. D.; Gavaskar, K.; Ovaska, T. V.; Rossi, K.; Thiel, Y.;
Wiberg, K. B. J . Am. Chem. Soc. 1991, 113, 5720. (f) Cooke, M. P., J r.
J . Org. Chem. 1993, 58, 2910. (g) Coldham, I.; Ferna`ndez, J . C.; Price,
K. N.; Snowden, D. J . J . Org. Chem. 2000, 65, 3788. (h) Deng, K.;
Bensari, A.; Cohen, T. J . Am. Chem. Soc. 2002, 124, 12106.
(4) Ishibashi, H.; Kobayashi, T.; Takamasu, D. Synlett 1999, 1286.
(5) For reviews, see: (a) Bailey, W. F.; Ovaska, T. V. Mechanisms
of Importance in Synthesis. In Advances in Detailed Reaction Mech-
anisms; Coxon, J . M., Ed.; J AI Press: Greenwich, CT, 1994; Vol. 3, pp
251-273. (b) Mealy, M. M.; Bailey, W. F. J . Organomet. Chem. 2002,
646, 59. (c) Clayden, J . Organolithiums: Selectivity for Synthesis;
Pergamon Press: New York, 2002; pp 293-335.
10.1021/jo020593r CCC: $25.00 © 2003 American Chemical Society
Published on Web 01/16/2003
1334
J . Org. Chem. 2003, 68, 1334-1338

Synthesis of 4a-Substituted cis-Hexahydrofluorenes
TABLE 1. Exp lor a tor y Cycliza tion s of Ar yllith iu m
Der ived fr om 2a
SCHEME 1
product ratiosb (% d1)c
temp, time,
entry
1
solvent
°C
min
7
5
n-C5H12-Et2O
(9:1 v/v)
22
60
34 (89)
66 (85)
2
3
4
120
270
30
61 (85)
89 (70)
78 (82)
39 (82)
11 (70)
17d (75)
n-C7H16-MTBE
40
(9:1 v/v)
5
6
45
45
45
45
87 (73)
95 (85)
4e (80)
5 (41)
n-C7H16-n-Bu2O
(9:1 v/v)
ated in virtually quantitative yield from 2-(o-bromoben-
zyl)-1-methylenecycloalkanes, as shown below, by low-
temperature lithium-bromine exchange with tert-butyl-
lithium (t-BuLi)7 followed by quench of the aryllithium
with methanol.
a
The aryllithium was generated at -78 °C by addition of 2.2
equiv of t-BuLi in heptane to a solution of bromide 2 in the
indicated solvent. TMEDA was added at -78 °C, the cooling bath
was then removed, and the mixture was allowed to stand at the
specified temperature for a period of time before the addition of
b
an excess of oxygen-free MeOH or MeOD. Ratios were deter-
mined by capillary GC. c Percent incorporation of deuterium (GC/
d
MS analysis) upon quench with MeOD. Product mixture con-
tained 5% of a C15H20 isomer. e Product mixture contained 9% of
a C15H20 isomer.
isomerization by warming reaction mixtures. The fact
organolithiums readily abstract protons from both ethers10
and TMEDA11 at elevated temperatures is a potential
difficulty with this approach. However, we had previously
observed that the ether solvent, rather than the (presum-
ably) complexed TMEDA, is generally responsible for
protonation when solutions of organolithiums are warmed
above ambient temperature12 and it was anticipated that
the small amount of ether in the solvent system would
lessen the possibility of unwanted protonation.13
The behavior of aryllithiums generated from 2-(o-
bromobenzyl)-1-methylenecycloalkanes was explored in
a series of experiments involving the 2-(o-bromobenzyl)-
1-methylenecyclohexane substrate (2). Initially, the aryl-
lithium was generated at -78 °C by addition of 2.2 molar
equiv of t-BuLi to an approximately 0.1 M solution of
bromide 2 in dry, oxygen-free n-pentane-diethyl ether
(9:1 v/v). Dry TMEDA (2.2 equiv) was then added, and
the organolithium solution was allowed to warm and
stand at room temperature under an atmosphere of argon
for various periods of time. Cursory inspection of the
results of a representative series of such experiments
(Table 1, entries 1-3) reveals that 5-exo cyclization of
the aryllithium derived from 2 is highly stereoselective:
cis-1,2,3,4,4a,9a-hexahydro-4a-methylfluorene8 (7) is the
exclusive cyclic product after quench with MeOH; 2-ben-
zyl-1-methylenecyclohexane (5) constitutes the balance
of the reaction product. The data also indicate that the
cyclization is very slow indeed:9 the isomerization pro-
ceeds to only ∼90% completion when reaction mixtures
are allowed to stand for 4.5 h at room temperature (Table
1, entry 3).
