Diastereomeric enols and enol derivatives of 8-fluoro-5,11-dihydro-10H- dibenzo[a,d]cyclohepten-10-one with a chiral 11-substituent

Article abstract of DOI:10.1002/ejoc.200500796

Aldol condensation of 8-fluoro-5,11-dihydro-10H-dibenzo[a,d]cyclohepten-10- one and (4S)-2,2-dimethyl-1,3-dioxolane-4-carbaldehyde provides access to the corresponding (E,Z)-α,β-unsaturated ketones with a (4R)-chiral 11-substituent. Subsequent hydrogenation affords a mixture of (11R)/ (11S)-epimeric ketones, which undergoes base-catalysed equilibration resulting in selective crystallisation of the (11R) epimer. The enol intermediate and acyclic enol derivatives are shown to exist as two slowly interconverting conformers with a high inversion barrier of the 10,11-disubstituted ring. Wiley-VCH Verlag GmbH & Co. KGaA, 2006.

Full text of DOI:10.1002/ejoc.200500796

FULL PAPER
DOI: 10.1002/ejoc.200500796
Diastereomeric Enols and Enol Derivatives of 8-Fluoro-5,11-dihydro-10H-
dibenzo[a,d]cyclohepten-10-one with a Chiral 11-Substituent
Frans Compernolle,*[a] Suzanne Toppet,[a] Thierry Brossette,[a] Hua Mao,[a]
Mohamed Koukni,[a] Tomasz Kozlecki,[a] Bart Medaer,[b] Michel Guillaume,[b]
Yolande Lang,[b] Stef Leurs,[b] and Georges J. Hoornaert*[a]
Keywords: Aldol reactions / Conformation analysis / Enols / Fused-ring systems / Hydrogenation
Aldol condensation of 8-fluoro-5,11-dihydro-10H-dibenzo-
equilibration resulting in selective crystallisation of the (11R)
[a,d]cyclohepten-10-one and (4S)-2,2-dimethyl-1,3-dioxol- epimer. The enol intermediate and acyclic enol derivatives
ane-4-carbaldehyde provides access to the corresponding
(E,Z)-α,β-unsaturated ketones with a (4R)-chiral 11-substitu-
ent. Subsequent hydrogenation affords a mixture of (11R)/
(11S)-epimeric ketones, which undergoes base-catalysed
are shown to exist as two slowly interconverting conformers
with a high inversion barrier of the 10,11-disubstituted ring.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2006)
Introduction
trans-Fused hydrofuran compounds of type 1 were re-
cently found to exhibit potent activity in the central nervous
system.[1] Racemic compounds 1 can be accessed by ring
opening of the ( )-2-fluoro-10,11-epoxide 2 with allyl- or
propargylmagnesium halides and further elaboration of the
trans-disposed alcohol products (Scheme 1).[2]
We also envisaged a homochiral approach starting with
aldol condensation of ketone 3 and either (4R)- or (4S)-2,2-
dimethyl-1,3-dioxolane-4-carbaldehyde to form the corre-
sponding unsaturated ketone 4. The stereogenic centre lo-
cated in the acetal-protected propanediol side-chain may
serve to control the two new centres generated upon re-
duction of the unsaturated ketone moiety and subsequent
ring closure to form the tetrahydrofuran ring.
Herein we describe our results with regard to the aldol
condensation of 3 and subsequent reduction of the unsatu-
rated ketone 4. The resulting epimeric ketones 5 intercon-
vert readily via their common enol intermediate, which can
be directly observed by NMR spectroscopy. The NMR
spectra, however, reveal the existence of two enolic forms
instead of one. To elucidate the nature of this phenomenon
various enol ether and enol ester models of enolised ketone
5 were submitted to conformational analysis by NMR spec-
troscopy and model calculations. This analysis revealed the
existence of a high inversion barrier for the 5H-dibenzo-
[a,d]cycloheptene ring system of the acyclic enol derivatives.
Scheme 1.
Some previous studies have already dealt with the non-
planarity of 5H-dibenzo[a,d]cycloheptene derivatives and
the thermodynamic parameters relevant to ring inver-
sion.[3,4]
[a] Laboratorium voor Organische Synthese, Department of
Chemistry, University of Leuven,
Results and Discussion
Celestijnenlaan 200F, 3001 Leuven-Heverlee, Belgium
Fax: +32-16-327-990
Starting ketone 3 was accessed by applying a reaction
sequence similar to that used for the analogous 8-chloro
ketone,[5,6] i.e. Friedel–Crafts reaction of fluorobenzene and
E-mail: frans.compernolle@chem.kuleuven.ac.be
[b] Johnson & Johnson Pharmaceutical Research & Development,
Turnhoutseweg 30, 2340 Beerse, Belgium
1586
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 1586–1592

Derivatives of 8-Fluoro-5,11-dihydro-10H-dibenzo[a,d]cyclohepten-10-one
FULL PAPER
phthalic anhydride, reduction and chain extension of the the hydrogenation in isopropyl alcohol by TLC or HPLC,
resulting keto acid, and final acid-catalysed cyclisation. it was found to proceed by formation of a long-lived, polar
Both the (4ЈR)-α,β-unsaturated ketone 4 (Scheme 2) and intermediate, presumably the enol form resulting from 1,4-
its (4ЈS) enantiomer were obtained by aldol condensation addition. This intermediate was not observed when triethyl-
of ketone 3 with the appropriate precursor (4S)-2,2-di- amine was added to the hydrogenation medium. The epi-
methyl-1,3-dioxolane-4-carbaldehyde (6)[7–10] or its (4R) an- meric ketones 5a and 5b could be separated by preparative
alogue.[11,12] The aldol reaction was carried out in THF HPLC but were found to interconvert readily, for example
using tBuOK as a base and MgBr2 as a co-reagent, which upon treatment with triethylamine. Finally, this epimer-
led to complete conversion of the initial aldol product into isation process could be used to our advantage as the (11R)
the dehydrated ketone 4. In contrast, only partial dehy- epimer 5a was found to crystallise selectively under base-
dration of the initial aldol product was observed when catalysed equilibration conditions (isopropyl alcohol con-
MgBr2 was omitted. Ketone 4 was formed as an approxi- taining triethylamine).
mate 9:1 mixture of (E)- and (Z)-isomers that could be sep-
This enolisation/epimerisation process is of crucial im-
arated by column chromatography. The assignment of the portance for the diastereoselectivity of the synthetic se-
structures was based on the characteristic coupling values quence leading to target compounds of type 1, and in this
observed for the carbonyl C-10 atom in the 1H-coupled 13
NMR spectrum. This carbon atom displays two JC,H enol intermediate. Thus, when 5a,b was treated with tBuOK
C
regard we were intrigued by the observation of a long-lived
3
couplings, one with the aromatic H-9 and the other with in THF for 5 min followed by addition of acetic acid
4
the vinylic proton, and a JC,F coupling with the F atom. (1 equiv.) and immediate TLC analysis, the enol was de-
3
4
While the values of JC,H9 and JC,F are similar for both tected as a transient polar component that quickly disap-
3
isomers, those for JC,H are very different [10 Hz for the peared from the THF solution. However, in contrast to the
vinyl
(Z)-isomer and 5 Hz for the (E)-isomer (Figure 1)].
exclusive generation of the ketone tautomers in less polar
solvents, H NMR analysis of epimeric ketones 5a or 5b in
1
[D6]dimethyl sulfoxide revealed partial conversion into two
enol components (ratio 1:1). After 15 min, the relative
amount of these enols was 25%, and after 1 d, a 33:27:20:20
tautomeric equilibrium containing 60% of ketones 5a,b and
40% of enol forms was established.
