Efficient oxidative ipso-fluorination of para-substituted phenols using pyridinium polyhydrogen fluoride in combination with hypervalent iodine(III) reagents

Article abstract of DOI:10.1016/j.tet.2004.05.083

Diacetoxyiodobenzene (PIDA) and bis(trifluoroacetoxy)iodobenzene (PIFA) in the presence of pyridinium polyhydrogen fluoride (PPHF) are effective for the fluorination of para-substituted phenols to give a variety of 4-fluorocyclohexa-2,5-dienones in a good yield. (R,S)-1,1′-Bi-5,6,7,8- tetrahydro-2-naphthol (and its monoacetate) yields atropoisomeric fluorocyclohexadienones. The 4-substituted carbamate open-chain phenols were readily converted to fluorohydroindolenone and fluorohydroquinolenone derivatives by intramolecular conjugate addition.

Full text of DOI:10.1016/j.tet.2004.05.083

Tetrahedron 60 (2004) 6629–6638
Efficient oxidative ipso-fluorination of para-substituted phenols
using pyridinium polyhydrogen fluoride in combination with
hypervalent iodine(III) reagents
a
a
a
Omar Karam,a Agnes Martin-Mingot, Marie-Paule Jouannetaud, Jean-Claude Jacquesy
,
*
`
and Alain Coussonb
a
` ´ ´
Laboratoire ‘Synthese et Reactivite des Substances Naturelles’, UMR 6514, 40, Avenue du Recteur Pineau, F-86022 Poitiers Cedex, France
Laboratoire Leon Brillouin - CEA Saclay, 91191 Gif-sur-Yvette Cedex, France
b
´
Received 8 January 2003; revised 6 January 2004; accepted 27 May 2004
Available online 24 June 2004
Abstract—Diacetoxyiodobenzene (PIDA) and bis(trifluoroacetoxy)iodobenzene (PIFA) in the presence of pyridinium polyhydrogen
fluoride (PPHF) are effective for the fluorination of para-substituted phenols to give a variety of 4-fluorocyclohexa-2,5-dienones in a good
yield. (R,S)-1,10-Bi-5,6,7,8-tetrahydro-2-naphthol (and its monoacetate) yields atropoisomeric fluorocyclohexadienones. The 4-substituted
carbamate open-chain phenols were readily converted to fluorohydroindolenone and fluorohydroquinolenone derivatives by intramolecular
conjugate addition.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
Hypervalent iodine(III) reagents have been used for the
synthesis of many 4,4-disubstitued cyclohexa-2,5-dienones
from phenols derivatives.10–16 In particular phenyliodine
bis(trifluoroacetate) (PIFA) or phenyliodine diacetate
(PIDA) have received a great deal of attention due to low
toxicity, ready availability, easy handling, and reactivities
similar to that of heavy metal reagents or anodic
oxidation.
The importance of fluorinated compounds, in particular to
the agrochemical and pharmaceutical industries, has
stimulated considerable interest in the development of
general and convenient fluorinating agents.1
Using electrophilic fluorinating reagents (fluorine,2
trifluoromethylhypofluorite CF3OF,3 perchloryl fluoride
ClO3F,4 N-fluoroperfluoroalkylsulfonylimides,5 Select-
The nucleophilic ipso-fluorination of 4-alkylphenols, using
pyridinium polyhydrogen fluoride (PPHF), and phenyl-
iodine bis(trifluoroacetate) PIFA, or phenyliodine-(di-
acetate) PIDA is much easier to handle and extremely
simplifies work-up. Having reported on its applicability in
preliminary communications,17–19 we now report in full the
use of remarkable combination of Olah’s reagent and
hypervalent iodine(III) reagent as a convenient general
purpose for ipso-fluorination of various para-alkylphenols.
6
fluore F-TEDA BF4 ) as the source of fluorine, was
previously reported for more or less efficient synthesis of
4-fluorocyclohexa-2,5-dienones. These reagents are also
strong oxidants, and require special equipment due to their
unstability and toxicity.7
Olah’s regent (pyridinium polyhydrogen fluoride) was
found to be convenient and effective nucleophilic fluorinat-
ing agent.8 The oxidative fluorination of phenols using
HF-base in combination with Pb(IV), was reported to give
ipso-fluorination, but the application of this method was
limited to few phenols derivatives and yields of dienones are
low or unspecified.9 Moreover, heavy metal oxidants are
highly toxic and must be handled very carefully.
The postulated mechanism implies reaction of the reagent
PIFA on the phenolic group and trapping of the resulting
intermediate by a nucleophilic fluorine (Scheme 1). The
structure of para-fluoroalkyldienones was supported by
spectral data and elemental analysis. The 1H NMR spectrum
showed signals for vinylic hydrogen at 6.2,d,6.4 (d,
JH–H¼10 Hz, H-2) and 6.9,d,7.2 (dd, JH–H¼10 Hz,
JH–F¼6 Hz, H-3) characteristic of an a,b-unsaturated
fluorodienone. This was supported by the presence in the
13C NMR spectra of the coupling constants between fluorine
Keywords: Ipsofluorination; Pyridinium polyhydrogen fluoride;
Hypervalent iodine; Fluorodienone.
*
Corresponding author. Tel.: þ33-5-49-453702; fax: þ33-5-49-453501;
e-mail address: omar.karam@univ-poitiers.fr
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.05.083

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O. Karam et al. / Tetrahedron 60 (2004) 6629–6638
Scheme 1.
and carbons, 160,J1,170, 22,J2,30, 7,J3,10 and
4,J4,7.
No reaction proceeded when using compounds 6 or 7
bearing a strong inductive electron-attracting NO2 or CN
substituents.
2.2. Ipso-fluorination of bicyclic phenols
2. Results and discussion
In order to extend this method, the bicyclic rings were
selected as branched phenols. Thus phenols 14 and 15 were
readily transformed by treatment with PIFA-PPHF into the
corresponding 4-fluorocyclohexa-2,5-dienone derivatives
17 and 18 in 42–66% yield (Table 2).
2.1. Ipso-fluorination of monocyclic para-substituted
phenols
The fluorination reaction of para-alkylphenols 1–3 was
examined by treatment with PIFA-PPHF in dichloro-
methane at 25 8C. The reaction proceeded smoothly to
give the 4-fluoro-4-alkylcyclohexa-2,5-dienones 8–11.
Formation of the known Pummerer ketone 9 (8%) as a by-
product was observed when starting from para-cresol 1.
This oxidative dimerization can be accounted for by similar
process.
The reactivity of bicyclic compounds led to study the
reaction of 4-chloronaphtalen-1-ol 16, by treatment with
PIDA-PPHF. The reaction resulted in the formation of
4-chloro-4-fluorodienone 19 (30%) and naphtoquinone 20
as a by-product.
The use of 1.2 mmol of phenyliodine bis(trifluoroacetate)
PIFA or phenyliodine diacetate PIDA and 0.1 mL of
pyridinium polyhydrogen fluoride (70:30; v:v) per one
mmol of phenol has been found to be effective.
Several variables were examined in effort to enhance the
formation of fluorodienones. Changing the ratio of HF and
pyridine or employing other amine poly-(hydrogen
fluoride), complexes did not improve the yield of dienones.