To this end, the aryllithium was generated from 2 at
-78 °C in dry, oxygen-free n-heptane-MTBE (9:1 v/v)
by lithium-bromine exchange, using t-BuLi in n-hep-
tane. Dry TMEDA (2.2 equiv) was then added, and the
organolithium solution was warmed and held at 40-45
°C for 30-45 min under a positive pressure of argon to
effect cyclization. The results of these experiments (Table
1, entries 4 and 5) demonstrate that, as expected, the
isomerization is significantly faster at elevated temper-
ature. Unfortunately, although proton abstraction from
solvent appears minimal, a C15H20 isomer of unknown
structure, possibly formed by methyl transfer from MTBE
to the alkyllithium product at the elevated temperature,10
was noted as a byproduct. The use of di-n-butyl ether in
place of MTBE in the solvent system obviated production
of this byproduct: warming a solution of the aryllithium
in n-heptane-di-n-butyl ether (9:1 v/v) to 45° for 45 min
afforded 95% of isomerically pure 7 (Table 1, entry 6).
Since both the aryllithium and the primary alkyl-
lithium formed upon cyclization appear to be persistent
over the course of these experiments, as adjudged by the
significant incorporation of deuterium upon quench of
reaction mixtures with MeOD (Table 1), it seemed
appropriate to attempt to increase the rate of the sluggish
(10) Wakefield, B. J . The Chemistry of Organolithium Compounds;
Pergamon Press: New York, 1974.
(7) (a) Bailey, W. F.; Punzalan, E. P. J . Org. Chem. 1990, 55, 5405.
(b) Negishi, E.; Swanson, D. R.; Rousset, C. J . J . Org. Chem. 1990, 55,
5404.
(8) Barrow, C. J .; Bright, S. T.; Coxon, J . M.; Steel, P. J . J . Org.
Chem. 1989, 54, 2542.
(9) By way of comparison, the half-time for cyclization of the parent
5-hexenyllithium in the presence of TMEDA is ∼6 min at -30 °C.
See: Bailey, W. F.; Carson, M. W. J . Org. Chem. 1998, 63, 361.
(11) Kohler, F. H.; Hertkorn, N.; Blumel, J . Chem. Ber. 1987, 120,
2081.
(12) Bailey, W. F.; Khanolkar, A. D.; Gavaskar, K. V. J . Am. Chem.
Soc. 1992, 114, 8053.
(13) Since, as noted elsewhere,7 it is necessary to conduct the
lithium-bromine exchange in a solvent system that contains a dialkyl
ether, it is not possible to prepare the aryllithium in good yield in a
pure hydrocarbon solvent.
J . Org. Chem, Vol. 68, No. 4, 2003 1335

Bailey et al.
ylcyclopenta[a]indene3 (8). However, in this instance, the
majority of the reaction product consisted of three
isomeric alkenes: GC/MS analysis revealed the presence
of 2-benzyl-1-methylenecyclopentane (4) as a minor
product (13%) and two trisubstituted alkenes (42%) that
were not further characterized. Apparently, under the
conditions used to drive the cyclization of the aryllithium
derived from 1, abstraction of an allylic proton from the
substrate to give an allyllithium, which finds ample
literature precedent,10 effectively competes with the ring-
closure.