The structure of the isomeric enol forms was elucidated
by comparing their NMR spectroscopic data with those of
the corresponding enol acetate 7 and methoxymethyl enol
ether 8 (prepared by acetylation and O-alkylation of 5a,b).
The NMR spectra of 7 and 8 also reveal the existence of
two isomeric components (ratio ca. 1:1), similar to the eno-
lic forms of 5. In the 13C NMR spectra, this structural rela-
tionship clearly appears from the similar double signals and
chemical-shift values found for C-10 and C-11 (Table 1).
For comparison purposes, Table 1 also lists the chemical-
shift values of the single signals observed for C-10 and C-
11 in the spectra of the cyclic enol ether 9, enol acetates 10
and 11, and the unsubstituted cycloalkene 12. Cyclic enol
ether 9 was obtained by acid hydrolysis of 5a,b while the
11-allyl and 11-propargyl compounds 10 and 11, respec-
tively, were derived by PCC and Swern oxidation of the
corresponding 10-alcohol derivatives,[1,2] followed by treat-
ment with Ac2O and DMAP.
Scheme 2.
1H NMR analysis further revealed different geminal
coupling constants for the 5-methylene protons of ketone
forms 5a,b (–16 Hz) and the enolic species (–13 Hz); the
latter value was also observed for enol acetate 10 and di-
benzocycloheptatriene 12 (measured at –65 °C). The magni-
tude of these geminal couplings can be related to the dihe-
dral angle, Φ, between one of the H-C-5 linkages and the
1
Figure 1. Characteristic coupling constants in the H-coupled 13C
NMR spectrum of (E)- and (Z)-isomers 4.
Hydrogenation of 4 in the presence of Pd/C as a catalyst π-lobes on the adjacent benzene rings, as exemplified by the
2
afforded a mixture of the epimeric ketones 5a,b in a rather large J value reported for planar fluorene (–22.3 Hz; Φ =
invariant ratio of about 3:2 (86% yield). This ratio could 30°) and the smaller values for other, non-planar systems
2
2
not be changed appreciably by varying the solvent (MeOH, (minimal J value for Φ = 90°).[13,14] The lower J values
EtOH, iPrOH, toluene, THF, EtOAc). When monitoring found for enol acetate 10 and cycloalkene 12 (–13 Hz) and
Eur. J. Org. Chem. 2006, 1586–1592
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1587

F. Compernolle, G. J. Hoornaert et al.
FULL PAPER
These activation parameters reflect the growing barrier
to ring inversion with increasing substitution at positions
C-10 and C-11 of the cycloheptatriene ring moiety (ca.
18 kcalmol–1 for the acyclic enol derivatives 7 and 8). Inter-
estingly, no splitting of signals was apparent in the NMR
spectra of cyclic enol ether 9 at room temperature. For ex-
ample, the signals for the geminal protons H-5 appear as a
simple AB quadruplet, which can be related to the ste-
reocentre in the dihydrofuran ring. However, at –65 °C in
Table 1. 13C NMR chemical-shift values of C-10 and C-11 (CDCl3,
25 °C).
1
CD2Cl2 split signal patterns were observed in both the H
and 13C NMR spectra, again revealing two diastereomeric
conformers (ratio ca. 1:1). In this case the barrier to ring
inversion (11 kcalmol–1) could be determined from the co-
alescence temperature (248 K) observed for one pair of ge-
minal protons in the hydrofuran ring moiety. Clearly, equili-
bration of the two invertomers is much faster for the cyclic
enol ether 9 than for the acyclic analogues 7 and 8. Hence,
inversion of the 5H-dibenzo[a,d]cycloheptene ring system in
the latter compounds is impeded by the substituents in po-
sitions 10 and 11.
5a,b (keto)
5 (enol)
7
8
C-10 (d)[a]
C-11 (s)
193.5
193.2
50.0
148.2
148.2
115.0
114.6
144.5
144.2
128.1
127.6
149.8
149.7
125.6
124.7
49.8
9
10
11
12
C-10 (d)[a]
C-11 (s)
150.9[b]
143.8
129.6
144.5
126.4
130.5
132.7
114.1[b]
[a] Doublet due to coupling with 8-F. [b] Split values at –65 °C
(CD2Cl2: δ = 150.1, 149.6; 113.9, 113.6 ppm).
The 11-allyl compound 10 also displays a high inversion
barrier (17 kcalmol–1), which was determined by measuring
the coalescence temperature (343 K) for conversion of the
two AB systems corresponding to CH2-5 and the allyl
methylene group into an A2 pattern. This barrier is again
much higher than that determined for the 10,11-unsubsti-
tuted compound 12 (10 kcalmol–1) and the inversion bar-
rier reported for the non-planar, saddle-shaped monocyclic
cycloheptatriene (6 kcalmol–1).[19–22]
Conformational modelling of enol acetates 7, 10 and 11
has revealed a preferred conformation with an endo orienta-
tion of the R group attached to the methylene group α to
C-11, i.e. this R group points towards the hollow side of
the 5H-dibenzo[a,d]cycloheptene ring, away from the axial
H atom at C-5 (Figure 2). This orientation also minimizes
repulsions of the α-methylene protons with the peri-H atom
at C-1 and the enolic O atom of the exo-oriented acetyl
group. Hence, to form a (near) isoenergetic diastereomeric
or enantiomeric conformer, ring inversion must be com-
bined with a 180° rotation of the 10- and 11-substituents
(7, 10, 11), and further rotation about the CH2-C-(4ЈR)
for ketones 5a,b (–16 Hz) therefore indicate severe bending
of the cycloheptatriene and cycloheptadiene ring moieties.