Similarly, 4-halophenols 4 and 5 were converted by
treatment with PIDA-PPHF to the corresponding fluoro-
cyclohexadienones 12 and 13 in fair yields (Table 1).
Reaction of phenols 4 and 5 with PIFA is very rapid giving a
complex mixture of products. In the presence of the more
acidic trifluoroacetic acid generated in the reaction, the
corresponding dienones 12 and 13 yield para-benzoquinone
and phenols resulting from dienone-phenol rearrangement.
2.3. Synthesis of atropoisomeric fluorocyclo-
hexadienones
The synthesis of atropoi0someric fluorocyclohexadienones,
starting from (R,S)-1,1 -bi-5,6,7,8-tetrahydro-2-naphthol
21a (and its monoacetate 21b) prepared by hydrogenation
of the commercially available (R,S)-1,10-bi-2-naphthol was
similarly achieved.
Table 1.
Phenols
Products (%)
The reaction was carried out as previously described,
pyridinium polyhydrogen fluoride, then C6H5I(OCOCF3)2
being added to a solution of the phenol in dichloromethane.
1 R¼CH3
2 R¼CH3CH2
3 R¼CH2CH2Br
4 R¼F
PIFA-PPHF
PIDA-PPHF
8 (68)
10 (61)
11 (48)
12 (67)
13 (40)
Table 3 shows that with 1.2 equiv. of PIFA fluorination of
phenol 26a yields a complex mixture of mono and difluoro
derivatives and of the starting material. Phenols acetates
being unreactive, reaction of monoester 21b gives only
racemic cyclohexadienones 22b and 23b.
5 R¼Cl
a
6 R¼NO2
—
a
7 R¼CN
—
a
No reaction.
Use of anodic oxidation on Pt20 or oxidant Pb((IV)9 was
reported to yield dienones 12 (26%) and 13 (15%). The
reaction between electrophilic fluorinating agents and
4-halophenols derivatives was reported to introduce fluorine
in ortho position of an aromatic ring21 or to give only traces
of 4-halo-4-fluorodienones in the crude reaction mixture.6
In these compounds the configuration R or S of the newly
created asymmetric center 4a, coupled with the atropo-
isomeric system (indicated as Ra or Sa), accounts for the
formation of these products. Structure of dienone 22b has
been determined by X-ray analysis (Fig. 1), implying for
dienone 23b the proposed structure.

O. Karam et al. / Tetrahedron 60 (2004) 6629–6638
6631
Table 2.
Phenols
Conditions
Products (%)
14 n¼1
15 n¼2
PIFA-PPHF
17 (42)
18 (66)
16
PIDA-PPHF
19 (30)
20 (20)
Table 3.
Entry
Substrate
PIFA (equiv.)
Products (%)
1
2
3
4
5
21a
21b
22a
23a
21a
1.2
1.2
1.2
1.2
2.4
21aþ22aþ23aþ24þ25þ26
22bþ23b (65)(molar ratio 40/60)
25þ26 (42) (molar ratio 28/72)
25þ24 (48) (molar ratio 83/17)
24þ25þ26 (45) (molar ratio 17/65/18)
Figure 1. X-ray diagram of compounds 22b and 23b.
Mild hydrolysis (NaHCO3/H2O) of esters 22b and 23b
yields the corresponding phenols 22a and 23a. Entries 3 and
4 show that fluorination of these phenols leads to racemic
ketones 25 and 26, and 24 and 25, respectively, confirming
that the configuration of atropoisomers has been maintained
during alkaline hydrolysis of esters 22b and 23b. Ketones
24, 25 and 26 are obtained directly when the reaction is
carried out on phenol 21a (entry 5). The second fluorination

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O. Karam et al. / Tetrahedron 60 (2004) 6629–6638
creates a second asymmetric center at C-40a, identical with
the first one. Six isomers could be formed and are effectively
obtained, corresponding to racemic ketones 24, 25 and 26.
preferentially on the face of the phenol opposite to the
carbonyl group (selectivity 28/72 with 22a, and 17/83 with
23a) and this is probably due to a repulsive interaction
between the solvated fluoride and the oxygen atom of the
carbonyl group.
Formation of a common difluorodienone 25 starting either
from phenol 22a or from phenol 23a was expected and its
structure has been confirmed by X-ray analysis22 (Fig. 2).
Structures of isomers 24 and 26 follow from those of their
respective precursors 23a and 22a.
2.4. Application to estrogen steroids
For preparation of angular fluorinated compounds, we
applied the reaction to estrogen steroids and found that
the best yield was obtained with estrone 27 to give
10b-fluoroestra-1,4-dien-3,17-dione 29.
A similar reaction can be carried out with the 11b-hydroxy
analog 28, to yield dienone 30 (58%). Presence of a
hydroxyl substituent at C-11 is known to be associated with
corticosteroid activities (Table 4).24
Table 4.
Phenols
Products (%)
Figure 2. X-ray diagram of compound 25.
It should be noticed that whereas ketones 24 and 26 exhibit
only ten different carbon signals in 13C NMR, twenty signals
are observed for ketone 25, in concordance with different
configurations for the asymmetric carbons. These results
deserve several comments.
27 R¼H
29 (77)
30 (58)
28 R¼OH
2.5. Synthesis of hydrindolenones and
hydroquinolenones
Fluorination of monoester 21b appears to be poorly
stereoselective (22b/23b molar ratio 40/60). This reflects,
according to the conformation of the substrate, a slight
preference for nucleophilic fluorination on the face
occupied by the acetoxy group (Scheme 2).
Syntheses of indole derivatives have been described by
oxidation of tyramine or tyrosine derivatives by treatment
with phenyliodine bis(trifluoroacetate) (PIFA) or phenyl-
iodine diacetate (PIDA), respectively.25,26 Formation of the
hexahydroindol-6-ones can be rationalized by intra-
molecular Michael-type reaction of the nitrogen group to
the double bond of the intermediate dienone.
We report the synthesis of fluoro hydroindol-6-ones and of
hydroquinolin-7-ones under the action of PIFA-pyridinium
polyhydrogen fluoride (PPHF) on monocyclic phenols,
followed by cyclization of the resulting open-chain
dienones.17,18
Scheme 2.
Fluorination of phenols was carried out using methodology
previously reported, pyridinium polyhydrogen fluoride then
C6H5I(OCOCF3)2 being added to a solution of the phenol in
dichloromethane.
On the other hand, from the results of entries 3–5 we can
infer that fluorination of 21a is much more selective, with a
pronounced preference for the face occupied by the
hydroxyl group (22a/23a calculated molar ratio 23/78).
Reaction of phenol 31 with PIFA-PPHF leads directly to
enone 33, the intermediate dienone isomerizing spon-
taneously in the reaction conditions (Table 5). Cyclization
of dienone 34 into the corresponding enones 35a was
performed by treatment with HCl in tetrahydrofuran.
This selectivity might be due to an anchimeric assistance
through an hydrogen bond between the hydroxyl group and
the solvated fluoride F(HF)n–. A similar effect was observed
previously in the addition of hydrogen fluoride on
unsaturated alcohols in the steroid series.23
In enones 33 and 35a the ring junction was expected to be
cis for steric reasons.25,26 This was confirmed by NMR
experiments complicated by the presence of two carbamate
bond rotamers in approximately 1:1 ratio.