SCHEME 2
TABLE 2. P r ep a r a tion of 4a -Su bstitu ted
cis-Hexa h yd r oflu or en es (Sch em e 2)a
entry
E
E-
yield,b %
1
2
3
4
5
CH3OH
D2O
Cl3CCCl3
PhSSPh
CH2O
H
D
Cl
SPh
91
78c
65
70
62
CH2OH
As noted above, 5-exo cyclization of the aryllithiums
generated from bromides 1 and 2 leads exclusively to cis-
fused products 7 and 8. This stereochemical outcome is
undoubtedly enforced by the fairly rigid geometry of the
transition state for the ring-closure14 and the conforma-
tional constraints of these substrates. Thus, as indicated
below, coordination of the lithium atom with the meth-
ylene π-bond exocyclic to a tethered cyclopentane or
cyclohexane ring can only occur on the face that is syn-
disposed to the aryl substituent.
a
The aryllithium was generated at -78 °C by addition of 2.2
equiv of t-BuLi in n-heptane to a solution of bromide 2 in
n-heptane-di-n-butyl ether (9:1 v/v), TMEDA (2.2 equiv) was
added at -78 °C, the cooling bath was then removed, and the
mixture was allowed to warm and stand at +45 °C for 45 min
b
before the addition of an excess of the electrophile. Isolated yield
of chromatographically pure product. c Determined by GC/MS
analysis of the product.
Given the preliminaries outlined above, conditions for
the preparation of 4a-substituted cis-hexahydrofluorenes
were readily established (Scheme 2). Thus, addition of
2.2 molar equiv of t-BuLi under argon at -78 °C to a 0.1
M solution of 2 in scrupulously dry and oxygen-free
n-heptane-di-n-butyl ether (9:1 v/v) generated the aryl-
lithium. TMEDA (2.2 equiv) was then added and the
reaction mixture was allowed to warm to room temper-
ature, and was then heated in an oil-bath under a
positive pressure of dry argon at 45 °C for 45 min to
complete the ring-closure. As demonstrated by the results
presented in Table 2, the 5-exo cyclization product may
be trapped by addition of any of a variety of electrophiles
to give stereoisomerically pure 4a-substituted cis-hexahy-
drofluorenes in 60-90% isolated yield. It might be noted
that product isolation is a simple matter since the only
other components of the reaction mixture are fairly minor
quantities of hydrocarbons generated by inadvertent
quench of the organolithiums by proton abstraction from
solvent or adventitious moisture.
In light of the inherent conformational flexibility of the
2-(o-bromobenzyl)-1-methylenecycloheptane (3) substrate,
it is perhaps not surprising that ring-closure of the
corresponding aryllithium is much less stereoselective
than is the analogous cyclization of an aryllithium
tethered to a five- or six-membered ring. Indeed, as
illustrated below, the aryllithium prepared from 3 by
lithium-bromine exchange cyclizes readily at +45 °C in
the presence of TMEDA to give octahydro-5a-methylcy-
(14) It should be noted that the lithium atom is intimately involved
in the cycloisomerization of unsaturated organolithiums and 5-hex-
enyllithium is unique among the 5-hexenylalkalis in it ability to
undergo facile cyclization; see: Bailey, W. F.; Punzalan, E. R. J . Am.
Chem. Soc. 1994, 116, 6577. Molecular orbital calculations indicate
the stereochemical course of these formally anionic cyclizations is a
consequence of a transition state for the process in which the lithium
atom is coordinated to the remote π-bond.6d Indeed, intramolecular
coordination of the lithium atom with the remote π-bond in the ground
state of 5-hexenyllithium has been experimentally confirmed; see:
Ro¨lle, T.; Hoffmann, R. W. J . Chem. Soc., Perkin Trans. 2 1995, 1953.