In MM+ geometry-optimised models of 10 and a simplified
11-Me analogue of ketone 5 with a favoured equatorial
methyl group, this can be seen from the Φ values estimated
for H-5eq (ca. 90° for 10; Φ1, Φ2 Ϸ 100° and 95° for the
11-Me analogue of ketone 5) with respect to the unsubsti-
tuted and F-substituted benzene ring.
1
The above 13C and H NMR spectroscopic data suggest
the existence of two diastereomeric structures 5-enol1 and
5-enol2, which can be attributed to a high inversion barrier
of the disubstituted dibenzocycloheptatriene ring system
combined with the stereogenic centre already present in the
acetal-protected propanediol side-chain. In support of this
hypothesis, we unveiled a slow interconversion of the analo-
gous diastereomeric components of enol derivatives 7 and
8 by applying two-dimensional exchange spectroscopy
(EXSY).[15–18] From this EXSY analysis and the coalesc-
ence experiments carried out for enol acetate 10, cycloal-
kene 12 and for the cyclic enol ether 9, we were able to
determine rate constants for the diastereomeric exchange
reaction (kexch) and relevant activation parameters ∆G‡
(Table 2).
Table 2. Rate constants and activation parameters (∆G‡) at tem-
1
peratures indicated, as derived from H NMR EXSY analysis and
coalescence experiments.
T [K] kexch [s–1]
∆G‡[a]
Solvent
Method
7
8
298
298
248
343
220
0.3
0.05
566
85
18
19
11
17
10
CDCl3
C6D6
CD2Cl2
EXSY[b]
EXSY[b]
coalesc.
coalesc.
coalesc.
9
10
12
CDCl2CDCl2
CD2Cl2
286
Figure 2. Combined ring inversion and 180° rotation at C-10 and
C-11 to form diastereomeric (7) or enantiomeric (10, 11) conform-
ers compared to fast ring inversion of cyclic enol ether 9.
[a] kcalmol–1. [b] For 7 and 8 no peak broadening was observed at
55 °C in CDCl3; coalescence could not be attained.
1588
www.eurjoc.org
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 1586–1592

Derivatives of 8-Fluoro-5,11-dihydro-10H-dibenzo[a,d]cyclohepten-10-one
FULL PAPER
DMSO (10.0 mL, 141.5 mmol) was added dropwise to a stirred
cold solution (–60 °C) of (COCl)2 (6.17 mL, 70.8 mmol) in CH2Cl2
(100 mL). After 10 min, [(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]meth-
anol (4.37 mL, 35.4 mmol) was added dropwise and the mixture
was stirred for 10 min. Et3N (19.7 mL, 141.5 mmol) was added and
stirring was continued for another 5 min. The mixture was warmed
to room temperature, stirred further for 10 min, filtered through a
pad of Celite, and the filter cake washed with CH2Cl2 (3×20 mL).
The filtrate was concentrated at 20 °C to remove CH2Cl2 to afford
the corresponding aldehyde (4S)-2,2-dimethyl-1,3-dioxolane-4-car-
linkage (7). The spatial relationship between the in-
vertomers is illustrated in Figure 2. Evidently, the rotational
barrier is lifted for ring inversion of the cyclic enol ether 9,
which has the two hydrogen atoms of the α-methylene
group in an almost invariant position above and below the
plane of the unsubstituted benzene ring.
Presumably, this low conformational mobility of the enol
intermediate also accounts for its slow conversion into
ketone tautomers 5a,b. Indeed, when protonation occurs
from the more accessible exo face at C-11 of the enol, the baldehyde (6) as a yellow oil. MgBr2 (3.26 g, 17.7 mmol) and
tBuOK (2.48 g, 22.1 mmol) were added to an ice-cooled solution
of ketone 3 (2.00 g, 8.85 mmol) in THF (30 mL). A solution of the
above aldehyde in THF (10 mL) was added dropwise at 0 °C and
the mixture was allowed to react at room temperature for 1 h. After
disappearance of the starting ketone, NH4Cl (satd. aq. solution,
20 mL) was added, and the mixture was extracted with CH2Cl2
(3×20 mL). The organic phase was dried with MgSO4 and the sol-
vents were evaporated. The residue was purified on a silica gel col-
umn using diethyl ether/hexane (25:75) to give 180 mg of the less
polar (Z)-isomer (6%) and 2.40 g of the more polar (E)-isomer
voluminous R group has to move further inside the hollow
side of the 5H-dibenzo[a,d]cycloheptene ring system while
the α-methylene protons are forced into the plane of the
peri-H atom and the enolic O atom.
Conclusion
In conclusion, we have developed a suitable approach to
prepare a homochiral precursor of target compounds 1.
This involves aldol condensation of the tricyclic ketone 3
with either (4S)- or (4R)-2,2-dimethyl-1,3-dioxolane-4-car-
baldehyde to give the (4ЈR)-α,β-unsaturated ketone 4 or its
(4ЈS) enantiomer. Hydrogenation of 4 furnishes a mixture
of 11-epimeric ketones 5a,b, which interconvert readily via
the common enol intermediate. This enol and the corre-
(80%). (E)-Isomer: M.p. 90–92 °C. IR (NaCl): ν = 3410 (s), 1660
˜
1
(s), 1600 (s), 1245, 1060 (s) cm–1. H NMR (CDCl3, 400 MHz): δ
= 1.33 (s, 3 H, CH3), 1.48 (s, 3 H, CH3), 3.82 (t, J = 6.7 Hz, 1 H,
CH2-O), 4.05 (t, J = 6.7 Hz, 1 H, CH2Ј-O), 3.86–4.16 (br., 2 H,
CH2-5), 4.58 (dt, J = 8.8, 6.7 Hz, 1 H, CH-O), 7.02 (d, J = 8.8 Hz,
1 H, =CH), 7.05 (dt, J = 8.0, 2.8 Hz, 1 H, Ar-H), 7.18–7.30 (m, 5
H, H-Ar), 7.66 (dd, J = 9.4, 2.7 Hz, 1 H, H-Ar) ppm. 13C NMR
sponding enol derivatives have been shown to exist as two (CDCl3, 100 MHz): δ = 25.8 (CH3), 26.0 (CH3), 40.0 (CH2-5), 69.3
2
(CH2-O), 73.0 (CH-O), 110.3 (Me2C), 117.6 (d, JC,F = 22.9 Hz,
slowly interconverting diastereomeric conformers due to the
high inversion barrier of the 10,11-disubstituted 5H-di-
benzo[a,d]cycloheptene ring.