A complete reversal of selectivity is observed in the second
fluorination (entries 3 and 4). The reaction occurs

O. Karam et al. / Tetrahedron 60 (2004) 6629–6638
6633
Table 5.
In summary, this study demonstrates the synthetic interest
of hypervalent iodine reagents in heterocyclization
chemistry, especially to prepare angular substituted fluoro-
cyclohexenones.
Phenols
Products (%)
3. Conclusion
A facile and efficient preparation of 4-fluorocyclohexa-2,5-
dienones compounds has been developed by using Pyri-
dinium Polyhydrogen Fluoride (PPHF) in combination with
the hypervalent iodine, diacetoxyiodobenzene (PIDA) and
bis(trifluoroacetoxy)iodobenzene (PIFA). Our investi-
gations provide preparative approaches to new and complex
fluorodienones. Hence, hypervalent iodine reagents show
promise in replacing highly toxic heavy metal oxidants and
should provide a useful tool for the syntheses of various
biologically active natural products containing phenolic
systems.
31
32
33 (35)
34 (43)
3
Moreover, the observed JHC – F coupling constant
(J¼20 Hz) is in agreement with a cis ring junction, higher
values being expected for a trans one.27
4. Experimental
4.1. General methods
¨
Melting points were obtained on a BUCHI apparatus and are
1
uncorrected. H NMR and 13C NMR were recorded on a
300 MHz spectrometer use CDCl3 as solvent with TMS as
internal standard. Chemical shifts values are reported ind ppm
downfield and J values are given in Hertz. Low resolution MS
was recorded on a device FINIGAN INCOS 500 in electronic
impact. All reactions were run under an inert atmosphere.
CH2Cl2 was distilled from P2O5. Organic extract mixtures
were dried over anhydrous MgSO4 and filtered and the solvent
was then removed under reduced pressure. All separations
were done under recrystallization or flash chromatography
(MPLC) conditions on silica gel (25–40 mm) completed, if
necessary, by preparative thin-layer chromatography (TLC)
performed on silica gel plates (60 GF254).
1
In H NMR experiments, coupling constants could not be
measured with ketone 35a, even at high temperature, on
account of the carbamate rotamers. This problem could be
circumvented by synthesizing the bromo analog 35b
(X¼Br) by reaction of pyridinium perbromide on ketone
35a in THF.28 In the resulting ketone 35b (X¼Br, 40%
yield) coupling constants JHBHC¼12 Hz, JHC–F¼12 Hz
confirm the cis ring junction.
2.6. Ipso-fluorination of nitrogen-substituted polycyclic
phenols
Crystal data for 22b, 23b and 25 were recorded at room
temperature with a Enraf-Nonius CAD4 diffractometer
equipped with a graphite monochromator and an X-ray
We have shown that the ipso-fluorination of polycyclic
phenols with PIFA-PPHF yields 4-fluorocyclohexa-
dienones. We have discovered that an analogous fluorina-
tion, can be performed on the nitrogen analogs 36 and 37 to
give the corresponding dienones (Table 6). The presence of
the carbamate moiety, meta to the hydroxyl group, does not
modify the reactivity of the aromatic ring. This novel
oxidative dearomatization of nitrogen-substituted poly-
cyclic phenols should find applications in natural product
chemistry.
˚
tube with a Mo anticathode (l¼0.71069 A). The structure
was solved using direct methods29 and refined using least
square calculation.30
4.2. Typical procedure for reaction PIFA or PIDA-
PPHF
To a stirred solution of the phenol (1 mmol) in methylene
chloride (20 ml), at first pyridinium polyhydrogen fluoride
(70:30; v:v) (0.1 mL) and then phenyliodine bis(trifluor-
oacetate) PIFA or phenyliodine diacetate PIDA (1.2 mmol)
was added. The mixture was stirred at room temperature for
30 min (PIFA), or 15 min (PIDA). Excess of solid K2CO3
was added and the resulting mixture was stirred under the
same conditions for 5 min. After filtration, the organic
filtrate was evaporated and the residue was flash chromato-
graphed over SiO2 to yield the dienone.
Table 6.
Phenols
Products (%)
36 n¼1
37 n¼2
38 n¼1 (39)
39 n¼2 (29)
4.2.1. Preparation of 4-fluoro-4-methyl-cyclohexa-2,5-
dienone (8).2 Obtained from para-cresol 1 (200 mg;

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O. Karam et al. / Tetrahedron 60 (2004) 6629–6638
1.85 mmol); PIFA (950 mg, 1.2 mmol); HF–pyridine
(70:30; v:v) (0.2 mL) as described in typical experimental
procedure. Chromatography from ethyl acetate–hexane
(5:95; v:v) gave the following compounds.
2.90 mmol); PIDA (1.1 g, 1.2 mmol); HF–pyridine (70:30;
v:v) (0.3 mL) as described in typical experimental
procedure. Chromatography from methylene chloride–
pentane (10:90; v:v) gave 13 (176 mg-41%). 1H NMR
(CDCl3) d 6.23 (d, 2H, J¼10 Hz, Ha); 7.04 (dd, 2H,
J¼10 Hz, JHF¼6 Hz, Hb). 13C NMR (CDCl3) d 99.3 (d,
J¼233 Hz, C–F); 127.8 (d, J3¼7.6 Hz, C-2þC-6); 141.3 (d,
J2¼25 Hz, C-3þC-5); 182.9 (d, J4¼5 Hz, CvO). MS (CI
isobutane) MHþ: 147 (100), 149 (36).
Dienone 8 (158 mg-68%). 1H NMR (CDCl3) d 1.64 (d, 3H,
JHF¼21.4 Hz, CH3); 6.21 (d, 2H, J¼10.2 Hz, Ha); 6.90 (dd,
2H, J¼9.6 Hz, JHF¼6 Hz, Hb). 13C NMR (CDCl3)d 26 (d,
J2¼27 Hz, –CH3); 86.5 (d, J¼161 Hz, C–F); 128.6 (d,
J3¼7.5 Hz, C-2þC-6); 146.5 (d, J2¼18 Hz, C-3þC-5); 184
(CvO). EI MS (C7H7FO) m/z 126 (28) [M]þ, 111 (28); 97
(100). HR MS (C7H7FO): calcd: 126.04809, found:
126.0480.
4.2.6. Preparation of 7a-fluoro-1, 2, 3, 7a-tetrahydro-
inden-5-one (17). Obtained from 5-indanol 14 (250 mg,
1.86 mmol); PIFA (1 g, 1.2 mmol); HF–pyridine (70:30;
v:v) (0.5 mL) as described in typical experimental pro-
cedure. Chromatography from ethyl acetate–hexane (12:88;
v:v) gave 17 (120 mg-41%). 1H NMR (CDCl3) d 0.8–3 (m,
6H), 6.10 (s, 1H, Ha); 6.22 (dd, 1H, J¼10, 2 Hz, Hb); 6.98
(dd, 1H, J¼10, 5 Hz, Hb). 13C NMR (CDCl3) d 92.5 (d,
J¼161 Hz, C-7a); 123.8 (d, J¼4 Hz, C-4); 131 (d, J¼7 Hz,
C-6); 140.5 (d, J¼19 Hz); 162.5 (d, J¼13 Hz, Ca); 185.7
(CvO). EI MS m/z: 152 (78); 133 (47); 134 (28); 109 (76);
96 (100). HR MS (C9H9FO): calcd: 152.06374, found:
152.0637
1
Pummerer ketone 9 (16 mg-8%). H NMR (CDCl3) d 1.57
(s, 3H, CH3); 2.32 (s, 3H, CH3Ar); 2.80 (dd, Jgem¼17.5,
3 Hz, 1H); 3.05 (dd, Jgem¼17.5, 3 Hz, 1H); 4.7 (m, 1H,
–CH–O); 5.9 (d, 1H, J¼10.2 Hz, CHv); 6.47 (d, 1H,
J¼10.2 Hz, CHv); 6.7 (d, 1H, J¼8 Hz, H ar); 6.99 (d, 1H,
J¼8 Hz, H ar); 7.01 (s, 1H, H ar). EI MS m/z: 214 (100); 199
(89); 185 (13); 171 (71).