The aryllithiums derived from the remaining 2-(o-
bromobenzyl)-1-methylenecycloalkanes (1 and 3) were
somewhat less well behaved when subjected to the
reaction conditions described above. Thus, as shown
below, the methylenecyclopentane substrate generated
from 1 was found to cyclize in an exclusively 5-exo fashion
to give, following methanol quench, 45% (36% isolated
yield) of stereoisomerically pure cis-tetrahydro-3a-meth-
1336 J . Org. Chem., Vol. 68, No. 4, 2003

Synthesis of 4a-Substituted cis-Hexahydrofluorenes
bromobenzyl)cycloheptanone as detailed in the Supporting
Information.
clohepta[a]indene (9) in 90% isolated yield as an ap-
proximately 55:45 mixture of cis-9 and trans-9, respec-
tively. Comparison of the 1H and 13C NMR spectra of the
product mixture with those reported by Ishibashi for the
cis- and trans-isomers of 9 confirmed the stereochemical
assignment.3
2-(o-Br om oben zyl)-1-m eth ylen ecyclopen tan e (1). A sus-
pension of 8.20 g (23.0 mmol) of methyl(triphenyl)phospho-
nium bromide and 2.58 g (23.0 mmol) of potassium tert-
butoxide in 75 mL of anhydrous THF was stirred at room
temperature for 1 h before addition of a solution of 4.83 g (19.2
mmol) of 2-(o-bromobenzyl)cyclopentanone in 25 mL of anhy-
drous THF. The reaction mixture was stirred at room tem-
perature for 7 h, solvent was then removed by rotary evapo-
ration, the viscous residue was triturated with pentane, and
the suspension was eluted with pentane from a short column
of silica gel. Concentration of the eluent afforded 2.10 g (44%)
of the known2 title compound as a viscous oil: 1H NMR (CDCl3)
δ 1.41-1.44 (m, 1 H), 1.55-1.60 (m, 1 H), 1.71-1.80 (m, 2 H),
2.41-2.44 (m, 2 H), 2.60 (dd, J ) 13.4, 10.0 Hz, 1 H), 2.80 (m,
1 H), 3.11 (dd, J ) 13.4, 5.0 Hz, 1 H), 4.90 (apparent s, 1 H),
4.98 (apparent s, 1 H), 7.06 (td, J ) 7.9, 3.8 Hz, 1 H), 7.20-
7.23 (m, 2 H), 7.56 (d, J ) 7.9 Hz, 1 H); 13C NMR (CDCl3) δ
24.09, 32.46, 33.23, 41.00, 44.00, 105.07, 124.84, 127.15,
127.58, 131.23, 132.82, 140.75, 155.82. An analogous procedure
was used to prepare 2-(o-bromobenzyl)-1-methylenecyclohex-
ane (2) and 2-(o-bromobenzyl)-1-methylenecycloheptane (3) as
detailed in the Supporting Information.
2-Ben zyl-1-m eth ylen ecyclop en ta n e (4). A solution of 162
mg (0.65 mmol) of 2-(o-bromobenzyl)-1-methylenecyclopentane
(1) in 5.8 mL of dry n-pentane and 0.7 mL of diethyl ether
was cooled to -78 °C (dry ice-acetone) under an atmosphere
of dry and oxygen-free argon and 1.09 mL of a 2.02 M solution
of t-BuLi in n-heptane (2.20 mmol) was added dropwise by
syringe. The mixture was stirred at -78 °C for 15 min, 1 mL
of oxygen-free methanol was added, and the flask was allowed
to warm to room temperature. The reaction mixture was
diluted with ether, washed with water, dried (MgSO4), and
concentrated by careful rotary evaporation to give 105 mg
(95%) of the known hydrocarbon2 as a colorless oil: 1H NMR
(CDCl3) δ 1.31-1.37 (m, 3 H), 1.51-1.57 (m, 1 H), 1.72-1.81
(m, 2 H), 2.35-2.42 (m, 2 H), 2.48 (dd, J ) 13.4, 9.8 Hz, 1H),
2.68 (m, 1 H), 2.98 (dd, J ) 13.4, 5.1 Hz, 1 H), 4.88 (apparent
s, 1 H), 4.97 (apparent s, 1 H), 7.21-7.34 (m, 5 H). An
analogous procedure was used to prepare 2-benzyl-1-methyl-
enecyclohexane (5) and 2-benzyl-1-methylenecycloheptane (6)
as detailed in the Supporting Information.