2
CH-Ar-F), 120.1 (d, JC,F = 21.4 Hz, CH-Ar-F), 126.7, 127.4,
128.9, 130.2 (CH-Ar), 130.1 (d, JC,F = 6.9 Hz, CH-Ar-F), 132.7,
139.5 (C-Ar), 136.3 (d, JC,F = 1.5 Hz, C-Ar-F), 138.7 (d, JC,F
6.1 Hz, C-Ar-F), 140.3 (=CH), 145.0 (=C=), 161.9 (d, JC,F
3
4
3
=
=
1
246.4 Hz, C-Ar-F), 189.3 (C=O) ppm. CIMS: m/z (%) = 339 (100)
[MH+], 281 (96) [MH+ – acetone], 263 (45) [MH+ – acetone – H2O].
EIMS: m/z (%) = 338 (2) [M+·], 280 (100) [M+· – acetone]. HRMS
calcd. for C21H19FO3 [M+·]: 338.1318; found 338.1306. (Z)-Isomer:
1H NMR (CDCl3, 400 MHz): δ = 1.42 (s, 3 H, CH3), 1.49 (s, 3 H,
CH3), 3.73 (d, J = 14.0 Hz, 1 H, CH2-5), 3.86 (dd, J = 8.4, 7.0 Hz,
1 H, CH2-O), 4.35 (d, J = 14.0 Hz, 1 H, CH2Ј-5), 4.61 (dd, J = 8.4,
7.0 Hz, 1 H, CH2Ј-O), 5.28 (q, J = 7.0 Hz, 1 H, CH-O), 6.38 (d, J
= 7.0 Hz, 1 H, =CH), 7.10–7.27 (m, 6 H, H-Ar), 7.65 (dd, J = 9.6,
2.8 Hz, 1 H, H-Ar) ppm. 13C NMR (CDCl3, 100 MHz): δ = 25.27
(CH3), 26.59 (CH3), 39.95 (CH2-5), 70.19 (CH2-O), 74.84 (CH-O),
Experimental Section
General Remarks: Melting points were determined with a Reichert-
Jung Thermovar apparatus or an Electrothermal IA 9000 digital
melting point apparatus, and are uncorrected. Infrared spectra were
recorded with a Perkin–Elmer 297 grating IR spectrophotometer
and a Perkin–Elmer 1720 Fourier transform spectrometer. Mass
spectra were recorded with a Hewlett Packard MS-Engine 5989A
apparatus for EI and CI spectra, and a Kratos MS50TC instrument
for exact mass measurements performed in the EI mode at a resolu-
tion of 10000. For the NMR spectra, a Bruker Avance 300 and a
Bruker AMX 400 spectrometer were used. Analytical and prepara-
tive thin layer chromatography were carried out using Merck silica
gel 60 PF-224; for column chromatography 70–230 mesh silica gel
60 (E. M. Merck) was used as the stationary phase.
2
109.98 (Me2C), 117.20 (d, JC,F = 22.86 Hz, CH-Ar-F), 120.05 (d,
2JC,F = 21.59 Hz, CH-Ar-F), 126.90, 127.30, 128.41, 129.04 (CH-
3
Ar), 130.36 (d, JC,F = 7.20 Hz, CH-Ar-F), 136.56, 138.72 (C-Ar),
136.70 (d, 3JC,F = 6.45 Hz, C-Ar-F), 138.76 (d, 4JC,F = 3.23 Hz, C-
1
Ar-F), 143.07 (=C=), 147.86 (=CH), 161.84 (d, JC,F = 246.18 Hz,
8-Fluoro-5,11-dihydro-10H-dibenzo[a,d]cyclohepten-10-one
(3):
C-Ar-F), 189.25 (C=O) ppm.
Compound 3 was prepared according to the procedure described
for the analogous 8-chloro compound.[5,6] M.p. 104–105 °C. 1H
NMR (CDCl3, 300 MHz): δ = 4.18 (s, 2 H, CH2-5 or CH2-11), 4.24
(s, 2 H, CH2-11 or CH2-5), 7.14 (td, J = 8.1, 2.9 Hz, 1 H, H-7),
7.17–7.37 (m, 5 H, H-Ar), 7.79 (dd, J = 9.5, 2.9 Hz, 1 H, H-9)
ppm. 13C NMR (CDCl3, 75 MHz): δ = 42.0 (CH2-5), 51.1 (CH2-
11), 117.0 (d, 2JC,F = 23.0 Hz, CH-Ar-F), 120.5 (d, 2JC,F = 20.7 Hz,
(11R)-11-{[(4R)-2,2-Dimethyl-1,3-dioxolan-4-yl]methyl}-8-fluoro-
5,11-dihydro-10H-dibenzo[a,d]cyclohepten-10-one (5a) and (11S)-11-
{[(4R)-2,2-Dimethyl-1,3-dioxolan-4-yl]methyl}-8-fluoro-5,11-dihy-
dro-10H-dibenzo[a,d]cyclohepten-10-one (5b): Et3N (0.63 mL,
4.50 mmol) and 10% palladium on carbon (150 mg) were added to
a solution of α,β-unsaturated ketone (E)-4 (1.00 g, 2.96 mmol) in
iPrOH (30 mL) and the mixture was hydrogenated at atmospheric
pressure in a Parr apparatus for 6 h. The mixture was filtered
through a pad of Celite and the catalyst washed with CH2Cl2
(4×20 mL). After evaporation of the solvent, the residue was puri-
fied by column chromatography (CH2Cl2) on silica gel. Further
HPLC separation (Waters 515 pump, 2-mL injection loop, Merck
3
CH-Ar-F), 128.0, 128.3, 129.8 (CH-Ar), 132.1 (d, JC,F = 6.9 Hz,
3
CH-Ar-F), 132.4 (C-Ar), 136.7 (d, JC,F = 6.9 Hz, C-Ar-F), 139.0,
1
140.0 (C-Ar), 162.2 (d, JC,F = 246.0 Hz, C-Ar-F), 193.6 (C=O)
ppm. CIMS: m/z (%) = 227 (100) [MH+].
(11E,Z)-11-{[(4R)-2,2-Dimethyl-1,3-dioxolan-4-yl]methylene}-8-
fluoro-5,11-dihydro-10H-dibenzo[a,d]cyclohepten-10-one (4): Dry
Eur. J. Org. Chem. 2006, 1586–1592
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1589

F. Compernolle, G. J. Hoornaert et al.
FULL PAPER
Hibar® 250 × 25 mm column LiChrosorb® SI 60 7 µm, Waters
2410 refractive index detector, diethyl ether/hexane = 60:40,
11 mLmin–1) gave 5a (tR = 13.2 min; 0.61 g, 61%) as a white crys-
talline powder and 5b (tR = 14.7 min; 0.35 g, 35%) as a colourless
oil.