4.2.2. Preparation of 4-fluoro-4-ethyl-cyclohexa-2,5-die-
none (10). Obtained from 4-ethylphenol 2 (1 g; 7.3 mmol);
PIFA (3.8 g, 1.2 mmol); HF–pyridine (70:30; v:v) (0.8 mL)
as described in typical experimental procedure. Chroma-
tography from ethyl acetate–hexane (5:95; v:v) gave 10
(625 mg-61%). 1H NMR (CDCl3) d 0.92 (t, 3H, CH3); 1.91
(m, 2H, CH2); 6.25 (d, 2H, J¼10 Hz); 6.85 (dd, 2H,
J¼10 Hz). 13C NMR (CDCl3) d 7.4 (d, J¼7 Hz, CH3); 31.8
(d, J¼24 Hz, CH2); 89. 5 (d, J¼163 Hz, C–F); 129.5 (d,
J¼8 Hz, C-2þC-6); 145 (d, J¼22 Hz, C-3þC-5); 185
(CvO). EI-MS m/z (C8H9FO): 140; 121; 95 (100). HR MS
(C8H9FO): calcd: 140.06374, found: 140.06370.
4.2.7. Preparation of 4a-fluoro-5,6,7,8-tetrahydro-4aH-
naphtalen-2-one (18). Obtained from 5,6,7,8-tetrahydro-
napht-2-ol 15 (300 mg, 2 mmol); PIFA (1 g, 1.2 mmol);
HF–pyridine (70:30; v:v) (0.6 mL) as described in typical
experimental procedure. Chromatography from ethyl
acetate–hexane (12:88; v:v) gave 18 (220 mg-66%). 1H
NMR (CDCl3) d 0.8–3 (m, 8H), 6.06 (s, 1H, Ha); 6.19 (dd,
1H, J1¼9.6 Hz, J2¼2.5 Hz, Hb); 6.90 (dd, 1H, J¼9.6, 6 Hz,
Hb). 13C NMR (CDCl3) d 20.53 (s, C-6); 27.4 (s, C-7); 32.0
(s, C-8); 38.3 (d, J¼25 Hz, C-5); 87.5 (d, J¼163 Hz, C-4a);
123.9 (d, J¼5 Hz, C-1); 129.35 (d, J¼7.6 Hz, C-3); 145.8
(d, J¼22.7 Hz, C-4), 158.7 (d, J¼19.4 Hz, C-8a), 185.5
(CvO). EI MS m/z:166 (72); 151 (16); 138 (50); 109 (92);
96 (100). HR MS (C10H11FO): calcd: 166.07939, found:
166.0790.
4.2.3. Preparation of 4-fluoro-4-(20-brom0oethyl)-cyclo-
hexa-2,5-dienone (11). Obtained from 4-(2 -bromoethyl)-
phenol 3 (150 mg, 0.83 mmol); PIFA (430 mg, 1.2 mmol);
HF–pyridine (70:30; v:v) (0.08 mL) as described in
typical experimental procedure. Chromatography from
ethyl acetate–hexane (5:95; v:v) gave 11 (87 mg-48%).
1H NMR (CDCl3) d 2.50 (m, 2H, CH2); 3.38 (t, 2H, CH2Br);
6.30 (d, 2H, J¼10 Hz); 6.93 (dd, 2H, J¼10 Hz). 13C
NMR (CDCl3) d 29 (CH3); 42 (d, J¼14 Hz, CH2); 89. 5
(d, J¼163 Hz, C–F); 129.5 (d, J¼8 Hz, C-2þC-6); 145
(d, J¼22 Hz, C-3þC-5); 185 (CvO). EI MS m/z
(C8H8BrFO): 220 (10), 218 (10), 111 (47), 109 (100), 107
(100). HR MS (C8H8BrFO): calcd: 217.97425, found:
217.97420.
4.2.8. Preparation of 4-chloro-4-fluoro-4H-naphtalen-1-
one (19). Obtained from 4-chloronapht-1-ol 16 (175 mg;
0.98 mmol) PIDA (383 mg); HF–pyridine (70:30; v:v)
(0.1 mL) as described in typical experimental procedure.
Chromatography from ethyl acetate–hexane (5:95; v:v)
gave the following compounds.
Dienone 19 (56 mg-29%). 1H NMR (CDCl3) d 6.40 (d, 1H,
J¼10 Hz, C-2); 7.17 (dd, 1H, J¼10 Hz, JHF¼6 Hz, C-3);
7.59 (t, 1H, C-7); 7.74 (t, 1H, C-6); 7.91 (d, 1H, C-5); 8.07
(d, 1H, C-8). 13C NMR (CDCl3) d 101.1 (d, J¼237.5 Hz,
C–F); 126.5 (s, C-7); 127.0 (s, C-6þC-8); 128.2 (d,
J3¼7.5 Hz, C-2); 130.7 (s, C-5); 133.9 (s, C-8a); 138.7 (d,
J2¼24 Hz, C-4a); 141.8 (d, J2¼25 Hz, C-3); 182.3 (d,
J4¼3.5 Hz, CvO). EI MS m/z (C10H6ClFO): 197 (11); 196
(33); 161 (100); 151 (20); 133 (98). HR MS (C10H6ClFO):
calcd: 196.0091, found: 196.0090.
4.2.4. Preparation of 4,4-difluorocyclohexa-2,5-dienone
(12). Obtained from 4-fluorophenol 4 (343 mg; 3.06 mmol);
PIDA (1.2 g, 1.2 mmol); HF–pyridine (70:30; v:v) (0.3 mL)
as described in typical experimental procedure. Chroma-
tography from methylene chloride–pentane (10:90; v:v)
1
gave 12 (266 mg-67%). H NMR (CDCl3) d 6.34 (d, 2H,
J¼10 Hz, Ha); 6.84 (2H, Hb). 13C NMR (CDCl3) d 110.3
(t, J¼225 Hz, CF2); 131.7 (t, J3¼9 Hz, C-2þC-6); 137.8 (t,
J2¼29 Hz, C-3þC-5); 184.1 (t, J4¼5 Hz, CvO). MS (CI
isobutane) MHþ: 131.