Gen er a l P r oced u r e for th e P r ep a r a tion of 4a -Su bsti-
tu ted cis-Hexa h yd r oflu or en es (Sch em e 2). An approxi-
mately 0.1 M solution of 2-(o-bromobenzyl)-1-methylenecyclo-
hexane (2) in anhydrous n-heptane-di-n-butyl ether (9:1 v/v)
was cooled to -78 °C under argon and a 2.2 molar equiv of
t-BuLi in heptane was added dropwise via syringe. The
reaction mixture was stirred for an additional 15 min at -78
°C, 2.2 molar equiv of dry, deoxygenated TMEDA was added
via syringe, the cooling bath was removed, and the pale-yellow
reaction mixture was allowed to warm to room temperature.
The flask was transferred to an oil bath that had been warmed
to +45 °C and the mixture was stirred, under a positive
pressure of argon, for 45 min. The reaction mixture was then
recooled to -78 °C, an excess (typically 1.1 equiv) of the
appropriate electrophile (Table 2) was added, and the resulting
mixture was then allowed to warm to room temperature and
worked up in the usual manner.
cis-1,2,3,4,4a,9a-Hexah ydr o-4a-m eth ylflu or en e (7, Table
2, en tr y 1). A solution of (cis-hexahydrofluorenyl-4a-methyl)-
lithium, prepared from 265 mg (1.00 mmol) of 2-(o-bromoben-
zyl)-1-methylenecyclohexane (2) as described above, was
quenched with dry, oxygen-free methanol. The product mixture
was diluted with ether, washed with several portions of water,
dried (MgSO4), and concentrated under reduced pressure. The
residue was purified by flash chromatography on silica gel
(pentane, Rf 0.40) and the eluent was washed with small
portions of cold, concentrated sulfuric acid until the acid layer
remained clear to remove traces of 2-benzyl-1-methylenecy-
clohexane (5). After being washed with water and 10% aqueous
sodium bicarbonate, the solution was dried (MgSO4) and
In summary, cyclization of an aryllithium tethered to
a 2-(o-bromobenzyl)-1-methylenecycloalkane is a kineti-
cally slow but thermodynamically favorable process that
proceeds in an exclusively 5-exo fashion to afford stere-
oisomerically pure cis-fused product (7 and 8) when the
methylenecycloalkane is five- or six-membered, but it is
less stereoselective when the methylenecycloalkane is
seven-membered. As demonstrated by the results sum-
marized in Table 1, this simple methodology provides an
experimentally convenient and highly steroselective route
to 4a-substituted cis-hexahydrofluorenes.
Exp er im en ta l Section
Gen er a l P r oced u r es. The concentration of commercial
solutions of t-BuLi in n-heptane was determined immediately
prior to use by the method of Watson and Eastham.15 Di-n-
butyl ether and diethyl ether were freshly distilled under dry
nitrogen from sodium/benzophenone; n-heptane was distilled
from sodium/benzophenone/tetraglyme; N,N,N′,N′-tetrameth-
ylethylenediamine (TMEDA) was purified by distillation under
nitrogen from calcium hydride. All bromides used to prepare
organolithiums were rendered essentially oxygen-free before
use by bubbling dry, deoxygenated argon gas through the neat
liquid for at least 5 min before use.
2-(o-Br om oben zyl)cyclop en ta n on e. A solution of KH-
MDS in 60 mL of THF, prepared under nitrogen at room
temperature from 2.00 g (0.050 mol) of oil-free potassium
hydride and 13.20 mL (0.062 mol) of 1,1,1,3,3,3-hexamethyl-
disilazane, was cooled to -78 °C, 3.50 g (0.042 mol) of freshly
distilled cyclopentanone was added, and the mixture was
stirred at -78 °C for 1 h before dropwise addition of a solution
of 15.6 g (0.062 mol) of o-bromobenzyl bromide in 30 mL of
anhydrous THF. The reaction mixture was stirred for a further
20 min at -78 °C and then allowed to warm and stir at room
temperature overnight before addition of 150 mL of 10%
aqueous HCl. The organic layer was separated, the aqueous
layer was extracted with ether, and the combined organic
layers were washed with water and brine, dried (Na2SO4), and
concentrated by rotary evaporation. The residue was chro-
matographed on silica gel (10% EtOAc-hexane, Rf 0.30) to give
4.83 g (46%) of the known ketone2 as a colorless oil: 1H NMR
(CDCl3) δ 1.55-1.74 (m, 2 H), 1.93-2.12 (m, 3 H), 2.30-2.36
(m, 2 H), 2.51 (dd, J ) 13.7, 9.5 Hz, 1 H), 3.13 (dd, J ) 13.7,
3.8 Hz, 1 H), 7.15-7.34 (m, 4 H). An analogous procedure was
used to prepare 2-(o-bromobenzyl)cyclohexanone and 2-(o-
(15) Watson, S. C.; Eastham, J . F. J . Organomet. Chem. 1967, 9,
165.