H, H-Ar), 7.50 (dd, J = 7.8, 2.7 Hz, 1 H, H-Ar); common signals:
δ = 3.71–3.83 (m, 5 H), 6.94 (dt, J = 8.4, 2.5 Hz, 1 H, H-Ar), 7.02
(dd, J = 9.8, 2.5 Hz, 1 H, H-Ar), 7.17–7.26 (m, 4 H, H-Ar), 7.50
(dd, J = 7.8, 2.7 Hz, 1 H, H-Ar) ppm. 13C NMR (CDCl3,
100 MHz; two isomers): δ = 20.8, 20.9 (CH3-OAc), 25.7, 25.7, 26.8,
27.0 (CH3), 34.5, 35.8 (CH2), 40.05, 40.1 (CH2-5), 68.6, 69.2 (CH2-
Selective Crystallisation under Epimerising Conditions: Following
hydrogenation of (E)-4 (1.00 g, 2.96 mmol) and workup as de-
scribed above, the residue consisting of 5a,b was dissolved in iPrOH
(5 mL), and Et3N (1.20 mL) was added. The mixture was stirred at
40 °C for 1 h and cooled slowly to room temp. The crystallised
product was collected by filtration and dried under vacuum to af-
ford pure ketone 5a as a white powder (0.86 g, 86%). 5a: M.p. 144–
2
O), 74.4, 75.4 (CH-O), 108.8, 108.9 (Me2C), 111.5, 111.6 (d, JC,F
2
= 22.9 Hz, CH-Ar-F), 116.0, 116.1 (d, JC,F = 21.6 Hz, CH-Ar-F),
126.1, 126.3, 126.9, 127.1, 127.2, 127.3, 128.6, 128.7 (CH-Ar),
3
127.9, 128.0 (d, JC,F = 8.4 Hz, CH-Ar-F), 127.6, 128.1 (C-11),
3
133.3, 134.3, 140.6, 140.8 (C-Ar), 134.0, 134.2 (d, JC,F = 6.9 Hz,
4
C-Ar-F), 137.1, 137.3 (d, JC,F = 3.1 Hz, C-Ar-F), 144.2, 144.5 (d,
1
4JC,F = 2.1 Hz, C-10), 161.2 (d, JC,F = 243.4 Hz, C-Ar-F), 168.9,
146 °C. IR (NaCl): ν = 3434 (s), 2985 (s), 1680 (s), 1415 (s), 1060,
˜
169.0 (C=O) ppm. CIMS: m/z (%) = 383 (12) [MH+], 325 (40)
[MH+ – acetone], 265 (100) [MH+ – acetone – AcOH].
880 cm–1. 1H NMR (CDCl3, 400 MHz): δ = 1.30 (s, 3 H, CH3),
1.37 (s, 3 H, CH3), 2.03 (ddd, J = 13.3, 9.1, 2.8 Hz, 1 H, CH2),
2.91 (ddd, J = 13.3, 10.7, 3.3 Hz, 1 H, CH2Ј), 3.71 (dd, J = 7.9,
6.4 Hz, 1 H, CH2O), 3.95 (d, J = 15.9 Hz, 1 H, CH2-5), 4.17 (dd,
(4R)-4-{[2-Fluoro-11-(methoxymethoxy)-5H-dibenzo[a,d]cyclohep-
ten-10-yl]methyl}-2,2-dimethyl-1,3-dioxolane (8): CH3OCH2I
J = 7.9, 6.1 Hz, 1 H, CH2ЈO), 4.22–4.27 (m, 1 H, CH-O), 4.70 (dd, (0.12 mL, 1.45 mmol) and NaH (0.12 g, 2.90 mmol) were added to
J = 10.7, 2.8 Hz, 1 H, CH-11), 4.83 (d, J = 15.9 Hz, 1 H, CH2Ј-5), an ice-cooled solution of ketone 5a (247 mg, 0.725 mmol) in THF
7.14–7.36 (m, 6 H, H-Ar), 7.77 (dd, J = 9.8, 2.9 Hz, 1 H, H-Ar)
(5 mL). The reaction mixture was stirred at room temp. for 6 h.
ppm. 13C NMR (CDCl3, 100 MHz): δ = 25.6 (CH3), 27.1 (CH3), After the disappearance of the ketone (TLC), NH4Cl (satd. aq.
32.2 (CH2), 42.0 (CH2-5), 50.4 (CH-11), 69.9 (CH2-O), 74.1 (CH- solution) was added, the mixture was extracted three times with
2
O), 109.1 (Me2C), 116.4 (d, JC,F = 22.7 Hz, CH-Ar-F), 119.8 (d,
CH2Cl2 and the organic phase was dried with MgSO4, filtered and
the solvents were evaporated. The residue was purified by column
chromatography on silica gel eluting with diethyl ether/heptane
(25:75) to yield enol ether 8 as an oil (190 mg, 68%). 1H NMR
(CDCl3, 400 MHz; two isomers): first isomer: δ = 1.30 (s, 3 H,
CH3), 1.40 (s, 3 H, CH3), 2.95 (dd, J = 13.6, 6.3 Hz, 1 H, CH2),
3.67–3.85 (m, 5 H, CH2-O + CH2-5 + CH2Ј), 3.59 (s, 3 H, -OCH3),
2JC,F = 21.5 Hz, CH-Ar-F), 125.8, 127.1, 127.9, 128.2 (CH-Ar),
131.8 (d, JC,F = 7.0 Hz, CH-Ar-F), 135.3 (C-Ar), 137.0 (d, JC,F
= 5.9 Hz, C-Ar-F), 138.2 (d, JC,F = 3.4 Hz, C-Ar-F), 140.0 (C-
3
3
4
1
4
Ar), 161.7 (d, JC,F = 246.4 Hz, C-Ar-F), 193.5 (d, JC,F = 1.5 Hz,
C=O) ppm. CIMS: m/z (%) = 341 (2) [MH+], 283 (100) [MH+
acetone]. EIMS: m/z (%) = 340 (1) [M+·], 282 (79) [M+· – acetone],
–
226 (100). HRMS calcd. for C21H21FO3 [M+·]: 340.1475; found 4.13–4.17 (m, 1 H, Σ3J = 25.5 Hz, CH-O), 4.83–4.88 (m, 2 H, O-
340.1479. 5b: Colourless oil. 1H NMR (CDCl3, 300 MHz): δ = 1.35
(s, 3 H, CH3), 1.45 (s, 3 H, CH3), 2.51 (ddd, J = 14.2, 8.4, 4.0 Hz,
CH2-O), 6.93–7.54 (m, 7 H, H-Ar) ppm; second isomer: δ = 1.28
(s, 3 H, CH3), 1.43 (s, 3 H, CH3), 3.19 (dd, J = 14.2, 4.7 Hz, 1 H,
1 H, CH2), 2.66 (ddd, J = 14.2, 8.0, 5.5 Hz, 1 H, CH2Ј), 3.74 (dd, CH2), 3.67–3.85 (m, 5 H, CH2-O + CH2-5 + CH2Ј), 3.53 (s, 3 H,
J = 8.0, 7.0 Hz, 1 H, CH2O), 4.03 (d, J = 16.1 Hz, 1 H, CH2-5), -OCH3), 4.25–4.28 (m, 1 H, Σ3J = 26.4 Hz, CH-O), 4.83–4.88 (m,
4.07 (dd, J = 8.0, 6.2 Hz, 1 H, CH2ЈO), 4.26–4.35 (m, 1 H, CH-O), 2 H, O-CH2-O), 6.93–7.54 (m, 7 H, H-Ar) ppm; common signals:
4.65 (dd, J = 8.0, 5.5 Hz, 1 H, CH-11), 4.75 (d, J = 16.1 Hz, 1 H, δ = 3.67–3.85 (m, 5 H, CH2-O + CH2-5 + CH2Ј), 4.83–4.88 (m, 2
CH2Ј-5), 7.14–7.36 (m, 6 H, H-Ar), 7.68 (dd, J = 9.8, 2.9 Hz, 1 H, H, O-CH2-O), 6.93–7.54 (m, 7 H, H-Ar) ppm. 13C NMR (CDCl3,
H-Ar) ppm. CIMS: m/z (%) = 341 (2) [MH+], 283 (100) [MH+
acetone].