1
1,4-Naphtoquinone 20 (31 mg-20%). H NMR (CDCl3) d
6.98 (s, 2H, H-2þH-3); 7.76 (m, 2H, H-6þH-7); 8.07 (d,
2H, H-5þH-8). 13C NMR (CDCl3) d 126.2 (C-5þC-8);
131.9 (C-4aþC-8a); 133.8 (C-6þC-7); 138.6 (C-2þC-3);
184.8 (C-1).
4.2.5. Preparation of 4-chloro-4-fluorocyclohexa-2,5-
dienone (13). Obtained from 4-chlorophenol 5 (373 mg;

O. Karam et al. / Tetrahedron 60 (2004) 6629–6638
6635
4.2.9. Preparation of (R,S)-1,10-bi-5,6,7,8-tetrahydro-
napht-2-ol (21a). To a suspension of Ru (5%)/C (0.75 g)
in ethyl acetate/ethanol (1/1) (100 ml) was added racemic
(R,S) 1,10-binapht-2-ol (5 g, 17.46 mmol). The mixture was
stirred at 165 8C under pressure of hydrogen (110 bars) for
4 h. After filtration, the organic filtrate was evaporated and
the residue was flash chromatographed from ethyl acetate/
recrystallized in ethyl acetate/hexane (10/90, v/v) and the
single crystal was selected for X-ray experiment.
Crystal color: colorless prisms, chemical formula
C22H23O3F, molecular weight M¼354.42, crystal system:
˚
˚
orthorhombique,
a¼8.182(2) A,
b¼11.151(7) A,
3
˚
˚
c¼19.990(4) A, volume of unit cell V¼1824(1) A , space
group P212121, Z¼4, Dc¼1.29 g cm23, F(000)¼752.24,
m(MoKa)¼0.86 cm21. 1H NMR (CDCl3) d 1.75 (m, 8H, 4
CH2, H-6þH-7þH-60þH-70); 2.09 (s, 3H, CH3); 2.28 (m,
6H, 3 CH2); 2.81 (m, 2 H); 6.34 (d, J¼10 Hz, 1H, H-3); 6.88
(m, 2H, H-4þH-30); 7.11 (d, J¼4.5 Hz, 1H, H-40). 13C NMR
(CDCl3) d 20.9 (d, J¼2.0 Hz), 21.0, 23.1 (d, J3¼5.4 Hz),
27.1 (d, J¼1 Hz), 27.8, 29.6, 29.8, 38.9 (d, J2¼28.8 Hz),
87.8 (d, J1¼162.7 Hz), 119.8, 126.3, 126.8, 129.7 (d,
J3¼8.0 Hz), 130.4, 130.8 (d, J3¼5.7 Hz), 135.4, 137.7,
145.9 (d, J2¼21.5 Hz), 146.5, 156.0 (d, J2¼18.8 Hz), 169.9,
183.8. MS m/z (%): 354 (13); 312 (48); 292 (100); 275 (30);
264 (47). HR MS: calcd for C22H23FO3: 354.1631, found:
354.16100. Anal. calcd C22H23FO3: C, 74.56; H, 6.54; F,
5.36, found: C, 74.40; H, 6.51; F, 5.57.
1
hexane (10/90) over SiO2 to yield 21a (3.9 g, 75.8%). H
NMR (CDCl3) d 1.70 (m, 8H, 4 CH2, H-6þH-7þH-60þH-
70); 2.20 (m, 4H, 2 CH2); 2.72 (m, 4H); 4.67 (2H, OH); 6.80
(d. 4H, H-3þH-30); 7.02 (d, 4H, H-4þH-40). 13C NMR
(CDCl3) d 23.0 and 23.9 (4 CH2, C-6þC-7þC-60þC-70);
27.1 and 29.2 (4 CH2, C-5þC-8þC-50þC-80); 113.0 (2 CH,
C-3þC-30); 118.9 (C-1þC-10); 130.1 and 137.1 (C-4aþC-
8aþC-4a00þC-8a0); 131.0 (CH, C-4þC-40); 151.4 (2 C–OH,
C-2þC-2 ). MS m/z (%): 294 (100); 248 (15). HR-MS:
(C20H22O2) calcd: 294.16198, found: 294.16370.
4.2.10. Preparation of 20-acetoxy-1,10-bi-5,6,7,8-tetra-
hydro-napht-2-ol (21b). To a solution of 21a (495 mg,
1.68 mmol) in dichloromethane (5 mL), acetic anhydride
(0.16 ml, 1.68 mmol) and pyridine (0.3 mL) were added.
The mixture was stirred for 12 h at room temperature. The
resulting mixture was poured into water (50 mL) and
extracted with dichloroethane. The combined extracts
were dried over MgSO4 and evaporated under reduced
pressure to give 21b (536 mg, 94.9%). 1H NMR (CDCl3) d
1.72 (m, 8H, 4 CH2, H-6þH-7þH-60þH-70); 1.91 (s, 3H,
CH3); 1.90–2.45 (m, 4H, 2 CH2); 2.78 (m, 4H); 4.75 (s, 1H,
OH); 6.77 (d, 2H, H-3); 6.89 and 6.98 (2d, H-4þH-30); 7.17
(d, 1H, H-40). 13C NMR (CDCl3) d 20.3 (CH3); 22.6, 22.8,
23.1 and 23.14 (4 CH2, C-6þC-7þC-60þC-70); 27.0, 27.3,
29.5 and 29.7 (4 CH2, C-5þC-8þC-50þC-80); 129.8 and
113.0 (2 CH, C-3þC-30); 122.1 and 122.2 (C-1þC-10);
129.8 and 130.3 (CH, C-4þC-40)0; 129.3, 135.8, 136.1 and
138.4 (C-4aþC-8aþC-4a0þC-8a ); 147.0 (C-OR, C-20);
150.5 (2 C-OH, C-2); 170.8 (CvO). MS m/z (%): 336
(56); 295 (100); 251 (37). HR MS: (C22H24O3) calcd:
336.17254, found: 336.17460.
(RSa,SRa)-1-[50,60,70,80-tetrahydro-20-acetoxy-naphtalen-
(4aH)]-4a-fluoro-5,6,7,8-tetrahydro-naphtalen-2-(4aH)-
one (22b) (more polar) (58 mg). Compound 22b was
recrystallized in ethyl acetate/hexane (10/90, v/v) and the
single crystal was selected for X-ray experiment.
Crystal color: colorless prisms, chemical formula
C22H23O3F, molecular weight M¼354.42, crystal system:
˚
˚
triclinique, a¼9.3763(9) A, b¼7.7472(5) A, c¼
˚
11.0316(9) A, a¼78.584(6)8, b¼86.462(7)8, g¼68.758(7)8
3
˚
volume of unit cell V¼921(1)A , space group P-1, Z¼2,
Dc¼1.29 g cm23, F(000)¼376.12, m(MoKa)¼0.86 cm21
.