J . Org. Chem, Vol. 68, No. 4, 2003 1337

Bailey et al.
concentrated to afford 170 mg (91%) of the known8 title
compound: 1H NMR (CDCl3) δ 1.34 (3H, s), 1.37-1.60 (m, 6
H), 1.72-1.79 (m, 2 H), 2.16 (quintet, J ) 6.4 Hz, 1 H), 2.73
(dd, J ) 15.4, 7.19 Hz, 1 H), 2.96 (dd, J ) 15.4, 7.0 Hz, 1 H),
7.18-7.36 (m, 4 H); 13C NMR (CDCl3) δ 22.20, 22.90, 25.74,
26.82, 35.40, 35.64, 45.30, 46.33, 121.62, 125.21, 125.93,
126.14, 142.40, 152.66. The deuterated material (Table 2, entry
2) was prepared in an analogous fashion, using D2O to quench
the product organolithium.
cis-1,2,3,4,4a ,9a -H exa h yd r o-4a -(ch lor om et h yl)flu or -
en e (Ta ble 2, en tr y 3). A solution of (cis-hexahydrofluorenyl-
4a-methyl)lithium, prepared as described above from 314 mg
(1.18 mmol) of 2-(o-bromobenzyl)-1-methylenecyclohexane (2),
was recooled to -78 °C and a solution of 308 mg (1.30 mmol)
of hexachloroethane in 5.0 mL of dry pentane was added. The
reaction mixture was allowed to warm to room temperature,
diluted with ether, washed with several portions of water,
dried (MgSO4), and concentrated under reduced pressure. The
residue was purified by flash chromatography on silica gel
(pentane, Rf 0.27) to give 170 mg (65%) of the known3 title
compound: 1H NMR (CDCl3) δ 1.15-1.22 (m, 2 H), 1.27-1.33
(m, 1 H), 1.48-1.56 (m, 2 H), 1.69-1.74 (m, 1 H), 1.83 (ddd, J
) 14.3, 10.6, 3.8 Hz, 1 H), 1.95-2.00 (m, 1 H), 2.42-2.49 (m,
1 H), 2.50 (dd, J ) 15.5, 3.5 Hz, 1 H), 3.02 (dd, J ) 15.5, 6.4
Hz, 1 H), 3.52 (AB-pattern, J AB ) 11.0 Hz, 2 H), 7.19-7.26
(m, 4 H); 13C NMR (CDCl3) δ 21.91, 23.60, 28.50, 30.05, 36.40,
41.41, 51.22, 52.32, 123.20, 125.85, 126.26, 127.20, 143.10,
146.16.
cis-1,2,3,4,4a ,9a -H exa h yd r o-4a -((p h en ylt h io)m et h yl)-
flu or en e (Ta ble 2, en tr y 4). A solution of (cis-hexahydrof-
luorenyl-4a-methyl)lithium, prepared as described above from
306 mg (1.16 mmol) of 2-(o-bromobenzyl)-1-methylenecyclo-
hexane (2), was recooled to -78 °C and a solution of 278 mg
(1.27 mmol) of diphenyl disulfide in 6.0 mL of dry pentane was
added. The reaction mixture was allowed to warm to room
temperature, diluted with ether, washed with several portions
of water, dried (MgSO4), and concentrated under reduced
pressure. The residue was purified by flash chromatography
on silica gel (pentane to remove excess (PhS)2 (Rf 0.05) followed
by 2% EtOAc-hexane, Rf 0.55) to give 238 mg (70%) of the
known3 title compound: 1H NMR (CDCl3) δ 1.17-1.27 (m, 2
H), 1.33-1.36 (m, 1 H), 1.46-1.54 (m, 2 H), 1.67-1.71 (m, 1
H), 1.76 (ddd, J ) 13.9, 10.3, 3.7 Hz, 1 H), 1.97-2.02 (m, 1 H),
2.48-2.51 (m, 1 H), 2.52 (dd, J ) 14.9, 4.1 Hz, 1 H), 3.00 (dd,
J ) 15.1, 6.4 Hz, 1 H), 3.14 (AB-pattern, J AB ) 12.4 Hz, 2 H),
7.13-7.23 (m, 9 H); 13C NMR (CDCl3) δ 22.12, 23.51, 28.24,
32.30, 36.40, 42.90, 44.33, 50.53, 122.90, 125.60, 125.70,
126.20, 126.80, 128.75, 129.10, 138.25, 142.83, 148.11.