–
100 MHz; two isomers): δ = 25.7, 25.8, 26.8, 27.1 (CH3), 33.5, 34.8
(CH2), 40.2 (CH2-5), 57.6, 57.8 (OCH3), 68.3, 69.8 (CH2-O), 74.8,
76.1 (CH-O), 97.2, 97.3 (O-CH2-O), 108.5, 109.0 (Me2C), 113.1,
8-Fluoro-11-{[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}-5H-di-
benzo[a,d]cyclohepten-10-yl Acetate (7): Et3N (88 µL, 0.635 mmol),
DMAP (20 mg, 0.159 mmol) and Ac2O (60 µL, 0.635 mmol) were
added to an ice-cooled solution of ketone 5a (108 mg, 0.318 mmol)
in CH2Cl2 (5 mL). The reaction mixture was stirred at room temp.
for 6 h. After disappearance of the ketone (TLC), NH4Cl (satd. aq.
solution) was added, the mixture was extracted three times with
CH2Cl2 and the organic phase dried with MgSO4, filtered and the
solvents were evaporated. The residue was purified by column
chromatography on silica gel eluting with CH2Cl2/heptane (1:1) to
2
2
113.2 (d, JC,F = 22.6 Hz, CH-Ar-F), 116.0, 116.2 (d, JC,F
=
21.6 Hz, CH-Ar-F), 124.7, 125.6 (C-10), 126.0, 126.2, 126.65,
126.7, 127.1, 127.4, 127.75, 127.8 (CH-Ar), 127.9, 128.0 (d, 3JC,F
=
8.4 Hz, CH-Ar-F), 133.2 (d, 3JC,F = 7.7 Hz, C-Ar-F), 134.4, 135.3,
140.1, 140.4 (C-Ar), 137.6, 137.7 (d, 4JC,F = 3.1 Hz, C-Ar-F), 149.7,
4
1
149.8 (d, JC,F = 2.1 Hz, C-11), 161.2, 161.25 (d, JC,F = 243.6 Hz,
C-Ar-F) ppm. CIMS: m/z (%) = 385 (5) [MH+], 327 (40) [MH+
acetone], 295 (100) [MH+ – acetone – MeOH], 265 (61) [MH+
acetone – CH3OCH2OH].
–
–
1
afford enol acetate 7 as an oil (106 mg, 87%). H NMR (CDCl3,
[(2R)-11-Fluoro-3,8-dihydro-2H-dibenzo[3,4:6,7]cyclohepta[1,2-b]fu-
ran-2-yl]methanol (9): Aqueous HCl (1 , 3 mL) was added to a
solution of ketone 5a (105 mg, 0.309 mmol) in THF (3 mL). The
reaction mixture was stirred at room temp. for 4–5 h. After the
disappearance of the ketone (TLC), Na2CO3 (satd. aq. solution)
was added, the mixture was extracted three times with CH2Cl2 and
the organic phase was dried with MgSO4, filtered and the solvents
400 MHz; two isomers): first isomer: δ = 1.26 (s, 3 H, CH3), 1.40
(s, 3 H, CH3), 2.29 (s, 3 H, OAc), 3.10 (dd, J = 14.0, 9.5 Hz, 1 H,
CH2), 3.18 (dd, J = 14.0, 4.6 Hz, 1 H, CH2Ј), 3.55 (dd, J = 8.2,
6.4 Hz, 1 H, CH2-O), 3.63 (d, J = 12.9 Hz, 1 H, CH2-5), 3.71–3.83
(m, 2 H, CH2Ј-O + CH2Ј-5), 4.11–4.17 (m, 1 H, Σ3J = 25.7 Hz,
CH-O), 6.94 (dt, J = 8.4, 2.5 Hz, 1 H, H-Ar), 7.02 (dd, J = 9.8,
2.5 Hz, 1 H, H-Ar), 7.17–7.26 (m, 4 H, H-Ar), 7.50 (dd, J = 7.8, were evaporated. The residue was purified by column chromatog-
2.7 Hz, 1 H, H-Ar) ppm; second isomer: δ = 1.29 (s, 3 H, CH3),
1.37 (s, 3 H, CH3), 2.27 (s, 3 H, OAc), 2.82 (dd, J = 13.6, 6.7 Hz,
raphy on silica gel eluting with CH2Cl2. Cyclic enol ether 9 was
isolated as an oil (85 mg, 98%). H NMR (CDCl3, 400 MHz): δ =
1
1 H, CH2), 3.27 (dd, J = 13.6, 6.4 Hz, 1 H, CH2Ј), 3.39 (t, J = 1.92 (s, 1 H, OH), 3.15 (dd, J = 15.2, 7.7 Hz, 1 H, CH2-3), 3.42
7.6 Hz, 1 H, CH2-O), 3.71–3.83 (m, 3 H, CH2Ј-O + CH2-5), 3.98–
(dd, J = 15.2, 10.2 Hz, 1 H, CH2Ј-3), 3.68 (d, J = 13.9 Hz, 1 H,
4.05 (m, 1 H, Σ3J = 26.0 Hz, CH-O), 6.94 (dt, J = 8.4, 2.5 Hz, 1 CH2-8), 3.72 (d, J = 13.9 Hz, 1 H, CH2Ј-8), 3.87 (dd, J = 12.0,
H, H-Ar), 7.02 (dd, J = 9.8, 2.5 Hz, 1 H, H-Ar), 7.17–7.26 (m, 4 5.8 Hz, 1 H, CH2-OH), 3.91 (dd, J = 12.0, 4.1 Hz, 1 H, CH2Ј-OH),
1590
www.eurjoc.org
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 1586–1592

Derivatives of 8-Fluoro-5,11-dihydro-10H-dibenzo[a,d]cyclohepten-10-one
FULL PAPER
4.93–5.01 (m, 1 H, Σ3J = 27.8 Hz, CH-2), 7.03 (dt, J = 8.6, 2.7 Hz, a solution of the above ketone (0.56 g, 2.12 mmol) in CH2Cl2
1 H, H-Ar), 7.22–7.32 (m, 6 H, H-Ar) ppm. 13C NMR (CDCl3,
(40 mL). After reaction at room temp. for 1 h, NH4Cl (satd. aq.