1H NMR (CDCl3) d 1.77 (m, 8H, 4 CH2, H-6þH-7þH-
60þH-70); 2.10 (s, 3H, CH3); 2.23 (m, 6H, 3 CH2); 2.77 (m,
2H); 6.35 (d, J¼10 Hz, 1H, H-3); 6.90 (m, 2H, H-4þH-30);
7.12 (d, J¼4.5 Hz, 1H, H-40). 13C NMR (CDCl3) d 20.7,
20.8 (d, J¼2.1 Hz), 21.3, 23.1 (d, J3¼8.5 Hz), 26.8, 27.4,
29.2, 29.9, 39.5 (d, J2¼26.0 Hz), 87.9 (d, J1¼163.5 Hz),
119.7, 126.3 (d, J¼3.6 Hz), 129.8 (d, J3¼8.0 Hz), 130.4,
130.9 (d, J3¼5.0 Hz), 135.5, 137.5, 145.9 (d, J2¼21.5 Hz),
146.8, 155.8 (d, J2¼18.8 Hz), 169.6, 183.8. MS m/z (%):
354 (8); 312 (100); 292 (23); 264 (16). HR MS: calcd for
C22H23FO3: 354.16312, found: 354.16130. Anal. calcd for
C22H23FO3: C, 74.56; H, 6.54; F, 5.36, found: C, 74.14; H,
6.59; F, 6.04.
Fluorination of 20-acetoxy-1,10-bi-5,6,7,8-tetrahydro-
napht-2-ol 21b. To a stirred solution 21b (467 mg,
1.39 mmol) in methylene chloride (20 ml), at first pyri-
dinium polyhydrogen fluoride (70:30; v:v) (0.3 mL) and
then phenyliodine bis(trifluoroacetate) (740 mg) was added.
The mixture was stirred at room temperature for 20 min.
Excess of solid K2CO3 was added and the resulting mixture
was stirred under the same conditions for 5 min. Chroma-
tography from ethyl acetate–hexane (10:90; v:v) gave 22b
and 23b (molar ratio 40/60) (322 mg, 65%).
4.2.11. Preparation of (RSa,SRa)-1-[50,60,70,80-tetra-
hydro-naphtalen(4aH)]-4a-fluoro-5,6,7,8-tetrahydro-
naphtalen-2-(4aH)-one (22a). To a solution of 22b
(150 mg, 0.42 mmol) in methanol (15 ml) KHCO3
(500 mg) was added. After 5 h, the mixture was filtered,
and the organic filtrate was evaporated to give 22a (125 mg,
95%). RMN 1H (CDCl3) d 1.30–1.90 (m, 8H, 4 CH2,
H-6þH-7þH-60þH-70); 2.10–2.40 (m, 6H); 2.60–2.80 (m,
2H); 6.29 (d, J¼10 Hz, 1H, H-3); 6.69 (d, J¼4.5 Hz, 1H,
H-30); 6.86 (m, 2H, H-4þH-40).
Relative yields have been determined by HPLC: chromato-
graphic conditions: column: spherisorb 5 mm Silica, 4.6–
250 mm, HPLC Technology LTD; eluent: AcOEt–
hexane¼2:8 (v:v), flow rate: 1 mL/min, detection
l¼280 nm; HPLC. System: WATERS.
The products have been separated using preparative TLC
(Plates Kieselgel 60 F254 MERCK).
4.2.12. Preparation of (RRa,SSa)-1-[50,60,70,80-tetra-
hydro-naphtalen(4aH)]-4a-fluoro-5,6,7,8-tetrahydro-
naphtalen-2-(4aH)-one (23a). To a solution of 23b
(102 mg, 0.30 mmol) in methanol (10 ml) KHCO3
(RRa,SSa)-1-[50,60,70,80-tetrahydro-20-acetoxy-naphtalen-
(4aH)]-4a-fluoro-5,6,7,8-tetrahydro-naphtalen-2-(4aH)-
one (23b) (less polar) (106 mg). Compound 23b was

6636
O. Karam et al. / Tetrahedron 60 (2004) 6629–6638
(400 mg) was added. After 5 h, the mixture was filtered, and
the organic filtrate was evaporated to give 23a (86 mg,
145.8 (d, J2¼25.6 Hz), 87.7 (d, JC–F¼165.7 Hz), 88.0 (d,
JC– F¼163.3 Hz), 38.5 (d, J2¼25.3 Hz), 39.1 (d, J2¼
23.4 Hz), 26.6, 26.7, 20.4, 29.0, 29.7, 156.0 (d, J2¼
19.1 Hz), 156.5 (d, J2¼19.2 Hz). MS m/z (%): 330 (12);
310 (30); 289 (71); 262 (100). HR MS calcd for
C20H20O2F2: 330.14314, found: 330.14190. Anal. calcd
for C20H20O2F2: C, 72.71; H, 6.10; F, 11.50, found: C,
72.60; H, 6.07; F, 12.17.
1
95.7%). RMN H (CDCl3) d 1.30–1.90 (m, 8H, 4 CH2,
H-6þH-7þH-60þH-70); 2.10–2.40 (m, 6H); 2.60–2.80 (m,
2H); 6.29 (d, J¼10 Hz, 1H, H-3); 6.69 (d, J¼4.5 Hz, 1H,
H-30); 6.86 (m, 2H, H-4þH-40).
Fluorination of (R,S)-1,10-bi-5,6,7,8-tetrahydronapht-2-ol
(21a). To a stirred solution 21a (575 mg, 1.95 mmol) in
methylene chloride (25 ml), at first pyridinium poly-
hydrogen fluoride (70:30; v:v) (0.4 mL) and then phenyl-
iodine bis(trifluoroacetate) (2.017 g, 4.8 mmol) was added.
The mixture was stirred at room temperature for 20 min.
Excess of solid K2CO3 was added and the resulting mixture
was stirred under the same conditions for 5 min. Chroma-
tography from ethyl acetate–hexane (10:90; v:v) gave 24,
25 and 26 (molar ratio 18/65/17) (289 mg, 45%).
4.2.13. Fluorination of compound 22a. To a stirred
solution 22a (180 mg, 0.67 mmol) in methylene chloride
(25 ml), at first pyridinium polyhydrogen fluoride (70:30;
v:v) (0.1 mL) and then phenyliodine bis(trifluoroacetate)
PIFA (414 mg, 0.80 mmol) was added. The mixture was
stirred at room temperature for 20 min. Excess of solid
K2CO3 was added and the resulting mixture was stirred
under the same conditions for 5 min. After filtration, the
organic filtrate was evaporated and the residue was flash
chromatographed from ethyl acetate–hexane (20:80; v:v)
over SiO2 to give 25 and 26 (molar ratio 28/72) (80 mg-
48%).
Relative yields have been determined by HPLC: chromato-
graphic conditions: column: Spherisorb 5 mm Silica, 4.6–
250 mm, HPLC Technology LTD; eluent: AcOEt–
hexane¼2:8 (v/v); flow rate: 1 mL/min; detection
l¼280 nm; HPLC. System: WATERS.
4.2.14. Fluorination of compound 23a. To a stirred
solution 23a (86 mg, 0.27 mmol) in methylene chloride
(7 ml), at first pyridinium polyhydrogen fluoride (70:30;
v:v) (0.03 mL) and then phenyliodine bis(trifluoroacetate)
PIFA (414 mg, 0.80 mmol) was added. The mixture was
stirred at room temperature for 20 min. Excess of solid
K2CO3 was added and the resulting mixture was stirred
under the same conditions for 5 min. After filtration, the
organic filtrate was evaporated and the residue was flash
chromatographed from ethyl acetate–hexane (20:80; v:v)
over SiO2 to give 25 and 24 (molar ratio 83/17) (95 mg-
48%).