cis-2-(1,2,3,4,4a ,9a -H exa h yd r oflu or en -4a -yl)et h a n ol
(Ta ble 2, en tr y 5). A solution of (cis-hexahydrofluorenyl-4a-
methyl)lithium, prepared as described above from 238 mg (0.90
mmol) of 2-(o-bromobenzyl)-1-methylenecyclohexane (2), was
recooled to -78 °C and a stream of formaldehyde gas (gener-
ated by heating dry paraformaldehyde and passing the gas
through a tube filled with dry CaCl2) was bubbled through the
reaction mixture for approximately 3 min. The reaction
mixture was allowed to warm to room temperature, diluted
with ether, washed with several portions of water, dried
(MgSO4), and concentrated under reduced pressure. The
residue was purified by flash chromatography on silica gel
(60% EtOAc-hexane, Rf 0.27) to give 120 mg (62%) of the
known3 alcohol: 1H NMR (CDCl3) δ 1.21-37 (m, 4 H), 1.41-
1.52 (m, 3 H), 1.66-1.69 (m, 1 H), 1.77 (ddd, J ) 14.0, 8.9, 6.1
Hz, 1 H), 1.77-1.88 (m, 1 H), 1.96-2.01 (ddd, J ) 14.0, 8.9,
5.84 Hz, 1 H), 2.20 (br quintet, J ) 6.3 Hz, 1 H), 2.55 (dd, J )
15.5, 5.1 Hz, 1 H), 2.98 (dd, J ) 15.5, 6.7 Hz, 1 H), 3.54 (ddd,
J ) 10.2, 9.06, 5.9 Hz, 1 H), 3.62 (ddd, J ) 10.2, 9.06, 6.2 Hz,
1 H), 7.09-7.3 (m, 3 H), 7.36 (br d, J ) 6.3 Hz, 1 H); 13C NMR
(CDCl3) δ 22.00, 23.20, 27.65, 33.85, 36.16, 41.00, 44.00, 48.12,
59.86, 122.46, 125.70, 126.03, 126.30, 142.97, 149.30.
and 1.0 mL of di-n-butyl ether was cooled to -78 °C under an
atmosphere of dry, oxygen-free argon and 1.20 mL of a 2.02
M solution of t-BuLi in n-heptane (2.42 mmol) was added
dropwise by syringe. The reaction mixture was stirred for an
additional 15 min at -78 °C, 256 mg (2.20 mmol) of dry,
deoxygenated TMEDA was added via syringe, the cooling bath
was removed, and the pale-yellow reaction mixture was
allowed to warm to room temperature. The flask was trans-
ferred to an oil bath that had been warmed to +45 °C and the
mixture was stirred, under a positive pressure of argon, for
45 min. The reaction mixture was quenched with MeOH and
then allowed to cool to room temperature. The solution was
diluted with ether, washed with several portions of water, and
dried (MgSO4). GC/MS analysis [25-m × 0.2-mm × 0.33-µm
cross-linked phenyl methyl (5%) silicone capillary column] of
the crude reaction mixture revealed the presence of the title
compound (vide infra, 45%) as well as 2-benzyl-1-methylenecy-
clopentane (4; 13%) and two isomeric alkenes (42%) that were
not further characterized. The solution was concentrated at
reduced pressure, the residue was purified by flash chroma-
tography on silica gel (pentane, Rf 0.39), and the eluent was
washed with small portions of cold, concentrated sulfuric acid
until the acid layer remained clear to remove traces of alkenes.