100 MHz): δ = 34.9 (CH2-3), 41.2 (CH2-8), 65.1 (CH2-OH), 80.2 solution, 15 mL) was added, the mixture was extracted three times
2
(CH-2), 111.3 (d, JC,F = 23.2 Hz, CH-Ar-F), 114.1 (C-3a), 116.3 with CH2Cl2 (15 mL) and the organic phase was dried with
(d, 2JC,F = 21.8 Hz, CH-Ar-F), 124.2, 126.5, 127.2, 128.2 (CH-Ar), MgSO4, filtered and the solvents were evaporated. The residue was
3
3
129.3 (d, JC,F = 8.2 Hz, CH-Ar-F), 130.5 (d, JC,F = 7.6 Hz, C-
purified by column chromatography on silica gel eluting with
CH2Cl2/hexane (60:40) to yield 11 as a white, crystalline product
Ar-F), 132.5, 135.1 (C-Ar), 132.7 (d, 4JC,F = 3.1 Hz, C-Ar-F), 151.0
4
1
(d, JC,F = 2.9 Hz, C-12b), 161.4 (d, JC,F = 243.7 Hz, C-Ar-F) (0.64 g, 98%). M.p. 151–153 °C. IR (NaCl): ν = 3304 (s), 1760 (s),
˜
ppm. CIMS: m/z (%) = 283 (100) [MH+].
1493, 1370, 1163, 909 cm–1. 1H NMR (CDCl3, 400 MHz): δ = 2.04
(t, J = 2.7 Hz, 1 H, ϵCH), 2.31 (s, 3 H, OAc), 3.55 (dd, J = 17.0,
2.7 Hz, 2 H, CH2), 3.75 (d, J = 13.0 Hz, 1 H, CH2-5), 3.83 (d, J =
13.0 Hz, 1 H, CH2Ј-5), 6.96 (dt, J = 8.4, 2.6 Hz, 1 H, H-Ar), 7.07
(dd, J = 9.8, 2.6 Hz, 1 H, H-Ar), 7.18–7.27 (m, 4 H, H-Ar), 7.59
(d,J = 7.5 Hz, 1 H, H-Ar) ppm. 13C NMR (CDCl3, 100 MHz): δ
= 20.8 (CH3), 21.6 (CH2), 40.0 (CH2-5), 69.2 (ϵCH), 81.2
11-Allyl-8-fluoro-5H-dibenzo[a,d]cyclohepten-10-yl Acetate (10):
PCC (32 mg, 0.151 mmol) was added to a solution of racemic trans-
(10R*,11S*)-11-allyl-8-fluoro-10,11-dihydro-5H-dibenzo[a,d]-
cyclohepten-10-ol (20.2 mg, 0.075 mmol) in CH2Cl2 (1 mL). After
reaction at room temp. for 4 h, NH4Cl (satd. aq. solution, 2 mL)
was added, the mixture was extracted three times with CH2Cl2 and
the organic phase dried with MgSO4, filtered and the solvents were
evaporated. The residue was purified by column chromatography
on silica gel eluting with CH2Cl2/hexane (50:50) to give the corre-
sponding ketone ( )-11-allyl-8-fluoro-5,11-dihydro-10H-di-
benzo[a,d]cyclohepten-10-one. Ac2O (14 µL, 0.151 mmol), DMAP
(5 mg, 0.038 mmol) and Et3N (21 µL, 0.151 mmol) were added to
a solution of the above 11-allyl ketone in CH2Cl2 (5 mL). After
reaction at room temp. for 2 h, NH4Cl (satd. aq. solution, 5 mL)
was added, the mixture was extracted three times with CH2Cl2
(5 mL) and the organic phase dried with MgSO4, filtered and the
solvents were evaporated. The residue was purified by column
chromatography on silica gel eluting with CH2Cl2/hexane (60:40) to
2
2
(CϵCH), 111.7 (d, JC,F = 23.1 Hz, CH-Ar-F), 116.3 (d, JC,F
=
21.7 Hz, CH-Ar-F), 126.2, 126.7, 127.0, 128.7 (CH-Ar), 126.4 (C-
3
3
11), 128.2 (d, JC,F = 8.3 Hz, CH-Ar-F), 133.9 (d, JC,F = 7.8 Hz,
4
C-Ar-F), 134.1, 140.2 (C-Ar), 136.8 (d, JC,F = 2.6 Hz, C-Ar-F),
4
1
144.5 (d, JC,F = 2.0 Hz, C-10), 161.2 (d, JC,F = 243.6 Hz, C-Ar-
F), 168.7 (C=O) ppm. CIMS: m/z (%) = 307 (76) [MH+], 265 (100)
[MH+ – ketene], 247 (41) [MH+ – ketene – H2O]. EIMS: m/z = 306
(18) [M+], 264 (100) [M+· – ketene]. HRMS calcd. for C20H15FO2
[M+·]: 306.1056; found 306.1050.
Acknowledgments
1
yield 10 as an oil (20 mg, 86% over two steps). H NMR (CDCl3,
The authors thank the FWO (Fund for Scientific Research, Flan-
ders, Belgium) and the Janssen Research Foundation for financial
support. We are indebted to R. De Boer for mass measurements.