The products have been separated using preparative TLC
(Plates Kieselgel 60 F254 MERCK).
(R p,R p,Sa p)-Bi-(4a-fluoro-5,6,7,8-tetrahydro-naphtalen-2-
1
(4aH)-one) (26) (30 mg). H NMR (CDCl3) d 1.05–2.40
(m, 16H); 6.26 (d, J¼9.9 Hz, 2H, H-3þH-30); 6.85 (m, 2H,
H-4þH-40). 13C NMR (CDCl3) d 128.4 (d, J3¼6 Hz), 183.3
(d, J4¼5.3 Hz), 129.1 (d, J3¼8.0 Hz), 145.8 (d, J2¼
23.1 Hz), 88.1 (d, JC–F¼163.8 Hz), 38.7 (d, J2¼25.5 Hz),
26.4, 20.5, 29.1, 156.1 (d, J2¼19.2 Hz). MS m/z (%): 330
(8); 310 (13); 289 (55); 262 (72); 55 (100). HR MS:
(C20H20O2F2) calcd: 330.14314, found: 330.14190.
4.2.15. Preparation of 10b-fluoroestra-1,4-dien-3,17-
dione (29).4 Obtained from estrone 27 (200 mg,
0.74 mmol); PIFA (516 mg, 1.5 mmol); HF–pyridine
(70:30; v:v) (0.2 mL) as described in typical experimental
procedure. Chromatography from ethyl acetate–hexane
(R p,R p,Ra p)-Bi-(4a-fluoro-5,6,7,8-tetrahydro-naphtalen-
2-(4aH)-one) (24) (13 mg). 1H NMR (CDCl3) d 1.05–2.40
(m, 16H); 6.26 (d, J¼9.9 Hz, 2H, H-3þH-30); 6.85 (m, 2H,
H-4þH-40). 13C NMR (CDCl3) d 128.0 (d, J3¼5.4 Hz),
182.7 (d, J4¼5.1 Hz), 129.1 (d, J3¼8.0 Hz), 145.4 (d,
J2¼21.7 Hz), 87.1 (d, JC – F¼164.8 Hz), 39.0 (d,
J2¼25.7 Hz), 27.0, 20.4, 29.2, 156.2 (d, J2¼19.4 Hz). MS
m/z (%): 330 (7); 310 (18); 289 (73); 262 (100). HR MS
(C20H20O2F2) calcd: 330.14314, found: 330.14190.
1
(25:75; v:v) gave 29 (165 mg-77%), mp: 143–144 8C. H
NMR (CDCl3) d 0.97 (s, 3H, –CH3); 6.09 (d, 1H, J¼1.5 Hz,
H-4); 6.19 (dd, 1H, J1¼9.6 Hz, J2¼1.5 Hz, H-2); 7.13 (dd,
1H, J¼9.6, 7.5 Hz, H-1). 13C NMR (CDCl3) d 13.6 (s,
C-18); 54.1 (d, J¼24.5 Hz, C-9); 89 (d, J¼168 Hz, C-10);
123.7 (d, J¼4.5 Hz, C-4); 129.4 (d, J¼8.5 Hz, C-2); 144.7
(d, J¼23.8 Hz, C-1); 159.7 (d, J¼19.3 Hz, C-5); 184.6
(C-3); 219.2 (C-17). EI MS m/z: 288 (11); 270 (6); 247 (10);
231 (12); 126 (100). IR (CH2Cl2): 2950, 1730, 1660,
(R p,S p,Ra p)-Bi-(4a-fluoro-5,6,7,8-tetrahydro-naphtalen-2-
(4aH)-one) (25) (55 mg). Compound 25 was recrystallized
in ethyl acetate–hexane (10:90, v:v) and the single crystal
was selected for X-ray experiment.
1600 cm21
.
Estrone 27 (10 mg, 5%) identical with the starting material.
Crystal color: colorless prisms, chemical formula
C22H23O3F, molecular weight M¼354.42, crystal system:
4.2.16. Preparation of 10b-fluoro-11-hydroxyestra-1,4-
dien-3,17-dione (30). Obtained from 11b-hydroxy-estrone
28 (130 mg, 0.45 mmol); PIFA (360 mg, 1.2 mmol); HF–
pyridine (70:30; v:v) (0.1 mL) as described in typical
experimental procedure. Chromatography from ethyl
acetate–hexane (40:60, v:v) gave 30 (80 mg-58%), mp:
160–161 8C. 1H NMR (CDCl3) d 1.20 (s, 3H, –CH3); 3.00
(d, J¼24 Hz, H-9); 4.51 (m, 1H, H-11);. 6.06 (d, 1H,
J¼1.5 Hz, H-4); 6.30 (dd, 1H, J1¼10 Hz, J2¼1.5 Hz, H-2);
7.30 (dd, 1H, J¼10, 6.6 Hz, H-1). 13C NMR (CDCl3) d 15.8
˚
˚
triclinique, a¼9.3763(9) A, b¼7.7472(5) A, c¼
˚
11.0316(9) A, a¼78.584(6)8, b¼86.462(7)8, g¼68.758(7)8
3
˚
volume of unit cell V¼921(1)A , space group P-1, Z¼2,
Dc¼1.29 g cm23, F(000)¼376.12, m(MoKa)¼0.86 cm21
.
1H NMR (CDCl3) d 1.05–2.40 (m, 16H); 6.26 (d, J¼9.9 Hz,
2H, H-3þH-30); 6.85 (m, 2H, H-4þH-40). 13C NMR
(CDCl3) d 128.0 (d, J3¼5.2 Hz), 128.4 (d, J3¼5.6 Hz),
182.8 (d, J4¼5.3 Hz), 183.3 (d, J4¼4.9 Hz), 129.0 (d,
J3¼7.9 Hz), 129.1 (d, J3¼8.0 Hz), 145.6 (d, J2¼22.2 Hz),

O. Karam et al. / Tetrahedron 60 (2004) 6629–6638
6637
(s, CH3218); 57.5 (d, J¼22 Hz, C-9); 69.2 (s, C-11); 90.5
(d, J¼164 Hz, C-10); 123.5 (d, J¼4 Hz, C-4); 130.6 (d,
J¼7 Hz, C-2); 143.2 (d, J¼22 Hz, C-1); 158.5 (d, J¼18 Hz,
C-5); 184.5 (C-3); 217.8 (C-17). EI MS m/z: 304 (6); 286
(8); 240 (30); 84 (100). HR MS (C18H21FO3): calcd:
304.14740, found: 304.14740.
was stirred for 2 h. The reaction mixture was filtered and the
organic phase was extracted three times with methylene
chloride, dried over MgSO4 and evaporated to dryness.
Chromatography from ethyl acetate–hexane (30:70, v:v)
1
gave 35b (42 mg, 40%). (Mixture of rotamers): H NMR
(CDCl3) d 4.87 and 4.98 (t, 1H, J¼12, 12 Hz), 5.48 and 5.53
(d, 1H, J¼12 Hz), 6.23 (d, 1H, J¼10.3 Hz), 7.15 and 7.17
(dd, 1H, J¼10.3, 10.5 Hz). 13C NMR (CDCl3) d 52.7 and
52.9 (2d, J¼10 Hz), 59.4 and 60.2 (2d, J¼23 Hz), 90.2 and
90.3 (2d, J¼179 Hz, C–F), 127.5 and 127.6 (2d, J¼9 Hz),
149.9 and 150.0 (2d, J¼26 Hz), 155.4 and 155.7 (N-CO),
189.2 (C-7). EI MS m/z (%): 321 (10), 319 (10), 301 (5), 299
(5), 240 (60), 220 (75), 192 (90), 56 (100).