After being washed with water and 10% aqueous sodium
bicarbonate, the solution was dried (MgSO4) and concentrated
to afford 67.0 mg (36%) of the known3 title compound: 1H NMR
(CDCl3) δ 1.34 (s, 3 H), 1.40-1.46 (m, 2 H), 1.60-1.63 (m, 1
H), 1.69-1.76 (m, 1 H), 1.89-2.00 (m, 2 H), 2.37 (m, 1 H), 2.61
(dd, J ) 16.6, 2.9 Hz, 1 H), 3.21 (dd, J ) 16.6, 8.8 Hz, 1 H),
7.14-7.26 (m, 4 H); 13C NMR (CDCl3) δ 26.20, 29.40, 35.23,
38.60, 42.00, 50.10, 56.50, 123.12, 124.44, 126.22, 126.61,
142.71, 152.15.
cis- a n d tr a n s-1,2,3,4,5,5a ,10,10a -Octa h yd r o-5a -m eth -
ylcycloh ep ta [a ]in d en e (9). A solution of 418 mg (1.50 mmol)
of 2-(o-bromobenzyl)-1-methylenecycloheptane (3) in 13.5 mL
of dry n-hexane and 1.5 mL of di-n-butyl ether was cooled to
-78 °C under an atmosphere of dry, oxygen-free argon and
1.64 mL of a 2.02 M solution of t-BuLi in n-heptane (3.30
mmol) was added dropwise by syringe. The reaction mixture
was stirred for an additional 15 min at -78 °C, 384 mg (3.30
mmol) of dry, deoxygenated TMEDA was added via syringe,
the cooling bath was removed, and the pale-yellow reaction
mixture was allowed to warm to room temperature. The flask
was transferred to an oil bath that had been warmed to +45
°C and the mixture was stirred, under a positive pressure of
argon, for 45 min. The reaction mixture was worked up as
described above for the preparation of 8 to give 270 mg (90%)
of the previously reported3 title compounds as an approxi-
mately 1.2:1.0 mixture of cis- and trans-isomers, respec-
tively: 1H NMR (CDCl3) [mixture of isomers] δ 1.07 (s), 1.25
(s), 1.3-1.97 (m), 2.2-2.24 (m), 2.40-2.50 (m), 2.61-2.7 (m),
2.81 (dd, J ) 15.3, 7.5 Hz), 3.23 (dd, J ) 16.3, 9.1 Hz), 7.01-
7.2 (m); 13C NMR (CDCl3) [cis-9] δ 24.23, 28.50, 30.10, 31.33,
32.90, 39.10, 39.30, 48.20, 51.00, 122.81, 124.20, 126.12,
126.35, 141.83, 152.81; [trans-9] δ 20.20, 26.25, 26.62, 26.90,
27.80, 38.03, 40.70, 49.10, 50.56, 121.92, 124.06, 126.00,
126.30, 141.90, 155.07.
Ack n ow led gm en t . We are grateful to Dr. J ames
Schwindeman of FMC, Lithium Division, for a generous
gift of t-BuLi in heptane. This work was supported by
a grant from Procter & Gamble Pharmaceuticals, Ma-
son, Ohio. T.D. thanks the Scientific and Technical
Research Council of Turkey (TUBITAK-NATO) for
grant support.
Su p p or tin g In for m a tion Ava ila ble: Preparation and
characterization of compounds 2, 3, 5, and 6. This material is
available free of charge via the Internet at http://pubs.acs.org.
cis-1,2,3,3a ,8,8a -Tetr a h yd r o-3a -m eth ylcyclop en ta [a ]in -
d en e (8). A solution of 274 mg (1.09 mmol) of 2-(o-bromoben-
zyl)-1-methylenecyclopentane (1) in 9.0 mL of dry n-heptane
J O020593R
1338 J . Org. Chem., Vol. 68, No. 4, 2003