400 MHz): δ = 2.27 (s, 3 H, OAc), 3.42 (ddt, J = 15.5, 5.9, 1.7 Hz,
1 H, CH2), 3.49 (ddt, J = 15.5, 6.5, 1.7 Hz, 1 H, CH2Ј), 3.73 (d, J
= 12.9 Hz, 1 H, CH2-5), 3.78 (d, J = 12.9 Hz, 1 H, CH2Ј-5), 5.05
(dq, J = 10.1, 1.7 Hz, 1 H, =CH2cis), 5.13 (dq, J = 17.1, 1.7 Hz, 1
H, =CH2trans), 5.89 (ddt, J = 17.1, 10.1, 6.3 Hz, 1 H, CH=CH2),
6.95 (dt, J = 8.4, 2.7 Hz, 1 H, H-Ar), 7.06 (dd, J = 9.9, 2.7 Hz, 1
H, H-Ar), 7.17–7.28 (m, 4 H, H-Ar), 7.48 (d, J = 7.6 Hz, 1 H, H-
Ar) ppm. 13C NMR (CDCl3, 100 MHz): δ = 20.9 (CH3), 36.4
[1] J. I. Andrés-Gil, F. J. Fernandez-Gadea, P. Gil-Lopetegui, A.
Diaz-Martinez, Janssen Pharmaceutica N. V. Patent Applica-
tion PCT/EP98/06352; WO 99/19317 22 April 1999.
[2] F. Compernolle, H. Mao, A. Tahri, T. Kozlecki, E.
Van der Eycken, B. Medaer, G. J. Hoornaert, Tetrahedron Lett.
2002, 43, 3011–3015.
[3] A. Hjelmencrantz, A. Friberg, U. Berg, J. Chem. Soc., Perkin
Trans. 2 2000, 1293–1300.
[4] M. Nogradi, W. D. Ollis, I. O. Sutherland, J. Chem. Soc., Chem.
Commun. 1970, 158.
2
(CH2), 40.2 (CH2-5), 111.6 (d, JC,F = 22.9 Hz, CH-Ar-F), 116.0
2
(d, JC,F = 21.8 Hz, CH-Ar-F), 116.0 (=CH2), 126.1, 126.9, 127.0,
3
128.4 (CH-Ar), 128.0 (d, JC,F = 8.3 Hz, CH-Ar-F), 129.6 (C-11),
3
134.3 (d, JC,F = 8.0 Hz, C-Ar-F), 134.9, 140.4 (C-Ar), 135.5
4
4
(CH=), 137.0 (d, JC,F = 3.1 Hz, C-Ar-F), 143.8 (d, JC,F
=
1
2.85 Hz, C-10), 161.2 (d, JC,F = 243.1 Hz, C-Ar-F), 168.9 (C=O)
[5] R. R. Fraser, R. N. Renaud, Can. J. Chem.1971, 49, 746–754.
[6] S. A. Rhone-Poulenc, Fr. M. 4395, Oct. 10, 1966; Chem. Abstr.
1968, 68, P68763K.
ppm. CIMS: m/z (%) = 309 (27) [MH+], 267 (100) [MH+
CH2=C=O], 249 (28) [MH+ – CH2=C=O – H2O].
–
8-Fluoro-11-(2-propynyl)-5H-dibenzo[a,d]cyclohepten-10-yl Acetate [7] C. Hubschwerlen, Synthesis 1986, 11, 962–964.
[8] C. Hubschwerlen, J. L. Specklin, J. Higelin, Org. Synth. 1995,
72, 1–5.
[9] G. C. Andrews, T. C. Crawford, B. E. Bacon, J. Org. Chem.
1981, 46, 2976–2977.
[10] M. Janson, I. Kvarnstrom, S. C. T. Svensson, B. Classon, B.
Samuelsson, Synthesis 1993, 129–133.
[11] C. R. Schmid, J. D. Bryant, M. Dowlatzedah, J. L. Phillips,
D. E. Prather, R. D. Schantz, N. L. Sear, C. S. Vianco, J. Org.
Chem. 1991, 56, 4056–4058.
[12] C. R. Schmid, J. D. Bryant, Org. Synth. 1995, 72, 6–13.
[13] M. Barfield, D. M. Grout, J. Am. Chem. Soc. 1963, 85, 1899.
[14] H. Günther, NMR Spectroscopy, 2nd ed., Wiley, New York,
1996, chapter 4, pp. 111–112.
[15] The NOESY spectra display some typical exchange correlation
peaks having the same sign as the diagonal peaks. EXSY analy-
sis of these peaks was done by integration of the areas of the
diagonal peaks and the exchange peaks found in the same row
or column.
(11): A solution of DMSO (1.69 mL, 23.8 mmol) in CH2Cl2
(15 mL) was added over 5 min to a cooled (–60 °C) solution of
oxalyl chloride (1.04 mL, 11.9 mmol) in CH2Cl2 (15 mL) contained
in a three-necked flask. The reagent solution was stirred for 10 min,
then a solution of trans-(10R*,11S)-8-fluoro-11-(2-propynyl)-
10,11-dihydro-5H-dibenzo[a,d]cyclohepten-10-ol (1.58 g,
5.94 mmol) in CH2Cl2 (15 mL) was added within about 5 min and
the reaction mixture was stirred at –60 °C for 15 min. Et3N
(4.97 mL, 35.6 mmol) was added and the cooling bath removed.
After reaction at room temp. for 30 min, Na2CO3 (satd. aq. sol.,
30 mL) was added. The aqueous phase was extracted with CH2Cl2
(3×25 mL) and the organic phase dried with MgSO4, filtered and
the solvents were evaporated. The residue was purified by column
chromatography on silica gel eluting with CH2Cl2/hexane (60:40) to
afford the 11-propargyl ketone ( )-8-fluoro-11-(2-propynyl)-5,11-
dihydro-10H-dibenzo[a,d]cyclohepten-10-one as a white, crystalline
product (1.17 g, 75 %). Ac2O (0.50 mL, 5.30 mmol), DMAP
(0.52 g, 4.24 mmol) and Et3N (0.74 mL, 5.30 mmol) were added to
[16] G. Fischer, E. Kleinpeter, Magn. Reson. Chem. 1991, 29, 204–
206.
Eur. J. Org. Chem. 2006, 1586–1592
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1591

F. Compernolle, G. J. Hoornaert et al.
FULL PAPER
[17] B. H. Meier, R. R. Ernst, J. Am. Chem. Soc. 1979, 101, 6441–
6442.
[18] J. Jeener, B. H. Meier, P. Bachmann, R. R. Ernst, J. Chem.
Phys. 1979, 71, 4546–4553.
[19] F. A. L. Anet, J. Am. Chem. Soc. 1964, 86, 458.
[20] F. R. Jensen, L. A. Smith, J. Am. Chem. Soc. 1964, 86, 956.
[21] H. Günther, NMR Spectroscopy, 2nd ed., Wiley, New York,
1996, chapter 8, p. 366.
[22] D. I. Freedberg, M. Kopelevich, F. A. L. Anet, J. Phys. Org.
Chem. 2001, 14, 625–635.
Received: October 12, 2005
Published Online: January 24, 2006
1592
www.eurjoc.org
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 1586–1592