4.2.17. Preparation of 3a-fluoro-6-oxo-2,3,3a,6,7,7a-
hexahydro-indole-1-carboxylic acid ethyl ester (33).
Obtained from (2-(4-hydroxyphenyl)-ethyl)-carbamic acid
ethyl ester 31 (208 mg, 1 mmol), PIFA (516 mg, 1.2 mmol);
HF–pyridine (70:30; v:v) (0.1 mL) as described in typical
experimental procedure. Chromatography from ethyl
acetate–hexane (30:70, v:v) gave 33 (80 mg-35%). 1H
NMR (CDCl3) d 1.28 (t, 3H, CH3); 2.36 (m, 3H); 3.19 (m,
1H); 3.73 (m, 2H); 4.13 (q, 2H, CH2); 4.48 (m, 1H); 6.09 (d,
1H, J¼10 Hz); 6.90 (dd, 1H, J1¼10 Hz, J2¼8 Hz). 13C
NMR (CDCl3) d 14.5 (CH3); 34.4; 42.5; 45; 61.5 (CH2); 91
(d, J¼170 Hz, C–F); 130 (d, J¼8.5 Hz); 143 (d, J¼27 Hz);
154.6 (N-CO); 195.13 (CvO). MS m/z: 227 (11), 207 (30),
170 (18), 128 (28), 56 (100). HR MS (C11H14FNO3): calcd:
227.09577, found: 227.09600.
4.2.21. Preparation of 4a-fluoro-7-oxo-3,4,4a,7-tetra-
hydro-2H-quinoline-1-carboxylic acid ethyl ester (39).
Obtained from 7-hydroxy-3,4-dihydro-2H-quinoline-1-
carboxylic acid ethyl ester 37 (221 mg, 1 mmol), PIFA
(516 mg, 1.2 mmol); HF–pyridine (70:30; v:v) (0.1 mL) as
described in typical experimental procedure. Chromato-
graphy from ethyl acetate–hexane (30:70, v:v) gave 39
1
(65 mg-29%). H NMR (CDCl3) d 3.81 (s, 3H, CH3OCO),
6.25 (m, 1H), 6.37 (m, 1H), 6.75 (m, 1H). 13C NMR
(CDCl3) d 33.8 (d, J¼25.5 Hz), 53.6 (CH3OCO), 85.1 (d,
J¼166.5 Hz), 119.8 (d, J¼4 Hz), 128.9 (d, J¼7 Hz), 142.4
(d, J¼20 Hz), 150.6 (d, J¼18 Hz), 154.7 (N-CO), 186.1. EI
MS m/z (%): 225 (96), 197 (40), 59 (100); HR-MS: calcd:
225.0796, found: 225.0801.
4.2.18. Preparation of 4-fluoro-4-(30-(N-ethoxy-
carbonyl)-propyl)-cyclohexadienone (34). Obtained from
(2-(4-hydroxyphenyl)-propyl)-carbamic acid ethyl ester 32
(100 mg, 0.45 mmol), PIFA (215 mg, 1.2 mmol); HF-
pyridine (70:30; v:v) (0.1 mL) as described in typical
experimental procedure. Chromatography from ethyl
acetate–hexane (30:70, v:v) gave 34 (50 mg-43%). 1H
NMR (CDCl3) d 1.23 (t, 3H, CH3); 1.60 (m, 4H, 2 CH2);
3.18 (q, 2H, CH2NH); 4.09 (q, 2H, CH2); 6.25 (d, 2H,
J¼10.2 Hz); 6.87 (dd, 2H, J¼10.2, 6.4 Hz). 13C NMR
(CDCl3) d 14.6 (CH3); 24.5; 35.7; 40.75 (3 CH2); 60.9
(CH2); 88 (d, J¼170 Hz, C–F); 129 (d, J¼7.6 Hz); 145 (d,
J¼22 Hz); 155 (N–CO); 184 (CvO). MS m/z: 221 (4); 192
(8); 112 (32); 102 (100). HR MS (C12H16FNO3): calcd:
241.1114, found: 241.1100.
4.2.22. Preparation of 3a-fluoro-6-oxo-2,3,3a,6-tetra-
hydro-indole-1-carboxylic acid ethyl ester (38). Obtained
from 6-hydroxy-2,3-dihydroindole-1-carboxylic acid ethyl
ester 36 (193 mg, 1 mmol), PIFA (516 mg, 1.2 mmol); HF–
pyridine (70:30; v:v) (0.1 mL) as described in typical
experimental procedure. Chromatography from ethyl
acetate–hexane (30:70, v:v) gave 38 (82 mg-39%). 1H
NMR (CDCl3) d 2–2.23 (m, 1H, 1H), 2.50 (td, 1H, 1H),
3.88 (s, 3H, CH3OCO), 3.96 (m, 2H, 1H), 6.28 (m, 1H), 6.48
(s, 1H), 6.82 (dd, J¼9.9, 3.0 Hz). 13C NMR (CDCl3) d 32.2
(d, J¼27.3 Hz), 47.8, 53.6 (CH3OCO), 91.1 (d,
J¼163.3 Hz), 107.7 (d, J¼2.8 Hz), 132.8 (d, J¼7.6 Hz),
134.7 (d, J¼16.5 Hz), 186.6. EI MS m/z (%): 211 (97), 183
(40), 166 (32), 59 (100). HR-MS: calcd: 211.0649, found:
211.0645.
4.2.19. Preparation of 4a-fluoro-7-oxo-3,4,4a,7,8,8a-
hexahydro-2H-quinoline-1-carboxylic acid ethyl ester
(35a). To a stirred suspension of dienone 34 (50 mg,
0.2 mmol) in THF (2 mL) hydrogen hydrochloride 1N
(0.4 mL) was added. The mixture was refluxed for 24 h. The
reaction mixture was filtered, and the organic phase was
extracted three times with methylene chloride, dried over
MgSO4, and evaporated to dryness. Chromatography from
ethyl acetate–hexane (30:70, v:v) gave 35a (30 mg, 58%).
References and notes
1
(Mixture of rotamers): H NMR (CDCl3) d 1.28 (t, 3H,
CH3); 1.5–2.36 (m, 7H); 2.65 (m, 2H, H-8), 2.9 (m, 1H, 1
H-5); 4.13 (q, 2H, CH); 4.15 (m, 1H); 4.85 (m, 1H), 5.97
(d, 1H, J¼10.3 Hz), 6.86 (dd, 1H, J¼10.3, 10.3 Hz). 13C
NMR (CDCl3) d 29.6 (d, J¼25 Hz), 37.8, 37.9, 61.8, 90.2
(d, J¼173 Hz, C–F), 129.0 (d, J¼8.5 Hz), 150.2 (d,
J¼28 Hz), 155 (N-CO), 196.5 (C-7). EI MS m/z (%): 241
(22), 221 (90), 56 (100); HR-MS: calcd: 241.1114, found:
241.1100.
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